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 HbA_1c, 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 programme in over 8000 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 non-inferiority). 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.

Introduction

In individuals with type 2 diabetes (T2D), adequate glycaemic control and cardiovascular (CV) risk factor management reduces the likelihood of late-stage diabetic micro- and macrovascular complications [1].

However, despite efforts with lifestyle intervention, most patients still require additional pharmacological therapy to achieve and maintain glycaemic control [1]. Although there are numerous pharmacological therapies available for the treatment of T2D, it is estimated that a third to nearly a half of patients still fail to meet their targets for glycaemic control, blood pressure, and low-density lipoprotein cholesterol (LDL-C) levels [2]. Furthermore, there is a need for treatments that maximize efficacy, adherence and improvement in CV risk as well as quality of life [3].

The vast majority (∼86%) of patients with T2D are overweight or obese [4]. In such patients, modest (≥ 5% of body weight) and sustained weight loss has been shown to improve glycaemic control and reduce the need for glucose-lowering medications [5], [6].

Diabetes significantly increases the risk of atherosclerotic CV disease [7], [8]. Since 2008, a number of CV outcomes trials have completed, evaluating the safety profile of new treatments for T2D [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20]. Differential effects of treatments on glycaemia, weight, hypertension and dyslipidaemia may further influence CV risk [8], [21], [22]. The recent joint American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) Consensus Report highlights the importance of considering CV disease history early in the diabetes treatment pathway. This is based on the evidence that several sodium–glucose co-transporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve CV outcomes and progression of renal impairment in patients with T2D at high CV risk [23].

Semaglutide has 94% amino acid sequence homology with native human GLP-1, with several modifications that enable increased binding of albumin and slowed degradation in plasma [24]. Subcutaneous semaglutide is a GLP-1RA currently approved by the US Food and Drug Administration (FDA) [25], European Medicines Agency [26], Health Canada [27], and Japan’s Ministry of Health, Labour and Welfare [28] for the once-weekly treatment of T2D. The phase 3 programme (PIONEER) for an oral form of semaglutide is underway with full results from PIONEER 1–6 expected in 2019.

Semaglutide works via the incretin pathway, which stimulates insulin and inhibits glucagon secretion from the pancreatic islets in a glucose-dependent manner, leading to lower blood glucose levels with low risk for hypoglycaemia [29]. Treatment with semaglutide results in weight loss, the mechanism of which is not fully understood, although studies in animal models have shown that liraglutide, another GLP-1RA, can access the central nervous system and likely mediates weight loss through its action on pro-opiomelanocortin/cocaine- and amphetamine-regulated transcript-expressing arcuate nucleus neurons [30]. Clinically, semaglutide has been shown to lower energy intake by reducing appetite and food cravings, improve control of eating and meal portion size management, and lower relative preference for fatty, energy-dense foods [31].

The SUSTAIN (Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes) clinical trial programme included seven randomized controlled phase 3 trials involving more than 8000 patients with T2D [14], [32], [33], [34], [35], [36], [37]. Six efficacy trials, SUSTAIN 1–5 and SUSTAIN 7, were designed to evaluate the efficacy and safety of semaglutide vs. comparators, and covered a broad range of the T2D treatment continuum [32], [33], [34], [35], [36], [37]. SUSTAIN 6 was a safety trial designed to evaluate CV and other long-term outcomes with semaglutide in patients with T2D who were at high CV risk [14]. Here, we provide an overview of the efficacy and safety profile of semaglutide in the SUSTAIN 1–5 and 7 clinical trials, as well as its CV safety profile in the SUSTAIN 6 trial.