Diabetes medications with cardiovascular protection in the wake of EXSCEL: is there a class effect for long-acting GLP-1 receptor agonists?

Abstract

In previous editorials 1-3 we proposed that metformin, pioglitazone, sodium glucose transporter 2 (SGLT2) inhibitors (in particular empagliflozin and canagliflozin) and liraglutide in combination could complement each other to prevent cardiovascular events and save lives in patients with type 2 diabetes at high cardiovascular risk. In published trials with glucagon-like peptide-1 (GLP-1) receptor agonists, cardiovascular benefit has been shown for the long-acting agents liraglutide (LEADER 4 ) and semaglutide (SUSTAIN 6 5 ), although not for the short-acting agent lixisenatide (ELIXA 6 ). In the light of this there has been particular interest in the result of the EXenatide Study of Cardiovascular Event Lowering (EXSCEL) with once-weekly exenatide (exenatide QW), as this could potentially give insight into whether there was a class effect with regard to long-acting GLP-1 receptor agonists. Thus, for many healthcare professionals who care for patients with diabetes, there was some disappointment when, on 23 May 2017, AstraZeneca issued a press release announcing that, whilst EXSCEL had met its primary safety objective, "the efficacy objective of superior reduction in Major Adverse Cardiovascular Events (MACE; a composite end point of cardiovascular death, non-fatal myocardial infarction and nonfatal stroke) did not reach statistical significance". 7 Nevertheless, the full results were awaited with interest.On 14 September 2017, during the European Association for the Study of Diabetes congress in Lisbon, Portugal, the results of EXSCEL were presented 8 and published simultaneously in the New England Journal of Medicine. 9 The atmosphere in the auditorium was noticeably different from that of other similar presentations of cardiovascular outcome studies: EMPA-REG, 1 LEADER, 2 SUSTAIN 6 10 and, most recently, CANVAS. 3 This was because there were no slides showing significantly reduced cardiovascular death or significantly reduced 3-point MACE (cardiovascular death, nonfatal myocardial infarction and non-fatal stroke) to be greeted with enthusiastic applause by a large enthralled audience. The study was large (14,752 patients) with high cardiovascular risk and yet the primary composite end point, 3-point MACE, the same as that in LEADER and SUSTAIN 6, did not achieve statistical significance (hazard ratio (HR) 0.91; 95% confidence interval (CI) 0.83 to 1, p=0.06). 8,9 Another cardiovascular outcome study with a long-acting exenatide-based medication was FREEDOM-CVO with ITCA 650. 11 At first sight the top-line results seem similar to those of EXSCEL in apparently showing non-inferiority but not superiority. 11 However, FREEDOM-CVO recruited only about 4000 patients solely for the purpose of fulfilling the pre-approval cardiovascular safety outcome required by the US Food and Drug Administration (FDA). A separate trial dedicated to demonstrating possible cardiovascular benefit for ITCA 650 is under consideration. 11 Nevertheless, it is noteworthy that the amino acid structure differs between exendin-4 and native GL...

Diabetes medications with cardiovascular protection as we enter a new decade: can SGLT2 inhibitors, long-acting GLP-1 receptor agonists, pioglitazone and metformin complement each other to save lives?

“…1,2 Figure 1 shows side by side the results of the seven CVOTs (including PIONEER 6see below) with GLP-1RAs and is in keeping with a class effect for this group of agents. As pointed out previously, 11,12 the cardiovascular benefit of the GLP-1 RAs is confined to long-acting agents, with no benefit from short-acting lixisenatide (Figure 1). The novel finding from REWIND is that the cardiovascular benefit of dulaglutide was the same whether or not the patients had prior established cardiovascular disease.…”

“…In previous editorials we proposed that SGLT2 inhibitors, longacting GLP-1RAs, pioglitazone and metformin in combination could complement each other to prevent cardiovascular events and save lives in patients with type 2 diabetes at high cardiovascular risk. [8][9][10][11][12] We came to this conclusion because of the accumulated evidence from multiple studies suggesting that pioglitazone exerts cardiovascular benefit by slowing down, or even reversing, the atherosclerotic process, [8][9][10][12][13][14][15] whereas SGLT2 inhibitors seem to exert their cardiovascular benefits by improving cardiac haemodynamics and reducing heart failure, [8][9][10]12 and possibly by switching myocardial fuel metabolism to ketones. 16 By contrast, GLP-1RAs appear to exert their cardiovascular benefit by mechanisms different from those of both pioglitazone and SGLT2 inhibitors.…”

Changing the approach to type 2 diabetes treatment: A comparison of glucagon‐like peptide‐1 receptor agonists and sulphonylureas across the continuum of care

“…-11 of 18 the evidence to date suggests a class benefit for the long-acting GLP-1 RAs in reducing three-point MACE, cardiovascular mortality and all-cause mortality. 62,84,93…”

Diabetes medications with cardiovascular protection after HARMONY Outcomes and DECLARE-TIMI 58: could metformin, pioglitazone, SGLT2 inhibitors and long-acting GLP-1 receptor agonists complement each other to save lives by different mechanisms?

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In previous editorials [1][2][3][4] we proposed that metformin, pioglitazone, sodium glucose transporter 2 (SGLT2) inhibitors (in particular empagliflozin and canagliflozin) and long-acting glucagon-like peptide-1 (GLP-1) receptor agonists (in particular liraglutide) in combination could complement each other to prevent cardiovascular events and save lives in patients with type 2 diabetes at high cardiovascular risk. Since those editorials, new information has come to light to increase our understanding in the field; in particular, a presentation on 2 October 2018 during the European Association for the Study of Diabetes Congress in Berlin, Germany of the results of the HARMONY Outcomes study 5,6 and, on 10 November 2018 during the American Heart Association, Scientific Sessions in Chicago, USA, the results of the DECLARE-TIMI 58 study.

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“…In making this statement we refer to our previous editorial 4 where we proposed that the difference in outcome between the LEADER (liraglutide) and EXSCEL (exenatide QW) cardiovascular outcome studies with regard to statistical significance might be related to the fact that the LEADER patients were at higher cardiovascular risk and had longer exposure to study medication than the EXSCEL patients due to a high discontinuation rate in EXSCEL. 4 Although only top line results are available, REWIND, which compared dulaglutide against placebo in 9,931 patients with type 2 diabetes who were at high cardiovascular risk or who had a prior cardiovascular event, also demon-…”