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The Wonders of GLP-1 Agonist — the LEADER Trial

Jun 25, 2016

In Depth: 76th ADA Scientific Sessions

Does liraglutide help in the reduction of cardiovascular diseases?

Cardiovascular disease (CAD), a comorbidity of diabetes, is on the rise. It is the cause of many deaths in type 2 diabetes mellitus (T2DM). Liraglutide, a GLP-1 agonist, has many benefits in the reduction of diabetes, improving B-cell function, reduction of body weight, decreasing circulating markers of low-grade inflammation, suppressing glucose secretion and helping in the reduction of hepatic sensitivity. Previous studies in animals confirmed that GLP-1 agonists have demonstrated a relaxing and vasodilatory effect on arteries. It also refines left ventricular ejection fraction (LVEF) in patients with cardiac failure. Additionally, it protects the heart against ischemic injury. Since LVEF is analyst for CAD mortality in patients with diabetes, it therefore increases the risk of ventricular dysfunction. Improvement in systolic function of the LV mediated through GLP-1 have encouraging therapeutic benefits in patients with CAD and type 2 diabetes.

The purpose of this study is to investigate whether liraglutide lowers the effects of cardiovascular diseases in type 2 diabetes. In this study, Metformin a biguanide which is normally the drug of choice is used alone to treat type 2 diabetes and this will act as a control. Another therapy of combined liraglutide and metformin is also used as the intervention. In a double blind, randomized placebo controlled crossover trial for 40 patients. Randomization is done by a computer in a 1:1 ratio. A 26 week study period including eight visits and a wash- out period is done and at each visits. Blood pressure, pulse, weight, waist, hip circumference and ECG are recorded. Liraglutide plus metformin was dosed as 0.6mg + 500 mg bid, then after 14 days as 1.2mg + (1000mg + 500mg) daily and after a total of 28 days as 1.8mg + 1000 mg bid. The placebo plus metformin is dosed the same way. For the statistical analysis, the primary endpoints was based on an estimator notion which controlled the period effects and assuming no period by treatment interactions including carry-over effects. The secondary analysis used modelling of the carry-over effect which is planned as a sensitivity analysis.

The statistical power was ≥90% for the primary end points and a P <0.05, meaning it was statistically significant. ANCOVA analysis was used to calculate the effect of its intervention. Patients who experienced severe hypoglycemia, or hyperglycemia, severe hypotension or hypertension, severe arrhythmia were treated. With those having a fasting blood glucose of >230mg/dL (13.3mmol/L) were withdrawn and offered additional antidiabetic treatment.

The LEADER trial randomly assigned diabetic patients at high risk for cardiovascular disease to receive liraglutide or placebo. The top-line result was a 13% reduction in heart attack, stroke, and cardiovascular death with liraglutide. In addition, the study found consistent reductions across a broad spectrum of cardiovascular outcomes and reductions in microvascular events, specifically in new persistent macroalbuminuria.

In yet another study which evaluates the cardiovascular outcome using Liraglutide in diabetic patients who happen to have Pancreatitis. Diabetes patients normally have a high risk of developing Pancreatitis. This could be due to an increase in hypertriglyceridemia, obesity or some antidiabetic drugs causing Pancreatitis. Previous studies reported an increased level of lipase and amylase which indicates Pancreatitis at baseline in type 2 diabetes. It has been demonstrated the values increases by administering liraglutide in T2DM with or without obesity. In this study called the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial 9340 participants with type 2 diabetes having CAD were recruited from 410 centers. They were randomized at a 1:1 of liraglutide to placebo. Participants with T2DM and elevated CAD were screened, patients who were drug naïve or on one or more antidiabetic drugs were noted. Those on GLP-1 or DPP-4 inhibitors were excluded. Their medical history was well noted. Liraglutide or its equivalent placebo dose on is added to their baseline treatment. Scheduled visits of 1, 3, 6 and every 6 months after randomization is done till 5 years when trial is completed. Endpoints like acute gallstone, pancreatitis, changes in serum lipase and amylase are measured. For statistical analysis, logarithmic transformation is used because amylase and lipase values are skewed to the right. A multivariable linear normal analysis of covariance was also used. All analyses were done using SAS version 9.3.

No subject had symptoms of pancreatitis at baseline, lipase activity was presented in 99.3% whilst amylase was 99.7%. Among subjects with T2DM, 16.6% had elevated lipase with a 3 fold elevation from baseline whilst amylase had 11.8% elevation which was more than 3 fold. Though in one study GLP-1 agonist receptor caused a decrease in CAD, in this study however it was found that GLP-1 receptor agonist caused an increase in pancreatic enzymes. It is therefore important for physicians to pay attention to clinical symptoms, diagnosing pancreatitis and treatment of diabetes using GLP-1 Agonist.

Practice Pearls:

  • LEVF is regarded as a strong predictor for cardiovascular mortality in patients with CAD and diabetes, since diabetes increase the risk of left ventricular dysfunction.
  • GLP-1 receptor agonist and dipeptidyl peptidase inhibitors are believed by the FDA to have a link between them and acute pancreatitis, therefore physicians be careful when prescribing these medication in T2DM.
  • The end results were a 13% reduction in heart attack, stroke, and cardiovascular death with liraglutide.

Anholm, Christian et al. “Adding Liraglutide to the Backbone Therapy of Biguanide in Patients with Coronary Artery Disease and Newly Diagnosed Type-2 Diabetes (the AddHope2 Study): A Randomised Controlled Study Protocol.” BMJ Open 4.7 (2014): e005942. PMC. Web. 15 June 2016.

Fox CS, Coady S, Sorlie PD, et al. “Increasing cardiovascular disease burden due to diabetes mellitus: the Framingham Heart Study. Circulation 2007; 115:1544–50. Web June 13 2016

Girman CJ, Kou TD Cai B, et al. Patients with type 2 diabetes mellitus have higher risk for acute pancreatitis compared with those without diabetes. Diabetes Obes Meta. 2010;33:2349-2354 Web 13 June 2016

Steinberg William M, Nauck Michael A, Zinman Bernard, et al.” Lipase and Amylase Activity in Subjects with Type 2 Diabetes: baseline data from over 9000 subjects in the LEADER Trial. Web June 13