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Abstract Hertzel C Gersteinet al

Summary
Background

Three different glucagon-like peptide-1 (GLP-1) receptor agonists reduce cardiovascular outcomes in people with type 2 diabetes at high cardiovascular risk with high glycated haemoglobin A1c (HbA1c) concentrations.

We assessed the effect of the GLP-1 receptor agonist dulaglutide on major adverse cardiovascular events when added to the existing antihyperglycaemic regimens of individuals with type 2 diabetes with and without previous cardiovascular disease and a wide range of glycaemic control.

Methods

This multicentre, randomised, double-blind, placebo-controlled trial was done at 371 sites in 24 countries.

Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo.

Randomisation was done by a computer-generated random code with strati cation by site. All investigators and participants were masked to treatment assignment. Participants were followed up at least every 6 months for incident cardiovascular and other serious clinical outcomes.

The primary outcome was the first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown causes), which was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01394952.

Findings

Between Aug 18, 2011, and Aug 14, 2013, 9901 participants (mean age 66·2 years [SD 6·5], median HbA1c 7·2% [IQR 6·6–8·1], 4589 [46·3%] women) were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952).

During a median follow-up of 5·4 years (IQR 5·1–5·9), the primary composite outcome occurred in 594 (12·0%) participants at an incidence rate of 2·4 per 100 person-years in the dulaglutide group and in 663 (13·4%) participants at an incidence rate of 2·7 per 100 person-years in the placebo group (hazard ratio [HR] 0·88, 95% CI 0·79–0·99; p=0·026).

All-cause mortality did not differ between groups (536 [10·8%] in the dulaglutide group vs 592 [12·0%] in the placebo group; HR 0·90, 95% CI 0·80–1·01; p=0·067). 2347 (47·4%) participants assigned to dulaglutide reported a gastrointestinal adverse event during follow-up compared with 1687 (34·1%) participants assigned to placebo (p<0·0001).

Interpretation

Dulaglutide could be considered for the management of glycaemic control in middle-aged and older people with type 2 diabetes with either previous cardiovascular disease or cardiovascular risk factors.

 

Evidence before this study

We searched PubMed for reports published in English between Jan 1, 2010, and March 31, 2019, of double-blind, randomised, placebo-controlled trials that were designed to test the effect of gluca

gon-like peptide-1 (GLP-1) receptor agonists on incident cardiovascular events in people with type 2 diabetes. Search terms were “type 2 diabetes”, “GLP1-RA”, “glucagon-like peptide receptor 1 agonist”, “glucagon-like peptide receptor 1 analogue”, “lixisenatide”, “liraglutide”, “semaglutide”, “taspoglutide”, “albiglutide”, “dulaglutide”, “cardiovascular disease”, and “randomized controlled trial”.

This search identifed five trials that assessed the

• effects of lixisenatide (ELIXA; n=6068),

• albiglutide (Harmony Outcomes; n=9463), liraglutide (LEADER; n=9340),

• semaglutide (SUSTAIN-6; n=3297), or

• long-acting exenatide (EXSCEL; n=14 752) versus placebo on incident cardiovascular outcomes in people with type 2 diabetes whose mean age ranged from 54 years to 64 years and mean glycated haemoglobin A1c (HbA1c) ranged from 7·7% to 8·8%.

The trials were done in people with previous cardiovascular disease (ELIXA and Harmony Outcomes), or with a prevalence of cardiovascular disease ranging from 73% to 83% (LEADER, SUSTAIN-6, and EXSCEL). Median follow-up durations ranged from 1·6 years to 3·8 years. Trials that reported a reduced hazard ratio (HR) for the primary composite cardiovascular outcome of the first occurrence of non-fatal myocardial infarction or stroke, or death from cardiovascular causes were

• LEADER (HR 0·87, 95% CI 0·78–0·97), SUSTAIN-6 (HR 0·74, 0·58–0·95), and

• Harmony Outcomes (HR 0·78, 0·68–0·90).

These five trials suggested that GLP-1 receptor agonists might only reduce cardiovascular outcomes in people with previous cardiovascular disease. They also were unable to determine the cardiovascular effects of GLP-1 receptor agonists across a wide range of glycaemic control.

Added value of this study

The REWIND trial of 9901 people had a long median follow-up period of 5·4 years, recruited a low proportion of people (31·5%) with previous cardiovascular disease, a high proportion of women (46·3%), and followed people with a mean HbA1c of 7·3%.

Findings showed that weekly injections of the GLP-1 receptor agonist dulaglutide reduced cardiovascular outcomes in both men and women with or without previous cardiovascular disease, and had an effect size similar to that observed in the other GLP-1 receptor agonist cardiovascular outcomes trials.

Implications of all the available evidence

GLP-1 receptor agonists that have been shown to reduce cardiovascular outcomes should be considered for the management of glycaemic control in people with type 2 diabetes with either previous cardiovascular disease or cardiovascular risk factors.

 

From the article

Introduction

Despite the widespread use of many proven cardio­ protective therapies and a concomitant fall in risk of cardiovascular events1 during the past 20 years, diabetes continues to increase the risk of death and cardiovascular events by 1·5–2 times.2,3

Although reasons for this higher incidence are debated, the importance of knowing whether glucose­lowering drugs alter these outcomes has justi ed many large cardiovascular trials in this population.4 Evidence that three glucagon­like peptide­1 (GLP­1) receptor agonists5–8 and three sodium­glucose co­transporter­2 (SGLT2) inhibitors9,10 reduce cardio­ vascular events in middle­aged and older (≥50 years) people with type 2 diabetes and mean glycated haemo­globin A1c (HbA1c) concentrations of 8·0% or more has changed clinical practice guidelines11,12 and fuelled debate regarding mechanisms linking diabetes to cardiovascular disease.

Dulaglutide is a GLP­1 receptor agonist approved for the management of hyperglycaemia in people with type 2 diabetes in many countries. It comprises two modifed human GLP­1 molecules covalently linked to an IgG4 heavy chain molecule, has a half­life of 5 days, and is administered subcutaneously at weekly doses of 0·75 mg or 1·5 mg.13

Evidence that it safely reduces glucose concentration, blood pressure, weight,14 and albuminuria,15 and has other actions suggesting possible cardiovascular benefits16 supported its testing in a large cardiovascular superiority trial. Moreover, the fact that the cardiovascular effects of other GLP­1 receptor agonists were being tested in middle­aged people with high HbA concentrations and a 4% or higher annual risk of cardiovascular events highlihted higher annual risk of cardiovascular events highlighted the need to test the e ect of dulaglutide on cardiovas­ cular events in people with a broader cardiovascular risk and a wider range of glycaemic control.

Thus, the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial was designed to assess whether the addition of dulaglutide to the diabetes medication regimen of middle­aged and older people with type 2 diabetes safely reduces the incidence of cardiovascular outcomes compared with placebo

Discussion

This long­ duration randomised controlled trial of people with type 2 diabetes and only a 31·5% prevalence of previous cardiovascular disease showed that a weekly injection of 1·5 mg dulaglutide reduced the risk of cardiovascular outcomes compared with placebo, with the Kaplan­Meier curves starting to diverge within the first year.

Across the three components of the composite primary outcome, the greatest between­group difference was seen in the number of non­fatal strokes. In this population of people with a mean duration of type 2 diabetes of 10 years, in whom 25% had a baseline HbA1c less than 6·6% and 25% had a level more than 8·1%, dulaglutide durably reduced HbA1c by a mean absolute amount of 0·6% more than placebo while not increasing hypoglycaemia.

It also modestly reduced weight, LDL cholesterol, and systolic blood pressure, modestly increased heart rate, and was well tolerated with high adherence.

For every 60 people with type 2 diabetes and additional cardiovascular risk factors who were treated with dulaglutide for a median of 5·4 years versus placebo, one cardiovascular event was prevented. The number needed to treat is 18 for people with a previous cardio­vascular event.

The REWIND trial differs from previous cardiovascular outcomes trials with GLP­1 receptor agonists7,8 in several ways. First, the other trials were designed to show non­ inferiority to placebo with respect to cardiovascular events, whereas REWIND prospectively tested the hypothesis that dulaglutide was superior.

Second, most of the participants in REWIND did not have previous cardiovascular disease or a previous cardiovascular event. Thus, the average cardiovascular incidence of participants assigned to placebo was 2·7%, which was lower than the annual placebo incidence rates for the same composite outcome of 3·9% or higher in the other trials.5

Moreover, the broad inclusion criteria, high proportion of women, and the representativeness of the recruited participants25 in REWIND suggest that dulaglutide might be effective for both primary and secondary cardiovascular prevention in a high proportion of people with type 2 diabetes.

Third, the 5·4­year median follow­up was much longer than that in the other cardiovascular outcomes trials, in which median follow­up ranged from 1·5 years to 3·8 years,5,7 showing that the cardiovascular bene ts of GLP­1 receptor agonists extend much longer than previously reported.

Fourth, our trial shows the durability and safety of the effect of dulaglutide on glucose, blood pressure, and weight, and represents the longest trial of the e ect of a GLP­1 receptor agonist on these measures. Finally, our ndings show that dulaglutide reduces cardiovascular events in people with HbA1c concentrations both within and higher than guideline­ recommended targets, without increasing weight or the risk of hypoglycaemia, and has e ect sizes that are similar to those in the other trials with higher baseline HbA1c concentrations.5–7,26,27

Several possibilities could account for the salutary effects of dulaglutide and other GLP­1 receptor agonists on cardiovascular outcomes. These include the reduction in HbA1c, LDL cholesterol, blood pressure, and weight.

Emerging evidence also suggests that these drugs might independently improve endothelial function, endothelial cell responses to ischaemia, and platelet function, and might have direct neuroprotective e ects.28 These drugs might also attenuate progression of atherosclerosis, vascular in ammation, and vasoconstriction.29

Irrespective of the mechanism, the unique features of this trial add to a growing body of literature describing the cardiovascular effects of GLP­1 receptor agonists,8 and suggest that most middle­aged and older people with type 2 diabetes can achieve cardiovascular benefits with GLP­1 receptor agonists such as dulaglutide.

Consistent with the findings from three cardiovascular outcomes trials of other GLP­1 receptor agonists,5,6,27,30 the REWIND trial raises the possibility of a greater effect on stroke than on myocardial infarction.

Although it also raises the possibility of some geographical variation of effect, this variation loses statistical signi cance after accounting for the seven subgroups that were assessed (for which the Bonferroni­corrected p value for signi cance is <0·05/7 or 0·007), and might therefore be a spurious nding.

Finally, the suggestion of a protective effect of dulaglutide on renal outcomes is consistent with the other trials in which renal outcomes were reported,5,6,27 and supports further analyses of these effects. The long­term effect of dulaglutide on renal outcomes has been assessed in an exploratory analysis, published elsewhere.31

Strengths of these ndings include the trial’s broad and representative inclusion criteria and recruited partici­ pants,25 long follow­up, high retention, measurement of clinically relevant outcomes, and investigator freedom to use any non­GLP­1 receptor agonist drug.

Although less than a third of participants had previous cardiovascular disease, the observed cardiovascular effect size is similar to the HR of 0·87 from a meta­analysis of outcome trials of other GLP­1 receptor agonists in mainly secondary prevention populations.32 This observation, and the fact that there was a numerically greater use of proven cardioprotective drugs in the placebo group (which might have diminished the effect size of dulaglutide) further support these ndings. The major limitation is the observation that more than 25% of participants were not taking study drug at the time of their last visit. Although this might have also diminished the benefit of allocation to dulaglutide, the observation that participants took study drug for more than 80% of the follow­up time is reassuring.

Our findings show that the addition of dulaglutide to the medical regimen of people with type 2 diabetes and a broad range of glycaemic control reduced a composite of cardiovascular outcomes over a 5 year period.

Moreover our results suggest that dulaglutide could be added to the management of people with diabetes and additional cardiovascular risk factors to reduce glucose concen­ trations, minimise hypoglycaemia, reduce weight and blood pressure, and reduce cardiovascular events.

 

EDITORIAL The Lancet

Is it time to REWIND the cardiorenal clock in diabetes?

Comment

Following the regulatory requirements of 2008, randomised trials of glucose-lowering therapies have demonstrated safety, and in some cases superiority, with respect to cardiorenal outcomes.

Sodium-glucose co-transporter-2 (SGLT2) inhibitors have been shown to reduce cardiorenal outcomes across a broad spectrum of type 2 diabetes in the presence or absence of established vascular disease, and across a broad range of kidney function.1 These benefits appear independent of glycaemic control and are mediated through a range of mechanisms including e ects on systemic and renal haemodynamics.2 The greatest cardiovascular benefit is seen for heart failure, with a relative risk reduction of more than 30% observed across the trials.1,2 These therapies have also shown kidney protection, decreasing the risks of kidney failure and reduction in kidney function by a third on top of standard of care.1,3,4

The dipeptidyl peptidase-4 inhibitors have shown, in patients with established atherosclerotic vascular disease or multiple risk factors, neutrality for major adverse cardiovascular events and composite renal outcomes.5 Heterogeneity in cardiovascular outcomes has been noted with the glucagon-like peptide-1 (GLP-1) receptor agonists, with some showing superiority for major adverse cardiovascular events, and others neutrality.6

From a renal perspective, GLP-1 receptor agonists reduced albuminuria but did not prevent a decline in estimated glomerular ltration rate (eGFR) or end-stage kidney disease.6,7 Incretin-based therapies have not consistently a ected rates of hospital admission for heart failure, and in some instances, might have worsened this outcome.

In The Lancet, Hertzel Gerstein and colleagues8,9 report cardiovascular and renal outcomes from the REWIND trial. 9901 individuals (46% women, mean age 66 years) with type 2 diabetes, inadequate glycaemic control, and an eGFR of at least 15 mL/min per 1·73 m2 were randomly assigned to the GLP-1 receptor agonist dulaglutide (1·5 mg once weekly) or placebo, in addition to baseline medical therapies. More than two-thirds of the participants were considered to be in the primary cardiovascular prevention with risk factors category; the secondary prevention cohort included patients with atherosclerotic vascular disease with or without history of a cardiovascular event (myocardial infarction or ischaemic stroke).

The primary outcome (the firrst occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes or unknown causes) occurred in 594 (12·0%) of 4949 participants in the dulaglutide group and in 663 (13·4%) of 4952 participants in the placebo group (hazard ratio [HR] 0·88, 95% CI 0·79–0·99, p=0·026), with consistent benefits observed in the primary and secondary prevention cohorts.8

The renal composite outcome, which was studied in an exploratory analysis, occurred in 848 (17·1%) participants in the dulaglutide group and in 970 (19·6%) participants in the placebo group (HR 0·85, 95% CI 0·77–0·93, p=0·0004).9 Dulaglutide was associated with a modest reduction in glycated haemoglobin A (HbA )1c, bodyweight, and blood pressure, and a small increase in heart rate. There was no imbalance in serious adverse events between groups.

Several features of the REWIND trial deserve mention. Compared with previous studies of GLP-1 receptor agonists, individuals included in the REWIND trial were at a lower risk of cardiovascular events, with an average incidence of major adverse cardiovascular events in the placebo group of 2·7%.

The study enrolled the largest primary prevention cohort as far as we are aware thus far, and showed no heterogeneity in efficacy relative to those with established atherosclerotic vascular disease.

As has been reported in previous GLP-1 receptor agonist trials,10,11 the absolute risk reduction was higher in patients with atherosclerotic vascular disease compared with those without the condition (number needed to treat for dulaglutide to prevent one cardiovascular event over 5·4 years was 18 in patients with a previous cardiovascular event and 60 in those with type 2 diabetes and additional cardiovascular risk factors).

The REWIND trial, to our knowledge, had the longest follow-up (5·4 years), highest proportion of women (46%), and lowest baseline median HbA1c (7·2%), as well as showing e cacy over and above excellent background therapy, which, similar to other GLP-1 receptor agonist studies, was independent of baseline glycaemia, duration of diabetes, and weight.12

The magnitude of benefit on the composite cardiovascular outcome (12%) was modest, and numerically lower than that seen in the positive GLP-1 receptor agonist studies—namely, LEADER, SUSTAIN-6, and Harmony Outcomes—but consistent with the overall effect size from a meta-analysis of all previous GLP-1 receptor agonist trials.6

The primary outcome seemed to be driven largely by a reduction in stroke; a trend that was also observed with semaglutide in SUSTAIN-6.13 No di erence was seen between groups in hospital admission for heart failure.

From a renal perspective, the composite outcome of the firrst occurrence of new macroalbuminuria, a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy was reported on the basis of an exploratory analysis.

The renal benefits are noteworthy, particularly the observation that dulaglutide reduced the risk of eGFR decline when assessed by either a 30%, 40%, or 50% decline in eGFR, with an intriguing suggestion of clearer bene ts for the latter two outcomes alone or in combination with end-stage kidney disease.

The magnitude of eGFR preservation (between-group difference of 0·42 mL/min per 1·73 m2) was observed as a result of most patients being on an angiotensin- converting enzyme inhibitor or angiotensin-receptor blocker, and in the context of a baseline median eGFR of 75 mL/min per 1·73 m2, although it appears to be of smaller magnitude than that seen with the SGLT2 inhibitors.1,4

Although mechanisms of action were not studied, the vascular and renal benefits of GLP-1 receptor agonists, mediated independently of HbA1c, blood pressure, and weight changes, are well described.3,14,15

REWIND also adds to the emerging thesis that human GLP-1 receptor agonists show superiority (versus exendin-4 based agents) in terms of major adverse cardiovascular events. Limitations of the REWIND trial include that about a quarter of the patients were not on study drug at the completion of the study (similar to other studies of GLP-1 receptor agonists in which duration of follow-up was shorter), and the renal outcomes were exploratory and should be studied in further trials.

How do we integrate this growing body of evidence into a treatment approach? Although SGLT2 inhibitors and GLP-1 receptor agonists are recommended in patients with established atherosclerotic vascular disease, we now have evidence from the DECLARE-TIMI 586 and REWIND trials that SGLT2 inhibitors and GLP-1 receptor agonists afford cardiovascular superiority even in primary prevention; with SGLT2 inhibitors preventing heart failure and GLP-1 receptor agonists preventing atherosclerotic events, and both potentially a ording renal protection. If we are to reduce the burgeoning pump, pipes, and aflter complications of diabetes,16 we will need to overcome clinical inertia, and embrace these disease-modifying therapies early, and preferably in combination.

The REWIND trial makes a strong case in this regard.

Subodh Verma, C David Mazer, Vlado Perkovic

 

From the Lancet 

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