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Are We Hitting the Sweet Spot with Medications for Type 2 Diabetes? Part 3

Ian Jackson

Former National Health Service (NHS) Prescribing Adviser and Senior Lecturer in Clinical Pharmacology and Therapeutics at a UK Medical/Pharmacy School. Director Green Pill Training Ltd.

Contact: ian.pharmacist@gmail.com

In this article we look behind the evidence for the use of glucagon-like peptides and analogues in the treatment of type 2 diabetes.

GLP Agonists and Mimetics: Going Against the Tide?

Glucagon-like peptide 1 (GLP-1) receptor agonists or GLP-1 analogues have advantages over older hypoglycaemic drugs, such as sulfonylureas, in that they cause less hypoglycaemic attacks and can help patients reduce weight.

In one large study involving 6068 patients with type 2 diabetics, who had had an acute coronary event within 180 days (ie.very high risk individuals), were randomly assigned to once-daily subcutaneous injections of lixisenatide or volume-matched placebo. The authors concluded the addition of lixisenatide to usual care did not significantly alter the rate of major cardiovascular events or other serious adverse events. (1)

The LEADER study was double-blind trial, whereby 9340 patients with type 2 diabetes and high cardiovascular risk were randomly assigned to receive liraglutide or placebo. The median follow-up was 3.8 years. The primary outcome of first occurrence of CV mortality, nonfatal MI, or non-fatal stroke was 13.0% for patients on liraglutide vs. 14.9% for those on placebo which gives a number needed to treat (NNT) of 53. In this study both the liraglutide and placebo arm had their medication intensified to achieve HbA1c≤7.0% when appropriate. The placebo group were more likely to be taking sulfonylureas to achieve this and as we have seen this increases the risks of hypoglycaemia and therefore cardiovascular risk. (2)

SUSTAIN-6 was a double-blind trail where Semaglutide GLP-1 receptor agonist. 1648 patients were on semaglutide (GLP-1 receptor agonist). 0.5mg or 1.0mg once weekly and 1648 patients were on placebo for 109 weeks. High risk patients at least one CV risk factor. Primary composite MACE 6.6% semaglutide and 8.9% placebo which gives an NNT=45 over 2 years.

Non-fatal stroke 1.6% in semaglutide and placebo 2.7% but levels of cardiac death were similar in both groups. During the trial, significantly more patients in the placebo group than in the semaglutide group received additional antihyperglycemic agents, including insulin, which was initiated more than twice as frequently in the placebo group. (3)

In the HARMONY study 4732 patients with CV and type 2 diabetes were assigned to receive albiglutide and 4732 to receive placebo.

The primary composite outcome was the first occurrence of cardiovascular death, myocardial infarction, or stroke  occurred in 7% of patients in the albiglutide group and in 9%  patients at an incidence rate after 1.5 years.

There were no differences in cardiac vascular death rates.  (4)

In the REWIND study 9901 participants were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952) median follow-up of 5·4 years

Primary composite outcome MACE 12% with dulaglutide and 13.4% with placebo (HR 0.88, CI 0.79-0.99) p=0.026 composite end point but no reduction in CV death or MI rates. Only a reduction in non fatal strokes. (5)


Glucagon-like peptide 1 (GLP-1) receptor agonists or GLP-1 analogues have been receiving a lot press coverage recently in terms of their weight reduction properties. On the face of it, some of these drugs have shown a reduction in cardiovascular events in type 2 diabetics. A couple of points need to be considered. These studies involved very high risk individuals eg. those who had just had a heart attack and also the fact that in the control arms of the studies the patients were more likely to be taking insulins or sulfonylureas, which increase the risk of hypoglycaemia. The control arm of these studies could therefore have a higher cardiovascular risk than the active arm.  The cardiovascular benefits of these drugs may not be as great as it first seems.


  1. Pfeffer M, et al. Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome. N Engl J Med 2015; 373:2247-2257.

2) Marso S, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2016; 375:311-322.

3) Marso S, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes (SUSTAIN-6) N Engl J Med 2016; 375:1834-1844

4) Hernandez A et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony). Lancet 2018; 392:1519-1529.

5) Gertein H, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes
(REWIND): a double-blind, randomised placebo-controlled trial Lancet 2019; 394: 121–30