Semaglutide in Patients with Type 2 Diabetes

Posted by • November 10th, 2016


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Regulatory guidance specifies the need to establish cardiovascular safety of new diabetes therapies in patients with type 2 diabetes in order to rule out excess cardiovascular risk. The preapproval Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6) conducted by Marso et al. was designed to assess the noninferiority of semaglutide as compared with placebo in terms of cardiovascular safety in patients with type 2 diabetes. Patients with type 2 diabetes at high cardiovascular risk received either once-weekly semaglutide, a glucagon-like peptide 1 analogue, or placebo. The rate of a first occurrence of cardiovascular death, nonfatal MI, or nonfatal stroke was significantly lower with semaglutide. Research is summarized in a new Original Article.

Clinical Pearl

To what class of drug does semaglutide belong?

Semaglutide, a glucagon-like peptide 1 (GLP-1) analogue with an extended half-life of approximately 1 week (which permits once-weekly subcutaneous administration), is currently in development but not yet approved for the treatment of type 2 diabetes. In the SUSTAIN-6 trial, patients were randomized in a 1:1:1:1 ratio to receive either 0.5 mg or 1.0 mg of once-weekly subcutaneous semaglutide or volume-matched placebo, which maintained blinding within dose.

Clinical Pearl

Is semaglutide noninferior to placebo with respect to cardiovascular safety in patients with type 2 diabetes?

The study by Marso et al. confirmed the authors’ primary hypothesis that semaglutide would be noninferior to placebo. Semaglutide-treated patients had a significant 26% lower risk of the primary composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke than did those receiving placebo. This lower risk was principally driven by a significant (39%) decrease in the rate of nonfatal stroke and a nonsignificant (26%) decrease in nonfatal myocardial infarction, with no significant difference in the rate of cardiovascular death. Similar risk reductions were observed with both doses of semaglutide. The number of patients who would need to be treated to prevent one event of the primary outcome over a period of 24 months was 45 on the basis of Kaplan–Meier estimates. The risk reduction for the primary outcome was seen despite an increase in pulse rate, a class effect for GLP-1–receptor agonists.


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Morning Report Questions

Q: Does the use of semaglutide in patients with type 2 diabetes improve microvascular outcomes?

A: In the study by Marso et al., semaglutide-treated patients had a lower risk of new or worsening nephropathy, according to differences in macroalbuminuria, but a higher risk of diabetic retinopathy complications than did those receiving placebo. Although the overall number of retinopathy events was low, there was an unexpected higher rate of retinopathy complications (vitreous hemorrhage, blindness, or the need for treatment with an intravitreal agent or photocoagulation) in the semaglutide group. An association between rapid glucose lowering and worsening of retinopathy has been reported in patients with type 1 diabetes. The applicability of such an association to the finding in SUSTAIN-6 is unclear, and a direct effect of semaglutide cannot be ruled out.

Q: How does semaglutide compare to other GLP-1–receptor agonists?

A: With the exception of complications of retinopathy, semaglutide had a safety profile in SUSTAIN-6 similar to that of other GLP-1–receptor agonists. The rate of malignant neoplasms was similar in the pooled semaglutide group and the pooled placebo group, although the highest rate was observed with the semaglutide dose of 1.0 mg. The rate of pancreatic cancer — an event of interest for this drug class — was lower with semaglutide, and no medullary thyroid carcinomas were reported in this trial. Pancreatitis occurred in low yet similar numbers of patients in the two pooled groups.

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