We are in the midst of a pandemic of type 2 diabetes mellitus (T2DM) as a consequence of the increasing prevalence of obesity. There are multiple metabolic abnormalities associated with T2DM that are amenable to targeting by novel drugs. Among these abnormalities is the loss of the incretin effect, defined as the increased stimulation of insulin secretion and suppression of glucagon elicited by oral as compared with intravenous administration of glucose under similar plasma glucose levels. The two most important incretins are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 is a 30 amino acid-long peptide produced and secreted by intestinal enteroendocrine L-cells and certain neurons within the nucleus of the solitary tract in the brainstem upon food consumption. In T2DM, there is almost total loss of the incretin effect, and this pathophysiology has been targeted by dipeptidyl peptidase-4 (DPP-4) inhibitors, or gliptins, which reduce the breakdown of GLP-1. Oral DDP-4 inhibitors (sitagliptin and 12 other drugs in the class) have a modest impact on reducing glycohemoglobin, are neutral on body weight and have a null effect on major adverse cardiac events (MACE). Parental GLP-1 agonists (exenatide and five other drugs in the class), or incretin mimetics, represent a more powerful approach and have been demonstrated to lower glycohemoglobin, reduce weight, and in some trials have demonstrated reductions in MACE—primarily myocardial infarction (MI) and/or ischemic stroke. As a working example, SUSTAIN-6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes) randomized 2735 patients with T2DM; 83% with cardiovascular (CV) disease to semaglutide (0.5/1.0 mg SQ weekly) versus placebo for two years. Glycohemoglobin was decreased from 8.7% to 7.6% and 7.3% in the 0.5 and 1.0 mg groups, respectively. There was a ~5% reduction in body weight with semaglutide. The composite primary outcome of nonfatal MI, nonfatal stroke or CV death occurred in 108 of 1648 patients (6.6%) in the combined semaglutide group and 146 of 1649 (8.9%) in the placebo group, HR = 0.74; 95% CI 0.58-0.95; P < 0.001 for noninferiority; P = 0.02 for superiority, with the composite being driven by a significant 39% reduction in stroke, nonsignificant 26% reduction in myocardial infarction, and no difference in CV death.

The advent of oral GLP-1 agonists raises the hope that similar benefits could be realized by an oral agent without the inconvenience and potential adverse effects of subcutaneous injection. Oral semaglutide has been developed and tested in a 26-week dose ranging (2.5, 5, 10, 20, and 40 mg) trial of 632 patients with T2DM, comparing oral semaglutide, parenteral semaglutide (1.0 mg sq weekly) and oral placebo. All dosages of oral semaglutide reduced mean glycohemoglobin significantly more than placebo, in a dose-dependent manner. The 40-mg oral semaglutide dose reduced glycohemoglobin by 1.8% and body weight by ~6.0%. Gastrointestinal adverse events (nausea, vomiting) occurred with oral and parenteral semaglutide with a similar frequency and of note in over half of those at the highest oral dose. Pancreatitis occurred in two patients on oral and one patient on parenteral semaglutide. Additional results concerning oral semaglutide have been reported from the PIONEER 1 (Efficacy and Safety of Oral Semaglutide Versus Placebo in Subjects With Type 2 Diabetes Mellitus Treated With Diet and Exercise Only) trial, which randomized patients with T2DM to three dose levels of once-daily oral semaglutide (3, 7 or 14 mg) or placebo for 26 weeks. The primary outcome of HbA1c reduction was met for semaglutide at all doses compared to placebo. With a baseline HbA1c of 8.0%, the goal of <7.0% was achieved by 59%, 72% and 80% of people on treatment with 3, 7 and 14 mg oral semaglutide, respectively, compared to 34% of the people treated with placebo. The baseline weight = 88 kg and BMI = 31.8 kg/m2, and the 3, 7 and 14 mg oral semaglutide groups experienced a weight loss of 1.7 kg, 2.5 kg and 4.1 kg, respectively, compared to a weight loss of 1.5 kg with placebo. Between 5% and 16% of people treated with oral semaglutide experienced the most common adverse event (nausea) compared to 6% of people treated with placebo. Premature treatment discontinuation due to adverse events was 2% to 7% with oral semaglutide, compared to 2% for placebo. Finally, the PIONEER 2 (Efficacy and Safety of Oral Semaglutide Versus Empagliflozin in Subjects With Type 2 Diabetes Mellitus) trial randomized n = 816 T2DM patients to oral semaglutide 14 mg daily versus the sodium-glucose transporter-2 inhibitor (SGLT-2) empagliflozin 25 mg and found that oral semaglutide was superior to empagliflozin with regard to the primary outcome of HbA1c reduction. Weight loss was greater with semaglutide, as was the percent of subjects achieving HbA1c <7%; however, 20% of the semaglutide group experienced nausea, and the proportion of subjects who discontinued due to adverse events was 11% for oral semaglutide 14 mg compared to 4% with empagliflozin. The overall PIONEER clinical development program involves 8,845 T2DM patients in 10 clinical trials expected to complete in 2018.

In summary, restoration of the incretin effect has been a viable drug development pathway for DDP-4 inhibitors and GLP-1 agonists. Oral formulations of GLP-1 agonists hold the promise for glycemic control and weight loss. Unlike DDP-4 inhibitors and SGLT-2 inhibitors, gastrointestinal side effects may be a dose-limiting toxicity of oral GLP-1 agonists; this should be explored in future cardiovascular safety trials. Future mechanistic studies are warranted to evaluate the anti-atherosclerotic effects of GLP-1 agonists and to understand the contribution of glycemic control and weight loss on MACE.

References

1. Thrasher J. Pharmacologic management of type 2 diabetes mellitus: available therapies. Am J Med 2017;130:S4-17.
2. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375:1834-44.
3. Davies M, Pieber TR, Hartoft-Nielsen ML, Hansen OKH, Jabbour S, Rosenstock J. Effect of oral semaglutide compared with placebo and subcutaneous semaglutide on glycemic control in patients with type 2 diabetes: a randomized clinical trial. JAMA 2017;318:1460-70.
4. Aroda VR, Rosenstock J, Terauchi Y, et al. Effect and safety of oral semaglutide monotherapy in type 2 diabetes—PIONEER 1 trial. Diabetes 2018;67.
5. Efficacy and Safety of Oral Semaglutide Versus Empagliflozin in Subjects With Type 2 Diabetes Mellitus (PIONEER 2). https://clinicaltrials.gov/ct2/show/NCT02863328

Clinical Topics: Diabetes and Cardiometabolic Disease

Keywords: Diabetes Mellitus, Diabetes Mellitus, Type 2, Metabolic Syndrome

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