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Low-Carbohydrate and Ketogenic Dietary Patterns for Type 2 Diabetes Management
The prevalence of diabetes continues to increase despite advances in treatment options. In 2019, according to the Centers for Disease Control and Prevention (CDC), 37.1 million (14.7%) US adults had diabetes. Among adults aged ≥ 65 years, the prevalence is even higher at 29.2%.1 Research has also estimated that 45% of adults have evidence of prediabetes or diabetes.2 According to the Veterans Health Administration, almost 25% of enrolled veterans have diabetes.3
Background
Diabetes is associated with an increased risk of microvascular complications (eg, retinopathy, nephropathy, and neuropathy) and macrovascular complications (eg, atherosclerotic cardiovascular disease) and is one of the most common causes of morbidity and mortality in the US.4 In 2017, diabetes was estimated to cost $327 billion in the US, up from $261 billion in 2012.5 During this same period, the excess costs per person with diabetes increased from $8417 to $9601.5
Type 2 diabetes mellitus (T2DM) and its associated insulin resistance is typically considered a chronic disease with progressive loss of β-cell function. Controlling glycemia, delaying microvascular changes, and preventing macrovascular disease are major management goals. Lifestyle interventions are essential in the management and prevention of T2DM. Medication management for T2DM usually progresses through several medications, ending in insulin therapy.6 Within 10 years of diagnosis, almost half of all individuals with T2DM will require insulin to manage their glycemia.7
Bariatric surgery and nutrition approaches have been successful in reversing T2DM. Recently, there has been increased interest in nutritional approaches to place T2DM in remission, reverse the disease process, and improve insulin resistance. Contrary to popular belief, before the discovery of insulin in 1921, low-carbohydrate (LC) diets were the most common treatment for T2DM.8 With the discovery of insulin and the eventual development of low-fat dietary recommendations, LC diets were no longer favored by most clinicians.8 Low-fat diets are, by definition, also high-carbohydrate diets. By the early 1980s, low-fat diets had become the standard of care dietary recommendation, and the goal for clinicians became glycemic maintenance (with increased use of medications) rather than preventing hyperglycemia.8
With growing evidence regarding the use of LC diets for T2DM, the US Department of Veterans Affairs (VA) and US Department of Defense (DoD), the American Diabetes Association (ADA), the European Association for the Study of Diabetes (EASD), Diabetes Canada, and Diabetes Australia all include LC diets as a viable option for treating T2DM.4,9-12 This article will highlight a case using a reduced carbohydrate approach in lifestyle management and provide clinicians with practical guidance in its implementation. We will review the evidence that informs these guidelines, describe a practical approach to nutritional counseling, and review medication management and deprescribing approaches. Finally, barriers to implementation will be explored.
ILLUSTRATIVE CASE
A 64-year-old woman presented to the clinical pharmacist for the management of T2DM after her tenth hospitalization related to hyperglycemia in 10 years. She had previously been managed by primary care clinicians, clinical dietitians, endocrinologists, and certified diabetes care and education specialists. Pertinent history included diabetic ketoacidosis, coronary artery disease, hyperlipidemia, hypertension, obstructive sleep apnea, obesity, metabolic dysfunction-associated steatotic liver disease, and mild nonproliferative diabetic retinopathy with clinically significant macular edema. The patient expressed frustration with poor glycemic control during her many years of insulin therapy and an inability to lose weight due to insulin dose titrations. The patient reported prior education including but not limited to standardized sample menus, consistent carbohydrate intake, calorie reduction, general healthful nutrition, and the “move more, eat less” approach. The patient was unable to titrate insulin dosage and did not experience weight loss despite compliance with these methods.
Her medications included glargine insulin 45 units once daily, aspart insulin 5 units before meals 3 times daily, and metformin 1000 mg twice daily. Her hemoglobin A1c (HbA1c) level was 11.8%. A review of prior therapies for T2DM included glyburide 5 mg twice daily, metformin 1000 mg twice daily, 70/30 insulin (up to 340 units/d), glargine insulin (range, 10-140 units/d), regular insulin (range, 30-240 units/d), aspart insulin (range, 15-45 units/d), and U-500 regular insulin (range, 125-390 units/d). She took metoprolol 25 mg extended release daily and hydrochlorothiazide 25 mg daily, but both were discontinued after the most recent hospitalization. A review of HbA1c readings showed poor glycemic control for > 12 years (range, 10.3% to > 12.3%).
Education for lifestyle modifications, including an LC diet, was presented to the patient to assist with weight loss, improve glycemic control, and reduce insulin resistance. In addition, a glucagon-like peptide-1 agonist (liraglutide) was added to her pharmacotherapy. Continued dietary modifications with LC intake led to consistent reductions in glargine and aspart insulin therapy. The patient remained motivated throughout clinic visits due to improved glycemic control with sustainable dietary modifications, consistently reported feeling better overall, and deprescribed diabetes drug therapies. She remained off her blood pressure medications. After4 months of LC dietary modifications, all insulin therapy was discontinued. She continued with liraglutide 1.8 mg daily and metformin 1000 mg twice daily with an HbA1c of 6.3%. Two months later, her HbA1c level was 6.0%. She also lost 8 lb and her body mass index improved from 31 to 29.
Low-Carbohydrate T2DM DIET MANAGEMENT
LC diets are commonly defined as < 130 g of carbohydrates per day.13 Very LC ketogenic (VLCK) diets often contain ≤ 50 g of carbohydrates per day to induce nutritional ketosis.13 One of the first randomized controlled trials (RCTs) that compared a VLCK diet (< 30 g of carbohydrates per day) with a low-fat diet for obesity demonstrated greater weight loss at 6 months with the LC diet. In addition, patients with diabetes randomized to the LC group also showed improved insulin sensitivity. Notably, this study was done in a population of veterans enrolled at the VA Philadelphia Health Care System.14
A 2008 study comparing an LC diet with a calorie-restricted, low-glycemic diet for individuals with T2DM found that the LC diet group experienced a greater reduction in HbA1c and insulin levels and weight.15 Comparing these 2 diet groups after 24 weeks, 95% of individuals in the LC group reduced or discontinued T2DM medications vs 62% in the low-glycemic group.15 Another study of individuals with T2DM compared a VLCK diet with a low-fat diet. After 34 weeks, 55% of individuals in the LC diet group achieved an HbA1c level below the threshold for diabetes vs 0% in the low-fat diet group.16 A 2018 study of patients with T2DM investigated the impact of a very LC diet compared with the standard of care.17 After 1 year, the LC diet group experienced a mean HbA1c reduction of 1.3%, and 60% of individuals who completed the study achieved an HbA1c level < 6.5% without T2DM medications (not including metformin). This study also demonstrated that medications were significantly reduced, including 100% discontinuation of sulfonylureas and 94% reduction or elimination of insulin.
A recent study of an LC diet (< 20% energy from carbohydrates) demonstrated reduced HbA1c levels, weight, and waist circumference vs a control diet after 6 months. The control diet derived 50% to 60% of energy from carbohydrates.18 This study is typical of other LC interventions, which did not calorie restrict and instead allowed ad libitum intake.14,15
With mounting evidence, the VA/DoD guidelines on T2DM management included LC diets as dietary options for treating T2DM. The ADA also determined that LC diets had the most evidence in improving glycemia and included LC diets as an option for medical nutrition therapy (Table 1).10,19
A systematic review and meta-analysis looking at RCTs of LC diets found evidence for remission of T2DM without significant adverse effects (AEs).20 Another recent systematic review and network meta-analysis of 42 RCTs found that the ketogenic diet was superior for a reduction in HbA1c levels compared with 9 other dietary patterns, including low-fat, Mediterranean, and vegetarian/vegan diets. Overall, ketogenic, Mediterranean, moderate-carbohydrate, and low-glycemic index diets demonstrated improved glycemic control.21
Ideally, a comprehensive behavioral program, such as the VA Move! or Whole Health program, should incorporate patient aligned care teams (PACTs), behavioral health clinicians, clinical pharmacists, and dietitians to provide medical-nutrition therapy using LC diets. However, many facilities may not have adequate experience, expertise, or support. We provide practical approaches to provide LC nutrition counseling, medication management, and deprescribing for any primary care clinician applying LC diets for their patients. For simplicity and practicality, we define 3 types of LC dietary patterns: (1) VLCK (< 50 g); (2) LC (50-100 g); and (3) moderate LC (101-150 g).
Nutrition
All nutrition approaches, including LC diets, should be patient centered, individualized, and sensitive to the patient's culture. Typically, many patients have previously been instructed to consume low-fat (and subsequently) high-carbohydrate (> 150 g) meals. Most well-meaning clinicians have provided common-approach diet education from mainstream health organizations in the form of standardized handouts. For example, the Carbohydrate Counting for People with Diabetes patient education handout from the Academy of Nutrition and Dietetics provides a sample menu with 3 meals and 1 snack totaling 195 g of carbohydrates.22 In contrast, an example ADA diet has sample diets with 3 meals and 2 snacks with approximately 20 to 70 g of carbohydrates.23 In the VA, there are excellent resources to review and standardize handouts that emphasize an LC nutrition approach to T2DM, including ketogenic versions.24,25 Table 2 shows example meal plans based on different LC patterns—VLCK, LC, and moderate LC.
Starting an LC dietary pattern should maximize nutrient-dense and minimally processed proteins. Clinicians should begin with a baseline nutritional assessment through a 24-hour recall or food diary. After this has been completed, the patient’s baseline diet is assessed, and a gradual carbohydrate reduction plan is discussed. Generally, carbohydrate reduction is recommended at 1 meal per day per week. High-carbohydrate meals and snacks are restructured to favor satiating, minimally processed, high-protein food sources. Individual food preferences are considered and included in the recommended LC plan. For example, LC diets can be formulated for vegetarians and vegans as well as those who prefer meat and seafood. Prioritizing satiating and nutrient-dense foods can help increase the probability of diet acceptance and adherence.
A recent studyshowed that restricting carbohydrates at breakfast reduces 24-hour postprandial hyperglycemia and improves glycemic variability.26 Many patients consume upward of 50 g of carbohydrates at breakfast.27 For example, it is not uncommon for a patient to consume cereal with milk or oatmeal, orange juice, a banana, and toast at breakfast. Instead, the patient is advised to consume any combination of eggs, meat, no-sugar-added Greek yogurt, or berries.
To keep things simple for lunch and dinner, the patient is offered high-quality, minimally processed protein of their choosing with any nonstarchy vegetable. Should a patient desire additional carbohydrates with meals, they may reduce the baseline serving of carbohydrates by 50%. For example, if a patient normally fills 50% of their plate with spaghetti, they may reduce the pasta portion to 25% and add a meatball or increase the amount of vegetables consumed with the meal to satiety.
Snacks may include cheese, eggs, peanut butter, nuts, seeds, berries, no-sugar-added Greek yogurt, or guacamole. Oftentimes, when LC meals are adopted, the desire or need for snacking is diminished due to the satiating effect of high-quality protein sources and nonstarchy vegetables.
Adverse Effects
AEs have been reported with VLCK diets, including headache, diarrhea, constipation, muscle cramps, halitosis, light-headedness, and muscle weakness.28 These AEs may be mitigated with increased fluid intake, sodium intake, and magnesium supplementation.29 Increasing fluids to a minimum of 2 L/d and adding sodium (eg, bouillon supplementation) can minimize AEs.30 Milk of magnesia (5 mL) or slow-release magnesium chloride 200 mEq/d is suggested to reduce muscle cramps.30 There have been no studies looking at sodium intake and worsening hypertension or chronic heart failure in the setting of an LC diet, but fluid and electrolyte intake should be monitored closely, especially in patients with uncontrolled hypertension and heart failure. Other concerns of higher protein on worsening kidney function have generally not been founded.31 In some individuals, an LC and higher fat diet may increase low-density lipoprotein cholesterol (LDL-C).32 Therefore a baseline lipid panel is recommended and should be monitored along with HbA1c levels. An elevated LDL-C response may be managed by increasing protein and reducing saturated fat intake while maintaining the reduced carbohydrate content of the diet.
Medication Management
The adoption of an LC diet can cause a swift and profound reduction in blood sugar.33 Utilizing PACTs can help prevent adverse drug events by involving clinical pharmacists to provide recommendations and dose reductions as patients adopt an LC diet. Each approach must be individualized to the patient and can depend on several factors, including the number and strength of medications, the degree of carbohydrate reduction, baseline blood glucose, as well as assessing for medical literacy and ability to implement recommendations. Additionally, patients should monitor their blood sugar regularly and communicate with their primary care team (pharmacist, PACT registered nurse, primary care clinician, and registered dietician). Ultimately, the goal when adopting an LC diet while taking antihyperglycemics is safely avoiding hypoglycemia while reducing the number of medications the patient is taking. We summarize a practical approach to medication management that was recently published (Table 3).33,34
Medications to Reduce or Discontinue
Medications that can cause hypoglycemia should be the first to be reduced or discontinued upon starting an LC diet, including bolus insulin (although a small amount may be needed to correct for high blood sugar), sulfonylureas, and meglitinides. Combination insulin should be stopped and changed to basal insulin to avoid the risk of hypoglycemia (see Table 4 for insulin deprescribing recommendations). The mechanism of action in preventing the breakdown of carbohydrates in the gastrointestinal tract makes the use of α-glucosidase inhibitors superfluous, and they can be discontinued, reducing pill burden and polypharmacy risks. Sodium-glucose transport protein 2 inhibitors (SGLT2i) should be discontinued for patients on VLCK diets due to the risk of euglycemic diabetic ketoacidosis. However, with LC and moderate LC plans, the SGLT2i may be used with caution as long as patients are made aware of ketoacidosis symptoms. To help prevent the risk of hypoglycemia, basal/long-acting insulin can be continued, but at a 50% reduced dose. Patients should closely monitor blood sugar to assess for appropriateness of dose reductions. While thiazolidinediones are not contraindicated, clinicians can consider discontinuation given both their penchant for inducing weight gain and their limited outcomes data.
Medications to Continue
Medications that pose minimal risk for hypoglycemia can be continued, including metformin, dipeptidyl peptidase 4 inhibitors, and glucagon-like peptide-1 agonists. However, even though these may pose a low risk of hypoglycemia, patients should still closely monitor their blood glucose so medications can be deprescribed as soon as safely and reasonably possible.
Other Medications
The improvement in metabolic health with the reduction of carbohydrates can render other classes of medications unnecessary or require adjustment. Patients should be counseled to monitor their blood pressure as significant and rapid improvements can occur. In the event of a systolic blood pressure of 100 to 110 mm Hg or signs of hypotension, down titration or discontinuation of antihypertensives should be initiated. Limited evidence exists on the preferred order of discontinuation but should be informed by other comorbidities, such as coronary artery disease and chronic kidney disease. Given an LC diet’s diuretic effect, tapering and stopping diuretics may be an option. Other medications requiring closer monitoring include lithium (can be affected by fluid and electrolyte shifts), warfarin (may alter vitamin K intake), valproate (which may be reduced), and zonisamide and topiramate (kidney stone risk).
Remission of T2DM with LC Diets
As patients adopt LC diets and medications are deprescribed and glycemia improves, HbA1c and fasting glucose levels may drop below the diagnostic threshold for T2DM.20 As new evidence emerges surrounding the management of T2DM from a lifestyle perspective, major health care organizations have acknowledged that T2DM is not necessarily an incurable, progressive disease, but rather a disease that can be reversed or put in remission.35-37 In 2016, the World Health Organization (WHO) global report on diabetes acknowledged that T2DM reversal can be achieved via weight loss and calorie restriction.35
In 2021, a consensus statement from the ADA, the Endocrine Society, the EASD, and Diabetes UK defined T2DM remission as an HbA1c level < 6.5% for at least 3 months with no T2DM medications.36 Diabetes Australia also published a position statement in 2021 about T2DM remission.37 Like the WHO, Diabetes Australia acknowledged that remission of T2DM is possible following intensive dietary changes or bariatric surgery.37 Before the 2021 consensus statement, some experts argued that excluding metformin from the T2DM medication list may not be warranted since metformin has indications beyond T2DM. In this case, remission of T2DM could be defined as an HbA1c level < 6.5% for at least 3 months and on metformin or no T2DM medications.8
Emerging Strategies
Emerging strategies, such as continuous glucose monitors (CGMs) and the use of intermittent fasting/time-restricted eating (TRE), can be used with the LC diet to help improve the monitoring and management of T2DM. In the recently published VA/DoD guidelines for T2DM, the work group suggested real-time CGMs for qualified patients with T2DM.4 These include patients on daily insulin who are not achieving glycemic control or to reduce the risk for hypoglycemia. CGMs have shown evidence of improved glycemic control and decreased hypoglycemia in those with T2DM.38,39 It is currently unknown if CGMs improve long-term glycemic control, but they appear promising for managing and reducing medications for those on an LC diet.40
TRE can be supplemented with an LC plan that incorporates “eating windows.” Common patterns include 14 hours of fasting and a 10-hour eating window (14F:10E), or 16 hours of fasting and an 8-hour eating window (16F:8E). By eating only in the specified window, patients generally reduce caloric intake and minimize insulin and glucose excursions during the fasting window. No changes need to be made to the macronutrient composition of the diet, and LC approaches can be used with TRE. The mechanism of action is likely multifactorial, targeting hyperinsulinemia and insulin resistance as well as producing a caloric deficit to enable weight loss.41 Eating windows may improve insulin sensitivity, reduce insulin resistance, and enhance overall glycemic control. The recent VA/DoD guidelines recommended against intermittent fasting due to concerns over the risk of hypoglycemia despite larger weight loss in TRE groups.4 Recently, a study using CGMs and TRE demonstrated both improved glycemic control and no hypoglycemic episodes in patients with T2DM on insulin.42 Patients who would like to supplement TRE with an LC plan as a strategy for improved glycemic control should work closely with their PACT to help manage their TRE and LC plan and consider a CGM adjunct, especially if on insulin.
Barriers
Managing T2DM often requires comprehensive lifestyle modifications of nutrition, exercise, sleep, stress management, and other psychosocial issues, as well as an interdisciplinary team-based approach.43 The advantage of working within the VA includes a uniform system within a network of care. However, many patients continue to use both federal and private health care. This use of out-of-network care may result in fragmented, potentially disjointed, or even contradictory dietary advice.
The VA PACT, whole health for holistic health, and weight loss interventions such as the MOVE! program provide lifestyle interventions like nutrition, physical activity, and behavior change. However, these well-intentioned approaches may provide alternative and even diverging recommendations, which place additional barriers to effective patient management. In patients who are advised and accept a trial of an LC plan, each member of the team should embrace the self-management decision of the patient and support the plan.29 Any conflicts, questions, or concerns should be communicated directly with the team in an interdisciplinary approach to provide a unified message and counsel.
The long-term effects and sustainability of an LC diet have been questioned in the literature.44-46 Recently, the use of an app-based coaching plan has demonstrated short- and long-term sustainability on an LC diet.47 In just 5 months in a large VA system, 590 patients using a virtual coaching platform and a VLCK diet plan were found to have lower HbA1c levels, reduced diabetic medication fills, lower body mass index, fewer outpatient visits, and lower prescription drug costs.
A 5-year follow-up found nearly 50% of participants sustained a VLCK diet for T2DM. For patients who participated in the study after 2 years, 72% sustained the VLCK diet in years 2 to 5. Most required nearly 50% fewer medications and in those that started with insulin, half did not require it at 5 years.48 Further research, however, is necessary to determine the long-term effects on cardiometabolic markers and health with LC diets. There are no long-term RCTs on outcomes data looking at T2DM morbidity or mortality. While there are prospective cohort studies on LC diets in the general population on mortality, they demonstrate mixed results. These studies may be confounded by heterogeneous definitions of LC diets, diet quality, and other health factors.49-51
Conclusions
The effective use of LC diets within a PACT with close and intensive lifestyle counseling and a safe approach to medication management and deprescribing can improve glycemic control, reduce the overall need for insulin, reduce medication use, and provide sustained weight loss. Additionally, the use of therapeutic carbohydrate reduction and subsequent medication deprescription may lead to sustained remission of T2DM. The current efficacy and sustainment of therapeutic carbohydrate reduction for patients with T2DM appears promising. Further research on LC diets, emerging strategies, and long-term effects on cardiometabolic risk factors, morbidity, and mortality will continue to inform future practice in our health care system.
Acknowledgments
We thank Cecile Seth who has been instrumental in pushing us forward and the Metabolic Multiplier group who has helped encourage and provide input into this article.
1. Centers for Disease Control and Prevention. Prevalence of Both Diagnosed and Undiagnosed Diabetes. Updated September 30, 2022. Accessed October 6, 2023. https://www.cdc.gov/diabetes/data/statistics-report/diagnosed-undiagnosed-diabetes.html
2. Centers for Disease Control and Prevention. Diabetes and Prediabetes. Updated September 6, 2022. Accessed October 6, 2023. https://www.cdc.gov/chronicdisease/resources/publications/factsheets/diabetes-prediabetes.htm 3. US Department of Veterans Affairs. Diabetes information - Nutrition and food services. Updated May 4, 2023. Accessed October 6, 2023. https://www.nutrition.va.gov/diabetes.asp
4. US Department of Veterans Affairs. Management of Type 2 Diabetes Mellitus (2023) - VA/DoD Clinical Practice Guidelines. Updated September 1, 2023. Accessed October 6, 2023. https://www.healthquality.va.gov/guidelines/CD/diabetes/
5. American Diabetes Association. Economic Costs of Diabetes in the U.S. in 2017. Diabetes Care. 2018;41(5):917-928. doi:10.2337/dci18-0007
6. Home P, Riddle M, Cefalu WT, et al. Insulin therapy in people with type 2 diabetes: opportunities and challenges?. Diabetes Care. 2014;37(6):1499-1508. doi:10.2337/dc13-2743
7. Donath MY, Ehses JA, Maedler K, et al. Mechanisms of β-cell death in type 2 diabetes. Diabetes. 2005;54(suppl 2):S108-S113. doi:10.2337/DIABETES.54.SUPPL_2.S108
8. Hallberg SJ, Gershuni VM, Hazbun TL, Athinarayanan SJ. Reversing type 2 diabetes: a narrative review of the evidence. Nutrients. 2019;11(4):766. Published 2019 Apr 1. doi:10.3390/nu11040766
9. Davies MJ, D’Alessio DA, Fradkin J, et al. Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018;41(12):2669. doi:10.2337/DCI18-0033
10. Evert AB, Dennison M, Gardner CD, et al. Nutrition therapy for adults with diabetes or prediabetes: a consensus report. Diabetes Care. 2019;42(5):731-754. doi:10.2337/DCI19-0014
11. Diabetes Canada position statement on low-carbohydrate diets for adults with diabetes: a rapid review. Can J Diabetes. 2020;44(4):295-299. doi:10.1016/J.JCJD.2020.04.001
12. Diabetes Australia. Position statements. Accessed October 6, 2023. https://www.diabetesaustralia.com.au/research-advocacy/position-statements/
13. Feinman RD, Pogozelski WK, Astrup A, et al. Dietary carbohydrate restriction as the first approach in diabetes management: critical review and evidence base. Nutrition. 2014;31(1):1-13. doi:10.1016/j.nut.2014.06.011
14. Samaha FF, Iqbal N, Seshadri P, et al. A low-carbohydrate as compared with a low-fat diet in severe obesity. N Engl J Med. 2003;348(21):2074-2081. doi:10.1056/NEJMOA02263715. Westman EC, Yancy WS, Mavropoulos JC, Marquart M, McDuffie JR. The effect of a low-carbohydrate, ketogenic diet versus a low-glycemic index diet on glycemic control in type 2 diabetes mellitus. Nutr Metab (Lond). 2008;5(1):36. doi:10.1186/1743-7075-5-36
16. Saslow LR, Mason AE, Kim S, et al. An online intervention comparing a very low-carbohydrate ketogenic diet and lifestyle recommendations versus a plate method diet in overweight individuals with type 2 diabetes: a randomized controlled trial. J Med Internet Res. 2017;19(2). doi:10.2196/JMIR.5806
17. Hallberg SJ, McKenzie AL, Williams PT, et al. Effectiveness and safety of a novel care model for the management of type 2 diabetes at 1 year: an open-label, non-randomized, controlled study. Diabetes Ther. 2018;9(2):583-612. doi:10.1007/S13300-018-0373-9
18. Gram-Kampmann EM, Hansen CD, Hugger MB, et al. Effects of a 6-month, low-carbohydrate diet on glycaemic control, body composition, and cardiovascular risk factors in patients with type 2 diabetes: An open-label randomized controlled trial. Diabetes Obes Metab. 2022;24(4):693-703. doi:10.1111/DOM.14633
19. Committee ADAPP. 5. Facilitating behavior change and well-being to improve health outcomes: standards of medical care in diabetes—2022. Diabetes Care. 2022;45(suppl 1):S60-S82. doi:10.2337/DC22-S005
20. Goldenberg JZ, Johnston BC. Low and very low carbohydrate diets for diabetes remission. BMJ. 2021;373:m4743. doi:10.1136/BMJ.N262
21. Jing T, Zhang S, Bai M, et al. Effect of dietary approaches on glycemic control in patients with type 2 diabetes: a systematic review with network meta-analysis of randomized trials. Nutrients. 2023;15(14):3156. doi:10.3390/nu15143156
22. Academy of Nutrition and Dietetics. Nutrition care manual. Accessed October 6, 2023. https://www.nutritioncaremanual.org/
23. Low carbohydrate and very low carbohydrate eating patterns in adults with diabetes. ShopDiabetes.org. Accessed August 5, 2022. https://shopdiabetes.org/products/low-carbohydrate-and-very-low-carbohydrate-eating-patterns-in-adults-with-diabetes-a-guide-for-health-care-providers
24. US Department of Veterans Affairs. Diabetes education - nutrition and food services. Published July 31, 2022. http://vaww.nutrition.va.gov/docs/pted/ModifiedKetogenicDiet.pdf [Source not verified]
25. US Department of Veterans Affairs, My HealtheVet. Lowdown on low-carb diets. Updated June 1, 2021. Accessed October 6, 2023. https://www.myhealth.va.gov/mhv-portal-web/ss20190724-low-carb-diet
26. Chang CR, Francois ME, Little JP. Restricting carbohydrates at breakfast is sufficient to reduce 24-hour exposure to postprandial hyperglycemia and improve glycemic variability. Am J Clin Nutr. 2019;109(5):1302-1309. doi:10.1093/AJCN/NQY261
27. Hall KD, Ayuketah A, Brychta R, et al. Ultra-processed diets cause excess calorie intake and weight gain: an inpatient randomized controlled trial of ad libitum food intake. Cell Metab. 2019;30(1):226. doi:10.1016/j.cmet.2019.05.020
28. Harvey CJ d. C, Schofield GM, Zinn C, Thornley S. Effects of differing levels of carbohydrate restriction on mood achievement of nutritional ketosis, and symptoms of carbohydrate withdrawal in healthy adults: a randomized clinical trial. Nutrition. 2019;67-68:100005. doi:10.1016/J.NUTX.2019.100005
29. Griauzde DH, Standafer Lopez K, Saslow LR, Richardson CR. A pragmatic approach to translating low- and very low-carbohydrate diets into clinical practice for patients with obesity and type 2 diabetes. Front Nutr. 2021;8:416. doi:10.3389/FNUT.2021.682137/BIBTEX
30. Westman EC, Tondt J, Maguire E, Yancy WS. Implementing a low-carbohydrate, ketogenic diet to manage type 2 diabetes mellitus. Expert Rev Endocrinol Metab. 2018;13(5):263-272. doi:10.1080/17446651.2018.1523713
31. Suyoto PST. Effect of low-carbohydrate diet on markers of renal function in patients with type 2 diabetes: a meta-analysis. Diabetes Metab Res Rev. 2018;34(7). doi:10.1002/DMRR.3032
32. Norwitz NG, Feldman D, Soto-Mota A, Kalayjian T, Ludwig DS. Elevated LDL cholesterol with a carbohydrate-restricted diet: evidence for a “lean mass hyper-responder” phenotype. Curr Dev Nutr. 2021;6(1). doi:10.1093/CDN/NZAB144
33. Murdoch C, Unwin D, Cavan D, Cucuzzella M, Patel M. Adapting diabetes medication for low carbohydrate management of type 2 diabetes: a practical guide. Br J Gen Pract. 2019;69(684):360-361. doi:10.3399/bjgp19X704525
34. Cucuzzella M, Riley K, Isaacs D. Adapting medication for type 2 diabetes to a low carbohydrate diet. Front Nutr. 2021;8:486. doi:10.3389/FNUT.2021.688540/BIBTEX
35. World Health Organization. Global report on diabetes. 2016. Accessed October 6, 2023. https://iris.who.int/bitstream/handle/10665/204871/9789241565257_eng.pdf?sequence=1
36. Riddle MC, Cefalu WT, Evans PH, et al. Consensus report: definition and interpretation of remission in type 2 diabetes. Diabetes Care. 2021;44(10):2438-2444. doi:10.2337/DCI21-0034
37. Diabetes Australia. Type 2 Diabetes remission position statement. 2021. Accessed October 6, 2023. https://www.diabetesaustralia.com.au/wp-content/uploads/2021_Diabetes-Australia-Position-Statement_Type-2-diabetes-remission_2.pdf
38. Martens T, Beck RW, Bailey R, et al. Effect of continuous glucose monitoring on glycemic control in patients with type 2 diabetes treated with basal insulin: a randomized clinical trial. JAMA. 2021;325(22):2262-2272. doi:10.1001/JAMA.2021.7444
39. Jackson MA, Ahmann A, Shah VN. Type 2 diabetes and the use of real-time continuous glucose monitoring. Diabetes Technol Ther. 2021;23(S1):S27-S34. doi:10.1089/DIA.2021.0007
40. Oser TK, Cucuzzella M, Stasinopoulos M, Moncrief M, McCall A, Cox DJ. An innovative, paradigm-shifting lifestyle intervention to reduce glucose excursions with the use of continuous glucose monitoring to educate, motivate, and activate adults with newly diagnosed type 2 diabetes: pilot feasibility study. JMIR Diabetes. 2022;7(1). doi:10.2196/34465
41. Światkiewicz I, Woźniak A, Taub PR. Time-restricted eating and metabolic syndrome: current status and future perspectives. Nutrients. 2021;13(1):221. doi:10.3390/NU13010221
42. Obermayer A, Tripolt NJ, Pferschy PN, et al. Efficacy and safety of intermittent fasting in people with insulin-treated type 2 diabetes (INTERFAST-2)—a randomized controlled trial. Diabetes Care. 2023;46(2):463-468. doi:10.2337/dc22-1622
43. American Diabetes Association. 5. Lifestyle management: standards of medical care in diabetes—2019. Diabetes Care. 2019;42(suppl 1):S46-S60. doi:10.2337/DC19-S005
44. Li S, Ding L, Xiao X. Comparing the efficacy and safety of low-carbohydrate diets with low-fat diets for type 2 diabetes mellitus patients: a systematic review and meta-analysis of randomized clinical trials. Int J Endocrinol. 2021;2021:8521756. Published 2021 Dec 6. doi:10.1155/2021/8521756
45. Choi JH, Kang JH, Chon S. Comprehensive understanding for application in Korean patients with type 2 diabetes mellitus of the consensus statement on carbohydrate-restricted diets by Korean Diabetes Association, Korean Society for the Study of Obesity, and Korean Society of Hypertension. Diabetes Metab J. 2022;46(3):377. doi:10.4093/DMJ.2022.0051
46. Jayedi A, Zeraattalab-Motlagh S, Jabbarzadeh B, et al. Dose-dependent effect of carbohydrate restriction for type 2 diabetes management: a systematic review and dose-response meta-analysis of randomized controlled trials. Am J Clin Nutr. 2022;116(1). doi:10.1093/AJCN/NQAC066
47. Strombotne KL, Lum J, Ndugga NJ, et al. Effectiveness of a ketogenic diet and virtual coaching intervention for patients with diabetes: a difference-in-differences analysis. Diabetes Obes Metab. 2021;23(12):2643-2650. doi:10.1111/DOM.14515
48. Virta Health. Virta Health highlights lasting, transformative health improvements in 5-year diabetes reversal study. June 5, 2022. Accessed October 6, 2023. https://www.virtahealth.com/blog/virta-sustainable-health-improvements-5-year-diabetes-reversal-study
49. Wan Z, Shan Z, Geng T, et al. Associations of moderate low-carbohydrate diets with mortality among patients with type 2 diabetes: a prospective cohort study. J Clin Endocrinol Metab. 2022;107(7):E2702-E2709. doi:10.1210/CLINEM/DGAC235
50. Akter S, Mizoue T, Nanri A, et al. Low carbohydrate diet and all cause and cause-specific mortality. Clin Nutr. 2021;40(4):2016-2024. doi:10.1016/J.CLNU.2020.09.022
51. Shan Z, Guo Y, Hu FB, Liu L, Qi Q. Association of low-carbohydrate and low-fat diets with mortality among US adults. JAMA Intern Med. 2020;180(4):513-523. doi:10.1001/JAMAINTERNMED.2019.6980
The prevalence of diabetes continues to increase despite advances in treatment options. In 2019, according to the Centers for Disease Control and Prevention (CDC), 37.1 million (14.7%) US adults had diabetes. Among adults aged ≥ 65 years, the prevalence is even higher at 29.2%.1 Research has also estimated that 45% of adults have evidence of prediabetes or diabetes.2 According to the Veterans Health Administration, almost 25% of enrolled veterans have diabetes.3
Background
Diabetes is associated with an increased risk of microvascular complications (eg, retinopathy, nephropathy, and neuropathy) and macrovascular complications (eg, atherosclerotic cardiovascular disease) and is one of the most common causes of morbidity and mortality in the US.4 In 2017, diabetes was estimated to cost $327 billion in the US, up from $261 billion in 2012.5 During this same period, the excess costs per person with diabetes increased from $8417 to $9601.5
Type 2 diabetes mellitus (T2DM) and its associated insulin resistance is typically considered a chronic disease with progressive loss of β-cell function. Controlling glycemia, delaying microvascular changes, and preventing macrovascular disease are major management goals. Lifestyle interventions are essential in the management and prevention of T2DM. Medication management for T2DM usually progresses through several medications, ending in insulin therapy.6 Within 10 years of diagnosis, almost half of all individuals with T2DM will require insulin to manage their glycemia.7
Bariatric surgery and nutrition approaches have been successful in reversing T2DM. Recently, there has been increased interest in nutritional approaches to place T2DM in remission, reverse the disease process, and improve insulin resistance. Contrary to popular belief, before the discovery of insulin in 1921, low-carbohydrate (LC) diets were the most common treatment for T2DM.8 With the discovery of insulin and the eventual development of low-fat dietary recommendations, LC diets were no longer favored by most clinicians.8 Low-fat diets are, by definition, also high-carbohydrate diets. By the early 1980s, low-fat diets had become the standard of care dietary recommendation, and the goal for clinicians became glycemic maintenance (with increased use of medications) rather than preventing hyperglycemia.8
With growing evidence regarding the use of LC diets for T2DM, the US Department of Veterans Affairs (VA) and US Department of Defense (DoD), the American Diabetes Association (ADA), the European Association for the Study of Diabetes (EASD), Diabetes Canada, and Diabetes Australia all include LC diets as a viable option for treating T2DM.4,9-12 This article will highlight a case using a reduced carbohydrate approach in lifestyle management and provide clinicians with practical guidance in its implementation. We will review the evidence that informs these guidelines, describe a practical approach to nutritional counseling, and review medication management and deprescribing approaches. Finally, barriers to implementation will be explored.
ILLUSTRATIVE CASE
A 64-year-old woman presented to the clinical pharmacist for the management of T2DM after her tenth hospitalization related to hyperglycemia in 10 years. She had previously been managed by primary care clinicians, clinical dietitians, endocrinologists, and certified diabetes care and education specialists. Pertinent history included diabetic ketoacidosis, coronary artery disease, hyperlipidemia, hypertension, obstructive sleep apnea, obesity, metabolic dysfunction-associated steatotic liver disease, and mild nonproliferative diabetic retinopathy with clinically significant macular edema. The patient expressed frustration with poor glycemic control during her many years of insulin therapy and an inability to lose weight due to insulin dose titrations. The patient reported prior education including but not limited to standardized sample menus, consistent carbohydrate intake, calorie reduction, general healthful nutrition, and the “move more, eat less” approach. The patient was unable to titrate insulin dosage and did not experience weight loss despite compliance with these methods.
Her medications included glargine insulin 45 units once daily, aspart insulin 5 units before meals 3 times daily, and metformin 1000 mg twice daily. Her hemoglobin A1c (HbA1c) level was 11.8%. A review of prior therapies for T2DM included glyburide 5 mg twice daily, metformin 1000 mg twice daily, 70/30 insulin (up to 340 units/d), glargine insulin (range, 10-140 units/d), regular insulin (range, 30-240 units/d), aspart insulin (range, 15-45 units/d), and U-500 regular insulin (range, 125-390 units/d). She took metoprolol 25 mg extended release daily and hydrochlorothiazide 25 mg daily, but both were discontinued after the most recent hospitalization. A review of HbA1c readings showed poor glycemic control for > 12 years (range, 10.3% to > 12.3%).
Education for lifestyle modifications, including an LC diet, was presented to the patient to assist with weight loss, improve glycemic control, and reduce insulin resistance. In addition, a glucagon-like peptide-1 agonist (liraglutide) was added to her pharmacotherapy. Continued dietary modifications with LC intake led to consistent reductions in glargine and aspart insulin therapy. The patient remained motivated throughout clinic visits due to improved glycemic control with sustainable dietary modifications, consistently reported feeling better overall, and deprescribed diabetes drug therapies. She remained off her blood pressure medications. After4 months of LC dietary modifications, all insulin therapy was discontinued. She continued with liraglutide 1.8 mg daily and metformin 1000 mg twice daily with an HbA1c of 6.3%. Two months later, her HbA1c level was 6.0%. She also lost 8 lb and her body mass index improved from 31 to 29.
Low-Carbohydrate T2DM DIET MANAGEMENT
LC diets are commonly defined as < 130 g of carbohydrates per day.13 Very LC ketogenic (VLCK) diets often contain ≤ 50 g of carbohydrates per day to induce nutritional ketosis.13 One of the first randomized controlled trials (RCTs) that compared a VLCK diet (< 30 g of carbohydrates per day) with a low-fat diet for obesity demonstrated greater weight loss at 6 months with the LC diet. In addition, patients with diabetes randomized to the LC group also showed improved insulin sensitivity. Notably, this study was done in a population of veterans enrolled at the VA Philadelphia Health Care System.14
A 2008 study comparing an LC diet with a calorie-restricted, low-glycemic diet for individuals with T2DM found that the LC diet group experienced a greater reduction in HbA1c and insulin levels and weight.15 Comparing these 2 diet groups after 24 weeks, 95% of individuals in the LC group reduced or discontinued T2DM medications vs 62% in the low-glycemic group.15 Another study of individuals with T2DM compared a VLCK diet with a low-fat diet. After 34 weeks, 55% of individuals in the LC diet group achieved an HbA1c level below the threshold for diabetes vs 0% in the low-fat diet group.16 A 2018 study of patients with T2DM investigated the impact of a very LC diet compared with the standard of care.17 After 1 year, the LC diet group experienced a mean HbA1c reduction of 1.3%, and 60% of individuals who completed the study achieved an HbA1c level < 6.5% without T2DM medications (not including metformin). This study also demonstrated that medications were significantly reduced, including 100% discontinuation of sulfonylureas and 94% reduction or elimination of insulin.
A recent study of an LC diet (< 20% energy from carbohydrates) demonstrated reduced HbA1c levels, weight, and waist circumference vs a control diet after 6 months. The control diet derived 50% to 60% of energy from carbohydrates.18 This study is typical of other LC interventions, which did not calorie restrict and instead allowed ad libitum intake.14,15
With mounting evidence, the VA/DoD guidelines on T2DM management included LC diets as dietary options for treating T2DM. The ADA also determined that LC diets had the most evidence in improving glycemia and included LC diets as an option for medical nutrition therapy (Table 1).10,19
A systematic review and meta-analysis looking at RCTs of LC diets found evidence for remission of T2DM without significant adverse effects (AEs).20 Another recent systematic review and network meta-analysis of 42 RCTs found that the ketogenic diet was superior for a reduction in HbA1c levels compared with 9 other dietary patterns, including low-fat, Mediterranean, and vegetarian/vegan diets. Overall, ketogenic, Mediterranean, moderate-carbohydrate, and low-glycemic index diets demonstrated improved glycemic control.21
Ideally, a comprehensive behavioral program, such as the VA Move! or Whole Health program, should incorporate patient aligned care teams (PACTs), behavioral health clinicians, clinical pharmacists, and dietitians to provide medical-nutrition therapy using LC diets. However, many facilities may not have adequate experience, expertise, or support. We provide practical approaches to provide LC nutrition counseling, medication management, and deprescribing for any primary care clinician applying LC diets for their patients. For simplicity and practicality, we define 3 types of LC dietary patterns: (1) VLCK (< 50 g); (2) LC (50-100 g); and (3) moderate LC (101-150 g).
Nutrition
All nutrition approaches, including LC diets, should be patient centered, individualized, and sensitive to the patient's culture. Typically, many patients have previously been instructed to consume low-fat (and subsequently) high-carbohydrate (> 150 g) meals. Most well-meaning clinicians have provided common-approach diet education from mainstream health organizations in the form of standardized handouts. For example, the Carbohydrate Counting for People with Diabetes patient education handout from the Academy of Nutrition and Dietetics provides a sample menu with 3 meals and 1 snack totaling 195 g of carbohydrates.22 In contrast, an example ADA diet has sample diets with 3 meals and 2 snacks with approximately 20 to 70 g of carbohydrates.23 In the VA, there are excellent resources to review and standardize handouts that emphasize an LC nutrition approach to T2DM, including ketogenic versions.24,25 Table 2 shows example meal plans based on different LC patterns—VLCK, LC, and moderate LC.
Starting an LC dietary pattern should maximize nutrient-dense and minimally processed proteins. Clinicians should begin with a baseline nutritional assessment through a 24-hour recall or food diary. After this has been completed, the patient’s baseline diet is assessed, and a gradual carbohydrate reduction plan is discussed. Generally, carbohydrate reduction is recommended at 1 meal per day per week. High-carbohydrate meals and snacks are restructured to favor satiating, minimally processed, high-protein food sources. Individual food preferences are considered and included in the recommended LC plan. For example, LC diets can be formulated for vegetarians and vegans as well as those who prefer meat and seafood. Prioritizing satiating and nutrient-dense foods can help increase the probability of diet acceptance and adherence.
A recent studyshowed that restricting carbohydrates at breakfast reduces 24-hour postprandial hyperglycemia and improves glycemic variability.26 Many patients consume upward of 50 g of carbohydrates at breakfast.27 For example, it is not uncommon for a patient to consume cereal with milk or oatmeal, orange juice, a banana, and toast at breakfast. Instead, the patient is advised to consume any combination of eggs, meat, no-sugar-added Greek yogurt, or berries.
To keep things simple for lunch and dinner, the patient is offered high-quality, minimally processed protein of their choosing with any nonstarchy vegetable. Should a patient desire additional carbohydrates with meals, they may reduce the baseline serving of carbohydrates by 50%. For example, if a patient normally fills 50% of their plate with spaghetti, they may reduce the pasta portion to 25% and add a meatball or increase the amount of vegetables consumed with the meal to satiety.
Snacks may include cheese, eggs, peanut butter, nuts, seeds, berries, no-sugar-added Greek yogurt, or guacamole. Oftentimes, when LC meals are adopted, the desire or need for snacking is diminished due to the satiating effect of high-quality protein sources and nonstarchy vegetables.
Adverse Effects
AEs have been reported with VLCK diets, including headache, diarrhea, constipation, muscle cramps, halitosis, light-headedness, and muscle weakness.28 These AEs may be mitigated with increased fluid intake, sodium intake, and magnesium supplementation.29 Increasing fluids to a minimum of 2 L/d and adding sodium (eg, bouillon supplementation) can minimize AEs.30 Milk of magnesia (5 mL) or slow-release magnesium chloride 200 mEq/d is suggested to reduce muscle cramps.30 There have been no studies looking at sodium intake and worsening hypertension or chronic heart failure in the setting of an LC diet, but fluid and electrolyte intake should be monitored closely, especially in patients with uncontrolled hypertension and heart failure. Other concerns of higher protein on worsening kidney function have generally not been founded.31 In some individuals, an LC and higher fat diet may increase low-density lipoprotein cholesterol (LDL-C).32 Therefore a baseline lipid panel is recommended and should be monitored along with HbA1c levels. An elevated LDL-C response may be managed by increasing protein and reducing saturated fat intake while maintaining the reduced carbohydrate content of the diet.
Medication Management
The adoption of an LC diet can cause a swift and profound reduction in blood sugar.33 Utilizing PACTs can help prevent adverse drug events by involving clinical pharmacists to provide recommendations and dose reductions as patients adopt an LC diet. Each approach must be individualized to the patient and can depend on several factors, including the number and strength of medications, the degree of carbohydrate reduction, baseline blood glucose, as well as assessing for medical literacy and ability to implement recommendations. Additionally, patients should monitor their blood sugar regularly and communicate with their primary care team (pharmacist, PACT registered nurse, primary care clinician, and registered dietician). Ultimately, the goal when adopting an LC diet while taking antihyperglycemics is safely avoiding hypoglycemia while reducing the number of medications the patient is taking. We summarize a practical approach to medication management that was recently published (Table 3).33,34
Medications to Reduce or Discontinue
Medications that can cause hypoglycemia should be the first to be reduced or discontinued upon starting an LC diet, including bolus insulin (although a small amount may be needed to correct for high blood sugar), sulfonylureas, and meglitinides. Combination insulin should be stopped and changed to basal insulin to avoid the risk of hypoglycemia (see Table 4 for insulin deprescribing recommendations). The mechanism of action in preventing the breakdown of carbohydrates in the gastrointestinal tract makes the use of α-glucosidase inhibitors superfluous, and they can be discontinued, reducing pill burden and polypharmacy risks. Sodium-glucose transport protein 2 inhibitors (SGLT2i) should be discontinued for patients on VLCK diets due to the risk of euglycemic diabetic ketoacidosis. However, with LC and moderate LC plans, the SGLT2i may be used with caution as long as patients are made aware of ketoacidosis symptoms. To help prevent the risk of hypoglycemia, basal/long-acting insulin can be continued, but at a 50% reduced dose. Patients should closely monitor blood sugar to assess for appropriateness of dose reductions. While thiazolidinediones are not contraindicated, clinicians can consider discontinuation given both their penchant for inducing weight gain and their limited outcomes data.
Medications to Continue
Medications that pose minimal risk for hypoglycemia can be continued, including metformin, dipeptidyl peptidase 4 inhibitors, and glucagon-like peptide-1 agonists. However, even though these may pose a low risk of hypoglycemia, patients should still closely monitor their blood glucose so medications can be deprescribed as soon as safely and reasonably possible.
Other Medications
The improvement in metabolic health with the reduction of carbohydrates can render other classes of medications unnecessary or require adjustment. Patients should be counseled to monitor their blood pressure as significant and rapid improvements can occur. In the event of a systolic blood pressure of 100 to 110 mm Hg or signs of hypotension, down titration or discontinuation of antihypertensives should be initiated. Limited evidence exists on the preferred order of discontinuation but should be informed by other comorbidities, such as coronary artery disease and chronic kidney disease. Given an LC diet’s diuretic effect, tapering and stopping diuretics may be an option. Other medications requiring closer monitoring include lithium (can be affected by fluid and electrolyte shifts), warfarin (may alter vitamin K intake), valproate (which may be reduced), and zonisamide and topiramate (kidney stone risk).
Remission of T2DM with LC Diets
As patients adopt LC diets and medications are deprescribed and glycemia improves, HbA1c and fasting glucose levels may drop below the diagnostic threshold for T2DM.20 As new evidence emerges surrounding the management of T2DM from a lifestyle perspective, major health care organizations have acknowledged that T2DM is not necessarily an incurable, progressive disease, but rather a disease that can be reversed or put in remission.35-37 In 2016, the World Health Organization (WHO) global report on diabetes acknowledged that T2DM reversal can be achieved via weight loss and calorie restriction.35
In 2021, a consensus statement from the ADA, the Endocrine Society, the EASD, and Diabetes UK defined T2DM remission as an HbA1c level < 6.5% for at least 3 months with no T2DM medications.36 Diabetes Australia also published a position statement in 2021 about T2DM remission.37 Like the WHO, Diabetes Australia acknowledged that remission of T2DM is possible following intensive dietary changes or bariatric surgery.37 Before the 2021 consensus statement, some experts argued that excluding metformin from the T2DM medication list may not be warranted since metformin has indications beyond T2DM. In this case, remission of T2DM could be defined as an HbA1c level < 6.5% for at least 3 months and on metformin or no T2DM medications.8
Emerging Strategies
Emerging strategies, such as continuous glucose monitors (CGMs) and the use of intermittent fasting/time-restricted eating (TRE), can be used with the LC diet to help improve the monitoring and management of T2DM. In the recently published VA/DoD guidelines for T2DM, the work group suggested real-time CGMs for qualified patients with T2DM.4 These include patients on daily insulin who are not achieving glycemic control or to reduce the risk for hypoglycemia. CGMs have shown evidence of improved glycemic control and decreased hypoglycemia in those with T2DM.38,39 It is currently unknown if CGMs improve long-term glycemic control, but they appear promising for managing and reducing medications for those on an LC diet.40
TRE can be supplemented with an LC plan that incorporates “eating windows.” Common patterns include 14 hours of fasting and a 10-hour eating window (14F:10E), or 16 hours of fasting and an 8-hour eating window (16F:8E). By eating only in the specified window, patients generally reduce caloric intake and minimize insulin and glucose excursions during the fasting window. No changes need to be made to the macronutrient composition of the diet, and LC approaches can be used with TRE. The mechanism of action is likely multifactorial, targeting hyperinsulinemia and insulin resistance as well as producing a caloric deficit to enable weight loss.41 Eating windows may improve insulin sensitivity, reduce insulin resistance, and enhance overall glycemic control. The recent VA/DoD guidelines recommended against intermittent fasting due to concerns over the risk of hypoglycemia despite larger weight loss in TRE groups.4 Recently, a study using CGMs and TRE demonstrated both improved glycemic control and no hypoglycemic episodes in patients with T2DM on insulin.42 Patients who would like to supplement TRE with an LC plan as a strategy for improved glycemic control should work closely with their PACT to help manage their TRE and LC plan and consider a CGM adjunct, especially if on insulin.
Barriers
Managing T2DM often requires comprehensive lifestyle modifications of nutrition, exercise, sleep, stress management, and other psychosocial issues, as well as an interdisciplinary team-based approach.43 The advantage of working within the VA includes a uniform system within a network of care. However, many patients continue to use both federal and private health care. This use of out-of-network care may result in fragmented, potentially disjointed, or even contradictory dietary advice.
The VA PACT, whole health for holistic health, and weight loss interventions such as the MOVE! program provide lifestyle interventions like nutrition, physical activity, and behavior change. However, these well-intentioned approaches may provide alternative and even diverging recommendations, which place additional barriers to effective patient management. In patients who are advised and accept a trial of an LC plan, each member of the team should embrace the self-management decision of the patient and support the plan.29 Any conflicts, questions, or concerns should be communicated directly with the team in an interdisciplinary approach to provide a unified message and counsel.
The long-term effects and sustainability of an LC diet have been questioned in the literature.44-46 Recently, the use of an app-based coaching plan has demonstrated short- and long-term sustainability on an LC diet.47 In just 5 months in a large VA system, 590 patients using a virtual coaching platform and a VLCK diet plan were found to have lower HbA1c levels, reduced diabetic medication fills, lower body mass index, fewer outpatient visits, and lower prescription drug costs.
A 5-year follow-up found nearly 50% of participants sustained a VLCK diet for T2DM. For patients who participated in the study after 2 years, 72% sustained the VLCK diet in years 2 to 5. Most required nearly 50% fewer medications and in those that started with insulin, half did not require it at 5 years.48 Further research, however, is necessary to determine the long-term effects on cardiometabolic markers and health with LC diets. There are no long-term RCTs on outcomes data looking at T2DM morbidity or mortality. While there are prospective cohort studies on LC diets in the general population on mortality, they demonstrate mixed results. These studies may be confounded by heterogeneous definitions of LC diets, diet quality, and other health factors.49-51
Conclusions
The effective use of LC diets within a PACT with close and intensive lifestyle counseling and a safe approach to medication management and deprescribing can improve glycemic control, reduce the overall need for insulin, reduce medication use, and provide sustained weight loss. Additionally, the use of therapeutic carbohydrate reduction and subsequent medication deprescription may lead to sustained remission of T2DM. The current efficacy and sustainment of therapeutic carbohydrate reduction for patients with T2DM appears promising. Further research on LC diets, emerging strategies, and long-term effects on cardiometabolic risk factors, morbidity, and mortality will continue to inform future practice in our health care system.
Acknowledgments
We thank Cecile Seth who has been instrumental in pushing us forward and the Metabolic Multiplier group who has helped encourage and provide input into this article.
The prevalence of diabetes continues to increase despite advances in treatment options. In 2019, according to the Centers for Disease Control and Prevention (CDC), 37.1 million (14.7%) US adults had diabetes. Among adults aged ≥ 65 years, the prevalence is even higher at 29.2%.1 Research has also estimated that 45% of adults have evidence of prediabetes or diabetes.2 According to the Veterans Health Administration, almost 25% of enrolled veterans have diabetes.3
Background
Diabetes is associated with an increased risk of microvascular complications (eg, retinopathy, nephropathy, and neuropathy) and macrovascular complications (eg, atherosclerotic cardiovascular disease) and is one of the most common causes of morbidity and mortality in the US.4 In 2017, diabetes was estimated to cost $327 billion in the US, up from $261 billion in 2012.5 During this same period, the excess costs per person with diabetes increased from $8417 to $9601.5
Type 2 diabetes mellitus (T2DM) and its associated insulin resistance is typically considered a chronic disease with progressive loss of β-cell function. Controlling glycemia, delaying microvascular changes, and preventing macrovascular disease are major management goals. Lifestyle interventions are essential in the management and prevention of T2DM. Medication management for T2DM usually progresses through several medications, ending in insulin therapy.6 Within 10 years of diagnosis, almost half of all individuals with T2DM will require insulin to manage their glycemia.7
Bariatric surgery and nutrition approaches have been successful in reversing T2DM. Recently, there has been increased interest in nutritional approaches to place T2DM in remission, reverse the disease process, and improve insulin resistance. Contrary to popular belief, before the discovery of insulin in 1921, low-carbohydrate (LC) diets were the most common treatment for T2DM.8 With the discovery of insulin and the eventual development of low-fat dietary recommendations, LC diets were no longer favored by most clinicians.8 Low-fat diets are, by definition, also high-carbohydrate diets. By the early 1980s, low-fat diets had become the standard of care dietary recommendation, and the goal for clinicians became glycemic maintenance (with increased use of medications) rather than preventing hyperglycemia.8
With growing evidence regarding the use of LC diets for T2DM, the US Department of Veterans Affairs (VA) and US Department of Defense (DoD), the American Diabetes Association (ADA), the European Association for the Study of Diabetes (EASD), Diabetes Canada, and Diabetes Australia all include LC diets as a viable option for treating T2DM.4,9-12 This article will highlight a case using a reduced carbohydrate approach in lifestyle management and provide clinicians with practical guidance in its implementation. We will review the evidence that informs these guidelines, describe a practical approach to nutritional counseling, and review medication management and deprescribing approaches. Finally, barriers to implementation will be explored.
ILLUSTRATIVE CASE
A 64-year-old woman presented to the clinical pharmacist for the management of T2DM after her tenth hospitalization related to hyperglycemia in 10 years. She had previously been managed by primary care clinicians, clinical dietitians, endocrinologists, and certified diabetes care and education specialists. Pertinent history included diabetic ketoacidosis, coronary artery disease, hyperlipidemia, hypertension, obstructive sleep apnea, obesity, metabolic dysfunction-associated steatotic liver disease, and mild nonproliferative diabetic retinopathy with clinically significant macular edema. The patient expressed frustration with poor glycemic control during her many years of insulin therapy and an inability to lose weight due to insulin dose titrations. The patient reported prior education including but not limited to standardized sample menus, consistent carbohydrate intake, calorie reduction, general healthful nutrition, and the “move more, eat less” approach. The patient was unable to titrate insulin dosage and did not experience weight loss despite compliance with these methods.
Her medications included glargine insulin 45 units once daily, aspart insulin 5 units before meals 3 times daily, and metformin 1000 mg twice daily. Her hemoglobin A1c (HbA1c) level was 11.8%. A review of prior therapies for T2DM included glyburide 5 mg twice daily, metformin 1000 mg twice daily, 70/30 insulin (up to 340 units/d), glargine insulin (range, 10-140 units/d), regular insulin (range, 30-240 units/d), aspart insulin (range, 15-45 units/d), and U-500 regular insulin (range, 125-390 units/d). She took metoprolol 25 mg extended release daily and hydrochlorothiazide 25 mg daily, but both were discontinued after the most recent hospitalization. A review of HbA1c readings showed poor glycemic control for > 12 years (range, 10.3% to > 12.3%).
Education for lifestyle modifications, including an LC diet, was presented to the patient to assist with weight loss, improve glycemic control, and reduce insulin resistance. In addition, a glucagon-like peptide-1 agonist (liraglutide) was added to her pharmacotherapy. Continued dietary modifications with LC intake led to consistent reductions in glargine and aspart insulin therapy. The patient remained motivated throughout clinic visits due to improved glycemic control with sustainable dietary modifications, consistently reported feeling better overall, and deprescribed diabetes drug therapies. She remained off her blood pressure medications. After4 months of LC dietary modifications, all insulin therapy was discontinued. She continued with liraglutide 1.8 mg daily and metformin 1000 mg twice daily with an HbA1c of 6.3%. Two months later, her HbA1c level was 6.0%. She also lost 8 lb and her body mass index improved from 31 to 29.
Low-Carbohydrate T2DM DIET MANAGEMENT
LC diets are commonly defined as < 130 g of carbohydrates per day.13 Very LC ketogenic (VLCK) diets often contain ≤ 50 g of carbohydrates per day to induce nutritional ketosis.13 One of the first randomized controlled trials (RCTs) that compared a VLCK diet (< 30 g of carbohydrates per day) with a low-fat diet for obesity demonstrated greater weight loss at 6 months with the LC diet. In addition, patients with diabetes randomized to the LC group also showed improved insulin sensitivity. Notably, this study was done in a population of veterans enrolled at the VA Philadelphia Health Care System.14
A 2008 study comparing an LC diet with a calorie-restricted, low-glycemic diet for individuals with T2DM found that the LC diet group experienced a greater reduction in HbA1c and insulin levels and weight.15 Comparing these 2 diet groups after 24 weeks, 95% of individuals in the LC group reduced or discontinued T2DM medications vs 62% in the low-glycemic group.15 Another study of individuals with T2DM compared a VLCK diet with a low-fat diet. After 34 weeks, 55% of individuals in the LC diet group achieved an HbA1c level below the threshold for diabetes vs 0% in the low-fat diet group.16 A 2018 study of patients with T2DM investigated the impact of a very LC diet compared with the standard of care.17 After 1 year, the LC diet group experienced a mean HbA1c reduction of 1.3%, and 60% of individuals who completed the study achieved an HbA1c level < 6.5% without T2DM medications (not including metformin). This study also demonstrated that medications were significantly reduced, including 100% discontinuation of sulfonylureas and 94% reduction or elimination of insulin.
A recent study of an LC diet (< 20% energy from carbohydrates) demonstrated reduced HbA1c levels, weight, and waist circumference vs a control diet after 6 months. The control diet derived 50% to 60% of energy from carbohydrates.18 This study is typical of other LC interventions, which did not calorie restrict and instead allowed ad libitum intake.14,15
With mounting evidence, the VA/DoD guidelines on T2DM management included LC diets as dietary options for treating T2DM. The ADA also determined that LC diets had the most evidence in improving glycemia and included LC diets as an option for medical nutrition therapy (Table 1).10,19
A systematic review and meta-analysis looking at RCTs of LC diets found evidence for remission of T2DM without significant adverse effects (AEs).20 Another recent systematic review and network meta-analysis of 42 RCTs found that the ketogenic diet was superior for a reduction in HbA1c levels compared with 9 other dietary patterns, including low-fat, Mediterranean, and vegetarian/vegan diets. Overall, ketogenic, Mediterranean, moderate-carbohydrate, and low-glycemic index diets demonstrated improved glycemic control.21
Ideally, a comprehensive behavioral program, such as the VA Move! or Whole Health program, should incorporate patient aligned care teams (PACTs), behavioral health clinicians, clinical pharmacists, and dietitians to provide medical-nutrition therapy using LC diets. However, many facilities may not have adequate experience, expertise, or support. We provide practical approaches to provide LC nutrition counseling, medication management, and deprescribing for any primary care clinician applying LC diets for their patients. For simplicity and practicality, we define 3 types of LC dietary patterns: (1) VLCK (< 50 g); (2) LC (50-100 g); and (3) moderate LC (101-150 g).
Nutrition
All nutrition approaches, including LC diets, should be patient centered, individualized, and sensitive to the patient's culture. Typically, many patients have previously been instructed to consume low-fat (and subsequently) high-carbohydrate (> 150 g) meals. Most well-meaning clinicians have provided common-approach diet education from mainstream health organizations in the form of standardized handouts. For example, the Carbohydrate Counting for People with Diabetes patient education handout from the Academy of Nutrition and Dietetics provides a sample menu with 3 meals and 1 snack totaling 195 g of carbohydrates.22 In contrast, an example ADA diet has sample diets with 3 meals and 2 snacks with approximately 20 to 70 g of carbohydrates.23 In the VA, there are excellent resources to review and standardize handouts that emphasize an LC nutrition approach to T2DM, including ketogenic versions.24,25 Table 2 shows example meal plans based on different LC patterns—VLCK, LC, and moderate LC.
Starting an LC dietary pattern should maximize nutrient-dense and minimally processed proteins. Clinicians should begin with a baseline nutritional assessment through a 24-hour recall or food diary. After this has been completed, the patient’s baseline diet is assessed, and a gradual carbohydrate reduction plan is discussed. Generally, carbohydrate reduction is recommended at 1 meal per day per week. High-carbohydrate meals and snacks are restructured to favor satiating, minimally processed, high-protein food sources. Individual food preferences are considered and included in the recommended LC plan. For example, LC diets can be formulated for vegetarians and vegans as well as those who prefer meat and seafood. Prioritizing satiating and nutrient-dense foods can help increase the probability of diet acceptance and adherence.
A recent studyshowed that restricting carbohydrates at breakfast reduces 24-hour postprandial hyperglycemia and improves glycemic variability.26 Many patients consume upward of 50 g of carbohydrates at breakfast.27 For example, it is not uncommon for a patient to consume cereal with milk or oatmeal, orange juice, a banana, and toast at breakfast. Instead, the patient is advised to consume any combination of eggs, meat, no-sugar-added Greek yogurt, or berries.
To keep things simple for lunch and dinner, the patient is offered high-quality, minimally processed protein of their choosing with any nonstarchy vegetable. Should a patient desire additional carbohydrates with meals, they may reduce the baseline serving of carbohydrates by 50%. For example, if a patient normally fills 50% of their plate with spaghetti, they may reduce the pasta portion to 25% and add a meatball or increase the amount of vegetables consumed with the meal to satiety.
Snacks may include cheese, eggs, peanut butter, nuts, seeds, berries, no-sugar-added Greek yogurt, or guacamole. Oftentimes, when LC meals are adopted, the desire or need for snacking is diminished due to the satiating effect of high-quality protein sources and nonstarchy vegetables.
Adverse Effects
AEs have been reported with VLCK diets, including headache, diarrhea, constipation, muscle cramps, halitosis, light-headedness, and muscle weakness.28 These AEs may be mitigated with increased fluid intake, sodium intake, and magnesium supplementation.29 Increasing fluids to a minimum of 2 L/d and adding sodium (eg, bouillon supplementation) can minimize AEs.30 Milk of magnesia (5 mL) or slow-release magnesium chloride 200 mEq/d is suggested to reduce muscle cramps.30 There have been no studies looking at sodium intake and worsening hypertension or chronic heart failure in the setting of an LC diet, but fluid and electrolyte intake should be monitored closely, especially in patients with uncontrolled hypertension and heart failure. Other concerns of higher protein on worsening kidney function have generally not been founded.31 In some individuals, an LC and higher fat diet may increase low-density lipoprotein cholesterol (LDL-C).32 Therefore a baseline lipid panel is recommended and should be monitored along with HbA1c levels. An elevated LDL-C response may be managed by increasing protein and reducing saturated fat intake while maintaining the reduced carbohydrate content of the diet.
Medication Management
The adoption of an LC diet can cause a swift and profound reduction in blood sugar.33 Utilizing PACTs can help prevent adverse drug events by involving clinical pharmacists to provide recommendations and dose reductions as patients adopt an LC diet. Each approach must be individualized to the patient and can depend on several factors, including the number and strength of medications, the degree of carbohydrate reduction, baseline blood glucose, as well as assessing for medical literacy and ability to implement recommendations. Additionally, patients should monitor their blood sugar regularly and communicate with their primary care team (pharmacist, PACT registered nurse, primary care clinician, and registered dietician). Ultimately, the goal when adopting an LC diet while taking antihyperglycemics is safely avoiding hypoglycemia while reducing the number of medications the patient is taking. We summarize a practical approach to medication management that was recently published (Table 3).33,34
Medications to Reduce or Discontinue
Medications that can cause hypoglycemia should be the first to be reduced or discontinued upon starting an LC diet, including bolus insulin (although a small amount may be needed to correct for high blood sugar), sulfonylureas, and meglitinides. Combination insulin should be stopped and changed to basal insulin to avoid the risk of hypoglycemia (see Table 4 for insulin deprescribing recommendations). The mechanism of action in preventing the breakdown of carbohydrates in the gastrointestinal tract makes the use of α-glucosidase inhibitors superfluous, and they can be discontinued, reducing pill burden and polypharmacy risks. Sodium-glucose transport protein 2 inhibitors (SGLT2i) should be discontinued for patients on VLCK diets due to the risk of euglycemic diabetic ketoacidosis. However, with LC and moderate LC plans, the SGLT2i may be used with caution as long as patients are made aware of ketoacidosis symptoms. To help prevent the risk of hypoglycemia, basal/long-acting insulin can be continued, but at a 50% reduced dose. Patients should closely monitor blood sugar to assess for appropriateness of dose reductions. While thiazolidinediones are not contraindicated, clinicians can consider discontinuation given both their penchant for inducing weight gain and their limited outcomes data.
Medications to Continue
Medications that pose minimal risk for hypoglycemia can be continued, including metformin, dipeptidyl peptidase 4 inhibitors, and glucagon-like peptide-1 agonists. However, even though these may pose a low risk of hypoglycemia, patients should still closely monitor their blood glucose so medications can be deprescribed as soon as safely and reasonably possible.
Other Medications
The improvement in metabolic health with the reduction of carbohydrates can render other classes of medications unnecessary or require adjustment. Patients should be counseled to monitor their blood pressure as significant and rapid improvements can occur. In the event of a systolic blood pressure of 100 to 110 mm Hg or signs of hypotension, down titration or discontinuation of antihypertensives should be initiated. Limited evidence exists on the preferred order of discontinuation but should be informed by other comorbidities, such as coronary artery disease and chronic kidney disease. Given an LC diet’s diuretic effect, tapering and stopping diuretics may be an option. Other medications requiring closer monitoring include lithium (can be affected by fluid and electrolyte shifts), warfarin (may alter vitamin K intake), valproate (which may be reduced), and zonisamide and topiramate (kidney stone risk).
Remission of T2DM with LC Diets
As patients adopt LC diets and medications are deprescribed and glycemia improves, HbA1c and fasting glucose levels may drop below the diagnostic threshold for T2DM.20 As new evidence emerges surrounding the management of T2DM from a lifestyle perspective, major health care organizations have acknowledged that T2DM is not necessarily an incurable, progressive disease, but rather a disease that can be reversed or put in remission.35-37 In 2016, the World Health Organization (WHO) global report on diabetes acknowledged that T2DM reversal can be achieved via weight loss and calorie restriction.35
In 2021, a consensus statement from the ADA, the Endocrine Society, the EASD, and Diabetes UK defined T2DM remission as an HbA1c level < 6.5% for at least 3 months with no T2DM medications.36 Diabetes Australia also published a position statement in 2021 about T2DM remission.37 Like the WHO, Diabetes Australia acknowledged that remission of T2DM is possible following intensive dietary changes or bariatric surgery.37 Before the 2021 consensus statement, some experts argued that excluding metformin from the T2DM medication list may not be warranted since metformin has indications beyond T2DM. In this case, remission of T2DM could be defined as an HbA1c level < 6.5% for at least 3 months and on metformin or no T2DM medications.8
Emerging Strategies
Emerging strategies, such as continuous glucose monitors (CGMs) and the use of intermittent fasting/time-restricted eating (TRE), can be used with the LC diet to help improve the monitoring and management of T2DM. In the recently published VA/DoD guidelines for T2DM, the work group suggested real-time CGMs for qualified patients with T2DM.4 These include patients on daily insulin who are not achieving glycemic control or to reduce the risk for hypoglycemia. CGMs have shown evidence of improved glycemic control and decreased hypoglycemia in those with T2DM.38,39 It is currently unknown if CGMs improve long-term glycemic control, but they appear promising for managing and reducing medications for those on an LC diet.40
TRE can be supplemented with an LC plan that incorporates “eating windows.” Common patterns include 14 hours of fasting and a 10-hour eating window (14F:10E), or 16 hours of fasting and an 8-hour eating window (16F:8E). By eating only in the specified window, patients generally reduce caloric intake and minimize insulin and glucose excursions during the fasting window. No changes need to be made to the macronutrient composition of the diet, and LC approaches can be used with TRE. The mechanism of action is likely multifactorial, targeting hyperinsulinemia and insulin resistance as well as producing a caloric deficit to enable weight loss.41 Eating windows may improve insulin sensitivity, reduce insulin resistance, and enhance overall glycemic control. The recent VA/DoD guidelines recommended against intermittent fasting due to concerns over the risk of hypoglycemia despite larger weight loss in TRE groups.4 Recently, a study using CGMs and TRE demonstrated both improved glycemic control and no hypoglycemic episodes in patients with T2DM on insulin.42 Patients who would like to supplement TRE with an LC plan as a strategy for improved glycemic control should work closely with their PACT to help manage their TRE and LC plan and consider a CGM adjunct, especially if on insulin.
Barriers
Managing T2DM often requires comprehensive lifestyle modifications of nutrition, exercise, sleep, stress management, and other psychosocial issues, as well as an interdisciplinary team-based approach.43 The advantage of working within the VA includes a uniform system within a network of care. However, many patients continue to use both federal and private health care. This use of out-of-network care may result in fragmented, potentially disjointed, or even contradictory dietary advice.
The VA PACT, whole health for holistic health, and weight loss interventions such as the MOVE! program provide lifestyle interventions like nutrition, physical activity, and behavior change. However, these well-intentioned approaches may provide alternative and even diverging recommendations, which place additional barriers to effective patient management. In patients who are advised and accept a trial of an LC plan, each member of the team should embrace the self-management decision of the patient and support the plan.29 Any conflicts, questions, or concerns should be communicated directly with the team in an interdisciplinary approach to provide a unified message and counsel.
The long-term effects and sustainability of an LC diet have been questioned in the literature.44-46 Recently, the use of an app-based coaching plan has demonstrated short- and long-term sustainability on an LC diet.47 In just 5 months in a large VA system, 590 patients using a virtual coaching platform and a VLCK diet plan were found to have lower HbA1c levels, reduced diabetic medication fills, lower body mass index, fewer outpatient visits, and lower prescription drug costs.
A 5-year follow-up found nearly 50% of participants sustained a VLCK diet for T2DM. For patients who participated in the study after 2 years, 72% sustained the VLCK diet in years 2 to 5. Most required nearly 50% fewer medications and in those that started with insulin, half did not require it at 5 years.48 Further research, however, is necessary to determine the long-term effects on cardiometabolic markers and health with LC diets. There are no long-term RCTs on outcomes data looking at T2DM morbidity or mortality. While there are prospective cohort studies on LC diets in the general population on mortality, they demonstrate mixed results. These studies may be confounded by heterogeneous definitions of LC diets, diet quality, and other health factors.49-51
Conclusions
The effective use of LC diets within a PACT with close and intensive lifestyle counseling and a safe approach to medication management and deprescribing can improve glycemic control, reduce the overall need for insulin, reduce medication use, and provide sustained weight loss. Additionally, the use of therapeutic carbohydrate reduction and subsequent medication deprescription may lead to sustained remission of T2DM. The current efficacy and sustainment of therapeutic carbohydrate reduction for patients with T2DM appears promising. Further research on LC diets, emerging strategies, and long-term effects on cardiometabolic risk factors, morbidity, and mortality will continue to inform future practice in our health care system.
Acknowledgments
We thank Cecile Seth who has been instrumental in pushing us forward and the Metabolic Multiplier group who has helped encourage and provide input into this article.
1. Centers for Disease Control and Prevention. Prevalence of Both Diagnosed and Undiagnosed Diabetes. Updated September 30, 2022. Accessed October 6, 2023. https://www.cdc.gov/diabetes/data/statistics-report/diagnosed-undiagnosed-diabetes.html
2. Centers for Disease Control and Prevention. Diabetes and Prediabetes. Updated September 6, 2022. Accessed October 6, 2023. https://www.cdc.gov/chronicdisease/resources/publications/factsheets/diabetes-prediabetes.htm 3. US Department of Veterans Affairs. Diabetes information - Nutrition and food services. Updated May 4, 2023. Accessed October 6, 2023. https://www.nutrition.va.gov/diabetes.asp
4. US Department of Veterans Affairs. Management of Type 2 Diabetes Mellitus (2023) - VA/DoD Clinical Practice Guidelines. Updated September 1, 2023. Accessed October 6, 2023. https://www.healthquality.va.gov/guidelines/CD/diabetes/
5. American Diabetes Association. Economic Costs of Diabetes in the U.S. in 2017. Diabetes Care. 2018;41(5):917-928. doi:10.2337/dci18-0007
6. Home P, Riddle M, Cefalu WT, et al. Insulin therapy in people with type 2 diabetes: opportunities and challenges?. Diabetes Care. 2014;37(6):1499-1508. doi:10.2337/dc13-2743
7. Donath MY, Ehses JA, Maedler K, et al. Mechanisms of β-cell death in type 2 diabetes. Diabetes. 2005;54(suppl 2):S108-S113. doi:10.2337/DIABETES.54.SUPPL_2.S108
8. Hallberg SJ, Gershuni VM, Hazbun TL, Athinarayanan SJ. Reversing type 2 diabetes: a narrative review of the evidence. Nutrients. 2019;11(4):766. Published 2019 Apr 1. doi:10.3390/nu11040766
9. Davies MJ, D’Alessio DA, Fradkin J, et al. Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018;41(12):2669. doi:10.2337/DCI18-0033
10. Evert AB, Dennison M, Gardner CD, et al. Nutrition therapy for adults with diabetes or prediabetes: a consensus report. Diabetes Care. 2019;42(5):731-754. doi:10.2337/DCI19-0014
11. Diabetes Canada position statement on low-carbohydrate diets for adults with diabetes: a rapid review. Can J Diabetes. 2020;44(4):295-299. doi:10.1016/J.JCJD.2020.04.001
12. Diabetes Australia. Position statements. Accessed October 6, 2023. https://www.diabetesaustralia.com.au/research-advocacy/position-statements/
13. Feinman RD, Pogozelski WK, Astrup A, et al. Dietary carbohydrate restriction as the first approach in diabetes management: critical review and evidence base. Nutrition. 2014;31(1):1-13. doi:10.1016/j.nut.2014.06.011
14. Samaha FF, Iqbal N, Seshadri P, et al. A low-carbohydrate as compared with a low-fat diet in severe obesity. N Engl J Med. 2003;348(21):2074-2081. doi:10.1056/NEJMOA02263715. Westman EC, Yancy WS, Mavropoulos JC, Marquart M, McDuffie JR. The effect of a low-carbohydrate, ketogenic diet versus a low-glycemic index diet on glycemic control in type 2 diabetes mellitus. Nutr Metab (Lond). 2008;5(1):36. doi:10.1186/1743-7075-5-36
16. Saslow LR, Mason AE, Kim S, et al. An online intervention comparing a very low-carbohydrate ketogenic diet and lifestyle recommendations versus a plate method diet in overweight individuals with type 2 diabetes: a randomized controlled trial. J Med Internet Res. 2017;19(2). doi:10.2196/JMIR.5806
17. Hallberg SJ, McKenzie AL, Williams PT, et al. Effectiveness and safety of a novel care model for the management of type 2 diabetes at 1 year: an open-label, non-randomized, controlled study. Diabetes Ther. 2018;9(2):583-612. doi:10.1007/S13300-018-0373-9
18. Gram-Kampmann EM, Hansen CD, Hugger MB, et al. Effects of a 6-month, low-carbohydrate diet on glycaemic control, body composition, and cardiovascular risk factors in patients with type 2 diabetes: An open-label randomized controlled trial. Diabetes Obes Metab. 2022;24(4):693-703. doi:10.1111/DOM.14633
19. Committee ADAPP. 5. Facilitating behavior change and well-being to improve health outcomes: standards of medical care in diabetes—2022. Diabetes Care. 2022;45(suppl 1):S60-S82. doi:10.2337/DC22-S005
20. Goldenberg JZ, Johnston BC. Low and very low carbohydrate diets for diabetes remission. BMJ. 2021;373:m4743. doi:10.1136/BMJ.N262
21. Jing T, Zhang S, Bai M, et al. Effect of dietary approaches on glycemic control in patients with type 2 diabetes: a systematic review with network meta-analysis of randomized trials. Nutrients. 2023;15(14):3156. doi:10.3390/nu15143156
22. Academy of Nutrition and Dietetics. Nutrition care manual. Accessed October 6, 2023. https://www.nutritioncaremanual.org/
23. Low carbohydrate and very low carbohydrate eating patterns in adults with diabetes. ShopDiabetes.org. Accessed August 5, 2022. https://shopdiabetes.org/products/low-carbohydrate-and-very-low-carbohydrate-eating-patterns-in-adults-with-diabetes-a-guide-for-health-care-providers
24. US Department of Veterans Affairs. Diabetes education - nutrition and food services. Published July 31, 2022. http://vaww.nutrition.va.gov/docs/pted/ModifiedKetogenicDiet.pdf [Source not verified]
25. US Department of Veterans Affairs, My HealtheVet. Lowdown on low-carb diets. Updated June 1, 2021. Accessed October 6, 2023. https://www.myhealth.va.gov/mhv-portal-web/ss20190724-low-carb-diet
26. Chang CR, Francois ME, Little JP. Restricting carbohydrates at breakfast is sufficient to reduce 24-hour exposure to postprandial hyperglycemia and improve glycemic variability. Am J Clin Nutr. 2019;109(5):1302-1309. doi:10.1093/AJCN/NQY261
27. Hall KD, Ayuketah A, Brychta R, et al. Ultra-processed diets cause excess calorie intake and weight gain: an inpatient randomized controlled trial of ad libitum food intake. Cell Metab. 2019;30(1):226. doi:10.1016/j.cmet.2019.05.020
28. Harvey CJ d. C, Schofield GM, Zinn C, Thornley S. Effects of differing levels of carbohydrate restriction on mood achievement of nutritional ketosis, and symptoms of carbohydrate withdrawal in healthy adults: a randomized clinical trial. Nutrition. 2019;67-68:100005. doi:10.1016/J.NUTX.2019.100005
29. Griauzde DH, Standafer Lopez K, Saslow LR, Richardson CR. A pragmatic approach to translating low- and very low-carbohydrate diets into clinical practice for patients with obesity and type 2 diabetes. Front Nutr. 2021;8:416. doi:10.3389/FNUT.2021.682137/BIBTEX
30. Westman EC, Tondt J, Maguire E, Yancy WS. Implementing a low-carbohydrate, ketogenic diet to manage type 2 diabetes mellitus. Expert Rev Endocrinol Metab. 2018;13(5):263-272. doi:10.1080/17446651.2018.1523713
31. Suyoto PST. Effect of low-carbohydrate diet on markers of renal function in patients with type 2 diabetes: a meta-analysis. Diabetes Metab Res Rev. 2018;34(7). doi:10.1002/DMRR.3032
32. Norwitz NG, Feldman D, Soto-Mota A, Kalayjian T, Ludwig DS. Elevated LDL cholesterol with a carbohydrate-restricted diet: evidence for a “lean mass hyper-responder” phenotype. Curr Dev Nutr. 2021;6(1). doi:10.1093/CDN/NZAB144
33. Murdoch C, Unwin D, Cavan D, Cucuzzella M, Patel M. Adapting diabetes medication for low carbohydrate management of type 2 diabetes: a practical guide. Br J Gen Pract. 2019;69(684):360-361. doi:10.3399/bjgp19X704525
34. Cucuzzella M, Riley K, Isaacs D. Adapting medication for type 2 diabetes to a low carbohydrate diet. Front Nutr. 2021;8:486. doi:10.3389/FNUT.2021.688540/BIBTEX
35. World Health Organization. Global report on diabetes. 2016. Accessed October 6, 2023. https://iris.who.int/bitstream/handle/10665/204871/9789241565257_eng.pdf?sequence=1
36. Riddle MC, Cefalu WT, Evans PH, et al. Consensus report: definition and interpretation of remission in type 2 diabetes. Diabetes Care. 2021;44(10):2438-2444. doi:10.2337/DCI21-0034
37. Diabetes Australia. Type 2 Diabetes remission position statement. 2021. Accessed October 6, 2023. https://www.diabetesaustralia.com.au/wp-content/uploads/2021_Diabetes-Australia-Position-Statement_Type-2-diabetes-remission_2.pdf
38. Martens T, Beck RW, Bailey R, et al. Effect of continuous glucose monitoring on glycemic control in patients with type 2 diabetes treated with basal insulin: a randomized clinical trial. JAMA. 2021;325(22):2262-2272. doi:10.1001/JAMA.2021.7444
39. Jackson MA, Ahmann A, Shah VN. Type 2 diabetes and the use of real-time continuous glucose monitoring. Diabetes Technol Ther. 2021;23(S1):S27-S34. doi:10.1089/DIA.2021.0007
40. Oser TK, Cucuzzella M, Stasinopoulos M, Moncrief M, McCall A, Cox DJ. An innovative, paradigm-shifting lifestyle intervention to reduce glucose excursions with the use of continuous glucose monitoring to educate, motivate, and activate adults with newly diagnosed type 2 diabetes: pilot feasibility study. JMIR Diabetes. 2022;7(1). doi:10.2196/34465
41. Światkiewicz I, Woźniak A, Taub PR. Time-restricted eating and metabolic syndrome: current status and future perspectives. Nutrients. 2021;13(1):221. doi:10.3390/NU13010221
42. Obermayer A, Tripolt NJ, Pferschy PN, et al. Efficacy and safety of intermittent fasting in people with insulin-treated type 2 diabetes (INTERFAST-2)—a randomized controlled trial. Diabetes Care. 2023;46(2):463-468. doi:10.2337/dc22-1622
43. American Diabetes Association. 5. Lifestyle management: standards of medical care in diabetes—2019. Diabetes Care. 2019;42(suppl 1):S46-S60. doi:10.2337/DC19-S005
44. Li S, Ding L, Xiao X. Comparing the efficacy and safety of low-carbohydrate diets with low-fat diets for type 2 diabetes mellitus patients: a systematic review and meta-analysis of randomized clinical trials. Int J Endocrinol. 2021;2021:8521756. Published 2021 Dec 6. doi:10.1155/2021/8521756
45. Choi JH, Kang JH, Chon S. Comprehensive understanding for application in Korean patients with type 2 diabetes mellitus of the consensus statement on carbohydrate-restricted diets by Korean Diabetes Association, Korean Society for the Study of Obesity, and Korean Society of Hypertension. Diabetes Metab J. 2022;46(3):377. doi:10.4093/DMJ.2022.0051
46. Jayedi A, Zeraattalab-Motlagh S, Jabbarzadeh B, et al. Dose-dependent effect of carbohydrate restriction for type 2 diabetes management: a systematic review and dose-response meta-analysis of randomized controlled trials. Am J Clin Nutr. 2022;116(1). doi:10.1093/AJCN/NQAC066
47. Strombotne KL, Lum J, Ndugga NJ, et al. Effectiveness of a ketogenic diet and virtual coaching intervention for patients with diabetes: a difference-in-differences analysis. Diabetes Obes Metab. 2021;23(12):2643-2650. doi:10.1111/DOM.14515
48. Virta Health. Virta Health highlights lasting, transformative health improvements in 5-year diabetes reversal study. June 5, 2022. Accessed October 6, 2023. https://www.virtahealth.com/blog/virta-sustainable-health-improvements-5-year-diabetes-reversal-study
49. Wan Z, Shan Z, Geng T, et al. Associations of moderate low-carbohydrate diets with mortality among patients with type 2 diabetes: a prospective cohort study. J Clin Endocrinol Metab. 2022;107(7):E2702-E2709. doi:10.1210/CLINEM/DGAC235
50. Akter S, Mizoue T, Nanri A, et al. Low carbohydrate diet and all cause and cause-specific mortality. Clin Nutr. 2021;40(4):2016-2024. doi:10.1016/J.CLNU.2020.09.022
51. Shan Z, Guo Y, Hu FB, Liu L, Qi Q. Association of low-carbohydrate and low-fat diets with mortality among US adults. JAMA Intern Med. 2020;180(4):513-523. doi:10.1001/JAMAINTERNMED.2019.6980
1. Centers for Disease Control and Prevention. Prevalence of Both Diagnosed and Undiagnosed Diabetes. Updated September 30, 2022. Accessed October 6, 2023. https://www.cdc.gov/diabetes/data/statistics-report/diagnosed-undiagnosed-diabetes.html
2. Centers for Disease Control and Prevention. Diabetes and Prediabetes. Updated September 6, 2022. Accessed October 6, 2023. https://www.cdc.gov/chronicdisease/resources/publications/factsheets/diabetes-prediabetes.htm 3. US Department of Veterans Affairs. Diabetes information - Nutrition and food services. Updated May 4, 2023. Accessed October 6, 2023. https://www.nutrition.va.gov/diabetes.asp
4. US Department of Veterans Affairs. Management of Type 2 Diabetes Mellitus (2023) - VA/DoD Clinical Practice Guidelines. Updated September 1, 2023. Accessed October 6, 2023. https://www.healthquality.va.gov/guidelines/CD/diabetes/
5. American Diabetes Association. Economic Costs of Diabetes in the U.S. in 2017. Diabetes Care. 2018;41(5):917-928. doi:10.2337/dci18-0007
6. Home P, Riddle M, Cefalu WT, et al. Insulin therapy in people with type 2 diabetes: opportunities and challenges?. Diabetes Care. 2014;37(6):1499-1508. doi:10.2337/dc13-2743
7. Donath MY, Ehses JA, Maedler K, et al. Mechanisms of β-cell death in type 2 diabetes. Diabetes. 2005;54(suppl 2):S108-S113. doi:10.2337/DIABETES.54.SUPPL_2.S108
8. Hallberg SJ, Gershuni VM, Hazbun TL, Athinarayanan SJ. Reversing type 2 diabetes: a narrative review of the evidence. Nutrients. 2019;11(4):766. Published 2019 Apr 1. doi:10.3390/nu11040766
9. Davies MJ, D’Alessio DA, Fradkin J, et al. Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018;41(12):2669. doi:10.2337/DCI18-0033
10. Evert AB, Dennison M, Gardner CD, et al. Nutrition therapy for adults with diabetes or prediabetes: a consensus report. Diabetes Care. 2019;42(5):731-754. doi:10.2337/DCI19-0014
11. Diabetes Canada position statement on low-carbohydrate diets for adults with diabetes: a rapid review. Can J Diabetes. 2020;44(4):295-299. doi:10.1016/J.JCJD.2020.04.001
12. Diabetes Australia. Position statements. Accessed October 6, 2023. https://www.diabetesaustralia.com.au/research-advocacy/position-statements/
13. Feinman RD, Pogozelski WK, Astrup A, et al. Dietary carbohydrate restriction as the first approach in diabetes management: critical review and evidence base. Nutrition. 2014;31(1):1-13. doi:10.1016/j.nut.2014.06.011
14. Samaha FF, Iqbal N, Seshadri P, et al. A low-carbohydrate as compared with a low-fat diet in severe obesity. N Engl J Med. 2003;348(21):2074-2081. doi:10.1056/NEJMOA02263715. Westman EC, Yancy WS, Mavropoulos JC, Marquart M, McDuffie JR. The effect of a low-carbohydrate, ketogenic diet versus a low-glycemic index diet on glycemic control in type 2 diabetes mellitus. Nutr Metab (Lond). 2008;5(1):36. doi:10.1186/1743-7075-5-36
16. Saslow LR, Mason AE, Kim S, et al. An online intervention comparing a very low-carbohydrate ketogenic diet and lifestyle recommendations versus a plate method diet in overweight individuals with type 2 diabetes: a randomized controlled trial. J Med Internet Res. 2017;19(2). doi:10.2196/JMIR.5806
17. Hallberg SJ, McKenzie AL, Williams PT, et al. Effectiveness and safety of a novel care model for the management of type 2 diabetes at 1 year: an open-label, non-randomized, controlled study. Diabetes Ther. 2018;9(2):583-612. doi:10.1007/S13300-018-0373-9
18. Gram-Kampmann EM, Hansen CD, Hugger MB, et al. Effects of a 6-month, low-carbohydrate diet on glycaemic control, body composition, and cardiovascular risk factors in patients with type 2 diabetes: An open-label randomized controlled trial. Diabetes Obes Metab. 2022;24(4):693-703. doi:10.1111/DOM.14633
19. Committee ADAPP. 5. Facilitating behavior change and well-being to improve health outcomes: standards of medical care in diabetes—2022. Diabetes Care. 2022;45(suppl 1):S60-S82. doi:10.2337/DC22-S005
20. Goldenberg JZ, Johnston BC. Low and very low carbohydrate diets for diabetes remission. BMJ. 2021;373:m4743. doi:10.1136/BMJ.N262
21. Jing T, Zhang S, Bai M, et al. Effect of dietary approaches on glycemic control in patients with type 2 diabetes: a systematic review with network meta-analysis of randomized trials. Nutrients. 2023;15(14):3156. doi:10.3390/nu15143156
22. Academy of Nutrition and Dietetics. Nutrition care manual. Accessed October 6, 2023. https://www.nutritioncaremanual.org/
23. Low carbohydrate and very low carbohydrate eating patterns in adults with diabetes. ShopDiabetes.org. Accessed August 5, 2022. https://shopdiabetes.org/products/low-carbohydrate-and-very-low-carbohydrate-eating-patterns-in-adults-with-diabetes-a-guide-for-health-care-providers
24. US Department of Veterans Affairs. Diabetes education - nutrition and food services. Published July 31, 2022. http://vaww.nutrition.va.gov/docs/pted/ModifiedKetogenicDiet.pdf [Source not verified]
25. US Department of Veterans Affairs, My HealtheVet. Lowdown on low-carb diets. Updated June 1, 2021. Accessed October 6, 2023. https://www.myhealth.va.gov/mhv-portal-web/ss20190724-low-carb-diet
26. Chang CR, Francois ME, Little JP. Restricting carbohydrates at breakfast is sufficient to reduce 24-hour exposure to postprandial hyperglycemia and improve glycemic variability. Am J Clin Nutr. 2019;109(5):1302-1309. doi:10.1093/AJCN/NQY261
27. Hall KD, Ayuketah A, Brychta R, et al. Ultra-processed diets cause excess calorie intake and weight gain: an inpatient randomized controlled trial of ad libitum food intake. Cell Metab. 2019;30(1):226. doi:10.1016/j.cmet.2019.05.020
28. Harvey CJ d. C, Schofield GM, Zinn C, Thornley S. Effects of differing levels of carbohydrate restriction on mood achievement of nutritional ketosis, and symptoms of carbohydrate withdrawal in healthy adults: a randomized clinical trial. Nutrition. 2019;67-68:100005. doi:10.1016/J.NUTX.2019.100005
29. Griauzde DH, Standafer Lopez K, Saslow LR, Richardson CR. A pragmatic approach to translating low- and very low-carbohydrate diets into clinical practice for patients with obesity and type 2 diabetes. Front Nutr. 2021;8:416. doi:10.3389/FNUT.2021.682137/BIBTEX
30. Westman EC, Tondt J, Maguire E, Yancy WS. Implementing a low-carbohydrate, ketogenic diet to manage type 2 diabetes mellitus. Expert Rev Endocrinol Metab. 2018;13(5):263-272. doi:10.1080/17446651.2018.1523713
31. Suyoto PST. Effect of low-carbohydrate diet on markers of renal function in patients with type 2 diabetes: a meta-analysis. Diabetes Metab Res Rev. 2018;34(7). doi:10.1002/DMRR.3032
32. Norwitz NG, Feldman D, Soto-Mota A, Kalayjian T, Ludwig DS. Elevated LDL cholesterol with a carbohydrate-restricted diet: evidence for a “lean mass hyper-responder” phenotype. Curr Dev Nutr. 2021;6(1). doi:10.1093/CDN/NZAB144
33. Murdoch C, Unwin D, Cavan D, Cucuzzella M, Patel M. Adapting diabetes medication for low carbohydrate management of type 2 diabetes: a practical guide. Br J Gen Pract. 2019;69(684):360-361. doi:10.3399/bjgp19X704525
34. Cucuzzella M, Riley K, Isaacs D. Adapting medication for type 2 diabetes to a low carbohydrate diet. Front Nutr. 2021;8:486. doi:10.3389/FNUT.2021.688540/BIBTEX
35. World Health Organization. Global report on diabetes. 2016. Accessed October 6, 2023. https://iris.who.int/bitstream/handle/10665/204871/9789241565257_eng.pdf?sequence=1
36. Riddle MC, Cefalu WT, Evans PH, et al. Consensus report: definition and interpretation of remission in type 2 diabetes. Diabetes Care. 2021;44(10):2438-2444. doi:10.2337/DCI21-0034
37. Diabetes Australia. Type 2 Diabetes remission position statement. 2021. Accessed October 6, 2023. https://www.diabetesaustralia.com.au/wp-content/uploads/2021_Diabetes-Australia-Position-Statement_Type-2-diabetes-remission_2.pdf
38. Martens T, Beck RW, Bailey R, et al. Effect of continuous glucose monitoring on glycemic control in patients with type 2 diabetes treated with basal insulin: a randomized clinical trial. JAMA. 2021;325(22):2262-2272. doi:10.1001/JAMA.2021.7444
39. Jackson MA, Ahmann A, Shah VN. Type 2 diabetes and the use of real-time continuous glucose monitoring. Diabetes Technol Ther. 2021;23(S1):S27-S34. doi:10.1089/DIA.2021.0007
40. Oser TK, Cucuzzella M, Stasinopoulos M, Moncrief M, McCall A, Cox DJ. An innovative, paradigm-shifting lifestyle intervention to reduce glucose excursions with the use of continuous glucose monitoring to educate, motivate, and activate adults with newly diagnosed type 2 diabetes: pilot feasibility study. JMIR Diabetes. 2022;7(1). doi:10.2196/34465
41. Światkiewicz I, Woźniak A, Taub PR. Time-restricted eating and metabolic syndrome: current status and future perspectives. Nutrients. 2021;13(1):221. doi:10.3390/NU13010221
42. Obermayer A, Tripolt NJ, Pferschy PN, et al. Efficacy and safety of intermittent fasting in people with insulin-treated type 2 diabetes (INTERFAST-2)—a randomized controlled trial. Diabetes Care. 2023;46(2):463-468. doi:10.2337/dc22-1622
43. American Diabetes Association. 5. Lifestyle management: standards of medical care in diabetes—2019. Diabetes Care. 2019;42(suppl 1):S46-S60. doi:10.2337/DC19-S005
44. Li S, Ding L, Xiao X. Comparing the efficacy and safety of low-carbohydrate diets with low-fat diets for type 2 diabetes mellitus patients: a systematic review and meta-analysis of randomized clinical trials. Int J Endocrinol. 2021;2021:8521756. Published 2021 Dec 6. doi:10.1155/2021/8521756
45. Choi JH, Kang JH, Chon S. Comprehensive understanding for application in Korean patients with type 2 diabetes mellitus of the consensus statement on carbohydrate-restricted diets by Korean Diabetes Association, Korean Society for the Study of Obesity, and Korean Society of Hypertension. Diabetes Metab J. 2022;46(3):377. doi:10.4093/DMJ.2022.0051
46. Jayedi A, Zeraattalab-Motlagh S, Jabbarzadeh B, et al. Dose-dependent effect of carbohydrate restriction for type 2 diabetes management: a systematic review and dose-response meta-analysis of randomized controlled trials. Am J Clin Nutr. 2022;116(1). doi:10.1093/AJCN/NQAC066
47. Strombotne KL, Lum J, Ndugga NJ, et al. Effectiveness of a ketogenic diet and virtual coaching intervention for patients with diabetes: a difference-in-differences analysis. Diabetes Obes Metab. 2021;23(12):2643-2650. doi:10.1111/DOM.14515
48. Virta Health. Virta Health highlights lasting, transformative health improvements in 5-year diabetes reversal study. June 5, 2022. Accessed October 6, 2023. https://www.virtahealth.com/blog/virta-sustainable-health-improvements-5-year-diabetes-reversal-study
49. Wan Z, Shan Z, Geng T, et al. Associations of moderate low-carbohydrate diets with mortality among patients with type 2 diabetes: a prospective cohort study. J Clin Endocrinol Metab. 2022;107(7):E2702-E2709. doi:10.1210/CLINEM/DGAC235
50. Akter S, Mizoue T, Nanri A, et al. Low carbohydrate diet and all cause and cause-specific mortality. Clin Nutr. 2021;40(4):2016-2024. doi:10.1016/J.CLNU.2020.09.022
51. Shan Z, Guo Y, Hu FB, Liu L, Qi Q. Association of low-carbohydrate and low-fat diets with mortality among US adults. JAMA Intern Med. 2020;180(4):513-523. doi:10.1001/JAMAINTERNMED.2019.6980
Extreme Heat and Hypoglycemia Risk in Older Insulin Users
TOPLINE:
Older adults (aged ≥ 65 years) with diabetes who received insulin may have an increased risk for serious hypoglycemic events in extreme heat.
METHODOLOGY:
- Thermoregulatory response is often compromised in older adults with diabetes, making them vulnerable to extreme heat.
- Researchers evaluated the association between ambient heat and risk for hypoglycemia in about 2 million and about 283,000 patients aged 65-100 years with diabetes from the United States and Taiwan, respectively, who received insulin.
- A serious hypoglycemic event was defined as a primary emergency department (ED) visit or an unplanned inpatient admission for hypoglycemia from June 1 to September 30.
- Medication use was determined by at least one prescription dispensing insulin within 90 days of the index event.
- The average heat index (HI), a combination of ambient temperature and humidity exposure, was calculated by ZIP code and grouped into percentiles: ≥ 99th, 95-98th, 85-94th, 76-84th, 25-74th, and < 25th.
TAKEAWAY:
- Among insulin users overall, 32,461 and 10,162 older adults from the United States and Taiwan, respectively, experienced a hypoglycemic event.
- The risk for a serious hypoglycemic event was about 40% higher among insulin users on days with a HI of ≥ 99th percentile than 25-74th percentile (unadjusted odds ratio, 1.38; 95% CI, 1.28-1.48).
- Conversely, on days with a low HI (< 25th percentile), the risk for hypoglycemia among insulin users decreased.
- No substantial differences were observed in the risk for hypoglycemic events and HI by climate region in either country, such as between the US Northeast and Southwest.
IN PRACTICE:
“Our finding of elevated risk of hypoglycemia-related ED visits in older adults using insulin and exposed to extreme heat underscores the need for patients and providers to be aware and cautious that extreme heat may increase the risk of hypoglycemia,” the authors wrote.
SOURCE:
The study was conducted by first author Aayush Visaria, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, and coauthors. The study was published online on December 7, 2023, in Diabetes Care.
LIMITATIONS:
- The individuals with hypoglycemia were older, were more frequently non-Hispanic Black in the United States, and had more comorbidities, so caution should be used before the results can be generalized to broader populations.
- The authors were unable to capture variables that can alter the risk for serious hypoglycemia, such as outdoor activity, exercise, and diet.
- Prescriptions may not reflect actual insulin use and adherence.
DISCLOSURES:
This study was funded by the US National Institutes of Health/National Institute on Aging. The authors declared no conflicts of interest.
A version of this article appeared on Medscape.com.
TOPLINE:
Older adults (aged ≥ 65 years) with diabetes who received insulin may have an increased risk for serious hypoglycemic events in extreme heat.
METHODOLOGY:
- Thermoregulatory response is often compromised in older adults with diabetes, making them vulnerable to extreme heat.
- Researchers evaluated the association between ambient heat and risk for hypoglycemia in about 2 million and about 283,000 patients aged 65-100 years with diabetes from the United States and Taiwan, respectively, who received insulin.
- A serious hypoglycemic event was defined as a primary emergency department (ED) visit or an unplanned inpatient admission for hypoglycemia from June 1 to September 30.
- Medication use was determined by at least one prescription dispensing insulin within 90 days of the index event.
- The average heat index (HI), a combination of ambient temperature and humidity exposure, was calculated by ZIP code and grouped into percentiles: ≥ 99th, 95-98th, 85-94th, 76-84th, 25-74th, and < 25th.
TAKEAWAY:
- Among insulin users overall, 32,461 and 10,162 older adults from the United States and Taiwan, respectively, experienced a hypoglycemic event.
- The risk for a serious hypoglycemic event was about 40% higher among insulin users on days with a HI of ≥ 99th percentile than 25-74th percentile (unadjusted odds ratio, 1.38; 95% CI, 1.28-1.48).
- Conversely, on days with a low HI (< 25th percentile), the risk for hypoglycemia among insulin users decreased.
- No substantial differences were observed in the risk for hypoglycemic events and HI by climate region in either country, such as between the US Northeast and Southwest.
IN PRACTICE:
“Our finding of elevated risk of hypoglycemia-related ED visits in older adults using insulin and exposed to extreme heat underscores the need for patients and providers to be aware and cautious that extreme heat may increase the risk of hypoglycemia,” the authors wrote.
SOURCE:
The study was conducted by first author Aayush Visaria, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, and coauthors. The study was published online on December 7, 2023, in Diabetes Care.
LIMITATIONS:
- The individuals with hypoglycemia were older, were more frequently non-Hispanic Black in the United States, and had more comorbidities, so caution should be used before the results can be generalized to broader populations.
- The authors were unable to capture variables that can alter the risk for serious hypoglycemia, such as outdoor activity, exercise, and diet.
- Prescriptions may not reflect actual insulin use and adherence.
DISCLOSURES:
This study was funded by the US National Institutes of Health/National Institute on Aging. The authors declared no conflicts of interest.
A version of this article appeared on Medscape.com.
TOPLINE:
Older adults (aged ≥ 65 years) with diabetes who received insulin may have an increased risk for serious hypoglycemic events in extreme heat.
METHODOLOGY:
- Thermoregulatory response is often compromised in older adults with diabetes, making them vulnerable to extreme heat.
- Researchers evaluated the association between ambient heat and risk for hypoglycemia in about 2 million and about 283,000 patients aged 65-100 years with diabetes from the United States and Taiwan, respectively, who received insulin.
- A serious hypoglycemic event was defined as a primary emergency department (ED) visit or an unplanned inpatient admission for hypoglycemia from June 1 to September 30.
- Medication use was determined by at least one prescription dispensing insulin within 90 days of the index event.
- The average heat index (HI), a combination of ambient temperature and humidity exposure, was calculated by ZIP code and grouped into percentiles: ≥ 99th, 95-98th, 85-94th, 76-84th, 25-74th, and < 25th.
TAKEAWAY:
- Among insulin users overall, 32,461 and 10,162 older adults from the United States and Taiwan, respectively, experienced a hypoglycemic event.
- The risk for a serious hypoglycemic event was about 40% higher among insulin users on days with a HI of ≥ 99th percentile than 25-74th percentile (unadjusted odds ratio, 1.38; 95% CI, 1.28-1.48).
- Conversely, on days with a low HI (< 25th percentile), the risk for hypoglycemia among insulin users decreased.
- No substantial differences were observed in the risk for hypoglycemic events and HI by climate region in either country, such as between the US Northeast and Southwest.
IN PRACTICE:
“Our finding of elevated risk of hypoglycemia-related ED visits in older adults using insulin and exposed to extreme heat underscores the need for patients and providers to be aware and cautious that extreme heat may increase the risk of hypoglycemia,” the authors wrote.
SOURCE:
The study was conducted by first author Aayush Visaria, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, and coauthors. The study was published online on December 7, 2023, in Diabetes Care.
LIMITATIONS:
- The individuals with hypoglycemia were older, were more frequently non-Hispanic Black in the United States, and had more comorbidities, so caution should be used before the results can be generalized to broader populations.
- The authors were unable to capture variables that can alter the risk for serious hypoglycemia, such as outdoor activity, exercise, and diet.
- Prescriptions may not reflect actual insulin use and adherence.
DISCLOSURES:
This study was funded by the US National Institutes of Health/National Institute on Aging. The authors declared no conflicts of interest.
A version of this article appeared on Medscape.com.
Walking Fast May Help Prevent Type 2 Diabetes
Walking is a simple, cost-free form of exercise that benefits physical, social, and mental health in many ways. Several clinical trials have shown that walking regularly is associated with a lower risk for cardiovascular events and all-cause mortality, and having a higher daily step count is linked to a decreased risk for premature death.
Walking and Diabetes
In recent years, the link between walking speed and the risk for multiple health problems has sparked keen interest. Data suggest that a faster walking pace may have a greater physiological response and may be associated with more favorable health advantages than a slow walking pace. A previous meta-analysis of eight cohort studies suggested that individuals in the fastest walking-pace category (median = 5.6 km/h) had a 44% lower risk for stroke than those in the slowest walking-pace category (median = 1.6 km/h). The risk for the former decreased by 13% for every 1 km/h increment in baseline walking pace.
Type 2 diabetes (T2D) is one of the most common metabolic diseases in the world. People with this type of diabetes have an increased risk for microvascular and macrovascular complications and a shorter life expectancy. Approximately 537 million adults are estimated to be living with diabetes worldwide, and this number is expected to reach 783 million by 2045.
Physical activity is an essential component of T2D prevention programs and can favorably affect blood sugar control. A meta-analysis of cohort studies showed that being physically active was associated with a 35% reduction in the risk of acquiring T2D in the general population, and regular walking was associated with a 15% reduction in the risk of developing T2D.
However, no studies have investigated the link between different walking speeds and the risk for T2D. A team from the Research Center at the Semnan University of Medical Sciences in Iran carried out a systematic review of the association between walking speed and the risk of developing T2D in adults; this review was published in the British Journal of Sports Medicine.
10 Cohort Studies
This systematic review used publications (1999-2022) available in the usual data sources (PubMed, Scopus, CENTRAL, and Web of Science). Random-effects meta-analyses were used to calculate relative risk (RR) and risk difference (RD) based on different walking speeds. The researchers rated the credibility of subgroup differences and the certainty of evidence using the Instrument to assess the Credibility of Effect Modification ANalyses (ICEMAN) and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tools, respectively.
Of the 508,121 potential participants, 18,410 adults from 10 prospective cohort studies conducted in the United States, Japan, and the United Kingdom were deemed eligible. The proportion of women was between 52% and 73%, depending on the cohort. Follow-up duration varied from 3 to 11.1 years (median, 8 years).
Five cohort studies measured walking speed using stopwatch testing, while the other five used self-assessed questionnaires. To define cases of T2D, seven studies used objective methods such as blood glucose measurement or linkage with medical records, and in three cohorts, self-assessment questionnaires were used (these were checked against patient records). All studies controlled age, sex, and tobacco consumption in the multivariate analyses, and some controlled just alcohol consumption, blood pressure, total physical activity volume, body mass index, time spent walking or daily step count, and a family history of diabetes.
The Right Speed
The authors first categorized walking speed into four prespecified levels: Easy or casual (< 2 mph or 3.2 km/h), average or normal (2-3 mph or 3.2-4.8 km/h), fairly brisk (3-4 mph or 4.8-6.4 km/h), and very brisk or brisk/striding (> 4 mph or > 6.4 km/h).
Four cohort studies with 6,520 cases of T2D among 160,321 participants reported information on average or normal walking. Participants with average or normal walking were at a 15% lower risk for T2D than those with easy or casual walking (RR = 0.85 [95% CI, 0.70-1.00]; RD = 0.86 [1.72-0]). Ten cohort studies with 18,410 cases among 508,121 participants reported information on fairly brisk walking. Those with fairly brisk walking were at a 24% lower risk for T2D than those with easy or casual walking (RR = 0.76 [0.65-0.87]; I2 = 90%; RD = 1.38 [2.01-0.75]).
There was no significant or credible subgroup difference by adjustment for the total physical activity or time spent walking per day. The dose-response analysis suggested that the risk for T2D decreased significantly at a walking speed of 4 km/h and above.
Study Limitations
This meta-analysis has strengths that may increase the generalizability of its results. The researchers included cohort studies, which allowed them to consider the temporal sequence of exposure and outcome. Cohort studies are less affected by recall and selection biases compared with retrospective case–control studies, which increase the likelihood of causality. The researchers also assessed the credibility of subgroup differences using the recently developed ICEMAN tool, calculated both relative and absolute risks, and rated the certainty of evidence using the GRADE approach.
Some shortcomings must be considered. Most of the studies included in the present review were rated as having a serious risk for bias, with the most important biases resulting from inadequate adjustment for potential confounders and the methods used for walking speed assessment and diagnosis of T2D. In addition, the findings could have been subject to reverse causality bias because participants with faster walking speed are more likely to perform more physical activity and have better cardiorespiratory fitness, greater muscle mass, and better health status. However, the subgroup analyses of fairly brisk and brisk/striding walking indicated that there were no significant subgroup differences by follow-up duration and that the significant inverse associations remained stable in the subgroup of cohort studies with a follow-up duration of > 10 years.
The authors concluded that While current strategies to increase total walking time are beneficial, it may also be reasonable to encourage people to walk at faster speeds to further increase the health benefits of walking.”
This article was translated from JIM, which is part of the Medscape Professional Network. A version of this article appeared on Medscape.com.
Walking is a simple, cost-free form of exercise that benefits physical, social, and mental health in many ways. Several clinical trials have shown that walking regularly is associated with a lower risk for cardiovascular events and all-cause mortality, and having a higher daily step count is linked to a decreased risk for premature death.
Walking and Diabetes
In recent years, the link between walking speed and the risk for multiple health problems has sparked keen interest. Data suggest that a faster walking pace may have a greater physiological response and may be associated with more favorable health advantages than a slow walking pace. A previous meta-analysis of eight cohort studies suggested that individuals in the fastest walking-pace category (median = 5.6 km/h) had a 44% lower risk for stroke than those in the slowest walking-pace category (median = 1.6 km/h). The risk for the former decreased by 13% for every 1 km/h increment in baseline walking pace.
Type 2 diabetes (T2D) is one of the most common metabolic diseases in the world. People with this type of diabetes have an increased risk for microvascular and macrovascular complications and a shorter life expectancy. Approximately 537 million adults are estimated to be living with diabetes worldwide, and this number is expected to reach 783 million by 2045.
Physical activity is an essential component of T2D prevention programs and can favorably affect blood sugar control. A meta-analysis of cohort studies showed that being physically active was associated with a 35% reduction in the risk of acquiring T2D in the general population, and regular walking was associated with a 15% reduction in the risk of developing T2D.
However, no studies have investigated the link between different walking speeds and the risk for T2D. A team from the Research Center at the Semnan University of Medical Sciences in Iran carried out a systematic review of the association between walking speed and the risk of developing T2D in adults; this review was published in the British Journal of Sports Medicine.
10 Cohort Studies
This systematic review used publications (1999-2022) available in the usual data sources (PubMed, Scopus, CENTRAL, and Web of Science). Random-effects meta-analyses were used to calculate relative risk (RR) and risk difference (RD) based on different walking speeds. The researchers rated the credibility of subgroup differences and the certainty of evidence using the Instrument to assess the Credibility of Effect Modification ANalyses (ICEMAN) and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tools, respectively.
Of the 508,121 potential participants, 18,410 adults from 10 prospective cohort studies conducted in the United States, Japan, and the United Kingdom were deemed eligible. The proportion of women was between 52% and 73%, depending on the cohort. Follow-up duration varied from 3 to 11.1 years (median, 8 years).
Five cohort studies measured walking speed using stopwatch testing, while the other five used self-assessed questionnaires. To define cases of T2D, seven studies used objective methods such as blood glucose measurement or linkage with medical records, and in three cohorts, self-assessment questionnaires were used (these were checked against patient records). All studies controlled age, sex, and tobacco consumption in the multivariate analyses, and some controlled just alcohol consumption, blood pressure, total physical activity volume, body mass index, time spent walking or daily step count, and a family history of diabetes.
The Right Speed
The authors first categorized walking speed into four prespecified levels: Easy or casual (< 2 mph or 3.2 km/h), average or normal (2-3 mph or 3.2-4.8 km/h), fairly brisk (3-4 mph or 4.8-6.4 km/h), and very brisk or brisk/striding (> 4 mph or > 6.4 km/h).
Four cohort studies with 6,520 cases of T2D among 160,321 participants reported information on average or normal walking. Participants with average or normal walking were at a 15% lower risk for T2D than those with easy or casual walking (RR = 0.85 [95% CI, 0.70-1.00]; RD = 0.86 [1.72-0]). Ten cohort studies with 18,410 cases among 508,121 participants reported information on fairly brisk walking. Those with fairly brisk walking were at a 24% lower risk for T2D than those with easy or casual walking (RR = 0.76 [0.65-0.87]; I2 = 90%; RD = 1.38 [2.01-0.75]).
There was no significant or credible subgroup difference by adjustment for the total physical activity or time spent walking per day. The dose-response analysis suggested that the risk for T2D decreased significantly at a walking speed of 4 km/h and above.
Study Limitations
This meta-analysis has strengths that may increase the generalizability of its results. The researchers included cohort studies, which allowed them to consider the temporal sequence of exposure and outcome. Cohort studies are less affected by recall and selection biases compared with retrospective case–control studies, which increase the likelihood of causality. The researchers also assessed the credibility of subgroup differences using the recently developed ICEMAN tool, calculated both relative and absolute risks, and rated the certainty of evidence using the GRADE approach.
Some shortcomings must be considered. Most of the studies included in the present review were rated as having a serious risk for bias, with the most important biases resulting from inadequate adjustment for potential confounders and the methods used for walking speed assessment and diagnosis of T2D. In addition, the findings could have been subject to reverse causality bias because participants with faster walking speed are more likely to perform more physical activity and have better cardiorespiratory fitness, greater muscle mass, and better health status. However, the subgroup analyses of fairly brisk and brisk/striding walking indicated that there were no significant subgroup differences by follow-up duration and that the significant inverse associations remained stable in the subgroup of cohort studies with a follow-up duration of > 10 years.
The authors concluded that While current strategies to increase total walking time are beneficial, it may also be reasonable to encourage people to walk at faster speeds to further increase the health benefits of walking.”
This article was translated from JIM, which is part of the Medscape Professional Network. A version of this article appeared on Medscape.com.
Walking is a simple, cost-free form of exercise that benefits physical, social, and mental health in many ways. Several clinical trials have shown that walking regularly is associated with a lower risk for cardiovascular events and all-cause mortality, and having a higher daily step count is linked to a decreased risk for premature death.
Walking and Diabetes
In recent years, the link between walking speed and the risk for multiple health problems has sparked keen interest. Data suggest that a faster walking pace may have a greater physiological response and may be associated with more favorable health advantages than a slow walking pace. A previous meta-analysis of eight cohort studies suggested that individuals in the fastest walking-pace category (median = 5.6 km/h) had a 44% lower risk for stroke than those in the slowest walking-pace category (median = 1.6 km/h). The risk for the former decreased by 13% for every 1 km/h increment in baseline walking pace.
Type 2 diabetes (T2D) is one of the most common metabolic diseases in the world. People with this type of diabetes have an increased risk for microvascular and macrovascular complications and a shorter life expectancy. Approximately 537 million adults are estimated to be living with diabetes worldwide, and this number is expected to reach 783 million by 2045.
Physical activity is an essential component of T2D prevention programs and can favorably affect blood sugar control. A meta-analysis of cohort studies showed that being physically active was associated with a 35% reduction in the risk of acquiring T2D in the general population, and regular walking was associated with a 15% reduction in the risk of developing T2D.
However, no studies have investigated the link between different walking speeds and the risk for T2D. A team from the Research Center at the Semnan University of Medical Sciences in Iran carried out a systematic review of the association between walking speed and the risk of developing T2D in adults; this review was published in the British Journal of Sports Medicine.
10 Cohort Studies
This systematic review used publications (1999-2022) available in the usual data sources (PubMed, Scopus, CENTRAL, and Web of Science). Random-effects meta-analyses were used to calculate relative risk (RR) and risk difference (RD) based on different walking speeds. The researchers rated the credibility of subgroup differences and the certainty of evidence using the Instrument to assess the Credibility of Effect Modification ANalyses (ICEMAN) and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tools, respectively.
Of the 508,121 potential participants, 18,410 adults from 10 prospective cohort studies conducted in the United States, Japan, and the United Kingdom were deemed eligible. The proportion of women was between 52% and 73%, depending on the cohort. Follow-up duration varied from 3 to 11.1 years (median, 8 years).
Five cohort studies measured walking speed using stopwatch testing, while the other five used self-assessed questionnaires. To define cases of T2D, seven studies used objective methods such as blood glucose measurement or linkage with medical records, and in three cohorts, self-assessment questionnaires were used (these were checked against patient records). All studies controlled age, sex, and tobacco consumption in the multivariate analyses, and some controlled just alcohol consumption, blood pressure, total physical activity volume, body mass index, time spent walking or daily step count, and a family history of diabetes.
The Right Speed
The authors first categorized walking speed into four prespecified levels: Easy or casual (< 2 mph or 3.2 km/h), average or normal (2-3 mph or 3.2-4.8 km/h), fairly brisk (3-4 mph or 4.8-6.4 km/h), and very brisk or brisk/striding (> 4 mph or > 6.4 km/h).
Four cohort studies with 6,520 cases of T2D among 160,321 participants reported information on average or normal walking. Participants with average or normal walking were at a 15% lower risk for T2D than those with easy or casual walking (RR = 0.85 [95% CI, 0.70-1.00]; RD = 0.86 [1.72-0]). Ten cohort studies with 18,410 cases among 508,121 participants reported information on fairly brisk walking. Those with fairly brisk walking were at a 24% lower risk for T2D than those with easy or casual walking (RR = 0.76 [0.65-0.87]; I2 = 90%; RD = 1.38 [2.01-0.75]).
There was no significant or credible subgroup difference by adjustment for the total physical activity or time spent walking per day. The dose-response analysis suggested that the risk for T2D decreased significantly at a walking speed of 4 km/h and above.
Study Limitations
This meta-analysis has strengths that may increase the generalizability of its results. The researchers included cohort studies, which allowed them to consider the temporal sequence of exposure and outcome. Cohort studies are less affected by recall and selection biases compared with retrospective case–control studies, which increase the likelihood of causality. The researchers also assessed the credibility of subgroup differences using the recently developed ICEMAN tool, calculated both relative and absolute risks, and rated the certainty of evidence using the GRADE approach.
Some shortcomings must be considered. Most of the studies included in the present review were rated as having a serious risk for bias, with the most important biases resulting from inadequate adjustment for potential confounders and the methods used for walking speed assessment and diagnosis of T2D. In addition, the findings could have been subject to reverse causality bias because participants with faster walking speed are more likely to perform more physical activity and have better cardiorespiratory fitness, greater muscle mass, and better health status. However, the subgroup analyses of fairly brisk and brisk/striding walking indicated that there were no significant subgroup differences by follow-up duration and that the significant inverse associations remained stable in the subgroup of cohort studies with a follow-up duration of > 10 years.
The authors concluded that While current strategies to increase total walking time are beneficial, it may also be reasonable to encourage people to walk at faster speeds to further increase the health benefits of walking.”
This article was translated from JIM, which is part of the Medscape Professional Network. A version of this article appeared on Medscape.com.
FROM THE BRITISH JOURNAL OF SPORTS MEDICINE
FDA Issues Warning About Counterfeit Ozempic
Clinicians and patients are advised to check the product packages they have received and not to use those labeled with lot number NAR0074 and serial number 430834149057. Some of these counterfeit products may still be available for purchase, the FDA said in a statement.
Together with Ozempic manufacturer Novo Nordisk, the FDA is investigating “thousands of units” of the 1-mg injection product. Information is not yet available regarding the drugs’ identity, quality, or safety. However, the pen needles have been confirmed as fake — thereby raising the potential risk for infection — as have the pen labels, accompanying health care professional and patient label information, and carton.
“FDA takes reports of possible counterfeit products seriously and works closely with other federal agencies and the private sector to help protect the nation’s drug supply. FDA’s investigation is ongoing, and the agency is working with Novo Nordisk to identify, investigate, and remove further suspected counterfeit semaglutide injectable products found in the US,” the statement says.
Patients are advised to only obtain Ozempic with a valid prescription through state-licensed pharmacies and to check the product before using for any signs of counterfeiting. There are several differences between the genuine and counterfeit products in the way the pen needle is packaged. The most obvious is that the paper tab covering the fake needle says “Novofine®” whereas the genuine one says “Novofine® Plus.”
There have been at least five adverse events reported from this lot; none were serious and all were consistent with gastrointestinal issues known to occur with the genuine product.
Counterfeit products should be reported to the FDA ‘s consumer complaint coordinator or to the criminal activity division.
A version of this article first appeared on Medscape.com.
Clinicians and patients are advised to check the product packages they have received and not to use those labeled with lot number NAR0074 and serial number 430834149057. Some of these counterfeit products may still be available for purchase, the FDA said in a statement.
Together with Ozempic manufacturer Novo Nordisk, the FDA is investigating “thousands of units” of the 1-mg injection product. Information is not yet available regarding the drugs’ identity, quality, or safety. However, the pen needles have been confirmed as fake — thereby raising the potential risk for infection — as have the pen labels, accompanying health care professional and patient label information, and carton.
“FDA takes reports of possible counterfeit products seriously and works closely with other federal agencies and the private sector to help protect the nation’s drug supply. FDA’s investigation is ongoing, and the agency is working with Novo Nordisk to identify, investigate, and remove further suspected counterfeit semaglutide injectable products found in the US,” the statement says.
Patients are advised to only obtain Ozempic with a valid prescription through state-licensed pharmacies and to check the product before using for any signs of counterfeiting. There are several differences between the genuine and counterfeit products in the way the pen needle is packaged. The most obvious is that the paper tab covering the fake needle says “Novofine®” whereas the genuine one says “Novofine® Plus.”
There have been at least five adverse events reported from this lot; none were serious and all were consistent with gastrointestinal issues known to occur with the genuine product.
Counterfeit products should be reported to the FDA ‘s consumer complaint coordinator or to the criminal activity division.
A version of this article first appeared on Medscape.com.
Clinicians and patients are advised to check the product packages they have received and not to use those labeled with lot number NAR0074 and serial number 430834149057. Some of these counterfeit products may still be available for purchase, the FDA said in a statement.
Together with Ozempic manufacturer Novo Nordisk, the FDA is investigating “thousands of units” of the 1-mg injection product. Information is not yet available regarding the drugs’ identity, quality, or safety. However, the pen needles have been confirmed as fake — thereby raising the potential risk for infection — as have the pen labels, accompanying health care professional and patient label information, and carton.
“FDA takes reports of possible counterfeit products seriously and works closely with other federal agencies and the private sector to help protect the nation’s drug supply. FDA’s investigation is ongoing, and the agency is working with Novo Nordisk to identify, investigate, and remove further suspected counterfeit semaglutide injectable products found in the US,” the statement says.
Patients are advised to only obtain Ozempic with a valid prescription through state-licensed pharmacies and to check the product before using for any signs of counterfeiting. There are several differences between the genuine and counterfeit products in the way the pen needle is packaged. The most obvious is that the paper tab covering the fake needle says “Novofine®” whereas the genuine one says “Novofine® Plus.”
There have been at least five adverse events reported from this lot; none were serious and all were consistent with gastrointestinal issues known to occur with the genuine product.
Counterfeit products should be reported to the FDA ‘s consumer complaint coordinator or to the criminal activity division.
A version of this article first appeared on Medscape.com.
Spending the Holidays With GLP-1 Receptor Agonists: 5 Things to Know
As an endocrinologist, I treat many patients who have diabetes, obesity, or both. Antiobesity medications, particularly the class of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), are our first support tools when nutrition and physical activity aren’t enough.
1. Be mindful of fullness cues.
GLP-1 RAs increase satiety; they help patients feel fuller sooner within a meal and longer in between meals. This means consuming the “usual” at a holiday gathering makes them feel as if they ate too much, and often this will result in more side effects, such as nausea and reflux.
Patient tip: A good rule of thumb is to anticipate feeling full with half of your usual portion. Start with half a plate and reassess your hunger level after finishing.
2. Distinguish between hunger and “food noise.”
Ask your patients, “Do you ever find yourself eating even when you’re not hungry?” Many people eat because of emotions (eg, stress, anxiety, happiness), social situations, or cultural expectations. This type of food consumption is what scientists call “hedonic food intake” and may be driven by the “food noise” that patients describe as persistent thoughts about food in the absence of physiologic hunger. Semaglutide (Ozempic, Wegovy) has been found to reduce cravings, though other research has shown that emotional eating may blunt the effect of GLP-1 RAs.
Patient tip: Recognize when you might be seeking food for reasons other than hunger, and try a different way to address the cue (eg, chat with a friend or family member, go for a walk).
3. Be careful with alcohol.
GLP-1 RAs are being researched as potential treatments for alcohol use disorder. Many patients report less interest in alcohol and a lower tolerance to alcohol when they are taking a GLP-1 RA. Additionally, GLP-1 RAs may be a risk factor for pancreatitis, which can be caused by consuming too much alcohol.
Patient tip: The standard recommendation remains true: If drinking alcohol, limit to one to two servings per day, but also know that reduced intake or interest is normal when taking a GLP-1 RA.
4. Be aware of sickness vs side effects.
With holiday travel and the winter season, it is common for people to catch a cold or a stomach bug. Symptoms of common illnesses might include fatigue, loss of appetite, or diarrhea. These symptoms overlap with side effects of antiobesity medications like semaglutide and tirzepatide.
Patient tip: If you are experiencing constitutional or gastrointestinal symptoms due to illness, speak with your board-certified obesity medicine doctor, who may recommend a temporary medication adjustment to avoid excess side effects.
5. Stay strong against weight stigma.
The holiday season can be a stressful time, especially as patients are reconnecting with people who have not been a part of their health or weight loss journey. Unfortunately, weight bias and weight stigma remain rampant. Many people don’t understand the biology of obesity and refuse to accept the necessity of medical treatment. They may be surrounded by opinions, often louder and less informed.
Patient tip: Remember that obesity is a medical disease. Tell your nosy cousin that it’s a private health matter and that your decisions are your own.
Dr. Tchang is Assistant Professor, Clinical Medicine, Division of Endocrinology, Diabetes, and Metabolism, Weill Cornell Medicine; Physician, Department of Medicine, Iris Cantor Women’s Health Center, Comprehensive Weight Control Center, New York, NY. She disclosed financial relationships with Gelesis and Novo Nordisk.
A version of this article appeared on Medscape.com.
As an endocrinologist, I treat many patients who have diabetes, obesity, or both. Antiobesity medications, particularly the class of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), are our first support tools when nutrition and physical activity aren’t enough.
1. Be mindful of fullness cues.
GLP-1 RAs increase satiety; they help patients feel fuller sooner within a meal and longer in between meals. This means consuming the “usual” at a holiday gathering makes them feel as if they ate too much, and often this will result in more side effects, such as nausea and reflux.
Patient tip: A good rule of thumb is to anticipate feeling full with half of your usual portion. Start with half a plate and reassess your hunger level after finishing.
2. Distinguish between hunger and “food noise.”
Ask your patients, “Do you ever find yourself eating even when you’re not hungry?” Many people eat because of emotions (eg, stress, anxiety, happiness), social situations, or cultural expectations. This type of food consumption is what scientists call “hedonic food intake” and may be driven by the “food noise” that patients describe as persistent thoughts about food in the absence of physiologic hunger. Semaglutide (Ozempic, Wegovy) has been found to reduce cravings, though other research has shown that emotional eating may blunt the effect of GLP-1 RAs.
Patient tip: Recognize when you might be seeking food for reasons other than hunger, and try a different way to address the cue (eg, chat with a friend or family member, go for a walk).
3. Be careful with alcohol.
GLP-1 RAs are being researched as potential treatments for alcohol use disorder. Many patients report less interest in alcohol and a lower tolerance to alcohol when they are taking a GLP-1 RA. Additionally, GLP-1 RAs may be a risk factor for pancreatitis, which can be caused by consuming too much alcohol.
Patient tip: The standard recommendation remains true: If drinking alcohol, limit to one to two servings per day, but also know that reduced intake or interest is normal when taking a GLP-1 RA.
4. Be aware of sickness vs side effects.
With holiday travel and the winter season, it is common for people to catch a cold or a stomach bug. Symptoms of common illnesses might include fatigue, loss of appetite, or diarrhea. These symptoms overlap with side effects of antiobesity medications like semaglutide and tirzepatide.
Patient tip: If you are experiencing constitutional or gastrointestinal symptoms due to illness, speak with your board-certified obesity medicine doctor, who may recommend a temporary medication adjustment to avoid excess side effects.
5. Stay strong against weight stigma.
The holiday season can be a stressful time, especially as patients are reconnecting with people who have not been a part of their health or weight loss journey. Unfortunately, weight bias and weight stigma remain rampant. Many people don’t understand the biology of obesity and refuse to accept the necessity of medical treatment. They may be surrounded by opinions, often louder and less informed.
Patient tip: Remember that obesity is a medical disease. Tell your nosy cousin that it’s a private health matter and that your decisions are your own.
Dr. Tchang is Assistant Professor, Clinical Medicine, Division of Endocrinology, Diabetes, and Metabolism, Weill Cornell Medicine; Physician, Department of Medicine, Iris Cantor Women’s Health Center, Comprehensive Weight Control Center, New York, NY. She disclosed financial relationships with Gelesis and Novo Nordisk.
A version of this article appeared on Medscape.com.
As an endocrinologist, I treat many patients who have diabetes, obesity, or both. Antiobesity medications, particularly the class of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), are our first support tools when nutrition and physical activity aren’t enough.
1. Be mindful of fullness cues.
GLP-1 RAs increase satiety; they help patients feel fuller sooner within a meal and longer in between meals. This means consuming the “usual” at a holiday gathering makes them feel as if they ate too much, and often this will result in more side effects, such as nausea and reflux.
Patient tip: A good rule of thumb is to anticipate feeling full with half of your usual portion. Start with half a plate and reassess your hunger level after finishing.
2. Distinguish between hunger and “food noise.”
Ask your patients, “Do you ever find yourself eating even when you’re not hungry?” Many people eat because of emotions (eg, stress, anxiety, happiness), social situations, or cultural expectations. This type of food consumption is what scientists call “hedonic food intake” and may be driven by the “food noise” that patients describe as persistent thoughts about food in the absence of physiologic hunger. Semaglutide (Ozempic, Wegovy) has been found to reduce cravings, though other research has shown that emotional eating may blunt the effect of GLP-1 RAs.
Patient tip: Recognize when you might be seeking food for reasons other than hunger, and try a different way to address the cue (eg, chat with a friend or family member, go for a walk).
3. Be careful with alcohol.
GLP-1 RAs are being researched as potential treatments for alcohol use disorder. Many patients report less interest in alcohol and a lower tolerance to alcohol when they are taking a GLP-1 RA. Additionally, GLP-1 RAs may be a risk factor for pancreatitis, which can be caused by consuming too much alcohol.
Patient tip: The standard recommendation remains true: If drinking alcohol, limit to one to two servings per day, but also know that reduced intake or interest is normal when taking a GLP-1 RA.
4. Be aware of sickness vs side effects.
With holiday travel and the winter season, it is common for people to catch a cold or a stomach bug. Symptoms of common illnesses might include fatigue, loss of appetite, or diarrhea. These symptoms overlap with side effects of antiobesity medications like semaglutide and tirzepatide.
Patient tip: If you are experiencing constitutional or gastrointestinal symptoms due to illness, speak with your board-certified obesity medicine doctor, who may recommend a temporary medication adjustment to avoid excess side effects.
5. Stay strong against weight stigma.
The holiday season can be a stressful time, especially as patients are reconnecting with people who have not been a part of their health or weight loss journey. Unfortunately, weight bias and weight stigma remain rampant. Many people don’t understand the biology of obesity and refuse to accept the necessity of medical treatment. They may be surrounded by opinions, often louder and less informed.
Patient tip: Remember that obesity is a medical disease. Tell your nosy cousin that it’s a private health matter and that your decisions are your own.
Dr. Tchang is Assistant Professor, Clinical Medicine, Division of Endocrinology, Diabetes, and Metabolism, Weill Cornell Medicine; Physician, Department of Medicine, Iris Cantor Women’s Health Center, Comprehensive Weight Control Center, New York, NY. She disclosed financial relationships with Gelesis and Novo Nordisk.
A version of this article appeared on Medscape.com.
ED Visits for Diabetes on the Rise in the US
Emergency department (ED) visits by adults with diabetes increased by more than 25% since 2012, with the highest rates among Blacks and those aged over 65 years, a new data brief from the Centers for Disease Control and Prevention’s National Center for Health Statistics shows.
In 2021, diabetes was the eighth leading cause of death in the United States, according to the brief, published online on December 19, 2023. Its frequency is increasing in young people, and increasing age is a risk factor for hospitalization.
The latest data show that in 2020-2021, the overall annual ED visit rate was 72.2 visits per 1000 adults with diabetes, with no significant difference in terms of sex (75.1 visits per 1000 women vs 69.1 visits per 1000 men). By race/ethnicity, Blacks had the highest rates, at 135.5 visits per 1000 adults, followed by Whites (69.9) and Hispanics (52.3). The rates increased with age for both women and men, and among the three race/ethnic groups.
Comorbidities Count
The most ED visits were made by patients with diabetes and two to four other chronic conditions (541.4 visits per 1000 visits). Rates for patients without other chronic conditions were the lowest (90.2).
Among individuals with diabetes aged 18-44 years, ED visit rates were the highest for those with two to four other chronic conditions (402.0) and lowest among those with five or more other conditions (93.8).
Among patients aged 45-64 years, ED visit rates were the highest for those with two to four other chronic conditions (526.4) and lowest for those without other conditions (87.7). In the 65 years and older group, rates were the highest for individuals with two to four other chronic conditions (605.2), followed by five or more conditions (217.7), one other condition (140.6), and no other conditions (36.5).
Notably, the ED visit rates for those with two to four or five or more other chronic conditions increased with age, whereas visits for those with no other chronic conditions or one other condition decreased with age.
Decade-Long Trend
ED visit rates among adults with diabetes increased throughout the past decade, from 48.6 visits per 1000 adults in 2012 to 74.9 per 1000 adults in 2021. Rates for those aged 65 and older were higher than all other age groups, increasing from 113.4 to 156.8. Increases were also seen among those aged 45-64 years (53.1 in 2012 to 89.2 in 2021) and 18-44 (20.9 in 2012 to 26.4 in 2016, then plateauing from 2016-2021).
Data are based on a sample of 4051 ED visits, representing about 18,238,000 average annual visits made by adults with diabetes to nonfederal, general, and short-stay hospitals during 2020-2021.
Taken together, these most recent estimates “show an increasing trend in rates by adults with diabetes in the ED setting,” the authors concluded.
A version of this article appeared on Medscape.com.
Emergency department (ED) visits by adults with diabetes increased by more than 25% since 2012, with the highest rates among Blacks and those aged over 65 years, a new data brief from the Centers for Disease Control and Prevention’s National Center for Health Statistics shows.
In 2021, diabetes was the eighth leading cause of death in the United States, according to the brief, published online on December 19, 2023. Its frequency is increasing in young people, and increasing age is a risk factor for hospitalization.
The latest data show that in 2020-2021, the overall annual ED visit rate was 72.2 visits per 1000 adults with diabetes, with no significant difference in terms of sex (75.1 visits per 1000 women vs 69.1 visits per 1000 men). By race/ethnicity, Blacks had the highest rates, at 135.5 visits per 1000 adults, followed by Whites (69.9) and Hispanics (52.3). The rates increased with age for both women and men, and among the three race/ethnic groups.
Comorbidities Count
The most ED visits were made by patients with diabetes and two to four other chronic conditions (541.4 visits per 1000 visits). Rates for patients without other chronic conditions were the lowest (90.2).
Among individuals with diabetes aged 18-44 years, ED visit rates were the highest for those with two to four other chronic conditions (402.0) and lowest among those with five or more other conditions (93.8).
Among patients aged 45-64 years, ED visit rates were the highest for those with two to four other chronic conditions (526.4) and lowest for those without other conditions (87.7). In the 65 years and older group, rates were the highest for individuals with two to four other chronic conditions (605.2), followed by five or more conditions (217.7), one other condition (140.6), and no other conditions (36.5).
Notably, the ED visit rates for those with two to four or five or more other chronic conditions increased with age, whereas visits for those with no other chronic conditions or one other condition decreased with age.
Decade-Long Trend
ED visit rates among adults with diabetes increased throughout the past decade, from 48.6 visits per 1000 adults in 2012 to 74.9 per 1000 adults in 2021. Rates for those aged 65 and older were higher than all other age groups, increasing from 113.4 to 156.8. Increases were also seen among those aged 45-64 years (53.1 in 2012 to 89.2 in 2021) and 18-44 (20.9 in 2012 to 26.4 in 2016, then plateauing from 2016-2021).
Data are based on a sample of 4051 ED visits, representing about 18,238,000 average annual visits made by adults with diabetes to nonfederal, general, and short-stay hospitals during 2020-2021.
Taken together, these most recent estimates “show an increasing trend in rates by adults with diabetes in the ED setting,” the authors concluded.
A version of this article appeared on Medscape.com.
Emergency department (ED) visits by adults with diabetes increased by more than 25% since 2012, with the highest rates among Blacks and those aged over 65 years, a new data brief from the Centers for Disease Control and Prevention’s National Center for Health Statistics shows.
In 2021, diabetes was the eighth leading cause of death in the United States, according to the brief, published online on December 19, 2023. Its frequency is increasing in young people, and increasing age is a risk factor for hospitalization.
The latest data show that in 2020-2021, the overall annual ED visit rate was 72.2 visits per 1000 adults with diabetes, with no significant difference in terms of sex (75.1 visits per 1000 women vs 69.1 visits per 1000 men). By race/ethnicity, Blacks had the highest rates, at 135.5 visits per 1000 adults, followed by Whites (69.9) and Hispanics (52.3). The rates increased with age for both women and men, and among the three race/ethnic groups.
Comorbidities Count
The most ED visits were made by patients with diabetes and two to four other chronic conditions (541.4 visits per 1000 visits). Rates for patients without other chronic conditions were the lowest (90.2).
Among individuals with diabetes aged 18-44 years, ED visit rates were the highest for those with two to four other chronic conditions (402.0) and lowest among those with five or more other conditions (93.8).
Among patients aged 45-64 years, ED visit rates were the highest for those with two to four other chronic conditions (526.4) and lowest for those without other conditions (87.7). In the 65 years and older group, rates were the highest for individuals with two to four other chronic conditions (605.2), followed by five or more conditions (217.7), one other condition (140.6), and no other conditions (36.5).
Notably, the ED visit rates for those with two to four or five or more other chronic conditions increased with age, whereas visits for those with no other chronic conditions or one other condition decreased with age.
Decade-Long Trend
ED visit rates among adults with diabetes increased throughout the past decade, from 48.6 visits per 1000 adults in 2012 to 74.9 per 1000 adults in 2021. Rates for those aged 65 and older were higher than all other age groups, increasing from 113.4 to 156.8. Increases were also seen among those aged 45-64 years (53.1 in 2012 to 89.2 in 2021) and 18-44 (20.9 in 2012 to 26.4 in 2016, then plateauing from 2016-2021).
Data are based on a sample of 4051 ED visits, representing about 18,238,000 average annual visits made by adults with diabetes to nonfederal, general, and short-stay hospitals during 2020-2021.
Taken together, these most recent estimates “show an increasing trend in rates by adults with diabetes in the ED setting,” the authors concluded.
A version of this article appeared on Medscape.com.
GLP-1 RAs Associated With Reduced Colorectal Cancer Risk in Patients With Type 2 Diabetes
according to a new analysis.
In particular, GLP-1 RAs were associated with decreased risk compared with other antidiabetic treatments, including insulin, metformin, sodium-glucose cotransporter 2 (SGLT2) inhibitors, sulfonylureas, and thiazolidinediones.
More profound effects were seen in patients with overweight or obesity, “suggesting a potential protective effect against CRC partially mediated by weight loss and other mechanisms related to weight loss,” Lindsey Wang, an undergraduate student at Case Western Reserve University, Cleveland, Ohio, and colleagues wrote in JAMA Oncology.
Testing Treatments
GLP-1 RAs, usually given by injection, are approved by the US Food and Drug Administration to treat type 2 diabetes. They can lower blood sugar levels, improve insulin sensitivity, and help patients manage their weight.
Diabetes, overweight, and obesity are known risk factors for CRC and make prognosis worse. Ms. Wang and colleagues hypothesized that GLP-1 RAs might reduce CRC risk compared with other antidiabetics, including metformin and insulin, which have also been shown to reduce CRC risk.
Using a national database of more than 101 million electronic health records, Ms. Wang and colleagues conducted a population-based study of more than 1.2 million patients who had medical encounters for type 2 diabetes and were subsequently prescribed antidiabetic medications between 2005 and 2019. The patients had no prior antidiabetic medication use nor CRC diagnosis.
The researchers analyzed the effects of GLP-1 RAs on CRC incidence compared with the other prescribed antidiabetic drugs, matching for demographics, adverse socioeconomic determinants of health, preexisting medical conditions, family and personal history of cancers and colonic polyps, lifestyle factors, and procedures such as colonoscopy.
During a 15-year follow-up, GLP-1 RAs were associated with decreased risk for CRC compared with insulin (hazard ratio [HR], 0.56), metformin (HR, 0.75), SGLT2 inhibitors (HR, 0.77), sulfonylureas (HR, 0.82), and thiazolidinediones (HR, 0.82) in the overall study population.
For instance, among 22,572 patients who took insulin, 167 cases of CRC occurred, compared with 94 cases among the matched GLP-1 RA cohort. Among 18,518 patients who took metformin, 153 cases of CRC occurred compared with 96 cases among the matched GLP-1 RA cohort.
GLP-1 RAs also were associated with lower but not statistically significant risk than alpha-glucosidase inhibitors (HR, 0.59) and dipeptidyl-peptidase-4 (DPP-4) inhibitors (HR, 0.93).
In patients with overweight or obesity, GLP-1 RAs were associated with a lower risk for CRC than most of the other antidiabetics, including insulin (HR, 0.5), metformin (HR, 0.58), SGLT2 inhibitors (HR, 0.68), sulfonylureas (HR, 0.63), thiazolidinediones (HR, 0.73), and DPP-4 inhibitors (HR, 0.77).
Consistent findings were observed in women and men.
“Our results clearly demonstrate that GLP-1 RAs are significantly more effective than popular antidiabetic drugs, such as metformin or insulin, at preventing the development of CRC,” said Nathan Berger, MD, co-lead researcher, professor of experimental medicine, and member of the Case Comprehensive Cancer Center.
Targets for Future Research
Study limitations include potential unmeasured or uncontrolled confounders, self-selection, reverse causality, and other biases involved in observational studies, the research team noted.
Further research is warranted to investigate the effects in patients with prior antidiabetic treatments, underlying mechanisms, potential variation in effects among different GLP-1 RAs, and the potential of GLP-1 RAs to reduce the risks for other obesity-associated cancers, the researchers wrote.
“To our knowledge, this is the first indication this popular weight loss and antidiabetic class of drugs reduces incidence of CRC, relative to other antidiabetic agents,” said Rong Xu, PhD, co-lead researcher, professor of medicine, and member of the Case Comprehensive Cancer Center.
The study was supported by the National Cancer Institute Case Comprehensive Cancer Center, American Cancer Society, Landon Foundation-American Association for Cancer Research, National Institutes of Health Director’s New Innovator Award Program, National Institute on Aging, and National Institute on Alcohol Abuse and Alcoholism. Several authors reported grants from the National Institutes of Health during the conduct of the study.
A version of this article appeared on Medscape.com.
according to a new analysis.
In particular, GLP-1 RAs were associated with decreased risk compared with other antidiabetic treatments, including insulin, metformin, sodium-glucose cotransporter 2 (SGLT2) inhibitors, sulfonylureas, and thiazolidinediones.
More profound effects were seen in patients with overweight or obesity, “suggesting a potential protective effect against CRC partially mediated by weight loss and other mechanisms related to weight loss,” Lindsey Wang, an undergraduate student at Case Western Reserve University, Cleveland, Ohio, and colleagues wrote in JAMA Oncology.
Testing Treatments
GLP-1 RAs, usually given by injection, are approved by the US Food and Drug Administration to treat type 2 diabetes. They can lower blood sugar levels, improve insulin sensitivity, and help patients manage their weight.
Diabetes, overweight, and obesity are known risk factors for CRC and make prognosis worse. Ms. Wang and colleagues hypothesized that GLP-1 RAs might reduce CRC risk compared with other antidiabetics, including metformin and insulin, which have also been shown to reduce CRC risk.
Using a national database of more than 101 million electronic health records, Ms. Wang and colleagues conducted a population-based study of more than 1.2 million patients who had medical encounters for type 2 diabetes and were subsequently prescribed antidiabetic medications between 2005 and 2019. The patients had no prior antidiabetic medication use nor CRC diagnosis.
The researchers analyzed the effects of GLP-1 RAs on CRC incidence compared with the other prescribed antidiabetic drugs, matching for demographics, adverse socioeconomic determinants of health, preexisting medical conditions, family and personal history of cancers and colonic polyps, lifestyle factors, and procedures such as colonoscopy.
During a 15-year follow-up, GLP-1 RAs were associated with decreased risk for CRC compared with insulin (hazard ratio [HR], 0.56), metformin (HR, 0.75), SGLT2 inhibitors (HR, 0.77), sulfonylureas (HR, 0.82), and thiazolidinediones (HR, 0.82) in the overall study population.
For instance, among 22,572 patients who took insulin, 167 cases of CRC occurred, compared with 94 cases among the matched GLP-1 RA cohort. Among 18,518 patients who took metformin, 153 cases of CRC occurred compared with 96 cases among the matched GLP-1 RA cohort.
GLP-1 RAs also were associated with lower but not statistically significant risk than alpha-glucosidase inhibitors (HR, 0.59) and dipeptidyl-peptidase-4 (DPP-4) inhibitors (HR, 0.93).
In patients with overweight or obesity, GLP-1 RAs were associated with a lower risk for CRC than most of the other antidiabetics, including insulin (HR, 0.5), metformin (HR, 0.58), SGLT2 inhibitors (HR, 0.68), sulfonylureas (HR, 0.63), thiazolidinediones (HR, 0.73), and DPP-4 inhibitors (HR, 0.77).
Consistent findings were observed in women and men.
“Our results clearly demonstrate that GLP-1 RAs are significantly more effective than popular antidiabetic drugs, such as metformin or insulin, at preventing the development of CRC,” said Nathan Berger, MD, co-lead researcher, professor of experimental medicine, and member of the Case Comprehensive Cancer Center.
Targets for Future Research
Study limitations include potential unmeasured or uncontrolled confounders, self-selection, reverse causality, and other biases involved in observational studies, the research team noted.
Further research is warranted to investigate the effects in patients with prior antidiabetic treatments, underlying mechanisms, potential variation in effects among different GLP-1 RAs, and the potential of GLP-1 RAs to reduce the risks for other obesity-associated cancers, the researchers wrote.
“To our knowledge, this is the first indication this popular weight loss and antidiabetic class of drugs reduces incidence of CRC, relative to other antidiabetic agents,” said Rong Xu, PhD, co-lead researcher, professor of medicine, and member of the Case Comprehensive Cancer Center.
The study was supported by the National Cancer Institute Case Comprehensive Cancer Center, American Cancer Society, Landon Foundation-American Association for Cancer Research, National Institutes of Health Director’s New Innovator Award Program, National Institute on Aging, and National Institute on Alcohol Abuse and Alcoholism. Several authors reported grants from the National Institutes of Health during the conduct of the study.
A version of this article appeared on Medscape.com.
according to a new analysis.
In particular, GLP-1 RAs were associated with decreased risk compared with other antidiabetic treatments, including insulin, metformin, sodium-glucose cotransporter 2 (SGLT2) inhibitors, sulfonylureas, and thiazolidinediones.
More profound effects were seen in patients with overweight or obesity, “suggesting a potential protective effect against CRC partially mediated by weight loss and other mechanisms related to weight loss,” Lindsey Wang, an undergraduate student at Case Western Reserve University, Cleveland, Ohio, and colleagues wrote in JAMA Oncology.
Testing Treatments
GLP-1 RAs, usually given by injection, are approved by the US Food and Drug Administration to treat type 2 diabetes. They can lower blood sugar levels, improve insulin sensitivity, and help patients manage their weight.
Diabetes, overweight, and obesity are known risk factors for CRC and make prognosis worse. Ms. Wang and colleagues hypothesized that GLP-1 RAs might reduce CRC risk compared with other antidiabetics, including metformin and insulin, which have also been shown to reduce CRC risk.
Using a national database of more than 101 million electronic health records, Ms. Wang and colleagues conducted a population-based study of more than 1.2 million patients who had medical encounters for type 2 diabetes and were subsequently prescribed antidiabetic medications between 2005 and 2019. The patients had no prior antidiabetic medication use nor CRC diagnosis.
The researchers analyzed the effects of GLP-1 RAs on CRC incidence compared with the other prescribed antidiabetic drugs, matching for demographics, adverse socioeconomic determinants of health, preexisting medical conditions, family and personal history of cancers and colonic polyps, lifestyle factors, and procedures such as colonoscopy.
During a 15-year follow-up, GLP-1 RAs were associated with decreased risk for CRC compared with insulin (hazard ratio [HR], 0.56), metformin (HR, 0.75), SGLT2 inhibitors (HR, 0.77), sulfonylureas (HR, 0.82), and thiazolidinediones (HR, 0.82) in the overall study population.
For instance, among 22,572 patients who took insulin, 167 cases of CRC occurred, compared with 94 cases among the matched GLP-1 RA cohort. Among 18,518 patients who took metformin, 153 cases of CRC occurred compared with 96 cases among the matched GLP-1 RA cohort.
GLP-1 RAs also were associated with lower but not statistically significant risk than alpha-glucosidase inhibitors (HR, 0.59) and dipeptidyl-peptidase-4 (DPP-4) inhibitors (HR, 0.93).
In patients with overweight or obesity, GLP-1 RAs were associated with a lower risk for CRC than most of the other antidiabetics, including insulin (HR, 0.5), metformin (HR, 0.58), SGLT2 inhibitors (HR, 0.68), sulfonylureas (HR, 0.63), thiazolidinediones (HR, 0.73), and DPP-4 inhibitors (HR, 0.77).
Consistent findings were observed in women and men.
“Our results clearly demonstrate that GLP-1 RAs are significantly more effective than popular antidiabetic drugs, such as metformin or insulin, at preventing the development of CRC,” said Nathan Berger, MD, co-lead researcher, professor of experimental medicine, and member of the Case Comprehensive Cancer Center.
Targets for Future Research
Study limitations include potential unmeasured or uncontrolled confounders, self-selection, reverse causality, and other biases involved in observational studies, the research team noted.
Further research is warranted to investigate the effects in patients with prior antidiabetic treatments, underlying mechanisms, potential variation in effects among different GLP-1 RAs, and the potential of GLP-1 RAs to reduce the risks for other obesity-associated cancers, the researchers wrote.
“To our knowledge, this is the first indication this popular weight loss and antidiabetic class of drugs reduces incidence of CRC, relative to other antidiabetic agents,” said Rong Xu, PhD, co-lead researcher, professor of medicine, and member of the Case Comprehensive Cancer Center.
The study was supported by the National Cancer Institute Case Comprehensive Cancer Center, American Cancer Society, Landon Foundation-American Association for Cancer Research, National Institutes of Health Director’s New Innovator Award Program, National Institute on Aging, and National Institute on Alcohol Abuse and Alcoholism. Several authors reported grants from the National Institutes of Health during the conduct of the study.
A version of this article appeared on Medscape.com.
‘We Will Rock You’ Into Real-time Diabetes Control
, reveals a series of experiments.
The research was published in The Lancet Diabetes & Endocrinology.
After developing a cell line in which music-sensitive calcium channels triggered the release of insulin-containing vesicles, the researchers conducted a series of studies identifying the optimal frequency, pitch, and volume of sounds for triggering release.
After settling on low-bass heavy popular music, they tested their system on mice with type 1 diabetes that had the insulin-releasing cells implanted in their abdomen. Applying the music directly at 60 dB led to near wild-type levels of insulin in the blood within 15 minutes.
“With only 4 hours required for a full refill, [the system] can provide several therapeutic doses a day,” says Martin Fussenegger, PhD, professor of biotechnology and bioengineering, Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland, and colleagues.
“This would match the typical needs of people with type 2 diabetes consuming three meals a day, and for whom administration of prandial insulin is an established treatment option, as they do not have capability for early postprandial insulin secretion from preformed insulin.”
As the system requires nothing more than portable battery-powered commercially available loudspeakers, the multiple daily dosing of biopharmaceuticals becomes “straightforward in the absence of medical infrastructure or staff, simply by having the patient listen to the prescribed music.”
It therefore “could be an interesting option for cell-based therapies, especially where the need for frequent dosing raises compliance issues.”
It is a “very exciting piece of work, no doubt,” said Anandwardhan A. Hardikar, PhD, group leader, Diabetes and Islet Biology Group, Translational Health Research Institute, Western Sydney University, Penrith NSW, Australia.
He pointed out that the concept of using music to drive gene expression “is something we’ve known for the last 20 years,” but bringing the different strands of research together to generate cells that can be implanted into mice is “an amazing idea.”
Dr. Hardikar, who was not involved in the study, said, however, the publication of the study as a correspondence “does not allow for a lot of the detail that I would have expected as an academic,” and consequently some questions remain.
The most important is whether the music itself is required to trigger the insulin release, as opposed simply to sounds in general.
Is Music or Sound the “Trigger?”
Music is “frequency, it’s the amplitude of the waveform, and it’s the duration for which those waveforms are present,” he noted, but the same profile can be achieved by cutting up and editing the melody so it becomes a jumble of sounds.
For Dr. Hardikar, the “best control” for the study would be to have no music as well as the edited song, with “bits of pieces” played randomly so “it sounds like it’s the same frequency and amplitude.”
Then it would be clear whether the effect is owing to the “noise, or we have to appreciate the melody.”
The other outstanding question is whether the results “can directly translate to larger animals,” such as humans, Dr. Hardikar said.
The authors point out that when translated into mechanical vibrations in the middle ear, the acoustic waves of music activate mechanosensitive ion channels, a form of trigger that is seen across the animal kingdom.
They go on to highlight that while gene switches have been developed for use in next-generation cell-based therapies for a range of conditions, small-molecular trigger compounds face a number of challenges and may cause adverse effects.
With “traceless triggers” such as light, ultrasound, magnetic fields, radio waves, electricity, and heat also facing issues, there is a “need for new switching modalities.”
The researchers therefore developed a music-inducible cellular control (MUSIC) system, which leverages the known intracellular calcium surge in response to music, via calcium-permeable mechanosensitive channels, to drive the release of biopharmaceuticals from vesicles.
They then generated MUSIC-controlled insulin-releasing cell lines, finding that, using a customized box containing off-the-shelf loudspeakers, they could induce channel activation and insulin release with 60 dB at 50 Hz, which is “within the safe range for the human ear.”
Further experiments revealed that insulin release was greatest at 50-100 Hz, and higher than that seen with potassium chloride, the “gold-standard” depolarization control for calcium channels.
The researchers then showed that with optimal stimulation at 50 Hz and 60 dB, channel activation and subsequent insulin release required at least 3 seconds of continuous music, “which might protect the cellular device from inadvertent activation during everyday activities.”
Next, they examined the impact of different musical genres on insulin release, finding that low-bass heavy popular music and movie soundtracks induced maximum release, while the responses were more diverse to classical and guitar-based music.
Specifically, “We Will Rock You,” by the British rock band Queen, induced the release of 70% of available insulin within 5 minutes and 100% within 15 minutes. This, the team notes, is “similar to the dynamics of glucose-triggered insulin release by human pancreatic islets.”
Exposing the cells to a second music session at different intervals revealed that full insulin refill was achieved within 4 hours, which “would be appropriate to attenuate glycemic excursions associated with typical dietary habits.”
Finally, the researchers tested the system in vivo, constructing a box with two off-the-shelf loudspeakers that focuses acoustic waves, via deflectors, onto the abdomens of mice with type 1 diabetes.
Exposing the mice, which had been implanted with microencapsulated MUSIC cells in the peritoneum, to low-bass acoustic waves at 60 dB (50 m/s2) for 15 minutes allowed them to achieve near wild-type levels of insulin in the blood and restored normoglycemia.
Moreover, “Queen’s song ‘We Will Rock You’ generated sufficient insulin to rapidly attenuate postprandial glycemic excursions during glucose tolerance tests,” the team says.
In contrast, animals without implants, or those that had implants but did not have music immersion, remained severely hyperglycemic, they add.
They also note that the effect was seen only when the sound waves “directly impinge on the skin just above the implantation site” for at least 15 minutes, with no increase in insulin release observed with commercially available headphones or ear plugs, such as Apple AirPods, or with loud environmental noises.
Consequently, “therapeutic MUSIC sessions would still be compatible with listening to other types of music or listening to all types of music via headphones,” the researchers write, and are “compatible with standard drug administration schemes.”
The study was supported by a European Research Council advanced grant and in part by the Swiss National Science Foundation NCCR Molecular Systems Engineering. One author acknowledges the support of the Chinese Scholarship Council.
No relevant financial relationships were declared.
A version of this article appeared on Medscape.com.
, reveals a series of experiments.
The research was published in The Lancet Diabetes & Endocrinology.
After developing a cell line in which music-sensitive calcium channels triggered the release of insulin-containing vesicles, the researchers conducted a series of studies identifying the optimal frequency, pitch, and volume of sounds for triggering release.
After settling on low-bass heavy popular music, they tested their system on mice with type 1 diabetes that had the insulin-releasing cells implanted in their abdomen. Applying the music directly at 60 dB led to near wild-type levels of insulin in the blood within 15 minutes.
“With only 4 hours required for a full refill, [the system] can provide several therapeutic doses a day,” says Martin Fussenegger, PhD, professor of biotechnology and bioengineering, Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland, and colleagues.
“This would match the typical needs of people with type 2 diabetes consuming three meals a day, and for whom administration of prandial insulin is an established treatment option, as they do not have capability for early postprandial insulin secretion from preformed insulin.”
As the system requires nothing more than portable battery-powered commercially available loudspeakers, the multiple daily dosing of biopharmaceuticals becomes “straightforward in the absence of medical infrastructure or staff, simply by having the patient listen to the prescribed music.”
It therefore “could be an interesting option for cell-based therapies, especially where the need for frequent dosing raises compliance issues.”
It is a “very exciting piece of work, no doubt,” said Anandwardhan A. Hardikar, PhD, group leader, Diabetes and Islet Biology Group, Translational Health Research Institute, Western Sydney University, Penrith NSW, Australia.
He pointed out that the concept of using music to drive gene expression “is something we’ve known for the last 20 years,” but bringing the different strands of research together to generate cells that can be implanted into mice is “an amazing idea.”
Dr. Hardikar, who was not involved in the study, said, however, the publication of the study as a correspondence “does not allow for a lot of the detail that I would have expected as an academic,” and consequently some questions remain.
The most important is whether the music itself is required to trigger the insulin release, as opposed simply to sounds in general.
Is Music or Sound the “Trigger?”
Music is “frequency, it’s the amplitude of the waveform, and it’s the duration for which those waveforms are present,” he noted, but the same profile can be achieved by cutting up and editing the melody so it becomes a jumble of sounds.
For Dr. Hardikar, the “best control” for the study would be to have no music as well as the edited song, with “bits of pieces” played randomly so “it sounds like it’s the same frequency and amplitude.”
Then it would be clear whether the effect is owing to the “noise, or we have to appreciate the melody.”
The other outstanding question is whether the results “can directly translate to larger animals,” such as humans, Dr. Hardikar said.
The authors point out that when translated into mechanical vibrations in the middle ear, the acoustic waves of music activate mechanosensitive ion channels, a form of trigger that is seen across the animal kingdom.
They go on to highlight that while gene switches have been developed for use in next-generation cell-based therapies for a range of conditions, small-molecular trigger compounds face a number of challenges and may cause adverse effects.
With “traceless triggers” such as light, ultrasound, magnetic fields, radio waves, electricity, and heat also facing issues, there is a “need for new switching modalities.”
The researchers therefore developed a music-inducible cellular control (MUSIC) system, which leverages the known intracellular calcium surge in response to music, via calcium-permeable mechanosensitive channels, to drive the release of biopharmaceuticals from vesicles.
They then generated MUSIC-controlled insulin-releasing cell lines, finding that, using a customized box containing off-the-shelf loudspeakers, they could induce channel activation and insulin release with 60 dB at 50 Hz, which is “within the safe range for the human ear.”
Further experiments revealed that insulin release was greatest at 50-100 Hz, and higher than that seen with potassium chloride, the “gold-standard” depolarization control for calcium channels.
The researchers then showed that with optimal stimulation at 50 Hz and 60 dB, channel activation and subsequent insulin release required at least 3 seconds of continuous music, “which might protect the cellular device from inadvertent activation during everyday activities.”
Next, they examined the impact of different musical genres on insulin release, finding that low-bass heavy popular music and movie soundtracks induced maximum release, while the responses were more diverse to classical and guitar-based music.
Specifically, “We Will Rock You,” by the British rock band Queen, induced the release of 70% of available insulin within 5 minutes and 100% within 15 minutes. This, the team notes, is “similar to the dynamics of glucose-triggered insulin release by human pancreatic islets.”
Exposing the cells to a second music session at different intervals revealed that full insulin refill was achieved within 4 hours, which “would be appropriate to attenuate glycemic excursions associated with typical dietary habits.”
Finally, the researchers tested the system in vivo, constructing a box with two off-the-shelf loudspeakers that focuses acoustic waves, via deflectors, onto the abdomens of mice with type 1 diabetes.
Exposing the mice, which had been implanted with microencapsulated MUSIC cells in the peritoneum, to low-bass acoustic waves at 60 dB (50 m/s2) for 15 minutes allowed them to achieve near wild-type levels of insulin in the blood and restored normoglycemia.
Moreover, “Queen’s song ‘We Will Rock You’ generated sufficient insulin to rapidly attenuate postprandial glycemic excursions during glucose tolerance tests,” the team says.
In contrast, animals without implants, or those that had implants but did not have music immersion, remained severely hyperglycemic, they add.
They also note that the effect was seen only when the sound waves “directly impinge on the skin just above the implantation site” for at least 15 minutes, with no increase in insulin release observed with commercially available headphones or ear plugs, such as Apple AirPods, or with loud environmental noises.
Consequently, “therapeutic MUSIC sessions would still be compatible with listening to other types of music or listening to all types of music via headphones,” the researchers write, and are “compatible with standard drug administration schemes.”
The study was supported by a European Research Council advanced grant and in part by the Swiss National Science Foundation NCCR Molecular Systems Engineering. One author acknowledges the support of the Chinese Scholarship Council.
No relevant financial relationships were declared.
A version of this article appeared on Medscape.com.
, reveals a series of experiments.
The research was published in The Lancet Diabetes & Endocrinology.
After developing a cell line in which music-sensitive calcium channels triggered the release of insulin-containing vesicles, the researchers conducted a series of studies identifying the optimal frequency, pitch, and volume of sounds for triggering release.
After settling on low-bass heavy popular music, they tested their system on mice with type 1 diabetes that had the insulin-releasing cells implanted in their abdomen. Applying the music directly at 60 dB led to near wild-type levels of insulin in the blood within 15 minutes.
“With only 4 hours required for a full refill, [the system] can provide several therapeutic doses a day,” says Martin Fussenegger, PhD, professor of biotechnology and bioengineering, Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland, and colleagues.
“This would match the typical needs of people with type 2 diabetes consuming three meals a day, and for whom administration of prandial insulin is an established treatment option, as they do not have capability for early postprandial insulin secretion from preformed insulin.”
As the system requires nothing more than portable battery-powered commercially available loudspeakers, the multiple daily dosing of biopharmaceuticals becomes “straightforward in the absence of medical infrastructure or staff, simply by having the patient listen to the prescribed music.”
It therefore “could be an interesting option for cell-based therapies, especially where the need for frequent dosing raises compliance issues.”
It is a “very exciting piece of work, no doubt,” said Anandwardhan A. Hardikar, PhD, group leader, Diabetes and Islet Biology Group, Translational Health Research Institute, Western Sydney University, Penrith NSW, Australia.
He pointed out that the concept of using music to drive gene expression “is something we’ve known for the last 20 years,” but bringing the different strands of research together to generate cells that can be implanted into mice is “an amazing idea.”
Dr. Hardikar, who was not involved in the study, said, however, the publication of the study as a correspondence “does not allow for a lot of the detail that I would have expected as an academic,” and consequently some questions remain.
The most important is whether the music itself is required to trigger the insulin release, as opposed simply to sounds in general.
Is Music or Sound the “Trigger?”
Music is “frequency, it’s the amplitude of the waveform, and it’s the duration for which those waveforms are present,” he noted, but the same profile can be achieved by cutting up and editing the melody so it becomes a jumble of sounds.
For Dr. Hardikar, the “best control” for the study would be to have no music as well as the edited song, with “bits of pieces” played randomly so “it sounds like it’s the same frequency and amplitude.”
Then it would be clear whether the effect is owing to the “noise, or we have to appreciate the melody.”
The other outstanding question is whether the results “can directly translate to larger animals,” such as humans, Dr. Hardikar said.
The authors point out that when translated into mechanical vibrations in the middle ear, the acoustic waves of music activate mechanosensitive ion channels, a form of trigger that is seen across the animal kingdom.
They go on to highlight that while gene switches have been developed for use in next-generation cell-based therapies for a range of conditions, small-molecular trigger compounds face a number of challenges and may cause adverse effects.
With “traceless triggers” such as light, ultrasound, magnetic fields, radio waves, electricity, and heat also facing issues, there is a “need for new switching modalities.”
The researchers therefore developed a music-inducible cellular control (MUSIC) system, which leverages the known intracellular calcium surge in response to music, via calcium-permeable mechanosensitive channels, to drive the release of biopharmaceuticals from vesicles.
They then generated MUSIC-controlled insulin-releasing cell lines, finding that, using a customized box containing off-the-shelf loudspeakers, they could induce channel activation and insulin release with 60 dB at 50 Hz, which is “within the safe range for the human ear.”
Further experiments revealed that insulin release was greatest at 50-100 Hz, and higher than that seen with potassium chloride, the “gold-standard” depolarization control for calcium channels.
The researchers then showed that with optimal stimulation at 50 Hz and 60 dB, channel activation and subsequent insulin release required at least 3 seconds of continuous music, “which might protect the cellular device from inadvertent activation during everyday activities.”
Next, they examined the impact of different musical genres on insulin release, finding that low-bass heavy popular music and movie soundtracks induced maximum release, while the responses were more diverse to classical and guitar-based music.
Specifically, “We Will Rock You,” by the British rock band Queen, induced the release of 70% of available insulin within 5 minutes and 100% within 15 minutes. This, the team notes, is “similar to the dynamics of glucose-triggered insulin release by human pancreatic islets.”
Exposing the cells to a second music session at different intervals revealed that full insulin refill was achieved within 4 hours, which “would be appropriate to attenuate glycemic excursions associated with typical dietary habits.”
Finally, the researchers tested the system in vivo, constructing a box with two off-the-shelf loudspeakers that focuses acoustic waves, via deflectors, onto the abdomens of mice with type 1 diabetes.
Exposing the mice, which had been implanted with microencapsulated MUSIC cells in the peritoneum, to low-bass acoustic waves at 60 dB (50 m/s2) for 15 minutes allowed them to achieve near wild-type levels of insulin in the blood and restored normoglycemia.
Moreover, “Queen’s song ‘We Will Rock You’ generated sufficient insulin to rapidly attenuate postprandial glycemic excursions during glucose tolerance tests,” the team says.
In contrast, animals without implants, or those that had implants but did not have music immersion, remained severely hyperglycemic, they add.
They also note that the effect was seen only when the sound waves “directly impinge on the skin just above the implantation site” for at least 15 minutes, with no increase in insulin release observed with commercially available headphones or ear plugs, such as Apple AirPods, or with loud environmental noises.
Consequently, “therapeutic MUSIC sessions would still be compatible with listening to other types of music or listening to all types of music via headphones,” the researchers write, and are “compatible with standard drug administration schemes.”
The study was supported by a European Research Council advanced grant and in part by the Swiss National Science Foundation NCCR Molecular Systems Engineering. One author acknowledges the support of the Chinese Scholarship Council.
No relevant financial relationships were declared.
A version of this article appeared on Medscape.com.
FROM THE LANCET DIABETES & ENDOCRINOLOGY
Erectile Dysfunction Rx: Give It a Shot
This transcript has been edited for clarity.
I’m Dr Rachel Rubin. I am a urologist with fellowship training in sexual medicine. Today I’m going to explain why I may recommend that your patients put a needle directly into their penises for help with erectile dysfunction (ED).
I know that sounds crazy, but in a recent video when I talked about erection hardness, I acknowledged that it may not be easy to talk with patients about their penises, but it’s important.
ED can be a marker for cardiovascular disease, with 50% of our 50-year-old patients having ED. As physicians, we must do a better job of talking to our patients about ED and letting them know that it’s a marker for overall health.
How do we treat ED? Primary care doctors can do a great deal for patients with ED, and there are other things that urologists can do when you run out of options in your own toolbox.
What’s important for a healthy erection? You need three things: healthy muscle, healthy nerves, and healthy arteries. If anything goes wrong with muscles, nerves, or arteries, this is what leads to ED. Think through the algorithm of your patient’s medical history: Do they have diabetes, which can affect their nerves? Do they have high blood pressure, which can affect their arteries? Do they have problems with testosterone, which can affect the smooth muscles of the penis? Understanding your patient’s history can be really helpful when you figure out what is the best treatment strategy for your patient.
For the penis to work, those smooth muscles have to relax; therefore, your brain has to be relaxed, along with your pelvic floor muscles. The smooth muscle of the penis has to be relaxed so it can fill with blood, increase in girth and size, and hold that erection in place.
To treat ED, we have a biopsychosocial toolbox. Biology refers to the muscles, arteries, and nerves. The psychosocial component is stress: If your brain is stressed, you have a lot of adrenaline around that can tighten those smooth muscles and cause you to lose an erection.
So, what are these treatments? I’ll start with lifestyle. A healthy heart means a healthy penis, so, all of the things you already recommend for lifestyle changes can really help with ED. Sleep is important. Does your patient need a sleep study? Do they have sleep apnea? Are they exercising? Recent data show that exercise may be just as effective, if not more effective, than Viagra. How about a good diet? The Mediterranean diet seems to be the most helpful. So, encourage your patients to make dietary, exercise, sleep, and other lifestyle changes if they want to improve erectile function.
What about sex education? Most physicians didn’t get great education about sex in medical school, but it’s very important to our patients who likewise have had inadequate sex education. Ask questions, talk to them, explain what is normal.
I can’t stress enough how important mental health is to a great sex life. Everyone would benefit from sex therapy and becoming better at sex. We need to get better at communicating and educating patients and their partners to maximize their quality of life. If you need to refer to a specialist, we recommend going to psychologytoday.com or aasect.org to find a local sex therapist. Call them and use them in your referral networks.
In the “bio” component of the biopsychosocial approach, we can do a lot to treat ED with medications and hormones. Testosterone has been shown to help with low libido and erectile function. Checking the patient’s testosterone level can be very helpful. Pills — we are familiar with Viagra, Cialis, Levitra, and Stendra. The oral PDE-5 inhibitors have been around since the late 1990s and they work quite well for many people with ED. Viagra and Cialis are generic now and patients can get them fairly inexpensively with discount coupons from GoodRx or Cost Plus Drugs. They may not even have to worry about insurance coverage.
Pills relax the smooth muscle of the penis so that it fills with blood and becomes erect, but they don’t work for everybody. If pills stop working, we often talk about synergistic treatments — combining pills and devices. Devices for ED should be discussed more often, and clinicians should consider prescribing them. We commonly discuss eyeglasses and wheelchairs, but we don’t talk about the sexual health devices that could help patients have more success and fun in the bedroom.
What are the various types of devices for ED? One common device is a vacuum pump, which can be very effective. This is how they work: The penis is lubricated and placed into the pump. A button on the pump creates suction that brings blood into the penis. The patient then applies a constriction band around the base of the penis to hold that erection in place.
“Sex tech” has really expanded to help patients with ED with devices that vibrate and hold the erection in place. Vibrating devices allow for a better orgasm. We even have devices that monitor erectile fitness (like a Fitbit for the penis), gathering data to help patients understand the firmness of their erections.
Devices are helpful adjuncts, but they don’t always do enough to achieve an erect penis that’s hard enough for penetration. In those cases, we can recommend injections that increase smooth muscle relaxation of the penis. I know it sounds crazy. If the muscles, arteries, and nerves of the penis aren’t functioning well, additional smooth muscle relaxation can be achieved by injecting alprostadil (prostaglandin E1) directly into the penis. It’s a tiny needle. It doesn’t hurt. These injections can be quite helpful for our patients, and we often recommend them.
But what happens when your patient doesn’t even respond to injections or any of the synergistic treatments? They’ve tried everything. Urologists may suggest a surgical option, the penile implant. Penile implants contain a pump inside the scrotum that fills with fluid, allowing a rigid erection. Penile implants are wonderful for patients who can no longer get erections. Talking to a urologist about the pros and the cons and the risks and benefits of surgically placed implants is very important.
Finally, ED is a marker for cardiovascular disease. These patients may need a cardiology workup. They need to improve their general health. We have to ask our patients about their goals and what they care about, and find a toolbox that makes sense for each patient and couple to maximize their sexual health and quality of life. Don’t give up. If you have questions, let us know.
Rachel S. Rubin, MD, is Assistant Clinical Professor, Department of Urology, Georgetown University, Washington, DC; Private practice, Rachel Rubin MD PLLC, North Bethesda, Maryland. She disclosed ties with Sprout, Maternal Medical, Absorption Pharmaceuticals, GSK, and Endo.
A version of this article appeared on Medscape.com.
This transcript has been edited for clarity.
I’m Dr Rachel Rubin. I am a urologist with fellowship training in sexual medicine. Today I’m going to explain why I may recommend that your patients put a needle directly into their penises for help with erectile dysfunction (ED).
I know that sounds crazy, but in a recent video when I talked about erection hardness, I acknowledged that it may not be easy to talk with patients about their penises, but it’s important.
ED can be a marker for cardiovascular disease, with 50% of our 50-year-old patients having ED. As physicians, we must do a better job of talking to our patients about ED and letting them know that it’s a marker for overall health.
How do we treat ED? Primary care doctors can do a great deal for patients with ED, and there are other things that urologists can do when you run out of options in your own toolbox.
What’s important for a healthy erection? You need three things: healthy muscle, healthy nerves, and healthy arteries. If anything goes wrong with muscles, nerves, or arteries, this is what leads to ED. Think through the algorithm of your patient’s medical history: Do they have diabetes, which can affect their nerves? Do they have high blood pressure, which can affect their arteries? Do they have problems with testosterone, which can affect the smooth muscles of the penis? Understanding your patient’s history can be really helpful when you figure out what is the best treatment strategy for your patient.
For the penis to work, those smooth muscles have to relax; therefore, your brain has to be relaxed, along with your pelvic floor muscles. The smooth muscle of the penis has to be relaxed so it can fill with blood, increase in girth and size, and hold that erection in place.
To treat ED, we have a biopsychosocial toolbox. Biology refers to the muscles, arteries, and nerves. The psychosocial component is stress: If your brain is stressed, you have a lot of adrenaline around that can tighten those smooth muscles and cause you to lose an erection.
So, what are these treatments? I’ll start with lifestyle. A healthy heart means a healthy penis, so, all of the things you already recommend for lifestyle changes can really help with ED. Sleep is important. Does your patient need a sleep study? Do they have sleep apnea? Are they exercising? Recent data show that exercise may be just as effective, if not more effective, than Viagra. How about a good diet? The Mediterranean diet seems to be the most helpful. So, encourage your patients to make dietary, exercise, sleep, and other lifestyle changes if they want to improve erectile function.
What about sex education? Most physicians didn’t get great education about sex in medical school, but it’s very important to our patients who likewise have had inadequate sex education. Ask questions, talk to them, explain what is normal.
I can’t stress enough how important mental health is to a great sex life. Everyone would benefit from sex therapy and becoming better at sex. We need to get better at communicating and educating patients and their partners to maximize their quality of life. If you need to refer to a specialist, we recommend going to psychologytoday.com or aasect.org to find a local sex therapist. Call them and use them in your referral networks.
In the “bio” component of the biopsychosocial approach, we can do a lot to treat ED with medications and hormones. Testosterone has been shown to help with low libido and erectile function. Checking the patient’s testosterone level can be very helpful. Pills — we are familiar with Viagra, Cialis, Levitra, and Stendra. The oral PDE-5 inhibitors have been around since the late 1990s and they work quite well for many people with ED. Viagra and Cialis are generic now and patients can get them fairly inexpensively with discount coupons from GoodRx or Cost Plus Drugs. They may not even have to worry about insurance coverage.
Pills relax the smooth muscle of the penis so that it fills with blood and becomes erect, but they don’t work for everybody. If pills stop working, we often talk about synergistic treatments — combining pills and devices. Devices for ED should be discussed more often, and clinicians should consider prescribing them. We commonly discuss eyeglasses and wheelchairs, but we don’t talk about the sexual health devices that could help patients have more success and fun in the bedroom.
What are the various types of devices for ED? One common device is a vacuum pump, which can be very effective. This is how they work: The penis is lubricated and placed into the pump. A button on the pump creates suction that brings blood into the penis. The patient then applies a constriction band around the base of the penis to hold that erection in place.
“Sex tech” has really expanded to help patients with ED with devices that vibrate and hold the erection in place. Vibrating devices allow for a better orgasm. We even have devices that monitor erectile fitness (like a Fitbit for the penis), gathering data to help patients understand the firmness of their erections.
Devices are helpful adjuncts, but they don’t always do enough to achieve an erect penis that’s hard enough for penetration. In those cases, we can recommend injections that increase smooth muscle relaxation of the penis. I know it sounds crazy. If the muscles, arteries, and nerves of the penis aren’t functioning well, additional smooth muscle relaxation can be achieved by injecting alprostadil (prostaglandin E1) directly into the penis. It’s a tiny needle. It doesn’t hurt. These injections can be quite helpful for our patients, and we often recommend them.
But what happens when your patient doesn’t even respond to injections or any of the synergistic treatments? They’ve tried everything. Urologists may suggest a surgical option, the penile implant. Penile implants contain a pump inside the scrotum that fills with fluid, allowing a rigid erection. Penile implants are wonderful for patients who can no longer get erections. Talking to a urologist about the pros and the cons and the risks and benefits of surgically placed implants is very important.
Finally, ED is a marker for cardiovascular disease. These patients may need a cardiology workup. They need to improve their general health. We have to ask our patients about their goals and what they care about, and find a toolbox that makes sense for each patient and couple to maximize their sexual health and quality of life. Don’t give up. If you have questions, let us know.
Rachel S. Rubin, MD, is Assistant Clinical Professor, Department of Urology, Georgetown University, Washington, DC; Private practice, Rachel Rubin MD PLLC, North Bethesda, Maryland. She disclosed ties with Sprout, Maternal Medical, Absorption Pharmaceuticals, GSK, and Endo.
A version of this article appeared on Medscape.com.
This transcript has been edited for clarity.
I’m Dr Rachel Rubin. I am a urologist with fellowship training in sexual medicine. Today I’m going to explain why I may recommend that your patients put a needle directly into their penises for help with erectile dysfunction (ED).
I know that sounds crazy, but in a recent video when I talked about erection hardness, I acknowledged that it may not be easy to talk with patients about their penises, but it’s important.
ED can be a marker for cardiovascular disease, with 50% of our 50-year-old patients having ED. As physicians, we must do a better job of talking to our patients about ED and letting them know that it’s a marker for overall health.
How do we treat ED? Primary care doctors can do a great deal for patients with ED, and there are other things that urologists can do when you run out of options in your own toolbox.
What’s important for a healthy erection? You need three things: healthy muscle, healthy nerves, and healthy arteries. If anything goes wrong with muscles, nerves, or arteries, this is what leads to ED. Think through the algorithm of your patient’s medical history: Do they have diabetes, which can affect their nerves? Do they have high blood pressure, which can affect their arteries? Do they have problems with testosterone, which can affect the smooth muscles of the penis? Understanding your patient’s history can be really helpful when you figure out what is the best treatment strategy for your patient.
For the penis to work, those smooth muscles have to relax; therefore, your brain has to be relaxed, along with your pelvic floor muscles. The smooth muscle of the penis has to be relaxed so it can fill with blood, increase in girth and size, and hold that erection in place.
To treat ED, we have a biopsychosocial toolbox. Biology refers to the muscles, arteries, and nerves. The psychosocial component is stress: If your brain is stressed, you have a lot of adrenaline around that can tighten those smooth muscles and cause you to lose an erection.
So, what are these treatments? I’ll start with lifestyle. A healthy heart means a healthy penis, so, all of the things you already recommend for lifestyle changes can really help with ED. Sleep is important. Does your patient need a sleep study? Do they have sleep apnea? Are they exercising? Recent data show that exercise may be just as effective, if not more effective, than Viagra. How about a good diet? The Mediterranean diet seems to be the most helpful. So, encourage your patients to make dietary, exercise, sleep, and other lifestyle changes if they want to improve erectile function.
What about sex education? Most physicians didn’t get great education about sex in medical school, but it’s very important to our patients who likewise have had inadequate sex education. Ask questions, talk to them, explain what is normal.
I can’t stress enough how important mental health is to a great sex life. Everyone would benefit from sex therapy and becoming better at sex. We need to get better at communicating and educating patients and their partners to maximize their quality of life. If you need to refer to a specialist, we recommend going to psychologytoday.com or aasect.org to find a local sex therapist. Call them and use them in your referral networks.
In the “bio” component of the biopsychosocial approach, we can do a lot to treat ED with medications and hormones. Testosterone has been shown to help with low libido and erectile function. Checking the patient’s testosterone level can be very helpful. Pills — we are familiar with Viagra, Cialis, Levitra, and Stendra. The oral PDE-5 inhibitors have been around since the late 1990s and they work quite well for many people with ED. Viagra and Cialis are generic now and patients can get them fairly inexpensively with discount coupons from GoodRx or Cost Plus Drugs. They may not even have to worry about insurance coverage.
Pills relax the smooth muscle of the penis so that it fills with blood and becomes erect, but they don’t work for everybody. If pills stop working, we often talk about synergistic treatments — combining pills and devices. Devices for ED should be discussed more often, and clinicians should consider prescribing them. We commonly discuss eyeglasses and wheelchairs, but we don’t talk about the sexual health devices that could help patients have more success and fun in the bedroom.
What are the various types of devices for ED? One common device is a vacuum pump, which can be very effective. This is how they work: The penis is lubricated and placed into the pump. A button on the pump creates suction that brings blood into the penis. The patient then applies a constriction band around the base of the penis to hold that erection in place.
“Sex tech” has really expanded to help patients with ED with devices that vibrate and hold the erection in place. Vibrating devices allow for a better orgasm. We even have devices that monitor erectile fitness (like a Fitbit for the penis), gathering data to help patients understand the firmness of their erections.
Devices are helpful adjuncts, but they don’t always do enough to achieve an erect penis that’s hard enough for penetration. In those cases, we can recommend injections that increase smooth muscle relaxation of the penis. I know it sounds crazy. If the muscles, arteries, and nerves of the penis aren’t functioning well, additional smooth muscle relaxation can be achieved by injecting alprostadil (prostaglandin E1) directly into the penis. It’s a tiny needle. It doesn’t hurt. These injections can be quite helpful for our patients, and we often recommend them.
But what happens when your patient doesn’t even respond to injections or any of the synergistic treatments? They’ve tried everything. Urologists may suggest a surgical option, the penile implant. Penile implants contain a pump inside the scrotum that fills with fluid, allowing a rigid erection. Penile implants are wonderful for patients who can no longer get erections. Talking to a urologist about the pros and the cons and the risks and benefits of surgically placed implants is very important.
Finally, ED is a marker for cardiovascular disease. These patients may need a cardiology workup. They need to improve their general health. We have to ask our patients about their goals and what they care about, and find a toolbox that makes sense for each patient and couple to maximize their sexual health and quality of life. Don’t give up. If you have questions, let us know.
Rachel S. Rubin, MD, is Assistant Clinical Professor, Department of Urology, Georgetown University, Washington, DC; Private practice, Rachel Rubin MD PLLC, North Bethesda, Maryland. She disclosed ties with Sprout, Maternal Medical, Absorption Pharmaceuticals, GSK, and Endo.
A version of this article appeared on Medscape.com.
Report: CKD Severity Linked to Thinning of Retina, Choroid Layers
Changes in tissue thickness in the back of the eye can correlate with worsening or improvement of renal problems and could help predict who will have worsening of kidney function, a new analysis report finds.
The research, published in the journal Nature Communications, is the first to show an association between chronic kidney disease (CKD) and the thickness of the retinal and choroidal layers in the back of the eye as measured by optical coherence tomography (OCT), a noninvasive imaging technology commonly used to evaluate eye diseases such as age-related macular degeneration (AMD), diabetic eye disease, and retinal detachments.
“These are common scans that people get at the opticians and now in many hospitals,” said Neeraj Dhaun, MD, PhD, a professor of nephrology at the University of Edinburgh, Scotland. (Opticians in the United Kingdom are the equivalent of optometrists in North America.)
CKD Severity Equals Thinner Retinas
“We scanned the back of eye of healthy people as well as patients with various types and degrees of kidney disease, and we found that two layers in the back of eye, the retina and the choroid, were thinner in patients with kidney disease compared to people who are healthy, and that the extent of this thinning predicts whether kidney function would decline going forward over a period of 2 or 3 years,” Dr. Dhaun, the corresponding author of the new paper, said.
The publication is a report of four different studies. The first study measured OCT metrics in 112 patients with CKD, 92 patients with a functional kidney transplant, and 86 control volunteers. The researchers found the retina was 5% thinner in patients with CKD than in healthy controls. They also found that patients with CKD had reduced macular volume: 8.44 ± .44 mm3 vs 8.73 ± .36 mm3 (P < .001). The choroid was also found to be thinner at each of three macular locations measured in patients with CKD vs control volunteers. At baseline, CKD and transplant patients had significantly lower estimated glomerular filtration rate (eGFR) at 55 ± 27 and 55 ± 24 mL/min/1.73 m2 compared with control volunteers at 97 ± 14 mL/min/1.73 m2.
The second study reported on OCT measurements and kidney histologic injury in 50 patients who had a kidney biopsy within 30 days of their OCT. It found that choroidal thinning at all three macular locations was independently associated with more extensive kidney scarring.
The third study focused on 25 patients with kidney failure who had a kidney transplant. Their eGFR improved from 8 ± 3 to 58 ± 21 mL/min/1.73 m2 in the first week after the transplant. The choroid in these patients thickened about 5% at 1 week and by about 10% at 1 month posttransplant. OCT of 22 kidney donors showed thickening of the choroid a week after nephrectomy before a tendency to thinning over the next year.
The fourth study found that for patients with stable CKD, every 1 mm3 decrease in macular volume correlated to an increased odds of a decline in eGFR by more than 10% at 1 year (2.48; 95% CI, 1.26-5.08; P = .01) and by more than 20% at 2 years (3.75; 95% CI, 1.26-5.08; P = .004).
Exploring the Kidney-Eye Connection
The potential explanation for the correlation between retinal and choroidal thickness and kidney function is unclear, Dr. Dhaun said.
“We don’t know the exact mechanisms, and these are difficult to define from studies in patients, which is why we are doing more work in animal models of kidney disease to see if we can establish the pathways that lead to the changes in the eye,” he said.
“However,” Dr. Dhaun added, “what we do know is that kidney disease affects the whole body. For example, kidney disease can lead to high blood pressure and heart disease, as well as diseases in the brain, and it is these effects of kidney disease on the body as whole that we are probably picking up in the back of the eye.”
OCT has the potential to make the monitoring of patients with CKD and kidney transplant more convenient than it is now, Dr. Dhaun said. “These scanners are available in the community, and what would be ideal at some point in the future is to be able to do a patient’s kidney health check in the community potentially incorporating OCT scanning alongside blood-pressure monitoring and other healthcare measures,” he said.
“The findings provide an exciting example of how noninvasive retinal imaging using OCT can provide quantitative biomarkers of systemic disease,” Amir Kashani, MD, PhD, the Boone Pickens Professor of Ophthalmology and Biomedical Engineering at the Wilmer Eye Institute of Johns Hopkins University in Baltimore, told this news organization. “It is striking that their findings demonstrate some potential of reversible changes in choroidal perfusion after kidney transplantation.”
The finding that choroidal thickness changes in CKD are at least partly reversible with kidney transplantation is a revelation, Dr. Kashani said, and may point to a greater role for ophthalmologists in managing systemic disease.
“Ophthalmologists can and should use their unique experience and understanding of the eye to help monitor and manage systemic conditions in collaboration with our medicine colleagues,” he said. “There are many systemic diseases that can impact the eye and ophthalmologist are uniquely positioned to help interpret those findings.”
Dr. Kashani noted that a particular strength of the report was the comparison of choroidal measurements in patients who had kidney transplantation and those that had a nephrectomy. “The consistent direction of changes in these two groups suggests the study findings are real and meaningful,” he said.
The study was independently supported. Dr. Dhaun and co-authors report no relevant financial relationships. Dr. Kashani disclosed a financial relationship with Carl Zeiss Meditec.
A version of this article first appeared on Medscape.com.
Changes in tissue thickness in the back of the eye can correlate with worsening or improvement of renal problems and could help predict who will have worsening of kidney function, a new analysis report finds.
The research, published in the journal Nature Communications, is the first to show an association between chronic kidney disease (CKD) and the thickness of the retinal and choroidal layers in the back of the eye as measured by optical coherence tomography (OCT), a noninvasive imaging technology commonly used to evaluate eye diseases such as age-related macular degeneration (AMD), diabetic eye disease, and retinal detachments.
“These are common scans that people get at the opticians and now in many hospitals,” said Neeraj Dhaun, MD, PhD, a professor of nephrology at the University of Edinburgh, Scotland. (Opticians in the United Kingdom are the equivalent of optometrists in North America.)
CKD Severity Equals Thinner Retinas
“We scanned the back of eye of healthy people as well as patients with various types and degrees of kidney disease, and we found that two layers in the back of eye, the retina and the choroid, were thinner in patients with kidney disease compared to people who are healthy, and that the extent of this thinning predicts whether kidney function would decline going forward over a period of 2 or 3 years,” Dr. Dhaun, the corresponding author of the new paper, said.
The publication is a report of four different studies. The first study measured OCT metrics in 112 patients with CKD, 92 patients with a functional kidney transplant, and 86 control volunteers. The researchers found the retina was 5% thinner in patients with CKD than in healthy controls. They also found that patients with CKD had reduced macular volume: 8.44 ± .44 mm3 vs 8.73 ± .36 mm3 (P < .001). The choroid was also found to be thinner at each of three macular locations measured in patients with CKD vs control volunteers. At baseline, CKD and transplant patients had significantly lower estimated glomerular filtration rate (eGFR) at 55 ± 27 and 55 ± 24 mL/min/1.73 m2 compared with control volunteers at 97 ± 14 mL/min/1.73 m2.
The second study reported on OCT measurements and kidney histologic injury in 50 patients who had a kidney biopsy within 30 days of their OCT. It found that choroidal thinning at all three macular locations was independently associated with more extensive kidney scarring.
The third study focused on 25 patients with kidney failure who had a kidney transplant. Their eGFR improved from 8 ± 3 to 58 ± 21 mL/min/1.73 m2 in the first week after the transplant. The choroid in these patients thickened about 5% at 1 week and by about 10% at 1 month posttransplant. OCT of 22 kidney donors showed thickening of the choroid a week after nephrectomy before a tendency to thinning over the next year.
The fourth study found that for patients with stable CKD, every 1 mm3 decrease in macular volume correlated to an increased odds of a decline in eGFR by more than 10% at 1 year (2.48; 95% CI, 1.26-5.08; P = .01) and by more than 20% at 2 years (3.75; 95% CI, 1.26-5.08; P = .004).
Exploring the Kidney-Eye Connection
The potential explanation for the correlation between retinal and choroidal thickness and kidney function is unclear, Dr. Dhaun said.
“We don’t know the exact mechanisms, and these are difficult to define from studies in patients, which is why we are doing more work in animal models of kidney disease to see if we can establish the pathways that lead to the changes in the eye,” he said.
“However,” Dr. Dhaun added, “what we do know is that kidney disease affects the whole body. For example, kidney disease can lead to high blood pressure and heart disease, as well as diseases in the brain, and it is these effects of kidney disease on the body as whole that we are probably picking up in the back of the eye.”
OCT has the potential to make the monitoring of patients with CKD and kidney transplant more convenient than it is now, Dr. Dhaun said. “These scanners are available in the community, and what would be ideal at some point in the future is to be able to do a patient’s kidney health check in the community potentially incorporating OCT scanning alongside blood-pressure monitoring and other healthcare measures,” he said.
“The findings provide an exciting example of how noninvasive retinal imaging using OCT can provide quantitative biomarkers of systemic disease,” Amir Kashani, MD, PhD, the Boone Pickens Professor of Ophthalmology and Biomedical Engineering at the Wilmer Eye Institute of Johns Hopkins University in Baltimore, told this news organization. “It is striking that their findings demonstrate some potential of reversible changes in choroidal perfusion after kidney transplantation.”
The finding that choroidal thickness changes in CKD are at least partly reversible with kidney transplantation is a revelation, Dr. Kashani said, and may point to a greater role for ophthalmologists in managing systemic disease.
“Ophthalmologists can and should use their unique experience and understanding of the eye to help monitor and manage systemic conditions in collaboration with our medicine colleagues,” he said. “There are many systemic diseases that can impact the eye and ophthalmologist are uniquely positioned to help interpret those findings.”
Dr. Kashani noted that a particular strength of the report was the comparison of choroidal measurements in patients who had kidney transplantation and those that had a nephrectomy. “The consistent direction of changes in these two groups suggests the study findings are real and meaningful,” he said.
The study was independently supported. Dr. Dhaun and co-authors report no relevant financial relationships. Dr. Kashani disclosed a financial relationship with Carl Zeiss Meditec.
A version of this article first appeared on Medscape.com.
Changes in tissue thickness in the back of the eye can correlate with worsening or improvement of renal problems and could help predict who will have worsening of kidney function, a new analysis report finds.
The research, published in the journal Nature Communications, is the first to show an association between chronic kidney disease (CKD) and the thickness of the retinal and choroidal layers in the back of the eye as measured by optical coherence tomography (OCT), a noninvasive imaging technology commonly used to evaluate eye diseases such as age-related macular degeneration (AMD), diabetic eye disease, and retinal detachments.
“These are common scans that people get at the opticians and now in many hospitals,” said Neeraj Dhaun, MD, PhD, a professor of nephrology at the University of Edinburgh, Scotland. (Opticians in the United Kingdom are the equivalent of optometrists in North America.)
CKD Severity Equals Thinner Retinas
“We scanned the back of eye of healthy people as well as patients with various types and degrees of kidney disease, and we found that two layers in the back of eye, the retina and the choroid, were thinner in patients with kidney disease compared to people who are healthy, and that the extent of this thinning predicts whether kidney function would decline going forward over a period of 2 or 3 years,” Dr. Dhaun, the corresponding author of the new paper, said.
The publication is a report of four different studies. The first study measured OCT metrics in 112 patients with CKD, 92 patients with a functional kidney transplant, and 86 control volunteers. The researchers found the retina was 5% thinner in patients with CKD than in healthy controls. They also found that patients with CKD had reduced macular volume: 8.44 ± .44 mm3 vs 8.73 ± .36 mm3 (P < .001). The choroid was also found to be thinner at each of three macular locations measured in patients with CKD vs control volunteers. At baseline, CKD and transplant patients had significantly lower estimated glomerular filtration rate (eGFR) at 55 ± 27 and 55 ± 24 mL/min/1.73 m2 compared with control volunteers at 97 ± 14 mL/min/1.73 m2.
The second study reported on OCT measurements and kidney histologic injury in 50 patients who had a kidney biopsy within 30 days of their OCT. It found that choroidal thinning at all three macular locations was independently associated with more extensive kidney scarring.
The third study focused on 25 patients with kidney failure who had a kidney transplant. Their eGFR improved from 8 ± 3 to 58 ± 21 mL/min/1.73 m2 in the first week after the transplant. The choroid in these patients thickened about 5% at 1 week and by about 10% at 1 month posttransplant. OCT of 22 kidney donors showed thickening of the choroid a week after nephrectomy before a tendency to thinning over the next year.
The fourth study found that for patients with stable CKD, every 1 mm3 decrease in macular volume correlated to an increased odds of a decline in eGFR by more than 10% at 1 year (2.48; 95% CI, 1.26-5.08; P = .01) and by more than 20% at 2 years (3.75; 95% CI, 1.26-5.08; P = .004).
Exploring the Kidney-Eye Connection
The potential explanation for the correlation between retinal and choroidal thickness and kidney function is unclear, Dr. Dhaun said.
“We don’t know the exact mechanisms, and these are difficult to define from studies in patients, which is why we are doing more work in animal models of kidney disease to see if we can establish the pathways that lead to the changes in the eye,” he said.
“However,” Dr. Dhaun added, “what we do know is that kidney disease affects the whole body. For example, kidney disease can lead to high blood pressure and heart disease, as well as diseases in the brain, and it is these effects of kidney disease on the body as whole that we are probably picking up in the back of the eye.”
OCT has the potential to make the monitoring of patients with CKD and kidney transplant more convenient than it is now, Dr. Dhaun said. “These scanners are available in the community, and what would be ideal at some point in the future is to be able to do a patient’s kidney health check in the community potentially incorporating OCT scanning alongside blood-pressure monitoring and other healthcare measures,” he said.
“The findings provide an exciting example of how noninvasive retinal imaging using OCT can provide quantitative biomarkers of systemic disease,” Amir Kashani, MD, PhD, the Boone Pickens Professor of Ophthalmology and Biomedical Engineering at the Wilmer Eye Institute of Johns Hopkins University in Baltimore, told this news organization. “It is striking that their findings demonstrate some potential of reversible changes in choroidal perfusion after kidney transplantation.”
The finding that choroidal thickness changes in CKD are at least partly reversible with kidney transplantation is a revelation, Dr. Kashani said, and may point to a greater role for ophthalmologists in managing systemic disease.
“Ophthalmologists can and should use their unique experience and understanding of the eye to help monitor and manage systemic conditions in collaboration with our medicine colleagues,” he said. “There are many systemic diseases that can impact the eye and ophthalmologist are uniquely positioned to help interpret those findings.”
Dr. Kashani noted that a particular strength of the report was the comparison of choroidal measurements in patients who had kidney transplantation and those that had a nephrectomy. “The consistent direction of changes in these two groups suggests the study findings are real and meaningful,” he said.
The study was independently supported. Dr. Dhaun and co-authors report no relevant financial relationships. Dr. Kashani disclosed a financial relationship with Carl Zeiss Meditec.
A version of this article first appeared on Medscape.com.
FROM NATURE COMMUNICATIONS