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Breakthrough results for empagliflozin and liraglutide in type 2 diabetes

Breakthrough results for empagliflozin and liraglutide in type 2 diabetes

Publication date: Thursday, 23 June 2016
Contributor(s): Jeremy Bray

Two landmark trials of the newer anti-diabetes drugs empagliflozin and liraglutide have demonstrated significant cardiovascular and renal benefits in patients with type 2 diabetes at high cardiovascular risk. These exciting results were presented at the recent American Diabetes Association (ADA) annual meeting in New Orleans.

Professor Cliff Bailey (Professor of Clinical Science, Aston University, Birmingham, UK) said, “We now have prospective studies with two different types of glucose-lowering agents in addition to metformin showing overall benefits against cardiovascular disease in type 2 diabetes through actions beyond glycaemic control.”

Empagliflozin

New data from the EMPA-REG OUTCOME trial and published simultaneously in the New England Journal of Medicine show that the oral sodium-glucose contransporter-2 (SGLT-2) inhibitor empagliflozin significantly slows the progression of kidney disease in patients with type 2 diabetes and at high cardiovascular risk.  

The primary goal in the EMPA-REG OUTCOME trial was to assess cardiovascular outcomes. This new paper reports the results of a pre-specified secondary objective of that trial, which was to examine the effects of empagliflozin on microvascular outcomes with a particular focus on progression of kidney disease in patients with type 2 diabetes at high risk for cardiovascular events.

In the initial trial over 6000 patients with type 2 diabetes and at high risk of cardiovascular events were randomly assigned to one of two doses of empagliflozin or placebo on top of standard therapy. Empagliflozin was shown to reduce the risk of major adverse cardiovascular events by 38% relative to placebo. In this new analysis of microvascular outcomes, incident or worsening nephropathy occurred in 525 of 4124 patients taking empagliflozin and 388 of 2061 in the placebo group (12.7% vs 18.8%; HR, 0.61; p 0 .001) which repreented a significant risk reduction of 39%. Kidney dialysis was also reduced by more than half among those taking empagliflozin, although the absolute numbers affected were small (HR, 0.45; p = 0.041). There were also significant risk reductions in progression to macroalbuminuria and serum creatinine levels, alongside benefits for other renal outcome measures with empagliflozin use (Table 1).

Overall among patients with type 2 diabetes who were at high risk for cardiovascular events, the use of empagliflozin was associated with slower progression of kidney disease than placebo when added to standard care. Empagliflozin was also associated with a significantly lower risk of clinically relevant renal events. The study authors recommended that these results require further validation in trials longer than the 3 years of this study and can only be applied to the high cardiovascular risk type 2 diabetes population.

Renal outcome measure

Empagliflozin group

 Placebo group

Risk reduction, p

Progression to macroalbuminuria

11.2%

16.2%

38%, p < 0.001

Doubling of the serum creatinine level

1.5%

2.6%

44%, p < 0.001

Initiation of renal replacement therapy

0.3%

0.6%

55%, 0.04

Rate of incident albuminuria

51.5%

51.2%

5%, 0.25

Selected results from the EMPA-REG OUTCOME study.

Liraglutide

The GLP-1 receptor analogue liraglutide also significantly reduces the risk of major cardiovascular (CV) events and death in adults with type 2 diabetes, according to data from the LEADER trial released at ADA. Liraglutide is, to date, the only GLP-1 receptor agonist to demonstrate a superior reduction of major CV events versus placebo in a cardiovascular outcomes trial.

There was a significant 22% reduction in cardiovascular death with liraglutide treatment vs placebo (95% CI: 0.66; 0.93, p=0.007) and also reductions in non-fatal myocardial infarction (HR=0.88, 95% CI: 0.75; 1.03, p=0.11) and non-fatal stroke (HR=0.89, 95% CI: 0.72; 1.11, p=0.30). Liraglutide significantly reduced the risk of the composite primary endpoint of CV death, non-fatal myocardial infarction or non-fatal stroke by 13% vs placebo (95% CI: 0.78; 0.97, p=0.01), in addition to standard of care.

LEADER was a multicentre, international, randomised, double-blind, placebo-controlled trial investigating the long-term effects of liraglutide up to 1.8 mg compared to placebo, both in addition to standard of care*, in people with type 2 diabetes at high risk of major cardiovascular events. The trial was initiated in September 2010 and randomised 9340 people with type 2 diabetes at high CV risk from 32 countries that were followed for 3.5–5 years. The primary endpoint was the first occurrence of a composite cardiovascular outcome comprising cardiovascular death, non-fatal myocardial infarction or non-fatal stroke.

All-cause death was significantly reduced by 15% with liraglutide compared to placebo (95% CI: 0.74; 0.97, p=0.02). The expanded CV endpoint was significantly reduced by 12% with liraglutide compared to placebo (95% CI: 0.81; 0.96, p=0.005). From a mean baseline of 8.7% in both groups, there was a greater reduction in HbA1c with liraglutide vs placebo, in addition to standard of care, at three years (estimated treatment difference [ETD]: -0.40 per cent, 95 per cent CI: -0.45; -0.34). Weight loss was also sustained over three years with liraglutide treatment vs placebo (ETD: -2.3 kg, 95 per cent CI: – 2.5; -2.0).

The proportion of adults experiencing adverse events was similar between the liraglutide and the placebo groups (62.3% vs 60.8%, respectively). The most common adverse events leading to the discontinuation of liraglutide were gastrointestinal events. The incidence of pancreatitis was non-significantly lower in the liraglutide group than in the placebo group.

Implications

Commenting on the new trials, Professor Anthony H Barnett (Emeritus Professor of Medicine and Hon. Consultant Physician, University of Birmingham and Heart of England NHS Foundation Trust, Birmingham) said, “We now have 2 major cardiovascular endpoint studies which show significant reduction in cardiovascular mortality and cardiovascular events with these newer anti-diabetes therapies in subjects with type 2 diabetes at high cardiovascular risk. These are the first such agents licensed to treat diabetes which demonstrate hard outcome CV benefits. Add to this other benefits which include good efficacy in lowering blood glucose, extremely low risk of hypoglycaemia and weight loss. We can see that we now have some very useful tools to help our patients manage their diabetes. These attributes plus evidence for CV protection in high risk individuals will undoubtedly promote the view that these drugs can be used routinely in clinical practice and perhaps much earlier in the management algorithm for type 2 diabetes.”

These results may well have a significant impact on future prescribing for patients with diabetes with Professor Barnett adding, “Indeed, I can envisage the day when we will no longer routinely prescribe oral agents which promote weight gain and/or increase the risk of hypoglycaemia as we now have really useful alternatives."  

Professor Bailey concluded, “These studies also indicate that the different agents are generating their cardiovascular benefits through different mechanisms, expanding our options to address the cardiovascular risk of type 2 diabetes with agents primarily directed towards glycaemic control.”

CV outcome measure

Liraglutide group

 Placebo group

Risk reduction, p

Primary composite outcome**

13%

14.9%

13%, 0.01

Expanded CV composite outcome†

20.3%

22.7%

12%, 0.005

Cardiovascular death

4.7%

6.0%

22%, 0.007

Any cause mortality

8.2%

9.6%

15%, 0.02

Selected results from the LEADER study.

*Standard of care was defined as lifestyle modifications, selective glucose lowering treatments and cardiovascular medications.
 ** The first occurrence of death from cardiovascular causes, nonfatal (including silent) myocardial infarction, or nonfatal stroke.
Death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina pectoris or heart failure.

ACTION

Both empagliflozin and liraglutide now provide clinicians with additional oral options in treating patients with type 2 diabetes. The EMPA-REG OUTCOME trial shows a significant reduction in risk of renal outcomes with empagliflozin and the LEADER trial demonstrates that liraglutide significantly reduces major cardiovascular (CV) events and death in adults with type 2 diabetes.

Wanner C et al. Empagliflozin and progression of kidney disease in type 2 diabetes. NEJM 2016; June 14, 2016DOI: 10.1056/NEJMoa1515920

Empagliflozin SPC

Marso SP et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. New England Journal of Medicine. 2016; published online, 13 June, DOI: 10.1056/NEJMoa1603827

Liraglutide SPC

Empagliflozin (Jardiance®) and liraglutide (Victoza®) are currently indicated in the treatment of type 2 diabetes mellitus to improve glycaemic control in adults as:

  • Monotherapy - when diet and exercise alone do not provide adequate glycaemic control in patients for whom use of metformin is considered inappropriate due to intolerance.

Combination therapy - in combination with other glucose-lowering medicinal products including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control

Topics covered:
Category: Evidence in Practice
Edition: Volume 1, Number 6, BJPCN Online 2016
Contributor(s): Jeremy Bray

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