GLP-1 Agonists in Diabetes and CV Risk: Tailor Therapy

Miriam E Tucker

December 19, 2017

The glucagonlike peptide-1 (GLP-1) receptor agonist class of glucose-lowering drugs may confer cardiovascular benefit in at-risk patients with type 2 diabetes, but there are differences among the individual agents, and therapy must therefore be individualized, new research suggests. 

Findings from a systematic review and meta-analysis of four large randomized cardiovascular-outcomes trials involving GLP-1 agonists were published online December 6 in Lancet Diabetes & Endocrinology by M Angelyn Bethel, MD, deputy director of the Diabetes Trials Unit, University of Oxford, United Kingdom, and colleagues.

Combined data for trials involving liraglutide (Victoza , Novo Nordisk), semaglutide (Ozempic, Novo Nordisk), lixisenatide (Adlyxin/Lyxumia, Sanofi), and extended-release exenatide (Bydureon, AstraZeneca) showed that the GLP-1 agonists produced a 10% relative risk reduction in the three-point composite outcome of cardiovascular mortality, nonfatal myocardial infarction, and nonfatal stroke (hazard ratio [HR], 0.90; = .033), as well as reductions in all-cause mortality.

"The ability of GLP-1 receptor agonists to reduce cardiovascular morbidity and mortality in patients with type 2 diabetes who are at moderate to high cardiovascular risk, in addition to their proven glucose-lowering ability, represents a major therapeutic advance," Dr Bethel and colleagues write.

However, the authors also note that "categorization of drugs by class is less useful when making individual patient treatment decisions. Differences between the GLP-1 receptor agonist drugs do exist in their structure, potency, and effect on cardiovascular risk.

"The choice of GLP-1 receptor agonist for an individual patient should be based on available evidence for effects on cardiovascular risk and incorporate drug characteristics important to patients, such as convenience, potency, ease of delivery, tolerability, and price."

Differences in GLP-1 Agonist Dosing May Explain Varying CVD Effects

Indeed, in an accompanying editorial, Simeon I Taylor, MD, of the division of endocrinology, diabetes, and nutrition, University of Maryland School of Medicine, Baltimore, delves into detail regarding the differences among the individual GLP-1 agonists, including some not included in the current meta-analysis, and the potential clinical implications of these.

In particular, Dr Taylor notes that the degree of cardiovascular protection for each agent generally parallels the dose-response curve seen for HbA1c-lowering. Based on calculations from head-to-head studies of glycemic control, he determined that rank order as: semaglutide, dulaglutide and liraglutide, extended-release exenatide, and albiglutide, short-acting exenatide, then lixisenatide.

"Despite limitations of this analysis (especially a reliance on processes to normalize HbA1c lowering), there was a remarkable degree of correlation (r = 0.998) between the point estimate for cardiovascular risk reduction and normalized HbA1c lowering," Dr Taylor writes.

Thus, he points out, the differences in cardiovascular effect among the individual agents may relate to the way they are dosed.

For example, "the absence of apparent cardioprotection in Evaluation of Lixisenatide in Acute Coronary Syndrome [ELIXA] trial might have been caused by selection of a lixisenatide dose that is too far to the left on the dose-response curve."

Asked to comment, Dr Bethel told Medscape Medical News, "Dr Taylor's approach to ranking the GLP-1 receptor agonists…which has identified a correlation between A1c lowering and [major adverse cardiovascular events] MACE risk reduction, is interesting.

"But, as he says himself, it is subject to a number of limitations, not the least of which is the assumption that HbA1c lowering and cardiovascular event reduction are mediated via similar mechanisms."

Nonetheless, she added, "we have also hypothesized that it is possible that dose, drug potency, or medication compliance issues may partially underlie some of the differences seen in the individual GLP-1 receptor agonist trial outcomes."

Overall, a Favorable Risk/Benefit Profile for GLP-1 Agonists

The meta-analysis combined data from four CV-outcomes trials: ELIXA, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results—A Long Term Evaluation (LEADER), Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN-6), and Exenatide Study of Cardiovascular Event Lowering (EXSCEL), involving a total of 33,457 moderate-high risk type 2 diabetes patients.

Of these four trials reported individually, only LEADER and SUSTAIN-6 showed a significant reduction in the primary outcome of three-point MACE.

But overall combining them, for three-point MACE (cardiovascular mortality, nonfatal myocardial infarction, and nonfatal stroke), the hazard ratio for relative risk reduction vs placebo was 0.90 (= .033). Significant relative risk reductions were also seen in cardiovascular mortality (HR, 0.87; = .007) and all-cause mortality (HR, 0.88; = .002).

However, there were no significant effects of GLP-1 agonists on fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, hospital admission for unstable angina, or hospital admission for heart failure compared with placebo.

There were also no differences in the proportions with severe hypoglycemia (odds ratio [OR], 0.93; = .56), acute pancreatitis (OR, 0.90; = .54), pancreatic cancer (OR, 0.83; = .70), or medullary thyroid cancer, but there was an overall numeric imbalance in papillary thyroid cancers (17 in GLP-1 agonist groups vs 10 placebo).

Differences Among GLP-1 Receptor Agonists and Clinical Impact

In addition to the dosing issue, Dr Taylor points out that the clinical profile of GLP-1 agonists may also differ by their pharmacokinetics, in that the short-acting ones with higher peaks of action may be more likely to predispose patients to nausea and vomiting, a known side effect that could affect adherence. Differences in molecular weight and binding properties may also differentially affect cardiovascular risk.  

Dr Taylor also notes that all four cardiovascular-outcomes trials "focus on analysis of mean data and implicitly support a one-size-fits-all therapeutic approach. However, there is considerable interindividual variation with respect to the magnitude of clinical benefit, suggesting that a personalized medicine strategy might enable physicians to select the best drug for each patient."

For example, both liraglutide and extended-release exenatide's cardiovascular benefits were seen only among obese patients, and not among those with body-mass indexes <30 kg/m2.

Dr Bethel advised that clinicians consult the new 2018 American Diabetes Association Standards of Medical Care for guidance on individualization of therapy.

Those guidelines say that in patients with atherosclerotic cardiovascular disease (ASCVD) in whom metformin isn't sufficient to meet glycemic targets, consideration should be given to an agent with proven cardiovascular risk reduction — such as the GLP-1 agonist liraglutide — and/or mortality reduction — such as that observed with the sodium glucose cotransporter-2 (SGLT2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Lilly).

Of course, Dr Bethel adds, this should be done "after consideration of drug-specific and patient factors, including potency, cost, convenience, and tolerability."

The study was funded by Amylin Pharmaceuticals (AstraZeneca). Dr Bethel has received research support from AstraZeneca, GlaxoSmithKline, and Merck; participated in advisory boards, steering committees, or data safety monitoring boards for Boehringer Ingelheim, AstraZeneca, NovoNordisk, and Theracos; and received honoraria for participation in academic conferences from Sanofi. Disclosures for the coauthors are listed in the paper. Dr Taylor has received grant support from the US National Institute of Diabetes and Digestive and Kidney Diseases and the American Diabetes Association. He has received personal fees from Ionis Pharmaceuticals, grants from Regeneron, and owns stock in Celgene, Abbott Laboratories, and Amgen. He was previously employed at Bristol-Myers Squibb (2002–2013). Bristol-Myers Squibb acquired the exenatide program as part of the acquisition of Amylin, but he was not involved in the exenatide program during his time at the company. He divested all Bristol-Myers Squibb stock in 2016, and the exenatide program was sold to AstraZeneca in 2014. Bristol-Myers Squibb and AstraZeneca jointly acquired Amylin Pharmaceuticals' exenatide program in 2012, but he has not had any role with respect to the exenatide program since he left Bristol-Myers Squibb in 2013.

Lancet Diabetes Endocrinol. Published online December 6, 2017. Abstract, Editorial

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