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JFP - Diabetes Volume 65, No. 12

Funding for this newsletter series was provided by


Szymon L. Wiernek, MD, PhD

Department of Medicine University of North Carolina-Chapel Hill
Chapel Hill, NC

Matthew A. Cavender, MD, MPH

Department of Medicine University of North Carolina-Chapel Hill
Chapel Hill, NC

Disclosures

Dr. Wiernek has nothing to disclose

Dr. Cavender reports the following disclosures: AstraZeneca (consulting, advisory board, and research support [non-salary]) and Merck (consulting and advisory board)

Acknowledgments

The authors thank Meredith Rogers, MS, CMPP, of The Lockwood Group (Stamford, CT, USA) for providing editorial support, which was in accordance with Good Publication Practice (GPP3) guidelines and funded by AstraZeneca (Wilmington, DE, USA).

Funding/Support

The development of the manuscript was supported by AstraZeneca.







Effect of Non–Insulin-Based Glucose-Lowering Therapies
on Cardiovascular Outcomes in Patients With Type 2 Diabetes


Introduction

Since 1990, the incidence of type 2 diabetes (T2D) has increased 3-fold in the United States.1 Internationally, the number of people with diabetes has increased from 108 million in 1980 to 422 million in 2014.2 The phenotype of diabetes can vary considerably; however, the pathophysiology is united in the finding of insulin resistance and subsequent elevation of blood glucose. There is a clear association between diabetes (both type 1 and type 2) and the development of microvascular complications such as retinopathy, nephropathy, or neuropathy that can result in significant morbidity. Data from the UKPDS (UK Prospective Diabetes Study), which randomized patients to intensive therapy with either sulfonylureas or insulin, clearly showed that the incidence of these microvascular events can be reduced with glycemic control.3

There is also a well-described relationship between diabetes and cardiovascular (CV) events.4 Contemporary data from the REACH (Reduction of Atherothrombosis for Continued Health) Registry, an international study of patients at risk for myocardial infarction (MI) that collected data from 2003 to 2008, have shown that the association between diabetes and CV events continues in the current era, despite the high utilization of therapies aimed at treating diabetes and preventing CV events. The magnitude of the absolute risk for CV events is highest in patients with diabetes and prior ischemic events (MI, stroke) and less in those patients with no prior ischemic events but having additional risk factors for coronary artery disease (CAD).5

Cardiovascular disease (CVD) has historically been the leading cause of morbidity and mortality across the world, regardless of the presence of diabetes. Over the past 30 years, outcomes of patients with CAD have improved greatly due to the identification of risk factors for CAD, development of effective therapies, and widespread revascularization therapy. As a result, the overall number of deaths attributable to CAD has decreased.6 In patients with diabetes, CVD remains the predominant cause of morbidity and mortality and is a significant contributor to the costs of diabetes. Thus, the improvements in CV outcomes previously seen are now threatened as the incidence of T2D increases.

Observational studies show a clear association between the degree of glycemic control, as measured by glycated hemoglobin (A1c), and future CV events.7 However, it remains unclear whether glycemic control alone is sufficient to reduce CV events. In fact, prior studies of intensive vs conservative glucose management showed no significant difference in ischemic events and raised questions regarding the relationship between intensive glucose control and the risk of ischemic events. In the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study, intensive glycemic control with a goal A1c of <6% did not reduce major CV events and demonstrated an increase in 5-year mortality.8,9 Although the ADVANCE (Action in Diabetes and Vascular Disease) study and the VADT (Veterans Affairs Diabetes Trial) also failed to show reductions in macrovascular events with intensive glucose control over standard glucose control, these studies did not find a relationship between intensive glucose control and an increase in the risk of death.10,11

Current guidelines for the treatment of patients with diabetes are focused on improving glycemic control and treating appropriate CV risk factors. Basic recommendations include blood pressure management with a goal of
<140 mm Hg systolic pressure, statin therapy in all patients ≥40 years of age with diabetes (moderate intensity for all, and high intensity if at high risk of CVD events), and aspirin therapy in all adults at increased CV risk (10-year risk of CVD events >10%).12 Oral antihyperglycemic medications remain the cornerstone of treatment for optimizing glucose control in patients with diabetes. In this review, we aim to present the basic mechanisms for each class of commonly used non–insulin-based glucose-lowering drugs and to discuss the effect of these medications on CV events.

Biguanides

The American Diabetes Association guidelines currently recommend metformin as first-line therapy for the treatment of patients with T2D. Metformin works through the inhibition of the mitochondrial respiratory chain complex I, resulting in a decrease of hepatic glucose production.13 Metformin has also been shown to decrease intestinal absorption of glucose and potentially reduce insulin resistance.14-16 In addition to its effects on glycemic control, the use of metformin is also associated with maintenance of body weight, and data have been inconsistent with respect to blood pressure reductions and improvements in lipid profile, but there may be benefits.17-20 Commonly reported adverse events include gastrointestinal side effects and increased risk for folic acid and vitamin B12 deficiency; however, lactic acidosis is a rare complication.21

In the UKPDS-34 study, metformin compared with diet alone resulted in a 42% reduction in diabetes-related death, 36% reduction in all-cause mortality, 39% reduction in MI, and 30% reduction in the risk of macrovascular events.22 Long-term (>10-year) follow-up data showed persistent differences in diabetes-related death, death from any cause, and MI.20 However, this study had relatively few CV events, including only 112 MIs (of which 39 were in patients treated with metformin and 73 in patients treated with diet alone). Furthermore, there were no statistical differences in outcomes when metformin was compared with intensive glycemic control using alternative agents, such as chlorpropamide, glibenclamide, or insulin.22 When combined with the longstanding utilization of metformin in clinical practice, these data have resulted in metformin being recommended as the first-line oral therapy for patients with diabetes.

Sulfonylureas

Sulfonylureas are oral glucose-lowering therapies that work by closing adenosine triphosphate (ATP)–sensitive
K-channels in the beta-cell plasma membrane, resulting in the stimulation of insulin secretion from pancreatic beta cells.23 These medications are highly prescribed across the world because of their low cost and long history of use in the clinical care of patients with diabetes. Despite this, the clinical utility of sulfonylureas remains controversial. Sulfonylureas have higher rates of hypoglycemia than other oral glucose-control therapies.24 This risk seems to be increased even further in older patients or those with chronic kidney disease.25,26 The hypoglycemic effects of sulfonylureas appear to be additive, such that the risk is increased further when combined with other oral glucose-control therapies or insulin.27,28 Other potential side effects include weight gain, hypertension (potentially mediated through the release of antidiuretic hormone), growth hormone release, depression, Parkinsonism, and gastrointestinal disturbances.29

Some observational studies have also suggested that sulfonylureas may be associated with increased risk of CV events and all-cause mortality. In a study of 107,806 patients from Denmark, sulfonylureas were associated with increased mortality in patients without previous MI, including widely used agents such as glimepiride (hazard ratio [HR], 1.32; 95% confidence interval [CI], 1.24–1.40), glibenclamide (HR, 1.19; 95% CI, 1.11–1.28), glipizide (HR, 1.27; 95% CI, 1.17–1.38), and tolbutamide (HR, 1.28; 95% CI, 1.17–1.39).30 Similar associations were seen in the cohort of patients with prior MI. The associations seen in observational studies have not been seen in randomized trials such as UKPDS; however, these trials were relatively underpowered for CV events and were not designed to specifically address the CV safety of these agents. Although these agents continue to be widely used across the world, the utilization of sulfonylureas is likely to decline over time as they are replaced by newer agents that have been rigorously studied and have a better CV safety profile.

Thiazolidinediones

Thiazolidinediones (TZDs) are effective glucose-lowering drugs that work by improving insulin sensitivity. The mechanism of action of these drugs, is unique in that it results in the activation of the peroxisome proliferator-activated receptor-gamma (PPAR-γ), which is located in the nucleus of cells and regulates nuclear transcription.31 When agonists bind to the receptor, a corepressor dissociates from the receptor, allowing transcription to begin. Currently, 3 PPAR receptors (PPAR-β/δ, PPAR-γ, PPAR-α) are known in humans.32 The TZD class of medications work specifically through the activation of PPAR-γ. Several dual PPAR agonists that work through more than one PPAR have been developed, but none have been approved for use in clinical practice in the United States.

Rosiglitazone and pioglitazone were approved for use in clinical practice by the US Food and Drug Administration (FDA) in 1999 based on their effectiveness in reducing A1c and improving glycemic control. However, TZDs were found to increase plasma volume, resulting in edema, weight gain, and increased risk of heart failure.33,34 Some studies have suggested that TZDs may increase the risk of bladder cancer or fractures; however, this association has not been consistently seen in clinical outcomes studies.35 Although there was some concern that rosiglitazone may increase the risk of CV events, these concerns have largely been alleviated following the completion of the RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes) study
(FIGURE).36 The RECORD study randomized patients with T2D to either rosiglitazone or metformin and a sulfonylurea (n=4447). There was no increase in the primary composite endpoint of CV hospitalization or death (HR, 0.99; 95% CI, 0.85–1.16; TABLE36-46) nor was there an increase in the risk of CV death (HR, 0.84; 95% CI, 0.59–1.18), MI (HR, 1.14; 95% CI, 0.80–1.63), or stroke (HR, 0.72; 95% CI, 0.49–1.06).36 Consistent with prior studies showing that TZDs increased plasma volume, there was an increase in the risk of the composite endpoint of death or hospitalization for heart failure (HR, 2.10; 95% CI, 1.35–3.27).36

Pioglitazone has also been studied in a well-powered randomized clinical study. In the PROACTIVE (PROspective pioglitAzone Clinical Trial In macroVascular Events) study, patients with T2D and known atherosclerosis (N=5238) were randomized to either pioglitazone or placebo.37 The primary endpoint of the study was the composite of death, nonfatal MI (including silent MI), stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle. Treatment with pioglitazone did not result in a statistically significant reduction in the primary endpoint (HR, 0.90; 95% CI, 0.80–1.02); however, there was a statistically significant reduction in the secondary endpoint of death, nonfatal MI, or stroke (HR, 0.84; 95% CI, 0.72–0.98).37 Pioglitazone was also recently studied in patients with insulin resistance and ischemic stroke or transient ischemic attack (TIA) (N=3876) in the Insulin Resistance Intervention after Stroke (IRIS) study. Treatment with pioglitazone reduced the incidence of fatal or nonfatal stroke or MI by 24% (HR, 0.76; 95% CI, 0.62–0.93).39 Pioglitazone is currently being studied and compared with sulfonylureas in TOSCA.IT (Thiazolidinediones Or Sulphonylureas and Cardiovascular Accidents Intervention Trial), a large study of patients with diabetes who are inadequately controlled on metformin.47 This important study will provide further data on the efficacy and safety of both TZDs and sulfonylureas in the treatment of patients with diabetes.

FIGURE. Primary cardiovascular composite end-points (MACE) in major randomized clinical studies assessing cardiovascular risk of oral antidiabetic agents36*


Abbreviation: MACE, major adverse cardiac events.
*For detailed definition of primary endpoints in each study, see TABLE.36-46

TABLE. Completed and ongoing major randomized clinical studies assessing cardiovascular risk of oral anti-diabetic medications36-46

  Study Study drug Population No. of pts Primary endpoint HR
(95% CI)
Sulfonylureas
 None
TZDs

RECORD36

Rosiglitazone + metformin or sulfonylurea vs metformin +sulfonylurea

Diabetes

4447

Composite of CV hospitalization, or CV death

0.99 (0.85–1.16)

PROACTIVE37,38

Pioglitazone vs placebo

Diabetes + CVD

5238

Composite of all-cause death, MI, stroke, ACS, vascular intervention, or amputation

0.90 (0.80–1.02)

IRIS39

Pioglitazone vs placebo

Diabetes + recent TIA/stroke

3876

Recurrent fatal or nonfatal stroke, or MI

0.76 (0.62–0.93)

TOSCA.IT

Pioglitazone vs sulfonylurea

Diabetes

3371

Composite of all-cause death, MI, stroke, or unplanned coronary revascularization

Ongoing
SGLT-2 inhibitors

EMPA-REG40

Empagliflozin vs placebo

Diabetes + CVD

7020

Composite of CV death, MI, or stroke

0.86 (0.74–0.99)

CANVAS

Canagliflozin vs placebo

Diabetes + CVD/or high CV risk

4331

Composite of CV death, MI, or stroke

Ongoing

CREDENCE

Canagliflozin vs placebo

Diabetes + diabetic nephropathy

4200

Composite of ESKD, doubling of serum creatinine, renal or CV death

Ongoing

DECLARE-TIMI 58

Dapagliflozin vs placebo

Diabetes + CVD/or high CV risk

17,150

Composite of CV death, MI, or ischemic stroke

Ongoing
GLP-1 receptor agonists

LEADER41

Liraglutide vs placebo

Diabetes + high CVD risk

9340

Composite of CV death, MI, or stroke

0.87 (0.78–0.97)

SUSTAIN-642

Semaglutide vs placebo

Diabetes + CVD/or high CV risk

3297

Composite of CV death, MI, or stroke

0.74 (0.58–0.95)

ELIXA43

Lixisenatide vs placebo

Diabetes + recent ACS

6068

Composite of CV death, MI, stroke, or hospitalization for UA

1.02 (0.89–1.17)

FREEDOM-CVO

Exenatide vs placebo

Diabetes + CVD

4156

Composite of CV death, MI, stroke, or hospitalization for UA

Completed, not published

EXSCEL

Exenatide vs placebo

Diabetes

14,000

Composite endpoint of cardiovascular death, MI, or stroke

Ongoing

REWIND

Dulaglutide vs placebo

Diabetes + CVD/or high CV risk

9622

Composite endpoint of cardiovascular death, MI, or stroke

Ongoing
DPP-4 inhibitors

SAVOR-TIMI 5344

Saxagliptin vs placebo

Diabetes + CVD/or high CV risk

16,492

Composite of CV death, MI, or stroke

1.00 (0.89–1.12)

EXAMINE45

Alogliptin vs placebo

Diabetes + recent ACS

5380

Composite of all-cause death, MI, stroke, urgent revascularization, or HF admission

0.98 (0.86–1.12)

TECOS46

Sitagliptin vs placebo

Diabetes + CVD

14,671

Composite of CV death, MI, stroke, or hospitalization for UA

0.98 (0.88–1.09)

CAROLINA

Linagliptin vs glimepiride

Diabetes + CVD/or high CV risk

6051

Composite of CV death, MI, stroke, or hospitalization for UA

Ongoing

CARMELINA

Linagliptin vs placebo

Diabetes + high CVD risk

8300

Composite of CV death, MI, stroke, or hospitalization for UA

Ongoing

Abbreviations: ACS, acute coronary syndrome; CI, confidence interval; CVD, cardiovascular disease; DPP-4, dipeptidyl peptidase-4; ESKD, end-stage kidney disease; GLP-1, glucagon-like peptide-1; HF, heart failure; HR, hazard ratio; LV, left ventricle; MI, myocardial infarction; SGLT-2, sodium-glucose cotransporter-2; TIA, transient ischemic attack; TZD, thiazolidinedione; UA, unstable angina.

SGLT-2 inhibitors

Glucose is filtered by the kidneys and then reabsorbed by the sodium-glucose cotransporter-2 (SGLT-2) found in the proximal tubule of the kidney. Inhibition of SGLT-2 results in the excretion of glucose through the urine (glycosuria). The SGLT-2 inhibitors are a novel class of oral anti-diabetes medications; 3 SGLT-2 inhibitors are currently available for use in clinical practice—dapagliflozin, canagliflozin, and empagliflozin. In addition to their effects on glucose control from the glycosuria that results from SGLT-2 inhibition, these agents cause a mild diuretic effect that effectively reduces blood pressure, decreases body weight, and improves left ventricular diastolic function.48-50 These agents have been shown to reduce A1c independently of insulin secretion, and thus have a relatively low risk of hypoglycemia.51 However, the incidence of urinary tract infections, particularly yeast infections in women, and volume depletion is increased in patients treated with SGLT-2 inhibitors.52

The EMPA-REG (Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes) study randomized patients with known CAD to treatment with either an SGLT-2 inhibitor (empagliflozin 10 mg or 25 mg) or placebo. After a median follow-up of approximately 3 years, treatment with empagliflozin reduced the incidence of CV death, nonfatal MI, or nonfatal stroke (10.5% vs 12.1%; HR, 0.86; 95% CI, 0.74–0.99).40 The benefit was predominantly driven by a significant reduction in CV death (3.7% vs 5.9%; HR, 0.62; 95% CI, 0.49–0.77; P<.001). However, there were also reductions in hospitalization for heart failure (4.1% vs 2.7%; HR, 0.65; 95% CI, 0.50–0.85; P=.002)40 and progression of renal disease (12.7% vs 18.8%; HR, 0.61; 95% CI, 0.53–0.70; P<.001).53

CVD-REAL (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors), a large observational study of 365,828 patients from the United States, United Kingdom, Germany, Denmark, Sweden, and Norway, recently found that treatment with SGLT-2 inhibitors (dapagliflozin, canagliflozin, empagliflozin) was associated with lower rates of hospitalization for heart failure (HR, 0.61; 95% CI, 0.51‒0.73) compared with other anti-diabetes medications.54 In addition, there are ongoing CV outcomes studies evaluating dapagliflozin and canagliflozin. The DECLARE-TIMI 58 (Dapagliflozin Effect on CardiovascuLAR Events) study will randomize approximately 17,000 patients to either dapagliflozin 10 mg daily or placebo. Unlike the EMPA-REG study that included only patients with established CVD, the DECLARE-TIMI 58 study will include both a primary prevention cohort (patients with multiple risk factors for CVD) and a secondary prevention cohort (patients with established CVD). The primary endpoint is the composite of CV death, MI, or ischemic stroke. The CANVAS (CANagliflozin cardioVascular Assessment Study) is analyzing canagliflozin (100 mg or 300 mg daily) in patients with T2D and either established CVD or at high risk of CVD to determine whether it reduces the incidence of CV death, nonfatal MI, or nonfatal stroke. In addition to these large CV outcomes studies, additional randomized studies are being planned to determine whether SGLT-2 inhibitors can improve outcomes in a variety of patient populations, including populations with heart failure and renal insufficiency.

GLP-1 receptor agonists

Glucagon-like peptide-1 (GLP-1) is secreted from the gut after the ingestion of food and plays an important role in glucose regulation.55 Active GLP-1 increases insulin secretion/synthesis while decreasing glucagon and slowing gastric emptying, which ultimately results in the lowering of plasma glucose. Injectable forms of recombinant GLP-1 (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide) have been developed and are approved for use in the treatment of T2D. These agents work as analogues of human GLP-1 by binding to the same receptors as endogenous GLP-1 and stimulating the secretion of insulin.56 These drugs have several potential mechanisms by which they could modulate CV risk, including modest weight reduction, improved blood pressure control, and improvements in ventricular function.57-59 The most common adverse effects include diarrhea, nausea, and vomiting.60

The CV effects of GLP-1 agonism with liraglutide were studied in the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) study. In this study, 9340 patients with T2D who were at increased risk of CV events were randomized to either liraglutide 1.8 mg daily or placebo. The primary endpoint of the study was CV death, MI, or stroke, and treatment with liraglutide reduced this endpoint by 13% (HR, 0.87; 95% CI, 0.78–0.97; P=.01). Liraglutide specifically reduced the rates of CV death (4.7% vs 6.0%; HR, 0.78; 95% CI, 0.66–0.93; P=.007) and MI (1.9% vs 1.6%; HR, 0.86; 95% CI, 0.73–1.00; P=.046).41 Similar CV effects were seen in a small randomized trial, SUSTAIN-6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes), evaluating the CV safety of semaglutide, a once weekly GLP-1 agonist.42 Reductions in CV events were not seen with the use of lixisenatide in the ELIXA (Evaluation of Lixisenatide in Acute Coronary Syndrome) study.43 Continuous subcutaneous delivery of exenatide was studied in the FREEDOM-CVO trial (a Randomized, Multi-Center Study to Evaluate Cardiovascular Outcomes With ITCA 650 in Patients Treated With Standard of Care for Type 2 Diabetes). ITCA 650 is known to have met the FDA-mandated noninferiority criteria, but the full results have not yet been published. CV outcomes studies evaluating exenatide (EXSCEL [Exenatide Study of Cardiovascular Event Lowering Trial]) and dulaglutide (REWIND [Researching Cardiovascular Events with a Weekly Incretin in Diabetes]) are ongoing.

DPP-4 inhibitors

Dipeptidyl peptidase-4 (DPP-4) inhibitors work through a mechanism that is related to GLP-1 receptor agonists. Native GLP-1 stimulates insulin secretion, but it is actively degraded by the enzyme DPP-4. Therefore, the pharmacological inhibition of the DPP-4 enzyme results in higher levels of GLP-1, resulting in reductions of blood glucose.55 DPP-4 inhibitors have been found to be effective in improving glucose control while having low rates of hypoglycemia. The most common adverse reactions are upper respiratory tract infections, urinary tract infections, nasopharyngitis, and headaches.61

The SAVOR-TIMI 53 study (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with T2D) randomized 16,492 patients with either established CVD or known risk factors for CVD to receive saxagliptin or placebo. After a median follow-up of more than 2 years, saxagliptin was found to neither increase nor decrease the risk of ischemic events.44 Similar results were found in the EXAMINE study (Examination of Cardiovascular Outcomes: Alogliptin vs Standard of Care in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome), which studied alogliptin in patients after an acute coronary syndrome event,62 and in TECOS (Trial Evaluating Cardiovascular Outcomes with Sitagliptin), which studied sitagliptin in patients with established CV events.46 Patients treated with saxagliptin and patients without a history of heart failure treated with alogliptin had small but statistically significant increases in hospitalization for heart failure.45,63 The risk of heart failure was not seen in the TECOS study with sitagliptin.46 Taken as a whole, currently available DPP-4 inhibitors do not increase the risk of ischemic events. When initiating therapy, physicians should be cognizant of the potential for heart failure and consider close follow-up in those patients at risk for developing heart failure (such as those with known congestive heart failure, renal dysfunction, or elevated brain natriuretic peptide). Currently, there are 2 ongoing randomized clinical studies with linagliptin (CAROLINA [Cardiovascular Outcome Study of Linagliptin] and CARMELINA [Cardiovascular and Renal Microvascular Outcome Study with Linagliptin]), as well as others that will provide further data on the CV effects of DPP-4 inhibition.

Conclusions

In the current era, patients with diabetes continue to be at risk for both ischemic events and heart failure. There are many therapies that are effective in lowering blood glucose, yet to date, few of these therapies—including metformin, which is used as first-line therapy for diabetes—have demonstrated strong evidence to support concomitant reductions in CV risk. Metformin, in a study with few events conducted over 20 years ago, showed reductions in MI. The TZD class of medications has not been shown to reduce macrovascular events. Randomized clinical studies of DPP-4 inhibitors have found that this class of medications is safe in patients at high risk for CV events and effective in improving glucose control. Studies of liraglutide and semaglutide have found that GLP-1 receptor agonists can reduce the risk of CV events. Similarly, inhibition of SGLT-2 in the kidney in patients with established CVD has been shown to reduce CV events and heart failure. Ongoing trials will be helpful in further understanding the role of SGLT-2 inhibition in other patient populations.


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