Introduction

The primary goals of type 2 diabetes treatment are prevention of microvascular, macrovascular, and other complications while maintaining quality of life. Strategies to control hyperglycemia are known to prevent microvascular complications such as retinopathy, neuropathy and nephropathy, but the impact on macrovascular complications has been limited, presumably as a consequence of the relatively small contribution of hyperglycemia to the pathogenesis of atherosclerosis. Although glycemic control is an essential component of treatment of type 2 diabetes, efforts to prevent macrovascular complications such as myocardial infarction, stroke, and peripheral vascular disease necessitate treatment of dyslipidemia, smoking cessation, blood pressure control, implementation of heart healthy dietary habits and regular physical activity, and possible treatment with aspirin and other medications. Although there may be an expectation that treatments for hyperglycemia should also prevent macrovascular complications in type 2 diabetes, it is important to recognize that microvascular complications are most impacted by glycemic control, whereas macrovascular complications are most impacted by control of traditional cardiovascular risk factors.

GLP-1 Biology

Glucagon-like peptide-1 (GLP-1) is peptide hormone that is secreted by enteroendocrine L-cells primarily in the distal small intestine and colon, alpha cells in pancreatic islets, and neurons in the central nervous system.¹ GLP-1 secreted in response to nutrient ingestion serves as an incretin hormone that mediates several beneficial regulatory effects on glucose assimilation and homeostasis. Among these physiologic effects, GLP-1 stimulates glucose-dependent insulin secretion from pancreatic islet cells (attenuated in the presence of a low plasma glucose concentration), suppresses secretion of the glucose-raising hormone glucagon from pancreatic islet alpha cells, delays gastric emptying, and suppresses appetite through mechanisms that may include binding to GLP-1 receptors in the arcuate nucleus, paraventricular nucleus, and dorsomedial nucleus of the hypothalamus.^2,3 GLP-1 receptors are also expressed in vascular endothelial and smooth muscle cells, an observation that has enhanced interest in potential cardiovascular effects of GLP-1 receptor agonists. The results of a recent study demonstrated that a variant in the GLP-1 receptor gene (rs10305492) was associated with lower fasting glucose concentrations, decreased risk of developing type 2 diabetes (OR 0.83; 95% confidence interval [CI] 0.76-0.91), and decreased risk of coronary heart disease (OR 0.93; 95% confidence interval [CI] 0.87-0.98) on the basis of data from up to 11,806 individuals assessed by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping.⁴ The results of this study provided support for the notion that treatment with GLP-1 receptor agonists may produce cardiovascular benefits. Five GLP-1 receptor agonists are currently available for clinical use (Table 1).

Table 1: GLP-1 Receptor Agonists Currently Available for Treatment of Type 2 Diabetes in the United States

Medication	Dosing
Albiglutide	30 to 50 mg SQ weekly
Dulaglutide	0.75 – 1.5 mg SQ weekly
Exenatide	5-10 μg SQ BID ER formulation: 2 mg SQ weekly
Liraglutide	1.2 – 1.8 mg SQ daily 3 mg SQ daily for weight loss
Lixisenatide	10-20 μg SQ daily

FDA Requirements for New Diabetes Medications

On the basis of controversial data suggesting that rosiglitazone may increase the risk of cardiovascular events, the US Food and Drug Administration (FDA) established a standard nearly 10 years ago that drugs developed for treatment of diabetes needed to be proven to not increase the risk of cardiovascular events. Rosiglitazone was later exonerated, but the requirement to prove non-inferiority to placebo for cardiovascular risk for new diabetes medications has persisted.⁵

LEADER Trial

The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial began in 2010 and involved 9,340 adults with increased cardiovascular risk and type 2 diabetes who were treated with liraglutide or placebo for a median treatment exposure of 3.5 years and median follow-up duration of 3.8 years.⁶ The purpose of the trial was to demonstrate non-inferiority of liraglutide compared to placebo for cardiovascular risk, in accordance with FDA guidelines. The inclusion criteria included a diagnosis of type 2 diabetes with HgbA1c > 7.0%, age > 50 years with at least one coexisting cardiovascular condition at study entry (coronary heart disease, cerebrovascular disease, peripheral vascular disease, chronic kidney disease of stage 3 or greater, or chronic heart failure of New York Heart Association class II or III) or age > 60 years with at least one cardiovascular risk factor as determined by the investigator (microalbuminuria or proteinuria, hypertension and left ventricular hypertrophy, left ventricular systolic or diastolic dysfunction, or an ankle-brachial index of < 0.9). The mean age was 64 +/- 7 years, the mean duration of diabetes was 12.8 +/- 8.1 years, the mean HgbA1c concentration was 8.7 +/- 1.5 %, and the mean body mass index was 32.5 ± 6.3 at study entry. Established cardiovascular disease was present in 81.3% and CKD (> stage 3) was present in 24.7%. Accordingly, the study population had a high risk of cardiovascular events. The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.

The median dose of liraglutide was 1.78 mg daily, which reflected the target dose of 1.8 mg daily or the highest tolerable dose. The HgbA1c concentration decreased by 0.4 (95% CI –0.45 to –0.34) at 36 months, body weight modestly decreased by 2.3 kg (95% CI –2.5 to –2.0), and systolic blood pressure decreased by –1.2 mm Hg (95% CI –1.9 to –0.5) during treatment with liraglutide compared to placebo, all P < 0.05.

The hazard ratio for the primary cardiovascular outcome was significantly reduced in the liraglutide group compared to placebo, with hazard ratio 0.87 (95% CI 0.78 to 0.97, P = 0.01). The expanded composite cardiovascular outcome (consisting of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, coronary revascularization, or hospitalization for unstable angina pectoris or heart failure) was also significantly reduced, with a hazard ratio of 0.88 (95% CI 0.81 to 0.96, P = 0.005). The rate of cardiovascular mortality was significantly lower in the liraglutide group, with hazard ratio 0.78 (95% CI 0.66 to 0.93, P=0.007), and total mortality (death from any cause) was also significantly lower in the liraglutide group, with hazard ratio 0.85 (95% CI 0.74 to 0.97, P = 0.02). The individual rates of nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure were nonsignificantly lower in the liraglutide group. The rate of incident nephropathy was significantly reduced by liraglutide compared to placebo (HR 0.78, 95% CI 0.67 to 0.92, P = 0.003), but the incidence of retinopathy was unaffected (HR 1.15, 95% CI 0.87 to 1.53, P = 0.33).

Severe hypoglycemia was less frequent in the liraglutide group (2.4 vs 3.3%, P = 0.02). Side-effects that lead to discontinuation of treatment were significantly more common in the liraglutide group (9.5 vs 7.3%, P < 0.001) and included nausea (1.6 vs. 0.4%), vomiting (0.7 vs. < 0.1%), diarrhea (0.6 vs. 0.1%), abdominal pain (0.2 vs. 0.1%), decreased appetite (0.2 vs. < 0.1%), and abdominal discomfort (0.2 vs. 0%), as anticipated. The incidence of acute gallstone disease was 3.1 versus 1.9% (P < 0.001). Despite the prior suggestion that GLP-1 receptor agonists may increase the risk of pancreatitis, the rates of acute and chronic pancreatitis were not significantly different in the liraglutide treatment group compared to placebo (0.4 vs. 0.5%, P = 0.44 and 0 vs. 0.04%, P = 0.16, respectively). A subsequent analysis of these data confirmed these findings, as well as demonstrating that the incidence of pancreatitis among a subgroup of 267 individuals with a previous history of pancreatitis was not increased during treatment with liraglutide compared to placebo.⁷ Although the difference did not reach statistical significance, the rate of pancreatic cancer was 0.3% in the liraglutide group compared to 0.1% in the placebo group (P = 0.06). In general, liraglutide was well tolerated with a placebo-controlled excess discontinuation rate of only 2.2%.

It is interesting to speculate why the primary composite outcome was driven primarily by cardiovascular and total mortality (P = 0.02 and 0.007, respectively), but the rates of many nonfatal events were not significantly different between the liraglutide and placebo groups. The incidence of total myocardial infarctions (fatal, nonfatal, and silent) was only borderline significantly different for liraglutide treatment compared to placebo (P = 0.046). It is somewhat surprising that none of the individual rates of fatal, nonfatal, and silent myocardial infarction, total stroke, nonfatal stroke, fatal stroke, transient ischemic attack, coronary revascularization, and hospitalization for unstable angina or heart failure were significantly different between treatment groups. These findings are still consistent with an antiatherosclerotic mechanism of cardiovascular event reduction during treatment with liraglutide, but the predominant effect on reduction in cardiovascular mortality suggest that other mechanisms may be responsible liraglutide mediated reduction in the primary and extended composite outcomes. A purely anti-atherosclerotic mechanism would not be anticipated to predominantly reduce cardiovascular mortality without significantly decreasing nonfatal events. The 20% reduction in the occurrence of confirmed hypoglycemia and 31% reduction in severe hypoglycemia are examples of nonatherosclerotic mechanisms by which treatment with liraglutide may have reduced cardiovascular mortality, but further analysis of the LEADER data and additional studies are needed to delineate the mechanisms by which liraglutide reduced the incidence of primary and extended composite outcomes in this study. An increased understanding of these mechanisms may shed light on the reasons why cardiovascular benefit has not been demonstrated with some other GLP-1 receptor agonists, as described below.

The subgroup analyses suggested that patients with established cardiovascular disease (>50 years old) and those with a glomerular filtration rate (GFR) < 60 ml/min/1.72 m2 may derive greater cardiovascular benefit from treatment with liraglutide compared to other subgroups. It is unclear why these two subgroups may have achieved more significant reductions in cardiovascular events, but subjects with established CVD or renal insufficiency both have increased risk of CHD events and therefore would be anticipated to be more likely to experience significant reductions in the incidence of cardiovascular. In contrast to the results for these two subgroups, the primary composite event rates were not significantly different when subjects were stratified for sex, age, geographic area, race or ethnicity, body mass index, HgbA1c concentration, duration of diabetes, heart failure, or number and type of anti-diabetic medications.

To summarize the results of the LEADER trial, the data demonstrated significant improvements in glycemic control, decreased incidence of severe hypoglycemia, modest weight loss, modest lowering of systolic blood pressure, decreased incidence of nephropathy, and a reduction in composite cardiovascular endpoints as well as total and cardiovascular mortality in high risk patients with type 2 diabetes treated with liraglutide compared to placebo. The rates of any adverse event (62.3 vs. 60.8%) or severe adverse event (32.2 vs. 32.8%) were not significantly different between the liraglutide and placebo treatment groups.

Results From Studies of Other GLP-1 Receptor Agonists

Since the effects of many medications on cardiovascular event rates are attributable to a class effect, and all GLP-1 receptor agonists reportedly have the same mechanism of action, it is reasonable to hypothesize that other GLP-1 receptor agonists will also prevent cardiovascular events. The limited data that are available from cardiovascular outcome trials using other GLP-1 receptor agonists have yielded inconsistent findings, with some trials showing no cardiovascular benefit.

The exploratory results from a large uncontrolled study population of 39,275 patients suggested that patients treated with exenatide twice daily had a significantly lower rate of cardiovascular events and hospitalizations compared to patients treated with other glucose-lowering medications.⁸ Despite these positive findings, the results from the subsequent randomized placebo-controlled EXenatide Study of Cardiovascular Event Lowering (EXSCEL) trial failed to demonstrate cardiovascular benefit in 14,752 high risk subjects with type 2 diabetes who were treated with long-acting exenatide 2 mg SQ weekly compared to placebo.^9,10 Fewer cardiovascular events occurred in the exenatide group, but the results were not significantly different from the placebo group. Full details from the study are still unavailable.

The results of another cardiovascular outcomes trial using lixisenatide also did not show cardiovascular benefit. In the Evaluation of Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus After Acute Coronary Syndrome During Treatment With Lixisenatide (ELIXA) trial, 6068 patients with type 2 diabetes and cardiovascular disease were treated with lixisenatide for a median duration of 2.1 years.¹¹ The subjects in this trial had a mean age of 60.3 +/- 9.6 years and HgbA1c 7.6 +/- 1.3%. The study demonstrated that lixisenatide was non-inferior to placebo for cardiovascular outcomes, but the primary composite cardiovascular outcome was not significantly reduced in the lixisenatide group (HR 1.02 ; 95% CI 0.89 to 1.17).

In contrast, the experimental GLP-1 receptor agonist, semaglutide, has been demonstrated to have cardiovascular benefit. The randomized placebo-controlled Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6) was designed to demonstrate the noninferiority of semaglutide compared to placebo for cardiovascular safety in 3297 patients with type 2 diabetes.¹² The study population consisted of 3297 subjects with type 2 diabetes and a mean age of 64.6 +/- 7.4, baseline HgbA1c 8.7 +/- 1.5, and baseline cardiovascular disease in 83% of the subjects. The results demonstrated a significant reduction in cardiovascular events in patients treated with semaglutide 0.5 or 1.0 mg subcutaneously weekly (hazard ratio 0.74; 95% confidence interval [CI] 0.58 to 0.95). Rates of nephropathy were lower, but complications of retinopathy were higher with semaglutide compared to placebo. Semaglutide is not yet FDA approved for clinical use in the United States.

Summary and Conclusions

In summary, GLP-1 has important postprandial physiological effects that include stimulation of insulin secretion in a glucose-dependent manner, suppression of glucagon secretion, decreased rate of gastric emptying, and suppression of appetite. Multiple GLP-1 receptor agonists have been developed for treatment of type 2 diabetes. All of the five currently clinically available drugs produce significant improvement in glycemic control in association with modest weight loss, but so far only liraglutide 1.2 to 1.8 mg SQ daily has been demonstrated to reduce the risk of cardiovascular events. The Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) of the FDA recently voted in favor of adding information from the LEADER trial to the labeling for liraglutide. Liraglutide is also FDA approved at the higher dose of 3 mg SQ daily for the purpose of weight loss. Long-acting exenatide and lixisenatide were non-inferior to placebo in relation to cardiovascular events, but neither demonstrated a significant reduction in cardiovascular events. Cardiovascular outcomes data are not yet available for albiglutide and dulaglutide, but the experimental GLP-1 agonist semaglutide has been shown to reduce the risk of cardiovascular events compared to placebo. It is possible that the differences in results from the various cardiovascular outcomes trials are related to differences in study populations or study design, but these features do not provide a clear explanation for the absence of a significant reduction in cardiovascular events with lixisenatide and extended release exenatide. Further studies are needed to clarify whether cardiovascular event reduction in response to treatment with GLP-1 receptor agonists is a class effect and to elucidate the mechanisms by which liraglutide and semaglutide reduce cardiovascular events. In the meantime, this class of drugs provides an effective option for treatment of hyperglycemia and mediating modest weight loss in type 2 diabetes.

References

1. Drucker DJ. The biology of incretin hormones. Cell Metab 2006;3:153-65.
2. Campbell JE, Drucker DJ. Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab 2013;17:819-37.
3. Flint A, Raben A, Astrup A, Holst JJ. Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J Clin Invest 1998;101:515-20.
4. Scott RA, Freitag DF, Li L, et al. A genomic approach to therapeutic target validation identnifies a glucose-lowering GLP1R variant protective for coronary heart disease. Sci Transl Med 2016;8:341ra76.
5. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for Industry: Diabetes Mellitus - Evaluating Cardiovascular Risk in Antidiabetic Therapies to Treat Type 2 Diabetes. Silver Spring: FDA, 2008.
6. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311-22.
7. Steinberg WM, Buse JB, Ghorbani MLM, et al. Amylase, lipase, and acute pancreatitis in people with type 2 diabetes treated with liraglutide: results from the LEADER randomized trial. Diabetes Care 2017;40:966-72.
8. Best JH, Hoogwerf BJ, Herman WH, et al. Risk of cardiovascular disease events with type 2 diabetes prescribed the glucagon-like peptide 1 (GLP-1) receptor agonist exenatide twice daily or other glucose-lowering therapies: a retrospective analysis of the LifeLink database. Diabetes Care 2011;34:90-5.
9. Holman RR< Bethel MA, George J, et al. Rationale and design of the EXenatide Study of Cardiovascular Event Lowering (EXSCEL) trial. Am Heart J 2016;174:103-10.
10. BYDUREON EXSCEL Trial Meets Primary Safety Objective in Type-2 Diabetes Patients at Wide Range of Cardiovascular Risk. AstraZeneca, 23 May 2017. Accessed 1 July 2017. https://www.astrazeneca-us.com/media/press-releases/2017/bydureon-exscel-trial-meets-primary-safety-objective-in-type-2-diabetes-patients-at-wide-range-of-cardiovascular-risk-05232017.html.
11. Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 2015;373:2247-57.
12. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375:1834-44.

Keywords: Glucagon-Like Peptide 1, Primary Prevention, Secondary Prevention, Diabetes Mellitus, Diabetes Mellitus, Type 2, Blood Pressure, Hypertrophy, Left Ventricular, Cardiovascular Diseases, Body Mass Index, Risk Factors, Angina, Unstable, Myocardial Infarction, Heart Failure, Hypoglycemia, Hypertension, Peripheral Vascular Diseases, Renal Insufficiency, Chronic, Metabolic Syndrome

< Back to Listings