Comparative efficacy, safety, and cardiovascular outcomes with once-weekly subcutaneous semaglutide in the treatment of type 2 diabetes: Insights from the SUSTAIN 1–7 trials

Abstract

In individuals with type 2 diabetes, glycaemic control and cardiovascular risk factor management reduces the likelihood of late-stage diabetic complications. Guidelines recommend treatment goals targeting HbA1c, body weight, blood pressure, and low-density lipoprotein cholesterol. Development of new treatments for type 2 diabetes requires an understanding of their mechanism and efficacy, as well as their relative effects compared to other treatment choices, plus demonstration of cardiovascular safety. Subcutaneous semaglutide is a glucagon-like peptide-1 receptor agonist currently approved in several countries for once-weekly treatment of type 2 diabetes. Semaglutide works via the incretin pathway, stimulating insulin and inhibiting glucagon secretion from the pancreatic islets, leading to lower blood glucose levels. Semaglutide also decreases energy intake by reducing appetite and food cravings, and lowering relative preference for fatty, energy-dense foods. Semaglutide was evaluated in the SUSTAIN clinical trial program in over 8,000 patients across the spectrum of type 2 diabetes. This review details the efficacy and safety profile of semaglutide in the SUSTAIN 1-5 and 7 trials, and its cardiovascular safety profile in the SUSTAIN 6 trial. Semaglutide consistently demonstrated superior and sustained glycemic control and weight loss vs all comparators evaluated. In SUSTAIN 6, involving patients at high risk of cardiovascular disease, semaglutide significantly decreased the occurrence of cardiovascular events compared with placebo/standard of care (hazard ratio 0.74, p<0.001 for noninferiority). Through a comprehensive phase 3 clinical trial program, we have a detailed understanding of semaglutide's efficacy, safety, cardiovascular effects and comparative role in the treatment of type 2 diabetes.

Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomised, phase 3a trial

“…1 Semaglutide is a GLP-1 analogue currently approved for once-weekly subcutaneous injection for treatment of type 2 diabetes, 2 and has been shown to decrease HbA1c and bodyweight effectively in patients who have uncontrolled hyperglycaemia on one or more oral glucose-lowering drugs. 3 Elimination of semaglutide occurs via multiple pathways involving both the liver and kidneys. 4 An oral semaglutide tablet has been developed, in which semaglutide is coformulated with the absorption enhancer, sodium N-(8-[2-hydroxybenzoyl]amino) caprylate, to facilitate semaglutide absorption across the gastric mucosa.…”

Reappraisal on pharmacological and mechanical treatments of heart failure

“…The FIGHT trial, a multicentre, double-blind, placebo-controlled randomized clinical trial of HFrEF, revealed that the use of liraglutide did not lead to greater post-hospitalization clinical stability [143]. In SUSTAIN 6, involving 3297 patients with type 2 diabetes who were at high cardiovascular risk, the rate of cardiovascular death, nonfatal MI, or nonfatal stroke was significantly lower among patients receiving semaglutide than among those receiving placebo, an outcome that confirmed the noninferiority of semaglutide [144,145].…”

Clinical review of the efficacy and safety of oral semaglutide in patients with type 2 diabetes considered for injectable GLP-1 receptor agonist therapy or currently on insulin therapy

“…A summary of selected efficacy outcomes from the SUSTAIN program is shown in Table 2. Subcutaneous semaglutide demonstrated superior and sustained reductions in HbA 1c versus all comparators, including other injectable therapies, and the 1 mg dose appears to have the greatest weight loss efficacy within the GLP-1RA class [22,25,26]. In addition, subcutaneous semaglutide was found to significantly reduce the risk of major adverse CV events in patients with T2D at high CV risk in the SUSTAIN 6 study [6], and is now approved by the FDA for reducing the risk of such events in patients with T2D and established CV disease [3].…”

“…Semaglutide is a GLP-1RA that has high (94%) homology with human GLP-1 but has structural modifications to increase binding to serum albumin and delay degradation in the plasma, giving a long elimination half-life suitable for once-weekly administration by subcutaneous injection [3,18,19]. The clinical effects of subcutaneous semaglutide were investigated in the SUSTAIN program, which encompassed the full spectrum of diabetes care, including early therapy (SUSTAIN 1), and comparisons with other GLP-1RA therapies (exenatide ER [SUSTAIN 3], dulaglutide [SUSTAIN 7]), and with insulin therapy (SUSTAIN 4) [20][21][22][23][24]. A summary of selected efficacy outcomes from the SUSTAIN program is shown in Table 2.…”