Type 2 Diabetes ICYMI

SAN DIEGO – A miracle of marsupial medicine is no more. Quincy the koala died in December, just months after becoming the first of his kind to be fitted with cutting-edge diabetes technology.

Courtesy San Diego Zoo

An endocrinologist is no longer checking his blood sugar levels on her smartphone a couple times a day, and zookeepers have stopped responding to glucose alerts by preparing tiny doses of insulin. But Quincy, the recipient of a continuous glucose monitor, has provided valuable insight that may benefit a variety of creatures beyond our furry, eucalyptus-eating cousins.

“Through this experience, I am hopeful that we’ll be able to offer better treatment in the future for any animals that are found to have diabetes,” the endocrinologist, Athena Philis-Tsimikas, MD, of Scripps Whittier Diabetes Institute, said in an interview.

And, she added, the experience of working with Quincy “provided an indication of where remote management of diabetes is going for the future, whether this is humans or animals.”

Quincy, a Queensland koala, reportedly died at the San Diego Zoo on Dec. 13 of pneumonia at the age of about 3 years. (Koalas can live into their teens.)

It’s not clear if his death was related to his diabetes. Dr. Philis-Tsimikas said. “Although infection can worsen with poor glucose control, my understanding from the veterinarian was that his diabetes had stabilized and was being successfully treated with a small dose of daily basal insulin,” she said. “He was not having wide fluctuations in glucose control, and the CGM had been removed to make it easier for him to get around his enclosures.”


Nine months before his death, Quincy was diagnosed with type 1 diabetes and transferred from the Los Angeles Zoo for medical reasons. Last June, after veterinarians consulted with Dr. Philis-Tsimikas, Quincy underwent an operation to fit him with a CGM so zookeepers could avoid having to wake him multiple times a day for skin pricks.

Koalas are among many species that can develop the equivalent of human diabetes. Dogs, cats, pigs, apes, horses, and even dolphins can become diabetic.

“The providers and caretakers could all respond with appropriate interventions based on the real-time readings. Improved treatment decisions were made despite not having any verbal communication,” Dr. Philis-Tsimikas said.

“I found it amazing that the CGM device could be placed on such a small body with very little subcutaneous fat,” she said. “It stayed in place and functioned successfully despite movement of the koala around his enclosure.”

In light of his small body and lack of body fat, could Quincy’s experience offer insight into the use of CGM technology in fragile humans such as babies and the elderly? Absolutely, Dr. Philis-Tsimikas said, noting that babies have been diagnosed with diabetes at as young as 9 months.

She said Quincy’s story, which got extensive media attention, provided another benefit. “His story was very relatable to many people with newly diagnosed type 1 diabetes and how difficult it can be to manage the highs and lows,” she said. “Quincy helped show us how this could be addressed with the new technology of a CGM and new types of basal insulin and pens that deliver half units.”

Dr. Philis-Tsimikas reports that her center conducts research with Dexcom and Novo Nordisk.

SAN DIEGO – A miracle of marsupial medicine is no more. Quincy the koala died in December, just months after becoming the first of his kind to be fitted with cutting-edge diabetes technology.

Courtesy San Diego Zoo

An endocrinologist is no longer checking his blood sugar levels on her smartphone a couple times a day, and zookeepers have stopped responding to glucose alerts by preparing tiny doses of insulin. But Quincy, the recipient of a continuous glucose monitor, has provided valuable insight that may benefit a variety of creatures beyond our furry, eucalyptus-eating cousins.

“Through this experience, I am hopeful that we’ll be able to offer better treatment in the future for any animals that are found to have diabetes,” the endocrinologist, Athena Philis-Tsimikas, MD, of Scripps Whittier Diabetes Institute, said in an interview.

And, she added, the experience of working with Quincy “provided an indication of where remote management of diabetes is going for the future, whether this is humans or animals.”

Quincy, a Queensland koala, reportedly died at the San Diego Zoo on Dec. 13 of pneumonia at the age of about 3 years. (Koalas can live into their teens.)

It’s not clear if his death was related to his diabetes. Dr. Philis-Tsimikas said. “Although infection can worsen with poor glucose control, my understanding from the veterinarian was that his diabetes had stabilized and was being successfully treated with a small dose of daily basal insulin,” she said. “He was not having wide fluctuations in glucose control, and the CGM had been removed to make it easier for him to get around his enclosures.”


Nine months before his death, Quincy was diagnosed with type 1 diabetes and transferred from the Los Angeles Zoo for medical reasons. Last June, after veterinarians consulted with Dr. Philis-Tsimikas, Quincy underwent an operation to fit him with a CGM so zookeepers could avoid having to wake him multiple times a day for skin pricks.

Koalas are among many species that can develop the equivalent of human diabetes. Dogs, cats, pigs, apes, horses, and even dolphins can become diabetic.

“The providers and caretakers could all respond with appropriate interventions based on the real-time readings. Improved treatment decisions were made despite not having any verbal communication,” Dr. Philis-Tsimikas said.

“I found it amazing that the CGM device could be placed on such a small body with very little subcutaneous fat,” she said. “It stayed in place and functioned successfully despite movement of the koala around his enclosure.”

In light of his small body and lack of body fat, could Quincy’s experience offer insight into the use of CGM technology in fragile humans such as babies and the elderly? Absolutely, Dr. Philis-Tsimikas said, noting that babies have been diagnosed with diabetes at as young as 9 months.

She said Quincy’s story, which got extensive media attention, provided another benefit. “His story was very relatable to many people with newly diagnosed type 1 diabetes and how difficult it can be to manage the highs and lows,” she said. “Quincy helped show us how this could be addressed with the new technology of a CGM and new types of basal insulin and pens that deliver half units.”

Dr. Philis-Tsimikas reports that her center conducts research with Dexcom and Novo Nordisk.

SAN DIEGO – A miracle of marsupial medicine is no more. Quincy the koala died in December, just months after becoming the first of his kind to be fitted with cutting-edge diabetes technology.

Courtesy San Diego Zoo

An endocrinologist is no longer checking his blood sugar levels on her smartphone a couple times a day, and zookeepers have stopped responding to glucose alerts by preparing tiny doses of insulin. But Quincy, the recipient of a continuous glucose monitor, has provided valuable insight that may benefit a variety of creatures beyond our furry, eucalyptus-eating cousins.

“Through this experience, I am hopeful that we’ll be able to offer better treatment in the future for any animals that are found to have diabetes,” the endocrinologist, Athena Philis-Tsimikas, MD, of Scripps Whittier Diabetes Institute, said in an interview.

And, she added, the experience of working with Quincy “provided an indication of where remote management of diabetes is going for the future, whether this is humans or animals.”

Quincy, a Queensland koala, reportedly died at the San Diego Zoo on Dec. 13 of pneumonia at the age of about 3 years. (Koalas can live into their teens.)

It’s not clear if his death was related to his diabetes. Dr. Philis-Tsimikas said. “Although infection can worsen with poor glucose control, my understanding from the veterinarian was that his diabetes had stabilized and was being successfully treated with a small dose of daily basal insulin,” she said. “He was not having wide fluctuations in glucose control, and the CGM had been removed to make it easier for him to get around his enclosures.”


Nine months before his death, Quincy was diagnosed with type 1 diabetes and transferred from the Los Angeles Zoo for medical reasons. Last June, after veterinarians consulted with Dr. Philis-Tsimikas, Quincy underwent an operation to fit him with a CGM so zookeepers could avoid having to wake him multiple times a day for skin pricks.

Koalas are among many species that can develop the equivalent of human diabetes. Dogs, cats, pigs, apes, horses, and even dolphins can become diabetic.

“The providers and caretakers could all respond with appropriate interventions based on the real-time readings. Improved treatment decisions were made despite not having any verbal communication,” Dr. Philis-Tsimikas said.

“I found it amazing that the CGM device could be placed on such a small body with very little subcutaneous fat,” she said. “It stayed in place and functioned successfully despite movement of the koala around his enclosure.”

In light of his small body and lack of body fat, could Quincy’s experience offer insight into the use of CGM technology in fragile humans such as babies and the elderly? Absolutely, Dr. Philis-Tsimikas said, noting that babies have been diagnosed with diabetes at as young as 9 months.

She said Quincy’s story, which got extensive media attention, provided another benefit. “His story was very relatable to many people with newly diagnosed type 1 diabetes and how difficult it can be to manage the highs and lows,” she said. “Quincy helped show us how this could be addressed with the new technology of a CGM and new types of basal insulin and pens that deliver half units.”

Dr. Philis-Tsimikas reports that her center conducts research with Dexcom and Novo Nordisk.

Patients with hypertension who show substantial progression of cerebral small vessel disease have a sixfold higher odds of developing mild cognitive impairment compared with similar patients who do not have signs of progression. Also today, antidepressants are tied to greater hip fracture incidence, a hospital readmission reduction program may be doing more harm than good, and the flu season rages on with 19 states showing high activity in the final week of 2018.

Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
 

Patients with hypertension who show substantial progression of cerebral small vessel disease have a sixfold higher odds of developing mild cognitive impairment compared with similar patients who do not have signs of progression. Also today, antidepressants are tied to greater hip fracture incidence, a hospital readmission reduction program may be doing more harm than good, and the flu season rages on with 19 states showing high activity in the final week of 2018.

Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
 

Patients with hypertension who show substantial progression of cerebral small vessel disease have a sixfold higher odds of developing mild cognitive impairment compared with similar patients who do not have signs of progression. Also today, antidepressants are tied to greater hip fracture incidence, a hospital readmission reduction program may be doing more harm than good, and the flu season rages on with 19 states showing high activity in the final week of 2018.

Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
 

LOS ANGELES – New ways to preserve beta cell function in youth with impaired glucose tolerance or recently diagnosed type 2 diabetes mellitus are needed, because neither metformin alone nor metformin plus glargine are making a dent.

Doug Brunk/MDedge News

At the same time, the SEARCH for Diabetes in Youth trial showed that the incidence of T2DM in U.S. youth continues to rise, especially among Native Americans and non-Hispanic blacks (P less than .001 for both associations; N Engl J Med. 2017;376:1419-29). In addition, the earlier Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study showed that rapid treatment failure in youth-onset T2DM was associated with loss of beta cell function (N Engl J Med. 2012;366:2247-56).

“Early treatment of youth with impaired glucose tolerance or type 2 diabetes may require other medications alone or in combination or for longer periods of time to combat the severe insulin resistance of puberty and arrest progressive loss of beta cell function,” Sonia Caprio, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease.

She based her remarks on a review of the recently completed multicenter Restoring Insulin Secretion (RISE) Pediatric Medication Study, (Diabetes Care 2018;41[8]:1717-25). It set out to answer the following question: In adolescents with impaired glucose tolerance or recently diagnosed T2DM, can beta cell function be preserved or improved during 12 months of active treatment and maintained for 3 months following the withdrawal of therapy?

To find out, Dr. Caprio, a pediatric endocrinologist at Yale University, New Haven, Conn., and her colleagues enrolled 91 youth who were randomized to one of two treatment arms: metformin alone titrated over 4 weeks from 500 mg/day to a 1,000 mg twice daily dose (modified if necessary due to GI symptoms), or to glargine followed by metformin. This group received once-daily insulin glargine, titrated twice weekly over 1 month based on daily self-monitoring of blood glucose to a goal of 80-90 mg/dL. Glargine was discontinued after 3 months and metformin was titrated. Beta-cell function (insulin sensitivity paired with beta-cell responses) was assessed by the two-step hyperglycemic clamp at baseline, 12 months (on treatment), and 15 months (3 months off treatment). All clinical data were collected 3 months after discontinuation of active treatment.

Dr. Caprio described the two-step hyperglycemic clamp as “a robust approach to quantification of insulin sensitivity and beta-cell responses to both glucose and the nonglucose secretagogue arginine. It provides mechanistic insights into how the tested interventions affected two key metabolic defects of type 2 diabetes: insulin sensitivity and beta cell responses.”

The mean age of patients was 14 years, 71% were female, their mean body mass index was 37 kg/m². The researchers observed no significant differences between treatment groups at baseline, 12 months, or 15 months in beta cell function, BMI percentile, hemoglobin A_1c, fasting glucose, or oral glucose tolerance test 2-hour glucose results. In both treatment groups, clamp-measured beta cell function was significantly lower at 12 and 15 months, compared with baseline. HbA_1c fell transiently at 6 months within both groups. BMI was higher in the glargine followed by metformin versus metformin alone group between 3 and 9 months. Only 5% of participants discontinued the interventions, and both treatments were well tolerated.

“These findings are discouraging,” Dr. Caprio said. “They contrast with previous studies in adults showing an improvement in beta cell function with metformin or insulin for type 2 diabetes prevention and treatment.” Results of the RISE Pediatric Medication Study “call for further studies to better understand the physiology underlying beta cell dysfunction in youth to identify effective treatment options. Better approaches to prevent and treat obesity in youth are critically needed.”

Dr. Caprio reported having no disclosures.

[email protected]

LOS ANGELES – New ways to preserve beta cell function in youth with impaired glucose tolerance or recently diagnosed type 2 diabetes mellitus are needed, because neither metformin alone nor metformin plus glargine are making a dent.

Doug Brunk/MDedge News

At the same time, the SEARCH for Diabetes in Youth trial showed that the incidence of T2DM in U.S. youth continues to rise, especially among Native Americans and non-Hispanic blacks (P less than .001 for both associations; N Engl J Med. 2017;376:1419-29). In addition, the earlier Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study showed that rapid treatment failure in youth-onset T2DM was associated with loss of beta cell function (N Engl J Med. 2012;366:2247-56).

“Early treatment of youth with impaired glucose tolerance or type 2 diabetes may require other medications alone or in combination or for longer periods of time to combat the severe insulin resistance of puberty and arrest progressive loss of beta cell function,” Sonia Caprio, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease.

She based her remarks on a review of the recently completed multicenter Restoring Insulin Secretion (RISE) Pediatric Medication Study, (Diabetes Care 2018;41[8]:1717-25). It set out to answer the following question: In adolescents with impaired glucose tolerance or recently diagnosed T2DM, can beta cell function be preserved or improved during 12 months of active treatment and maintained for 3 months following the withdrawal of therapy?

To find out, Dr. Caprio, a pediatric endocrinologist at Yale University, New Haven, Conn., and her colleagues enrolled 91 youth who were randomized to one of two treatment arms: metformin alone titrated over 4 weeks from 500 mg/day to a 1,000 mg twice daily dose (modified if necessary due to GI symptoms), or to glargine followed by metformin. This group received once-daily insulin glargine, titrated twice weekly over 1 month based on daily self-monitoring of blood glucose to a goal of 80-90 mg/dL. Glargine was discontinued after 3 months and metformin was titrated. Beta-cell function (insulin sensitivity paired with beta-cell responses) was assessed by the two-step hyperglycemic clamp at baseline, 12 months (on treatment), and 15 months (3 months off treatment). All clinical data were collected 3 months after discontinuation of active treatment.

Dr. Caprio described the two-step hyperglycemic clamp as “a robust approach to quantification of insulin sensitivity and beta-cell responses to both glucose and the nonglucose secretagogue arginine. It provides mechanistic insights into how the tested interventions affected two key metabolic defects of type 2 diabetes: insulin sensitivity and beta cell responses.”

The mean age of patients was 14 years, 71% were female, their mean body mass index was 37 kg/m². The researchers observed no significant differences between treatment groups at baseline, 12 months, or 15 months in beta cell function, BMI percentile, hemoglobin A_1c, fasting glucose, or oral glucose tolerance test 2-hour glucose results. In both treatment groups, clamp-measured beta cell function was significantly lower at 12 and 15 months, compared with baseline. HbA_1c fell transiently at 6 months within both groups. BMI was higher in the glargine followed by metformin versus metformin alone group between 3 and 9 months. Only 5% of participants discontinued the interventions, and both treatments were well tolerated.

“These findings are discouraging,” Dr. Caprio said. “They contrast with previous studies in adults showing an improvement in beta cell function with metformin or insulin for type 2 diabetes prevention and treatment.” Results of the RISE Pediatric Medication Study “call for further studies to better understand the physiology underlying beta cell dysfunction in youth to identify effective treatment options. Better approaches to prevent and treat obesity in youth are critically needed.”

Dr. Caprio reported having no disclosures.

[email protected]

LOS ANGELES – New ways to preserve beta cell function in youth with impaired glucose tolerance or recently diagnosed type 2 diabetes mellitus are needed, because neither metformin alone nor metformin plus glargine are making a dent.

Doug Brunk/MDedge News

At the same time, the SEARCH for Diabetes in Youth trial showed that the incidence of T2DM in U.S. youth continues to rise, especially among Native Americans and non-Hispanic blacks (P less than .001 for both associations; N Engl J Med. 2017;376:1419-29). In addition, the earlier Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study showed that rapid treatment failure in youth-onset T2DM was associated with loss of beta cell function (N Engl J Med. 2012;366:2247-56).

“Early treatment of youth with impaired glucose tolerance or type 2 diabetes may require other medications alone or in combination or for longer periods of time to combat the severe insulin resistance of puberty and arrest progressive loss of beta cell function,” Sonia Caprio, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease.

She based her remarks on a review of the recently completed multicenter Restoring Insulin Secretion (RISE) Pediatric Medication Study, (Diabetes Care 2018;41[8]:1717-25). It set out to answer the following question: In adolescents with impaired glucose tolerance or recently diagnosed T2DM, can beta cell function be preserved or improved during 12 months of active treatment and maintained for 3 months following the withdrawal of therapy?

To find out, Dr. Caprio, a pediatric endocrinologist at Yale University, New Haven, Conn., and her colleagues enrolled 91 youth who were randomized to one of two treatment arms: metformin alone titrated over 4 weeks from 500 mg/day to a 1,000 mg twice daily dose (modified if necessary due to GI symptoms), or to glargine followed by metformin. This group received once-daily insulin glargine, titrated twice weekly over 1 month based on daily self-monitoring of blood glucose to a goal of 80-90 mg/dL. Glargine was discontinued after 3 months and metformin was titrated. Beta-cell function (insulin sensitivity paired with beta-cell responses) was assessed by the two-step hyperglycemic clamp at baseline, 12 months (on treatment), and 15 months (3 months off treatment). All clinical data were collected 3 months after discontinuation of active treatment.

Dr. Caprio described the two-step hyperglycemic clamp as “a robust approach to quantification of insulin sensitivity and beta-cell responses to both glucose and the nonglucose secretagogue arginine. It provides mechanistic insights into how the tested interventions affected two key metabolic defects of type 2 diabetes: insulin sensitivity and beta cell responses.”

The mean age of patients was 14 years, 71% were female, their mean body mass index was 37 kg/m². The researchers observed no significant differences between treatment groups at baseline, 12 months, or 15 months in beta cell function, BMI percentile, hemoglobin A_1c, fasting glucose, or oral glucose tolerance test 2-hour glucose results. In both treatment groups, clamp-measured beta cell function was significantly lower at 12 and 15 months, compared with baseline. HbA_1c fell transiently at 6 months within both groups. BMI was higher in the glargine followed by metformin versus metformin alone group between 3 and 9 months. Only 5% of participants discontinued the interventions, and both treatments were well tolerated.

“These findings are discouraging,” Dr. Caprio said. “They contrast with previous studies in adults showing an improvement in beta cell function with metformin or insulin for type 2 diabetes prevention and treatment.” Results of the RISE Pediatric Medication Study “call for further studies to better understand the physiology underlying beta cell dysfunction in youth to identify effective treatment options. Better approaches to prevent and treat obesity in youth are critically needed.”

Dr. Caprio reported having no disclosures.

[email protected]

Most patients should receive it, with exceptions as noted below. Metformin is the cornerstone of diabetes therapy and should be considered in all patients with type 2 diabetes. Both the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (AACE)^1,2 recommend it as first-line treatment for type 2 diabetes. It lowers blood glucose levels by inhibiting hepatic glucose production, and it does not tend to cause hypoglycemia.

However, metformin is underused. A 2012 study showed that only 50% to 70% of patients with type 2 diabetes treated with a sulfonylurea, dipeptidyl peptidase-4 (DPP-4) inhibitor, thiazolidinedione, or glucagon-like peptide-1 analogue also received metformin.³ This occurred despite guidelines recommending continuing metformin when starting other diabetes drugs.⁴

EVIDENCE METFORMIN IS EFFECTIVE

The United Kingdom Prospective Diabetes Study (UKPDS)⁵ found that metformin significantly reduced the incidence of:

• Any diabetes-related end point (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.53–0.87)
• Myocardial infarction (HR 0.61, 95% CI 0.41–0.89)
• Diabetes-related death (HR 0.58, 95% CI 0.37–0.91)
• All-cause mortality (HR 0.64; 95% CI 0.45–0.91).

The Hyperinsulinemia: Outcomes of Its Metabolic Effects (HOME) trial,⁶ a multicenter trial conducted in the Netherlands, evaluated the effect of adding  metformin (vs placebo) to existing insulin regimens. Metformin recipients had a significantly lower rate of macrovascular mortality (HR 0.61, 95% CI 0.40–0.94, P = .02), but not of the primary end point, an aggregate of microvascular and macrovascular morbidity and mortality.

The Study on the Prognosis and Effect of Antidiabetic Drugs on Type 2 Diabetes Mellitus With Coronary Artery Disease trial,⁷ a multicenter trial conducted in China, compared the effects of metformin vs glipizide on cardiovascular outcomes. At about 3 years of treatment, the metformin group had a significantly lower rate of the composite primary end point of recurrent cardiovascular events (HR 0.54, 95% CI 0.30–0.90). This end point included nonfatal myocardial infarction, nonfatal stroke, arterial revascularization by percutaneous transluminal coronary angioplasty or by coronary artery bypass graft, death from a cardiovascular cause, and death from any cause.

These studies prompted the ADA to emphasize that metformin can reduce the risk of cardiovascular events or death. Metformin also has been shown to be weight-neutral or to induce slight weight loss. Furthermore, it is inexpensive.

WHAT ABOUT THE RENAL EFFECTS?

Because metformin is renally cleared, it has caused some concern about nephrotoxicity, especially lactic acidosis, in patients with impaired renal function. But the most recent guidelines have relaxed the criteria for metformin use in this patient population.

Revised labeling

Metformin’s labeling,⁸ revised in 2016, states the following:

• If the estimated glomerular filtration rate (eGFR) is below 30 mL/min/1.73 m², metformin is contraindicated
• If the eGFR is between 30 and 45 mL/min/1.73 m², metformin is not recommended
• If the eGFR is below 45 mL/min/1.73 m² in a patient taking metformin, the risks and benefits of continuing treatment should be assessed, the dosage may need to be adjusted, and renal function should be monitored more frequently.⁸

These labeling revisions were based on a systematic review by Inzucchi et al⁹ that found metformin is not associated with increased rates of lactic acidosis in patients with mild to moderate kidney disease. Subsequently, an observational study published in 2018 by Lazarus et al¹⁰ showed that metformin increases the risk of acidosis only at eGFR levels below 30 mL/min/1.73 m². Also, a Cochrane review published in 2003 did not find a single case of lactic acidosis in 347 trials with 70,490 patient-years of metformin treatment.¹¹

Previous guidelines used serum creatinine levels, with metformin contraindicated at levels of 1.5 mg/dL or above for men and 1.4 mg/dL for women, or with abnormal creatinine clearance. The ADA and the AACE now use the eGFR^1,2 instead of the serum creatinine level to measure kidney function because it better accounts for factors such as the patient’s age, sex, race, and weight.

Despite the evidence, the common patient perception is that metformin is nephrotoxic, and it is important for practitioners to dispel this myth during clinic visits.

What about metformin use with contrast agents?

Labeling has a precautionary note stating that metformin should be held at the time of, or prior to, any imaging procedure involving iodinated contrast agents in patients with an eGFR between 30 and 60 mL/min/1.73 m²; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will receive intra-arterial iodinated contrast. The eGFR should be reevaluated 48 hours after the imaging procedure.⁸

Additionally, if the iodinated contrast agent causes acute kidney injury, metformin could accumulate, with resultant lactate accumulation.

The American College of Radiology (ACR) has proposed less stringent guidelines for metformin during radiocontrast imaging studies. This change is based on evidence that lactic acidosis is rare­—about 10 cases per 100,000 patient-years—and that there are no reports of lactic acidosis after intravenously administered iodinated contrast in properly selected patients.^12,13

The ACR divides patients taking metformin into 2 categories:

• No evidence of acute kidney injury and eGFR greater than 30 mL/min/1.73 m²
• Either acute kidney injury or chronic kidney disease with eGFR below 30 mL/min/1.73 m² or undergoing arterial catheter studies with a high chance of embolization to the renal arteries.¹⁴

For the first group, they recommend against discontinuing metformin before or after giving iodinated contrast or checking kidney function after the procedure.

For the second group, they recommend holding metformin before and 48 hours after the procedure. It should not be restarted until renal function is confirmed to be normal.

The ADA recommends¹ continuing metformin after initiating insulin. However, in clinical practice, it is often not done.

Clinical trials have shown that combining metformin with insulin significantly improves glycemic control, prevents weight gain, and decreases insulin requirements.^15,16 One trial¹⁶ also looked at cardiovascular end points during a 4-year follow-up period;  combining metformin with insulin decreased the macrovascular disease-related event rate compared with insulin alone.

In the HOME trial,⁶ which added metformin to the existing insulin regimen, both groups gained weight, but the metformin group had gained about 3 kg less than the placebo group at the end of the 4.3-year trial. Metformin did not increase the risk of hypoglycemia, but it also did not reduce the risk of microvascular disease.

Concomitant metformin reduces costs

These days, practitioners can choose from a large selection of diabetes drugs. These include insulins with better pharmacokinetic profiles, as well as newer classes of noninsulin agents such as sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 analogues.

Metformin is less expensive than these newer drugs, and using it concomitantly with other diabetes drugs can decrease their dosage requirements, which in turn decreases their monthly costs.

GASTROINTESTINAL EFFECTS

Metformin’s gastrointestinal adverse effects such as diarrhea, flatulence, nausea, and vomiting are a barrier to its use. The actual incidence rate of diarrhea varies widely in randomized trials and observational studies, and gastrointestinal effects are worse in metformin-naive patients, as well as those who have chronic gastritis or Helicobacter pylori infection.¹⁷

We have found that starting metformin at a low dose and up-titrating it over several weeks increases tolerability. We often start patients at 500 mg/day and increase the dosage by 1 500-mg tablet every 1 to 2 weeks. Also, we have noticed that intolerance is more likely in patients who eat a high-carbohydrate diet, but there is no high-level evidence to back this up because patients in clinical trials all undergo nutrition counseling and are therefore more likely to adhere to the low-carbohydrate diet.

Also, the extended-release formulation is more tolerable than the immediate-release formulation and has similar glycemic efficacy. It may be an option as first-line therapy or for patients who have significant adverse effects from immediate-release metformin.¹⁸ For patients on the immediate-release formulation, taking it with meals helps lessen some gastrointestinal effects, and this should be emphasized at every visit.

Finally, we limit the metformin dose to 2,000 mg/day, rather than the 2,550 mg/day allowed on labeling. Garber et al¹⁹ found that the lower dosage still provides the maximum clinical efficacy.

OTHER CAUTIONS

Metformin should be avoided in patients with acute or unstable heart failure because of the increased risk of lactic acidosis.

It also should be avoided in patients with hepatic impairment, according to the labeling. But this remains controversial in practice. Zhang et al²⁰ showed that continuing metformin in patients with diabetes and cirrhosis decreases the mortality risk by 57% compared with those taken off metformin.

Diet and lifestyle measures need to be emphasized at each visit. Wing et al²¹ showed that calorie restriction regardless of weight loss is beneficial for glycemic control and insulin sensitivity in obese patients with diabetes.

TAKE-HOME POINTS

Metformin improves glycemic control without tending to cause weight gain or hypoglycemia. It may also have cardiovascular benefits. Metformin is an inexpensive agent that should be continued, if tolerated, in those who need additional agents for glycemic control. It should be considered in all adult patients with type 2 diabetes.   

Most patients should receive it, with exceptions as noted below. Metformin is the cornerstone of diabetes therapy and should be considered in all patients with type 2 diabetes. Both the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (AACE)^1,2 recommend it as first-line treatment for type 2 diabetes. It lowers blood glucose levels by inhibiting hepatic glucose production, and it does not tend to cause hypoglycemia.

However, metformin is underused. A 2012 study showed that only 50% to 70% of patients with type 2 diabetes treated with a sulfonylurea, dipeptidyl peptidase-4 (DPP-4) inhibitor, thiazolidinedione, or glucagon-like peptide-1 analogue also received metformin.³ This occurred despite guidelines recommending continuing metformin when starting other diabetes drugs.⁴

EVIDENCE METFORMIN IS EFFECTIVE

The United Kingdom Prospective Diabetes Study (UKPDS)⁵ found that metformin significantly reduced the incidence of:

• Any diabetes-related end point (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.53–0.87)
• Myocardial infarction (HR 0.61, 95% CI 0.41–0.89)
• Diabetes-related death (HR 0.58, 95% CI 0.37–0.91)
• All-cause mortality (HR 0.64; 95% CI 0.45–0.91).

The Hyperinsulinemia: Outcomes of Its Metabolic Effects (HOME) trial,⁶ a multicenter trial conducted in the Netherlands, evaluated the effect of adding  metformin (vs placebo) to existing insulin regimens. Metformin recipients had a significantly lower rate of macrovascular mortality (HR 0.61, 95% CI 0.40–0.94, P = .02), but not of the primary end point, an aggregate of microvascular and macrovascular morbidity and mortality.

The Study on the Prognosis and Effect of Antidiabetic Drugs on Type 2 Diabetes Mellitus With Coronary Artery Disease trial,⁷ a multicenter trial conducted in China, compared the effects of metformin vs glipizide on cardiovascular outcomes. At about 3 years of treatment, the metformin group had a significantly lower rate of the composite primary end point of recurrent cardiovascular events (HR 0.54, 95% CI 0.30–0.90). This end point included nonfatal myocardial infarction, nonfatal stroke, arterial revascularization by percutaneous transluminal coronary angioplasty or by coronary artery bypass graft, death from a cardiovascular cause, and death from any cause.

These studies prompted the ADA to emphasize that metformin can reduce the risk of cardiovascular events or death. Metformin also has been shown to be weight-neutral or to induce slight weight loss. Furthermore, it is inexpensive.

WHAT ABOUT THE RENAL EFFECTS?

Because metformin is renally cleared, it has caused some concern about nephrotoxicity, especially lactic acidosis, in patients with impaired renal function. But the most recent guidelines have relaxed the criteria for metformin use in this patient population.

Revised labeling

Metformin’s labeling,⁸ revised in 2016, states the following:

• If the estimated glomerular filtration rate (eGFR) is below 30 mL/min/1.73 m², metformin is contraindicated
• If the eGFR is between 30 and 45 mL/min/1.73 m², metformin is not recommended
• If the eGFR is below 45 mL/min/1.73 m² in a patient taking metformin, the risks and benefits of continuing treatment should be assessed, the dosage may need to be adjusted, and renal function should be monitored more frequently.⁸

These labeling revisions were based on a systematic review by Inzucchi et al⁹ that found metformin is not associated with increased rates of lactic acidosis in patients with mild to moderate kidney disease. Subsequently, an observational study published in 2018 by Lazarus et al¹⁰ showed that metformin increases the risk of acidosis only at eGFR levels below 30 mL/min/1.73 m². Also, a Cochrane review published in 2003 did not find a single case of lactic acidosis in 347 trials with 70,490 patient-years of metformin treatment.¹¹

Previous guidelines used serum creatinine levels, with metformin contraindicated at levels of 1.5 mg/dL or above for men and 1.4 mg/dL for women, or with abnormal creatinine clearance. The ADA and the AACE now use the eGFR^1,2 instead of the serum creatinine level to measure kidney function because it better accounts for factors such as the patient’s age, sex, race, and weight.

Despite the evidence, the common patient perception is that metformin is nephrotoxic, and it is important for practitioners to dispel this myth during clinic visits.

What about metformin use with contrast agents?

Labeling has a precautionary note stating that metformin should be held at the time of, or prior to, any imaging procedure involving iodinated contrast agents in patients with an eGFR between 30 and 60 mL/min/1.73 m²; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will receive intra-arterial iodinated contrast. The eGFR should be reevaluated 48 hours after the imaging procedure.⁸

Additionally, if the iodinated contrast agent causes acute kidney injury, metformin could accumulate, with resultant lactate accumulation.

The American College of Radiology (ACR) has proposed less stringent guidelines for metformin during radiocontrast imaging studies. This change is based on evidence that lactic acidosis is rare­—about 10 cases per 100,000 patient-years—and that there are no reports of lactic acidosis after intravenously administered iodinated contrast in properly selected patients.^12,13

The ACR divides patients taking metformin into 2 categories:

• No evidence of acute kidney injury and eGFR greater than 30 mL/min/1.73 m²
• Either acute kidney injury or chronic kidney disease with eGFR below 30 mL/min/1.73 m² or undergoing arterial catheter studies with a high chance of embolization to the renal arteries.¹⁴

For the first group, they recommend against discontinuing metformin before or after giving iodinated contrast or checking kidney function after the procedure.

For the second group, they recommend holding metformin before and 48 hours after the procedure. It should not be restarted until renal function is confirmed to be normal.

The ADA recommends¹ continuing metformin after initiating insulin. However, in clinical practice, it is often not done.

Clinical trials have shown that combining metformin with insulin significantly improves glycemic control, prevents weight gain, and decreases insulin requirements.^15,16 One trial¹⁶ also looked at cardiovascular end points during a 4-year follow-up period;  combining metformin with insulin decreased the macrovascular disease-related event rate compared with insulin alone.

In the HOME trial,⁶ which added metformin to the existing insulin regimen, both groups gained weight, but the metformin group had gained about 3 kg less than the placebo group at the end of the 4.3-year trial. Metformin did not increase the risk of hypoglycemia, but it also did not reduce the risk of microvascular disease.

Concomitant metformin reduces costs

These days, practitioners can choose from a large selection of diabetes drugs. These include insulins with better pharmacokinetic profiles, as well as newer classes of noninsulin agents such as sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 analogues.

Metformin is less expensive than these newer drugs, and using it concomitantly with other diabetes drugs can decrease their dosage requirements, which in turn decreases their monthly costs.

GASTROINTESTINAL EFFECTS

Metformin’s gastrointestinal adverse effects such as diarrhea, flatulence, nausea, and vomiting are a barrier to its use. The actual incidence rate of diarrhea varies widely in randomized trials and observational studies, and gastrointestinal effects are worse in metformin-naive patients, as well as those who have chronic gastritis or Helicobacter pylori infection.¹⁷

We have found that starting metformin at a low dose and up-titrating it over several weeks increases tolerability. We often start patients at 500 mg/day and increase the dosage by 1 500-mg tablet every 1 to 2 weeks. Also, we have noticed that intolerance is more likely in patients who eat a high-carbohydrate diet, but there is no high-level evidence to back this up because patients in clinical trials all undergo nutrition counseling and are therefore more likely to adhere to the low-carbohydrate diet.

Also, the extended-release formulation is more tolerable than the immediate-release formulation and has similar glycemic efficacy. It may be an option as first-line therapy or for patients who have significant adverse effects from immediate-release metformin.¹⁸ For patients on the immediate-release formulation, taking it with meals helps lessen some gastrointestinal effects, and this should be emphasized at every visit.

Finally, we limit the metformin dose to 2,000 mg/day, rather than the 2,550 mg/day allowed on labeling. Garber et al¹⁹ found that the lower dosage still provides the maximum clinical efficacy.

OTHER CAUTIONS

Metformin should be avoided in patients with acute or unstable heart failure because of the increased risk of lactic acidosis.

It also should be avoided in patients with hepatic impairment, according to the labeling. But this remains controversial in practice. Zhang et al²⁰ showed that continuing metformin in patients with diabetes and cirrhosis decreases the mortality risk by 57% compared with those taken off metformin.

Diet and lifestyle measures need to be emphasized at each visit. Wing et al²¹ showed that calorie restriction regardless of weight loss is beneficial for glycemic control and insulin sensitivity in obese patients with diabetes.

TAKE-HOME POINTS

Metformin improves glycemic control without tending to cause weight gain or hypoglycemia. It may also have cardiovascular benefits. Metformin is an inexpensive agent that should be continued, if tolerated, in those who need additional agents for glycemic control. It should be considered in all adult patients with type 2 diabetes.   

Most patients should receive it, with exceptions as noted below. Metformin is the cornerstone of diabetes therapy and should be considered in all patients with type 2 diabetes. Both the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (AACE)^1,2 recommend it as first-line treatment for type 2 diabetes. It lowers blood glucose levels by inhibiting hepatic glucose production, and it does not tend to cause hypoglycemia.

However, metformin is underused. A 2012 study showed that only 50% to 70% of patients with type 2 diabetes treated with a sulfonylurea, dipeptidyl peptidase-4 (DPP-4) inhibitor, thiazolidinedione, or glucagon-like peptide-1 analogue also received metformin.³ This occurred despite guidelines recommending continuing metformin when starting other diabetes drugs.⁴

EVIDENCE METFORMIN IS EFFECTIVE

The United Kingdom Prospective Diabetes Study (UKPDS)⁵ found that metformin significantly reduced the incidence of:

• Any diabetes-related end point (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.53–0.87)
• Myocardial infarction (HR 0.61, 95% CI 0.41–0.89)
• Diabetes-related death (HR 0.58, 95% CI 0.37–0.91)
• All-cause mortality (HR 0.64; 95% CI 0.45–0.91).

The Hyperinsulinemia: Outcomes of Its Metabolic Effects (HOME) trial,⁶ a multicenter trial conducted in the Netherlands, evaluated the effect of adding  metformin (vs placebo) to existing insulin regimens. Metformin recipients had a significantly lower rate of macrovascular mortality (HR 0.61, 95% CI 0.40–0.94, P = .02), but not of the primary end point, an aggregate of microvascular and macrovascular morbidity and mortality.

The Study on the Prognosis and Effect of Antidiabetic Drugs on Type 2 Diabetes Mellitus With Coronary Artery Disease trial,⁷ a multicenter trial conducted in China, compared the effects of metformin vs glipizide on cardiovascular outcomes. At about 3 years of treatment, the metformin group had a significantly lower rate of the composite primary end point of recurrent cardiovascular events (HR 0.54, 95% CI 0.30–0.90). This end point included nonfatal myocardial infarction, nonfatal stroke, arterial revascularization by percutaneous transluminal coronary angioplasty or by coronary artery bypass graft, death from a cardiovascular cause, and death from any cause.

These studies prompted the ADA to emphasize that metformin can reduce the risk of cardiovascular events or death. Metformin also has been shown to be weight-neutral or to induce slight weight loss. Furthermore, it is inexpensive.

WHAT ABOUT THE RENAL EFFECTS?

Because metformin is renally cleared, it has caused some concern about nephrotoxicity, especially lactic acidosis, in patients with impaired renal function. But the most recent guidelines have relaxed the criteria for metformin use in this patient population.

Revised labeling

Metformin’s labeling,⁸ revised in 2016, states the following:

• If the estimated glomerular filtration rate (eGFR) is below 30 mL/min/1.73 m², metformin is contraindicated
• If the eGFR is between 30 and 45 mL/min/1.73 m², metformin is not recommended
• If the eGFR is below 45 mL/min/1.73 m² in a patient taking metformin, the risks and benefits of continuing treatment should be assessed, the dosage may need to be adjusted, and renal function should be monitored more frequently.⁸

These labeling revisions were based on a systematic review by Inzucchi et al⁹ that found metformin is not associated with increased rates of lactic acidosis in patients with mild to moderate kidney disease. Subsequently, an observational study published in 2018 by Lazarus et al¹⁰ showed that metformin increases the risk of acidosis only at eGFR levels below 30 mL/min/1.73 m². Also, a Cochrane review published in 2003 did not find a single case of lactic acidosis in 347 trials with 70,490 patient-years of metformin treatment.¹¹

Previous guidelines used serum creatinine levels, with metformin contraindicated at levels of 1.5 mg/dL or above for men and 1.4 mg/dL for women, or with abnormal creatinine clearance. The ADA and the AACE now use the eGFR^1,2 instead of the serum creatinine level to measure kidney function because it better accounts for factors such as the patient’s age, sex, race, and weight.

Despite the evidence, the common patient perception is that metformin is nephrotoxic, and it is important for practitioners to dispel this myth during clinic visits.

What about metformin use with contrast agents?

Labeling has a precautionary note stating that metformin should be held at the time of, or prior to, any imaging procedure involving iodinated contrast agents in patients with an eGFR between 30 and 60 mL/min/1.73 m²; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will receive intra-arterial iodinated contrast. The eGFR should be reevaluated 48 hours after the imaging procedure.⁸

Additionally, if the iodinated contrast agent causes acute kidney injury, metformin could accumulate, with resultant lactate accumulation.

The American College of Radiology (ACR) has proposed less stringent guidelines for metformin during radiocontrast imaging studies. This change is based on evidence that lactic acidosis is rare­—about 10 cases per 100,000 patient-years—and that there are no reports of lactic acidosis after intravenously administered iodinated contrast in properly selected patients.^12,13

The ACR divides patients taking metformin into 2 categories:

• No evidence of acute kidney injury and eGFR greater than 30 mL/min/1.73 m²
• Either acute kidney injury or chronic kidney disease with eGFR below 30 mL/min/1.73 m² or undergoing arterial catheter studies with a high chance of embolization to the renal arteries.¹⁴

For the first group, they recommend against discontinuing metformin before or after giving iodinated contrast or checking kidney function after the procedure.

For the second group, they recommend holding metformin before and 48 hours after the procedure. It should not be restarted until renal function is confirmed to be normal.

The ADA recommends¹ continuing metformin after initiating insulin. However, in clinical practice, it is often not done.

Clinical trials have shown that combining metformin with insulin significantly improves glycemic control, prevents weight gain, and decreases insulin requirements.^15,16 One trial¹⁶ also looked at cardiovascular end points during a 4-year follow-up period;  combining metformin with insulin decreased the macrovascular disease-related event rate compared with insulin alone.

In the HOME trial,⁶ which added metformin to the existing insulin regimen, both groups gained weight, but the metformin group had gained about 3 kg less than the placebo group at the end of the 4.3-year trial. Metformin did not increase the risk of hypoglycemia, but it also did not reduce the risk of microvascular disease.

Concomitant metformin reduces costs

These days, practitioners can choose from a large selection of diabetes drugs. These include insulins with better pharmacokinetic profiles, as well as newer classes of noninsulin agents such as sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 analogues.

Metformin is less expensive than these newer drugs, and using it concomitantly with other diabetes drugs can decrease their dosage requirements, which in turn decreases their monthly costs.

GASTROINTESTINAL EFFECTS

Metformin’s gastrointestinal adverse effects such as diarrhea, flatulence, nausea, and vomiting are a barrier to its use. The actual incidence rate of diarrhea varies widely in randomized trials and observational studies, and gastrointestinal effects are worse in metformin-naive patients, as well as those who have chronic gastritis or Helicobacter pylori infection.¹⁷

We have found that starting metformin at a low dose and up-titrating it over several weeks increases tolerability. We often start patients at 500 mg/day and increase the dosage by 1 500-mg tablet every 1 to 2 weeks. Also, we have noticed that intolerance is more likely in patients who eat a high-carbohydrate diet, but there is no high-level evidence to back this up because patients in clinical trials all undergo nutrition counseling and are therefore more likely to adhere to the low-carbohydrate diet.

Also, the extended-release formulation is more tolerable than the immediate-release formulation and has similar glycemic efficacy. It may be an option as first-line therapy or for patients who have significant adverse effects from immediate-release metformin.¹⁸ For patients on the immediate-release formulation, taking it with meals helps lessen some gastrointestinal effects, and this should be emphasized at every visit.

Finally, we limit the metformin dose to 2,000 mg/day, rather than the 2,550 mg/day allowed on labeling. Garber et al¹⁹ found that the lower dosage still provides the maximum clinical efficacy.

OTHER CAUTIONS

Metformin should be avoided in patients with acute or unstable heart failure because of the increased risk of lactic acidosis.

It also should be avoided in patients with hepatic impairment, according to the labeling. But this remains controversial in practice. Zhang et al²⁰ showed that continuing metformin in patients with diabetes and cirrhosis decreases the mortality risk by 57% compared with those taken off metformin.

Diet and lifestyle measures need to be emphasized at each visit. Wing et al²¹ showed that calorie restriction regardless of weight loss is beneficial for glycemic control and insulin sensitivity in obese patients with diabetes.

TAKE-HOME POINTS

Metformin improves glycemic control without tending to cause weight gain or hypoglycemia. It may also have cardiovascular benefits. Metformin is an inexpensive agent that should be continued, if tolerated, in those who need additional agents for glycemic control. It should be considered in all adult patients with type 2 diabetes.   

Electronic health records predict physician burnout. Also today, a new risk-prediction model for diabetes under development, firibastat is looking good for difficult-to-treat hypertension, and differences in gut bacteria can distinguish IBD from IBS.

Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
 

Electronic health records predict physician burnout. Also today, a new risk-prediction model for diabetes under development, firibastat is looking good for difficult-to-treat hypertension, and differences in gut bacteria can distinguish IBD from IBS.

Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
 

Electronic health records predict physician burnout. Also today, a new risk-prediction model for diabetes under development, firibastat is looking good for difficult-to-treat hypertension, and differences in gut bacteria can distinguish IBD from IBS.

Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
 

LOS ANGELES – Mounting evidence indicates that obesity in childhood and adolescence increases the risk for future cardiovascular disease (CVD), according to Stephen R. Daniels, MD, PhD.

Doug Brunk/MDedge News

“Some of this increased risk is related to the high level of tracking of obesity from childhood to adolescence to adulthood,” Dr. Daniels, who chairs the department of pediatrics at the University of Colorado, Aurora, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “But I think it’s also clear that childhood obesity is associated with risk factors for adult CVD, including hypertension, dyslipidemia, and type 2 diabetes. There’s a combination of things going on over the life course.”

Numerous studies have demonstrated a dose-response relationship between increased weight and all-cause mortality in cardiovascular disease for men and women. This operates through a variety of mechanisms, Dr. Daniels said, including hypertension, dyslipidemia, left ventricular hypertrophy, vascular inflammation, type 2 diabetes, and obstructive sleep apnea. “While overt cardiovascular disease does not occur in children, many of the mechanisms recognized in adults are also present in children and adolescents,” he said. “The trends for increasing prevalence and severity of obesity in children and the comorbid conditions associated with obesity are worrisome.”

The current prevalence of obesity in children and adolescents stands at about 18%, according to the latest National Health and Nutrition Examination Survey. However, the prevalence of severe obesity in youth aged 2-19 years has been increasing “fairly dramatically,” and now stands at 9% among girls and 8% among boys. Hispanics and non-Hispanic blacks are disproportionately affected. That may turn out to be important in terms of the future, Dr. Daniels said, because according to simulation models, childhood obesity and overweight will continue to be a major public health problem in the future (N Engl J Med. 2017;377:2145-53).


Direct evidence is also beginning to emerge of a link between obesity in youth and adult cardiovascular disease. The factors in childhood that predict adult obesity include a higher level of body mass index, obesity present at an older age (adolescence vs. childhood), and the presence of obesity in parents, which reflects both genes and environment. Researchers led by Paul W. Franks, PhD, evaluated 4,857 American Indian children without diabetes who were born between 1945 and 1984 and followed them for death before age 55 (N Engl J Med. 2010;362[6]:485-93). They assessed whether BMI, glucose tolerance, blood pressure, and cholesterol levels predicted premature death. There were 166 deaths from endogenous causes (3.4%) over a median follow-up of 24 years. Factors significantly associated with mortality included obesity (incident rate ratio 2.30), glucose tolerance (IRR 1.73), and hypertension (IRR 1.57).

In a separate analysis, researchers investigated the long-term effects of childhood weight on coronary heart disease (CHD) by studying 276,835 Danish schoolchildren for whom measurements of height and weight were available. They followed the individuals until they turned age 25 or older and used national registries to assess the fatal and nonfatal rates of CHD events (N Engl J Med. 2007;357:2329-37). The researchers found that higher BMI during childhood was associated with an increased risk of CVD in adulthood. However, they did not have data on BMI in adulthood, “which leaves open the question of whether childhood obesity works through adult obesity or also has an independent effect,” said Dr. Daniels, who is also pediatrician-in-chief at Children’s Hospital Colorado, Denver.

More recently, investigators studied 37,674 apparently healthy Israeli men from age 17 into adulthood (N Engl J Med. 2011;364:1315-25). Outcomes were coronary disease and diabetes. They found that an elevated BMI in adolescence is an independent risk factor for CVD in later life, while an elevated BMI in adulthood is an independent risk factor for both CVD and diabetes.

In the Fels Longitudinal Study, researchers enrolled 151 adults with metabolic syndrome and 154 without metabolic syndrome, with a mean age of 51 years (J Pediatr. 2008;152:191-200). “The idea was to look back at this cohort and see when the first differences might be observable between boys and girls who ultimately would develop metabolic syndrome and those who would not,” said Dr. Daniels, who was one of the study investigators. The first appearance of differences between adults with and without metabolic syndrome occurred at ages 8 and 13 for BMI and 6 and 13 for waist circumference in boys and girls, respectively. Odds ratios (ORs) for the metabolic syndrome in adulthood if BMI were elevated in childhood ranged from 1.4 to 1.9 in boys and from 0.8 to 2.8 in girls. At the same time, odds ratios for the metabolic syndrome in adulthood if waist circumference was elevated ranged from 2.5 to 31.4 in boys and 1.7 to 2.5 in girls.

“I think it’s safe to say that BMI and waist circumference may be important in predicting metabolic syndrome later in life and, ultimately, cardiovascular disease,” Dr. Daniels said.

He noted that as the prevalence and severity of obesity have increased in childhood, the prevalence of type 2 diabetes has also increased. “The time from diagnosis of diabetes to a CVD event is approximately 10-15 years in adults, and there is often a prediagnosis period of hyperglycemia, which ranges from 5-10 years,” Dr. Daniels said. “If the time course of CVD related to diabetes is the same for adolescents as adults, it is anticipated that adolescents with diabetes will begin having substantial CVD morbidity and mortality in their 30s or 40s. This will be a public health disaster. Emerging evidence from the TODAY study (Treatment Options for type 2 Diabetes in Adolescents and Youth) and other studies is emphasizing that at least some individuals with adolescent type 2 diabetes may have a more malignant form of disease than in adults. This is striking and important to consider as we look at how to prevent cardiovascular disease.”

Obesity in childhood is also associated with structural and functional abnormalities of the vasculature, according to studies that measure vascular structure via intima-media thickness of the carotid arteries, femoral arteries, abdominal aorta, or other arteries, as well as those that measure vascular stiffness via measures of intrinsic “visco-elastic” properties of the arterial wall. In one study of individuals aged 10-24 years, Dr. Daniels and his associates performed carotid ultrasound for carotid intima-media thickness on 182 patients who were lean, 136 who were obese, and 128 who had type 2 diabetes (Circulation 2009;119(22):2913-9). It demonstrated that youth with obesity and obesity-related type 2 diabetes have abnormalities in carotid thickness and stiffness that are only partially explained by traditional cardiovascular risk factors.

“We all know that obesity is very difficult to treat,” he concluded. “That’s true in children and adolescents as it is in adults. I think this argues for prevention of obesity, for us starting earlier, creating an optimal cardiovascular health situation that we can maintain during the course of childhood and adolescence. The payoff will be great if we can accomplish that.”

Dr. Daniels reported having no disclosures.

[email protected]

LOS ANGELES – Mounting evidence indicates that obesity in childhood and adolescence increases the risk for future cardiovascular disease (CVD), according to Stephen R. Daniels, MD, PhD.

Doug Brunk/MDedge News

“Some of this increased risk is related to the high level of tracking of obesity from childhood to adolescence to adulthood,” Dr. Daniels, who chairs the department of pediatrics at the University of Colorado, Aurora, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “But I think it’s also clear that childhood obesity is associated with risk factors for adult CVD, including hypertension, dyslipidemia, and type 2 diabetes. There’s a combination of things going on over the life course.”

Numerous studies have demonstrated a dose-response relationship between increased weight and all-cause mortality in cardiovascular disease for men and women. This operates through a variety of mechanisms, Dr. Daniels said, including hypertension, dyslipidemia, left ventricular hypertrophy, vascular inflammation, type 2 diabetes, and obstructive sleep apnea. “While overt cardiovascular disease does not occur in children, many of the mechanisms recognized in adults are also present in children and adolescents,” he said. “The trends for increasing prevalence and severity of obesity in children and the comorbid conditions associated with obesity are worrisome.”

The current prevalence of obesity in children and adolescents stands at about 18%, according to the latest National Health and Nutrition Examination Survey. However, the prevalence of severe obesity in youth aged 2-19 years has been increasing “fairly dramatically,” and now stands at 9% among girls and 8% among boys. Hispanics and non-Hispanic blacks are disproportionately affected. That may turn out to be important in terms of the future, Dr. Daniels said, because according to simulation models, childhood obesity and overweight will continue to be a major public health problem in the future (N Engl J Med. 2017;377:2145-53).


Direct evidence is also beginning to emerge of a link between obesity in youth and adult cardiovascular disease. The factors in childhood that predict adult obesity include a higher level of body mass index, obesity present at an older age (adolescence vs. childhood), and the presence of obesity in parents, which reflects both genes and environment. Researchers led by Paul W. Franks, PhD, evaluated 4,857 American Indian children without diabetes who were born between 1945 and 1984 and followed them for death before age 55 (N Engl J Med. 2010;362[6]:485-93). They assessed whether BMI, glucose tolerance, blood pressure, and cholesterol levels predicted premature death. There were 166 deaths from endogenous causes (3.4%) over a median follow-up of 24 years. Factors significantly associated with mortality included obesity (incident rate ratio 2.30), glucose tolerance (IRR 1.73), and hypertension (IRR 1.57).

In a separate analysis, researchers investigated the long-term effects of childhood weight on coronary heart disease (CHD) by studying 276,835 Danish schoolchildren for whom measurements of height and weight were available. They followed the individuals until they turned age 25 or older and used national registries to assess the fatal and nonfatal rates of CHD events (N Engl J Med. 2007;357:2329-37). The researchers found that higher BMI during childhood was associated with an increased risk of CVD in adulthood. However, they did not have data on BMI in adulthood, “which leaves open the question of whether childhood obesity works through adult obesity or also has an independent effect,” said Dr. Daniels, who is also pediatrician-in-chief at Children’s Hospital Colorado, Denver.

More recently, investigators studied 37,674 apparently healthy Israeli men from age 17 into adulthood (N Engl J Med. 2011;364:1315-25). Outcomes were coronary disease and diabetes. They found that an elevated BMI in adolescence is an independent risk factor for CVD in later life, while an elevated BMI in adulthood is an independent risk factor for both CVD and diabetes.

In the Fels Longitudinal Study, researchers enrolled 151 adults with metabolic syndrome and 154 without metabolic syndrome, with a mean age of 51 years (J Pediatr. 2008;152:191-200). “The idea was to look back at this cohort and see when the first differences might be observable between boys and girls who ultimately would develop metabolic syndrome and those who would not,” said Dr. Daniels, who was one of the study investigators. The first appearance of differences between adults with and without metabolic syndrome occurred at ages 8 and 13 for BMI and 6 and 13 for waist circumference in boys and girls, respectively. Odds ratios (ORs) for the metabolic syndrome in adulthood if BMI were elevated in childhood ranged from 1.4 to 1.9 in boys and from 0.8 to 2.8 in girls. At the same time, odds ratios for the metabolic syndrome in adulthood if waist circumference was elevated ranged from 2.5 to 31.4 in boys and 1.7 to 2.5 in girls.

“I think it’s safe to say that BMI and waist circumference may be important in predicting metabolic syndrome later in life and, ultimately, cardiovascular disease,” Dr. Daniels said.

He noted that as the prevalence and severity of obesity have increased in childhood, the prevalence of type 2 diabetes has also increased. “The time from diagnosis of diabetes to a CVD event is approximately 10-15 years in adults, and there is often a prediagnosis period of hyperglycemia, which ranges from 5-10 years,” Dr. Daniels said. “If the time course of CVD related to diabetes is the same for adolescents as adults, it is anticipated that adolescents with diabetes will begin having substantial CVD morbidity and mortality in their 30s or 40s. This will be a public health disaster. Emerging evidence from the TODAY study (Treatment Options for type 2 Diabetes in Adolescents and Youth) and other studies is emphasizing that at least some individuals with adolescent type 2 diabetes may have a more malignant form of disease than in adults. This is striking and important to consider as we look at how to prevent cardiovascular disease.”

Obesity in childhood is also associated with structural and functional abnormalities of the vasculature, according to studies that measure vascular structure via intima-media thickness of the carotid arteries, femoral arteries, abdominal aorta, or other arteries, as well as those that measure vascular stiffness via measures of intrinsic “visco-elastic” properties of the arterial wall. In one study of individuals aged 10-24 years, Dr. Daniels and his associates performed carotid ultrasound for carotid intima-media thickness on 182 patients who were lean, 136 who were obese, and 128 who had type 2 diabetes (Circulation 2009;119(22):2913-9). It demonstrated that youth with obesity and obesity-related type 2 diabetes have abnormalities in carotid thickness and stiffness that are only partially explained by traditional cardiovascular risk factors.

“We all know that obesity is very difficult to treat,” he concluded. “That’s true in children and adolescents as it is in adults. I think this argues for prevention of obesity, for us starting earlier, creating an optimal cardiovascular health situation that we can maintain during the course of childhood and adolescence. The payoff will be great if we can accomplish that.”

Dr. Daniels reported having no disclosures.

[email protected]

LOS ANGELES – Mounting evidence indicates that obesity in childhood and adolescence increases the risk for future cardiovascular disease (CVD), according to Stephen R. Daniels, MD, PhD.

Doug Brunk/MDedge News

“Some of this increased risk is related to the high level of tracking of obesity from childhood to adolescence to adulthood,” Dr. Daniels, who chairs the department of pediatrics at the University of Colorado, Aurora, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “But I think it’s also clear that childhood obesity is associated with risk factors for adult CVD, including hypertension, dyslipidemia, and type 2 diabetes. There’s a combination of things going on over the life course.”

Numerous studies have demonstrated a dose-response relationship between increased weight and all-cause mortality in cardiovascular disease for men and women. This operates through a variety of mechanisms, Dr. Daniels said, including hypertension, dyslipidemia, left ventricular hypertrophy, vascular inflammation, type 2 diabetes, and obstructive sleep apnea. “While overt cardiovascular disease does not occur in children, many of the mechanisms recognized in adults are also present in children and adolescents,” he said. “The trends for increasing prevalence and severity of obesity in children and the comorbid conditions associated with obesity are worrisome.”

The current prevalence of obesity in children and adolescents stands at about 18%, according to the latest National Health and Nutrition Examination Survey. However, the prevalence of severe obesity in youth aged 2-19 years has been increasing “fairly dramatically,” and now stands at 9% among girls and 8% among boys. Hispanics and non-Hispanic blacks are disproportionately affected. That may turn out to be important in terms of the future, Dr. Daniels said, because according to simulation models, childhood obesity and overweight will continue to be a major public health problem in the future (N Engl J Med. 2017;377:2145-53).


Direct evidence is also beginning to emerge of a link between obesity in youth and adult cardiovascular disease. The factors in childhood that predict adult obesity include a higher level of body mass index, obesity present at an older age (adolescence vs. childhood), and the presence of obesity in parents, which reflects both genes and environment. Researchers led by Paul W. Franks, PhD, evaluated 4,857 American Indian children without diabetes who were born between 1945 and 1984 and followed them for death before age 55 (N Engl J Med. 2010;362[6]:485-93). They assessed whether BMI, glucose tolerance, blood pressure, and cholesterol levels predicted premature death. There were 166 deaths from endogenous causes (3.4%) over a median follow-up of 24 years. Factors significantly associated with mortality included obesity (incident rate ratio 2.30), glucose tolerance (IRR 1.73), and hypertension (IRR 1.57).

In a separate analysis, researchers investigated the long-term effects of childhood weight on coronary heart disease (CHD) by studying 276,835 Danish schoolchildren for whom measurements of height and weight were available. They followed the individuals until they turned age 25 or older and used national registries to assess the fatal and nonfatal rates of CHD events (N Engl J Med. 2007;357:2329-37). The researchers found that higher BMI during childhood was associated with an increased risk of CVD in adulthood. However, they did not have data on BMI in adulthood, “which leaves open the question of whether childhood obesity works through adult obesity or also has an independent effect,” said Dr. Daniels, who is also pediatrician-in-chief at Children’s Hospital Colorado, Denver.

More recently, investigators studied 37,674 apparently healthy Israeli men from age 17 into adulthood (N Engl J Med. 2011;364:1315-25). Outcomes were coronary disease and diabetes. They found that an elevated BMI in adolescence is an independent risk factor for CVD in later life, while an elevated BMI in adulthood is an independent risk factor for both CVD and diabetes.

In the Fels Longitudinal Study, researchers enrolled 151 adults with metabolic syndrome and 154 without metabolic syndrome, with a mean age of 51 years (J Pediatr. 2008;152:191-200). “The idea was to look back at this cohort and see when the first differences might be observable between boys and girls who ultimately would develop metabolic syndrome and those who would not,” said Dr. Daniels, who was one of the study investigators. The first appearance of differences between adults with and without metabolic syndrome occurred at ages 8 and 13 for BMI and 6 and 13 for waist circumference in boys and girls, respectively. Odds ratios (ORs) for the metabolic syndrome in adulthood if BMI were elevated in childhood ranged from 1.4 to 1.9 in boys and from 0.8 to 2.8 in girls. At the same time, odds ratios for the metabolic syndrome in adulthood if waist circumference was elevated ranged from 2.5 to 31.4 in boys and 1.7 to 2.5 in girls.

“I think it’s safe to say that BMI and waist circumference may be important in predicting metabolic syndrome later in life and, ultimately, cardiovascular disease,” Dr. Daniels said.

He noted that as the prevalence and severity of obesity have increased in childhood, the prevalence of type 2 diabetes has also increased. “The time from diagnosis of diabetes to a CVD event is approximately 10-15 years in adults, and there is often a prediagnosis period of hyperglycemia, which ranges from 5-10 years,” Dr. Daniels said. “If the time course of CVD related to diabetes is the same for adolescents as adults, it is anticipated that adolescents with diabetes will begin having substantial CVD morbidity and mortality in their 30s or 40s. This will be a public health disaster. Emerging evidence from the TODAY study (Treatment Options for type 2 Diabetes in Adolescents and Youth) and other studies is emphasizing that at least some individuals with adolescent type 2 diabetes may have a more malignant form of disease than in adults. This is striking and important to consider as we look at how to prevent cardiovascular disease.”

Obesity in childhood is also associated with structural and functional abnormalities of the vasculature, according to studies that measure vascular structure via intima-media thickness of the carotid arteries, femoral arteries, abdominal aorta, or other arteries, as well as those that measure vascular stiffness via measures of intrinsic “visco-elastic” properties of the arterial wall. In one study of individuals aged 10-24 years, Dr. Daniels and his associates performed carotid ultrasound for carotid intima-media thickness on 182 patients who were lean, 136 who were obese, and 128 who had type 2 diabetes (Circulation 2009;119(22):2913-9). It demonstrated that youth with obesity and obesity-related type 2 diabetes have abnormalities in carotid thickness and stiffness that are only partially explained by traditional cardiovascular risk factors.

“We all know that obesity is very difficult to treat,” he concluded. “That’s true in children and adolescents as it is in adults. I think this argues for prevention of obesity, for us starting earlier, creating an optimal cardiovascular health situation that we can maintain during the course of childhood and adolescence. The payoff will be great if we can accomplish that.”

Dr. Daniels reported having no disclosures.

[email protected]

This week, the barbershop may become a key battleground in the fight against hypertension, the American Diabetes Association upgrades newer antihyperglycemics, refreshed appropriate use criteria for peripheral artery disease are released, and body mass index as a measure of cardiometabolic risk gets a boost.

Subscribe to Cardiocast wherever you get your podcasts.

Amazon Alexa

Apple Podcasts

This week, the barbershop may become a key battleground in the fight against hypertension, the American Diabetes Association upgrades newer antihyperglycemics, refreshed appropriate use criteria for peripheral artery disease are released, and body mass index as a measure of cardiometabolic risk gets a boost.

Subscribe to Cardiocast wherever you get your podcasts.

Amazon Alexa

Apple Podcasts

This week, the barbershop may become a key battleground in the fight against hypertension, the American Diabetes Association upgrades newer antihyperglycemics, refreshed appropriate use criteria for peripheral artery disease are released, and body mass index as a measure of cardiometabolic risk gets a boost.

Subscribe to Cardiocast wherever you get your podcasts.

Amazon Alexa

Apple Podcasts

LOS ANGELES – Clinicians treating patients with diabetes rely heavily on the U.K. Prospective Diabetes Study (UKPDS) Risk Engine and the Framingham Risk Score to predict outcomes, but the populations used for developing these tools differ significantly from the current U.S. diabetes population.

MDedge News/Doug Brunk

“All these risk engines have various degrees of accuracy along with several limitations, including that they are derived from data from various populations,” Vivian A. Fonseca, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “Sometimes the results may not be generalizable. That’s one of the big problems with the risk engines we’re using.”

To address these shortcomings, Dr. Fonseca, Hui Shao, PhD, and Lizheng Shi, PhD, have developed the Building, Relating, Assessing, Validating Outcomes (BRAVO) of Diabetes Model, a patient-level microsimulation model based on data from the ACCORD trial. The model predicts both primary and secondary CVD events, microvascular events, the progress of hemoglobin A_1c and other key biomarkers over time, quality-adjusted life-year (QALY) function decrements associated with complications, and an ability to predict outcomes in patients from other regions in the world. The risk engine contains three modules for 17 equations in total, including angina, blindness, and hypoglycemia (Pharmacoeconomics. 2018;36[9]:1125-34). “There are lots of data now showing that if you get hypoglycemia, your risk of a cardiovascular event goes up greatly over the subsequent 2 years,” said Dr. Fonseca, who is chief of the section of endocrinology at Tulane University Health Science Center, New Orleans. “No other risk engine has that.”

When he and his associates applied the UKPDS Risk Engine to the ACCORD cohort, they found that the UPKDS Risk Engine overpredicted the risk of stroke (2.3% vs. 1.4% observed), MI (6.5% vs. 4.9% observed), and all-cause mortality (10.3% vs. 4% observed); yet it underpredicted congestive heart failure (2.2% vs. 4% observed), end-stage renal disease (0.5% vs. 3% observed), and blindness (1.35% vs. 8.1% observed). In the ACCORD cohort, baseline duration varied from 0 to 35 years. “Using left truncated regression, we can piece together the segmented follow-up times for 10,251 patients to a complete diabetes progression track from 0 years to 40 years after diabetes onset,” he said.

Dr. Fonseca said that BRAVO improves four aspects of diabetes risk prediction compared with other tools: It better captures the effects of body weight on cardiovascular risks, cost, and QALYs; it better captures hypoglycemia; it has a globalization module to calibrate regional variation of cardiovascular risks; and it has both utility and QALY equations developed from the same study cohort. Internal validations studies found that BRAVO predicted outcomes from the ACCORD trial, including congestive heart failure, MI, stroke, angina, blindness, end-stage renal disease, and neuropathy. Data from the ASPEN, CARDS, and ADVANCE trials were used to conduct external validation, and the incidence rates of 28 endpoints correlated with that of BRAVO “extremely well.” In addition, BRAVO has been calibrated against 18 large randomized, controlled trials conducted after the year 2000. “Regional variation in CVD [cardiovascular disease] outcomes were included as an important risk factor in the simulation,” said Dr. Fonseca, who is also assistant dean for clinical research at Tulane. Results to date show a high prediction accuracy (R-squared value = .91).

He and his associates are currently examining ways to apply BRAVO in clinical practice, including for risk stratification. “Let’s say you have a large health system, and you want to separate out your patients who have high, medium, or low risk for diabetes and make sure they get they get the right care according to their stratification,” he explained. “A couple of large health systems are trying this out right now.”

BRAVO can also be used as a tool for cost-effectiveness analysis and program evaluation. In fact, he and his colleagues at five medical centers are working with the American Diabetes Association “to see what effect a certain intervention will have on outcomes in people with diabetes over a number of years, and how cost effective it might be.”

Finally, BRAVO can be used for diabetes management in clinical practice. “Based on an individual’s characteristics, the BRAVO model potentially simulates future outcomes such as complications and mortality, providing a transparent platform for shared decision making,” he said.

Dr. Fonseca disclosed that he has an ownership interest in the development of BRAVO.

[email protected]

LOS ANGELES – Clinicians treating patients with diabetes rely heavily on the U.K. Prospective Diabetes Study (UKPDS) Risk Engine and the Framingham Risk Score to predict outcomes, but the populations used for developing these tools differ significantly from the current U.S. diabetes population.

MDedge News/Doug Brunk

“All these risk engines have various degrees of accuracy along with several limitations, including that they are derived from data from various populations,” Vivian A. Fonseca, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “Sometimes the results may not be generalizable. That’s one of the big problems with the risk engines we’re using.”

To address these shortcomings, Dr. Fonseca, Hui Shao, PhD, and Lizheng Shi, PhD, have developed the Building, Relating, Assessing, Validating Outcomes (BRAVO) of Diabetes Model, a patient-level microsimulation model based on data from the ACCORD trial. The model predicts both primary and secondary CVD events, microvascular events, the progress of hemoglobin A_1c and other key biomarkers over time, quality-adjusted life-year (QALY) function decrements associated with complications, and an ability to predict outcomes in patients from other regions in the world. The risk engine contains three modules for 17 equations in total, including angina, blindness, and hypoglycemia (Pharmacoeconomics. 2018;36[9]:1125-34). “There are lots of data now showing that if you get hypoglycemia, your risk of a cardiovascular event goes up greatly over the subsequent 2 years,” said Dr. Fonseca, who is chief of the section of endocrinology at Tulane University Health Science Center, New Orleans. “No other risk engine has that.”

When he and his associates applied the UKPDS Risk Engine to the ACCORD cohort, they found that the UPKDS Risk Engine overpredicted the risk of stroke (2.3% vs. 1.4% observed), MI (6.5% vs. 4.9% observed), and all-cause mortality (10.3% vs. 4% observed); yet it underpredicted congestive heart failure (2.2% vs. 4% observed), end-stage renal disease (0.5% vs. 3% observed), and blindness (1.35% vs. 8.1% observed). In the ACCORD cohort, baseline duration varied from 0 to 35 years. “Using left truncated regression, we can piece together the segmented follow-up times for 10,251 patients to a complete diabetes progression track from 0 years to 40 years after diabetes onset,” he said.

Dr. Fonseca said that BRAVO improves four aspects of diabetes risk prediction compared with other tools: It better captures the effects of body weight on cardiovascular risks, cost, and QALYs; it better captures hypoglycemia; it has a globalization module to calibrate regional variation of cardiovascular risks; and it has both utility and QALY equations developed from the same study cohort. Internal validations studies found that BRAVO predicted outcomes from the ACCORD trial, including congestive heart failure, MI, stroke, angina, blindness, end-stage renal disease, and neuropathy. Data from the ASPEN, CARDS, and ADVANCE trials were used to conduct external validation, and the incidence rates of 28 endpoints correlated with that of BRAVO “extremely well.” In addition, BRAVO has been calibrated against 18 large randomized, controlled trials conducted after the year 2000. “Regional variation in CVD [cardiovascular disease] outcomes were included as an important risk factor in the simulation,” said Dr. Fonseca, who is also assistant dean for clinical research at Tulane. Results to date show a high prediction accuracy (R-squared value = .91).

He and his associates are currently examining ways to apply BRAVO in clinical practice, including for risk stratification. “Let’s say you have a large health system, and you want to separate out your patients who have high, medium, or low risk for diabetes and make sure they get they get the right care according to their stratification,” he explained. “A couple of large health systems are trying this out right now.”

BRAVO can also be used as a tool for cost-effectiveness analysis and program evaluation. In fact, he and his colleagues at five medical centers are working with the American Diabetes Association “to see what effect a certain intervention will have on outcomes in people with diabetes over a number of years, and how cost effective it might be.”

Finally, BRAVO can be used for diabetes management in clinical practice. “Based on an individual’s characteristics, the BRAVO model potentially simulates future outcomes such as complications and mortality, providing a transparent platform for shared decision making,” he said.

Dr. Fonseca disclosed that he has an ownership interest in the development of BRAVO.

[email protected]

LOS ANGELES – Clinicians treating patients with diabetes rely heavily on the U.K. Prospective Diabetes Study (UKPDS) Risk Engine and the Framingham Risk Score to predict outcomes, but the populations used for developing these tools differ significantly from the current U.S. diabetes population.

MDedge News/Doug Brunk

“All these risk engines have various degrees of accuracy along with several limitations, including that they are derived from data from various populations,” Vivian A. Fonseca, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “Sometimes the results may not be generalizable. That’s one of the big problems with the risk engines we’re using.”

To address these shortcomings, Dr. Fonseca, Hui Shao, PhD, and Lizheng Shi, PhD, have developed the Building, Relating, Assessing, Validating Outcomes (BRAVO) of Diabetes Model, a patient-level microsimulation model based on data from the ACCORD trial. The model predicts both primary and secondary CVD events, microvascular events, the progress of hemoglobin A_1c and other key biomarkers over time, quality-adjusted life-year (QALY) function decrements associated with complications, and an ability to predict outcomes in patients from other regions in the world. The risk engine contains three modules for 17 equations in total, including angina, blindness, and hypoglycemia (Pharmacoeconomics. 2018;36[9]:1125-34). “There are lots of data now showing that if you get hypoglycemia, your risk of a cardiovascular event goes up greatly over the subsequent 2 years,” said Dr. Fonseca, who is chief of the section of endocrinology at Tulane University Health Science Center, New Orleans. “No other risk engine has that.”

When he and his associates applied the UKPDS Risk Engine to the ACCORD cohort, they found that the UPKDS Risk Engine overpredicted the risk of stroke (2.3% vs. 1.4% observed), MI (6.5% vs. 4.9% observed), and all-cause mortality (10.3% vs. 4% observed); yet it underpredicted congestive heart failure (2.2% vs. 4% observed), end-stage renal disease (0.5% vs. 3% observed), and blindness (1.35% vs. 8.1% observed). In the ACCORD cohort, baseline duration varied from 0 to 35 years. “Using left truncated regression, we can piece together the segmented follow-up times for 10,251 patients to a complete diabetes progression track from 0 years to 40 years after diabetes onset,” he said.

Dr. Fonseca said that BRAVO improves four aspects of diabetes risk prediction compared with other tools: It better captures the effects of body weight on cardiovascular risks, cost, and QALYs; it better captures hypoglycemia; it has a globalization module to calibrate regional variation of cardiovascular risks; and it has both utility and QALY equations developed from the same study cohort. Internal validations studies found that BRAVO predicted outcomes from the ACCORD trial, including congestive heart failure, MI, stroke, angina, blindness, end-stage renal disease, and neuropathy. Data from the ASPEN, CARDS, and ADVANCE trials were used to conduct external validation, and the incidence rates of 28 endpoints correlated with that of BRAVO “extremely well.” In addition, BRAVO has been calibrated against 18 large randomized, controlled trials conducted after the year 2000. “Regional variation in CVD [cardiovascular disease] outcomes were included as an important risk factor in the simulation,” said Dr. Fonseca, who is also assistant dean for clinical research at Tulane. Results to date show a high prediction accuracy (R-squared value = .91).

He and his associates are currently examining ways to apply BRAVO in clinical practice, including for risk stratification. “Let’s say you have a large health system, and you want to separate out your patients who have high, medium, or low risk for diabetes and make sure they get they get the right care according to their stratification,” he explained. “A couple of large health systems are trying this out right now.”

BRAVO can also be used as a tool for cost-effectiveness analysis and program evaluation. In fact, he and his colleagues at five medical centers are working with the American Diabetes Association “to see what effect a certain intervention will have on outcomes in people with diabetes over a number of years, and how cost effective it might be.”

Finally, BRAVO can be used for diabetes management in clinical practice. “Based on an individual’s characteristics, the BRAVO model potentially simulates future outcomes such as complications and mortality, providing a transparent platform for shared decision making,” he said.

Dr. Fonseca disclosed that he has an ownership interest in the development of BRAVO.

[email protected]

The American Diabetes Association is out with new standard-of-care guidelines that – among other things – reject injectable insulin as the main first-line treatment for type 2 diabetes mellitus (T2DM), debut a cardiac risk calculator, and offer new recommendations regarding medications for patients with kidney disease, clogged arteries, and heart failure.

The ADA’s newly released 2019 Standards of Medical Care in Diabetes “emphasize a patient-centered approach that considers the multiple health and life factors of each person living with diabetes,” said William T. Cefalu, MD, the ADA’s chief scientific, medical, and mission officer, in a statement.

The 193-page guidelines are now available online at the Diabetes Care website and will be available via an app and the print edition of the journal.

Here’s a closer look at a few of the many new and revised recommendations in the 2019 Standards of Care.
 

Diabetes treatment

In a new guideline, the standards of care says glucagonlike peptide–1 (GLP-1) receptor agonists should be “a first-line treatment” – ahead of insulin – “for most [type 2] patients who need the greater efficacy of an injectable medication.”

However, the recommendations note that the “high costs and tolerability issues are important barriers to the use of GLP-1 receptor agonists.”

A new recommendation suggests the use of sodium-glucose cotransporter 2 inhibitors or GLP-1 receptor agonists “with demonstrated cardiovascular disease benefit” in patients with type 2 diabetes who have confirmed atherosclerotic cardiovascular disease.

A related new recommendation says sodium-glucose cotransporter 2 inhibitors are the preferred treatment for these patients who have heart failure or are at high risk of developing it.

In a new recommendation, the ADA suggests that patients with type 2 diabetes and chronic kidney disease potentially take a sodium-glucose cotransporter 2 inhibitor or a GLP-1 receptor agonist, which has been shown to reduce the risk of chronic kidney disease progression, cardiac events, or both.

There’s a greater focus on insulin as the preferred treatment for hyperglycemia in gestational diabetes mellitus “as it does not cross the placenta to a measurable extent.” The ADA also warns against metformin and glyburide as first-line agents because they “both cross the placenta to the fetus.”

Diabetes monitoring and screening

The ADA now recommends use of the American College of Cardiology’s atherosclerotic cardiovascular disease risk calculator, the ASCVD Risk Estimator Plus. The calculator assesses the risk of this disease over 10 years and is “generally a useful tool.”

The ACA recommends screening for cardiac risk factors at least once a year in patients with diabetes.

Physicians are no longer advised to check the feet of patients with diabetes at every visit; now the recommendation is for those at high risk of ulceration only. However, an annual examination of feet is recommended for all patients with diabetes.

The ADA now recommends that patients with type 2 diabetes or prediabetes undergo screening for nonalcoholic steatohepatitis and liver fibrosis if they have elevated liver enzymes or an ultrasound examination shows signs of fatty liver.

Gabapentin is now listed along with pregabalin and duloxetine as first-line drug treatments for neuropathic pain in diabetes.

The American Diabetes Association is out with new standard-of-care guidelines that – among other things – reject injectable insulin as the main first-line treatment for type 2 diabetes mellitus (T2DM), debut a cardiac risk calculator, and offer new recommendations regarding medications for patients with kidney disease, clogged arteries, and heart failure.

The ADA’s newly released 2019 Standards of Medical Care in Diabetes “emphasize a patient-centered approach that considers the multiple health and life factors of each person living with diabetes,” said William T. Cefalu, MD, the ADA’s chief scientific, medical, and mission officer, in a statement.

The 193-page guidelines are now available online at the Diabetes Care website and will be available via an app and the print edition of the journal.

Here’s a closer look at a few of the many new and revised recommendations in the 2019 Standards of Care.
 

Diabetes treatment

In a new guideline, the standards of care says glucagonlike peptide–1 (GLP-1) receptor agonists should be “a first-line treatment” – ahead of insulin – “for most [type 2] patients who need the greater efficacy of an injectable medication.”

However, the recommendations note that the “high costs and tolerability issues are important barriers to the use of GLP-1 receptor agonists.”

A new recommendation suggests the use of sodium-glucose cotransporter 2 inhibitors or GLP-1 receptor agonists “with demonstrated cardiovascular disease benefit” in patients with type 2 diabetes who have confirmed atherosclerotic cardiovascular disease.

A related new recommendation says sodium-glucose cotransporter 2 inhibitors are the preferred treatment for these patients who have heart failure or are at high risk of developing it.

In a new recommendation, the ADA suggests that patients with type 2 diabetes and chronic kidney disease potentially take a sodium-glucose cotransporter 2 inhibitor or a GLP-1 receptor agonist, which has been shown to reduce the risk of chronic kidney disease progression, cardiac events, or both.

There’s a greater focus on insulin as the preferred treatment for hyperglycemia in gestational diabetes mellitus “as it does not cross the placenta to a measurable extent.” The ADA also warns against metformin and glyburide as first-line agents because they “both cross the placenta to the fetus.”

Diabetes monitoring and screening

The ADA now recommends use of the American College of Cardiology’s atherosclerotic cardiovascular disease risk calculator, the ASCVD Risk Estimator Plus. The calculator assesses the risk of this disease over 10 years and is “generally a useful tool.”

The ACA recommends screening for cardiac risk factors at least once a year in patients with diabetes.

Physicians are no longer advised to check the feet of patients with diabetes at every visit; now the recommendation is for those at high risk of ulceration only. However, an annual examination of feet is recommended for all patients with diabetes.

The ADA now recommends that patients with type 2 diabetes or prediabetes undergo screening for nonalcoholic steatohepatitis and liver fibrosis if they have elevated liver enzymes or an ultrasound examination shows signs of fatty liver.

Gabapentin is now listed along with pregabalin and duloxetine as first-line drug treatments for neuropathic pain in diabetes.

The American Diabetes Association is out with new standard-of-care guidelines that – among other things – reject injectable insulin as the main first-line treatment for type 2 diabetes mellitus (T2DM), debut a cardiac risk calculator, and offer new recommendations regarding medications for patients with kidney disease, clogged arteries, and heart failure.

The ADA’s newly released 2019 Standards of Medical Care in Diabetes “emphasize a patient-centered approach that considers the multiple health and life factors of each person living with diabetes,” said William T. Cefalu, MD, the ADA’s chief scientific, medical, and mission officer, in a statement.

The 193-page guidelines are now available online at the Diabetes Care website and will be available via an app and the print edition of the journal.

Here’s a closer look at a few of the many new and revised recommendations in the 2019 Standards of Care.
 

Diabetes treatment

In a new guideline, the standards of care says glucagonlike peptide–1 (GLP-1) receptor agonists should be “a first-line treatment” – ahead of insulin – “for most [type 2] patients who need the greater efficacy of an injectable medication.”

However, the recommendations note that the “high costs and tolerability issues are important barriers to the use of GLP-1 receptor agonists.”

A new recommendation suggests the use of sodium-glucose cotransporter 2 inhibitors or GLP-1 receptor agonists “with demonstrated cardiovascular disease benefit” in patients with type 2 diabetes who have confirmed atherosclerotic cardiovascular disease.

A related new recommendation says sodium-glucose cotransporter 2 inhibitors are the preferred treatment for these patients who have heart failure or are at high risk of developing it.

In a new recommendation, the ADA suggests that patients with type 2 diabetes and chronic kidney disease potentially take a sodium-glucose cotransporter 2 inhibitor or a GLP-1 receptor agonist, which has been shown to reduce the risk of chronic kidney disease progression, cardiac events, or both.

There’s a greater focus on insulin as the preferred treatment for hyperglycemia in gestational diabetes mellitus “as it does not cross the placenta to a measurable extent.” The ADA also warns against metformin and glyburide as first-line agents because they “both cross the placenta to the fetus.”

Diabetes monitoring and screening

The ADA now recommends use of the American College of Cardiology’s atherosclerotic cardiovascular disease risk calculator, the ASCVD Risk Estimator Plus. The calculator assesses the risk of this disease over 10 years and is “generally a useful tool.”

The ACA recommends screening for cardiac risk factors at least once a year in patients with diabetes.

Physicians are no longer advised to check the feet of patients with diabetes at every visit; now the recommendation is for those at high risk of ulceration only. However, an annual examination of feet is recommended for all patients with diabetes.

The ADA now recommends that patients with type 2 diabetes or prediabetes undergo screening for nonalcoholic steatohepatitis and liver fibrosis if they have elevated liver enzymes or an ultrasound examination shows signs of fatty liver.

Gabapentin is now listed along with pregabalin and duloxetine as first-line drug treatments for neuropathic pain in diabetes.

Women with active migraines are less likely to have type 2 diabetes mellitus (T2DM) and show a decrease in migraine symptoms prior to diagnosis of T2DM, indicating an inverse relationship between hyperglycemia, hyperinsulinism, and migraines, according to recent research published in JAMA Neurology.

“Because plasma glucose concentration rises with time up to the point of type 2 diabetes occurrence, the prevalence of migraine symptoms may decrease,” Guy Fagherazzi, PhD, at the Center for Research in Epidemiology and Population Health at the Gustave Roussy Institute in Villejuif, France, and his colleagues wrote in their study. “Consequently, tracking the evolution and especially the decrease of migraine frequency in individuals with migraine at high risk of diabetes, such as individuals with obesity, irrespective of age could be the sign of an emerging increased blood glucose levels, prediabetes, or type 2 diabetes.”

The researchers used data from the prospective Etude Epidémiologique Auprès des Femmes de la Mutuelle Générale de l’Education Nationale (E3N) study, initiated in 1990 and identified 74,247 women (mean age, 61 years old) with self-reported migraine in a 2002 follow-up questionnaire who had 10-year follow-up data during 2004-2014. The women in the cohort were born during 1925-1950 and completed biennial questionnaires about their health, including migraine status and medications, since 1992. The participants were divided into groups based on no migraine (49,199 participants), active migraine (7,839 participants), or prior migraine history (17,209 participants), and patients with T2DM at baseline were excluded.

Dr. Fagherazzi and his colleagues found 2,372 cases of type 2 diabetes over the follow-up period. Women who had active migraine status were less likely to have T2DM (hazard ratio, 0.80; 95% confidence interval, 0.67-0.96) than were the participants who did not have migraines, and this inverse association persisted after the researchers adjusted for factors such as myocardial infarction, education level, family history of diabetes, body mass index, smoking status, hypertension, physical activity, oral contraceptive use, menopausal status, menopausal hormone therapy, handedness, antimigraine preparations, and other prescribed migraine drugs (HR, 0.70; 95% CI, 0.58-0.85).

In the participants who developed T2DM, the researchers also found that there was a decrease in the prevalence of active migraine in the 24 years prior to T2DM diagnosis from 22% (95% CI, 16%-27%) to 11% (95% CI, 10%-12%) after adjusting for T2DM risk factors, which was then followed by an up to 22-year plateau in migraine prevalence of 11% for these participants.

“The linear decrease of migraine prevalence long before and the plateau long after type 2 diabetes diagnosis is novel and the association deserves to be studied in other populations,” Dr. Fagherazzi and his colleagues wrote. “The potential beneficial role of both hyperglycemia and hyperinsulinism on migraine occurrence needs to be further explored.”

The researchers noted limitations in the study, such as self-reported migraine by participants in the cohort, exclusion of non–pharmacologically treated T2DM cases, observational nature of the study, and homogenized population in the E3N cohort consisting of mainly women in menopause who were teachers and belonged to the same health insurance plan.

This study was funded by a grant from the French Research agency. The E3N cohort study was funded by the “Mutuelle Générale de l’Education Nationale,” European Community, French League against Cancer, Gustave Roussy, and French Institute of Health and Medical Research. Dr. Kurth is an advisory board member for CoLucid and has received funding for a research project from Amgen, honoraria from Lilly, lecture support from Novartis and Daiichi Sankyo, and travel support from the International Headache Society, as well as provided BMJ with editorial services.

SOURCE: Fagherazzi G et al. JAMA Neurol. 2018. doi: 10.1001/jamaneurol.2018.3960.

Women with active migraines are less likely to have type 2 diabetes mellitus (T2DM) and show a decrease in migraine symptoms prior to diagnosis of T2DM, indicating an inverse relationship between hyperglycemia, hyperinsulinism, and migraines, according to recent research published in JAMA Neurology.

“Because plasma glucose concentration rises with time up to the point of type 2 diabetes occurrence, the prevalence of migraine symptoms may decrease,” Guy Fagherazzi, PhD, at the Center for Research in Epidemiology and Population Health at the Gustave Roussy Institute in Villejuif, France, and his colleagues wrote in their study. “Consequently, tracking the evolution and especially the decrease of migraine frequency in individuals with migraine at high risk of diabetes, such as individuals with obesity, irrespective of age could be the sign of an emerging increased blood glucose levels, prediabetes, or type 2 diabetes.”

The researchers used data from the prospective Etude Epidémiologique Auprès des Femmes de la Mutuelle Générale de l’Education Nationale (E3N) study, initiated in 1990 and identified 74,247 women (mean age, 61 years old) with self-reported migraine in a 2002 follow-up questionnaire who had 10-year follow-up data during 2004-2014. The women in the cohort were born during 1925-1950 and completed biennial questionnaires about their health, including migraine status and medications, since 1992. The participants were divided into groups based on no migraine (49,199 participants), active migraine (7,839 participants), or prior migraine history (17,209 participants), and patients with T2DM at baseline were excluded.

Dr. Fagherazzi and his colleagues found 2,372 cases of type 2 diabetes over the follow-up period. Women who had active migraine status were less likely to have T2DM (hazard ratio, 0.80; 95% confidence interval, 0.67-0.96) than were the participants who did not have migraines, and this inverse association persisted after the researchers adjusted for factors such as myocardial infarction, education level, family history of diabetes, body mass index, smoking status, hypertension, physical activity, oral contraceptive use, menopausal status, menopausal hormone therapy, handedness, antimigraine preparations, and other prescribed migraine drugs (HR, 0.70; 95% CI, 0.58-0.85).

In the participants who developed T2DM, the researchers also found that there was a decrease in the prevalence of active migraine in the 24 years prior to T2DM diagnosis from 22% (95% CI, 16%-27%) to 11% (95% CI, 10%-12%) after adjusting for T2DM risk factors, which was then followed by an up to 22-year plateau in migraine prevalence of 11% for these participants.

“The linear decrease of migraine prevalence long before and the plateau long after type 2 diabetes diagnosis is novel and the association deserves to be studied in other populations,” Dr. Fagherazzi and his colleagues wrote. “The potential beneficial role of both hyperglycemia and hyperinsulinism on migraine occurrence needs to be further explored.”

The researchers noted limitations in the study, such as self-reported migraine by participants in the cohort, exclusion of non–pharmacologically treated T2DM cases, observational nature of the study, and homogenized population in the E3N cohort consisting of mainly women in menopause who were teachers and belonged to the same health insurance plan.

This study was funded by a grant from the French Research agency. The E3N cohort study was funded by the “Mutuelle Générale de l’Education Nationale,” European Community, French League against Cancer, Gustave Roussy, and French Institute of Health and Medical Research. Dr. Kurth is an advisory board member for CoLucid and has received funding for a research project from Amgen, honoraria from Lilly, lecture support from Novartis and Daiichi Sankyo, and travel support from the International Headache Society, as well as provided BMJ with editorial services.

SOURCE: Fagherazzi G et al. JAMA Neurol. 2018. doi: 10.1001/jamaneurol.2018.3960.

Women with active migraines are less likely to have type 2 diabetes mellitus (T2DM) and show a decrease in migraine symptoms prior to diagnosis of T2DM, indicating an inverse relationship between hyperglycemia, hyperinsulinism, and migraines, according to recent research published in JAMA Neurology.

“Because plasma glucose concentration rises with time up to the point of type 2 diabetes occurrence, the prevalence of migraine symptoms may decrease,” Guy Fagherazzi, PhD, at the Center for Research in Epidemiology and Population Health at the Gustave Roussy Institute in Villejuif, France, and his colleagues wrote in their study. “Consequently, tracking the evolution and especially the decrease of migraine frequency in individuals with migraine at high risk of diabetes, such as individuals with obesity, irrespective of age could be the sign of an emerging increased blood glucose levels, prediabetes, or type 2 diabetes.”

The researchers used data from the prospective Etude Epidémiologique Auprès des Femmes de la Mutuelle Générale de l’Education Nationale (E3N) study, initiated in 1990 and identified 74,247 women (mean age, 61 years old) with self-reported migraine in a 2002 follow-up questionnaire who had 10-year follow-up data during 2004-2014. The women in the cohort were born during 1925-1950 and completed biennial questionnaires about their health, including migraine status and medications, since 1992. The participants were divided into groups based on no migraine (49,199 participants), active migraine (7,839 participants), or prior migraine history (17,209 participants), and patients with T2DM at baseline were excluded.

Dr. Fagherazzi and his colleagues found 2,372 cases of type 2 diabetes over the follow-up period. Women who had active migraine status were less likely to have T2DM (hazard ratio, 0.80; 95% confidence interval, 0.67-0.96) than were the participants who did not have migraines, and this inverse association persisted after the researchers adjusted for factors such as myocardial infarction, education level, family history of diabetes, body mass index, smoking status, hypertension, physical activity, oral contraceptive use, menopausal status, menopausal hormone therapy, handedness, antimigraine preparations, and other prescribed migraine drugs (HR, 0.70; 95% CI, 0.58-0.85).

In the participants who developed T2DM, the researchers also found that there was a decrease in the prevalence of active migraine in the 24 years prior to T2DM diagnosis from 22% (95% CI, 16%-27%) to 11% (95% CI, 10%-12%) after adjusting for T2DM risk factors, which was then followed by an up to 22-year plateau in migraine prevalence of 11% for these participants.

“The linear decrease of migraine prevalence long before and the plateau long after type 2 diabetes diagnosis is novel and the association deserves to be studied in other populations,” Dr. Fagherazzi and his colleagues wrote. “The potential beneficial role of both hyperglycemia and hyperinsulinism on migraine occurrence needs to be further explored.”

The researchers noted limitations in the study, such as self-reported migraine by participants in the cohort, exclusion of non–pharmacologically treated T2DM cases, observational nature of the study, and homogenized population in the E3N cohort consisting of mainly women in menopause who were teachers and belonged to the same health insurance plan.

This study was funded by a grant from the French Research agency. The E3N cohort study was funded by the “Mutuelle Générale de l’Education Nationale,” European Community, French League against Cancer, Gustave Roussy, and French Institute of Health and Medical Research. Dr. Kurth is an advisory board member for CoLucid and has received funding for a research project from Amgen, honoraria from Lilly, lecture support from Novartis and Daiichi Sankyo, and travel support from the International Headache Society, as well as provided BMJ with editorial services.

SOURCE: Fagherazzi G et al. JAMA Neurol. 2018. doi: 10.1001/jamaneurol.2018.3960.