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Oral Semaglutide for Glycemic Control in T2D

JAMA; 2017 Oct 17; Davies, Pieber, et al

Oral semaglutide resulted in better glycemic control than placebo over 26 weeks in patients with type 2 diabetes (T2D), a recent study found. The randomized, parallel-group, 26-week trial with 5-week follow up at 100 sites in 14 countries was conducted between December 2013 and December 2014. Of 1,106 participants assessed, 632 with T2D and insufficient glycemic control using diet and exercise alone or a stable dose of metformin were randomized. The primary endpoint was change in hemoglobin A1c (HbA1c) from baseline to week 26. Researchers found:

  • Of the 632 randomized patients (mean age 57 years, 62.7% men, diabetes duration, 6.3 years), 583 (92%) completed the trial.
  • Mean change in HbA1c level from baseline to week 26 decreased with oral semaglutide (0.7% to -1.9%) and subcutaneous semaglutide (-1.9%) and placebo (0.3%).
  • Oral semaglutide HbA1c reductions were significant vs placebo (-0.4% to 1.6%).
  • Reductions in body weight were also greater with oral semaglutide and subcutaneous semaglutide vs placebo.

Citation:

Davies M, Pieber TR, Hartoft-Nielsen M, 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(15):1460–1470. doi:10.1001/jama.2017.14752.

Commentary:

GLP-1 receptor agonists (RAs) have emerged as an important, powerful class of medications that has robust efficacy in decreasing HgbA1c at a low risk of hypoglycemia, and generally also leads to weight loss. These medications decrease hyperglycemia by increasing insulin release and decreasing glucagon secretion in a glucose-dependent manner.1 Since the effect occurs when glucose is ingested, GLP-1s have a low risk of hypoglycemia. Additionally, two GLP-1s, liraglutide and semaglutide, have been shown in randomized trials to decrease cardiovascular outcomes.2,3 Currently, all the GLP-1 RA are given by injection. Many patients prefer oral medications to injectable medications, but since the GLP-1 RAs are a complex protein, they are digested if given orally. The current study looked at semaglutide co-formulated with the absorption enhancer sodium caprylate, which causes a localized increase in pH and protects the GLP-1 molecule against proteolytic degradation. This phase 2 dose finding study shows excellent efficacy with no increase in side effects across a range of doses for this novel form of GLP-1 RA delivery, and we await phase 3 studies. —Neil Skolnik, MD

  1. Meloni AR, DeYoung MB, Lowe C, Parkes DG. GLP-1 receptor activated insulin secretion from pancreatic β-cells: mechanism and glucose dependence. Diabetes Obes Metab. 2013;15(1):15-27. doi:10.1111/j.1463-1326.2012.01663.x.
  2. Marso SP, Daniels GH, Brown-Frandsen K, et al; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311-322. doi:10.1056/NEJMoa1603827.
  3. Marso SP, Bain SC, Consoli A, et al; SUSTAIN-6 investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834-1844. doi:10.1056/NEJMoa1607141.