Semaglutide results in better glycemic control than placebo in diabetes

1. This randomized clinical trial showed that, among patients with type 2 diabetes, oral semaglutide resulted in better glycemic control compared to placebo over 26 weeks.

2. A decrease in mean HBA1C in the subcutaneous semaglutide group was also significantly greater than the placebo group.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Glucagon-like peptide-1 (GLP-1) receptor antagonists have expanded the range of diabetes treatment options, and now, the first oral GLP-1 analog—semaglutide in tablet form—is in clinical development. Despite the availability of multiple type 2 diabetes mellitus (T2DM) treatments, physicians and patients must carefully consider the risks and adverse effects (hypoglycemia, weight gain) of any specific therapy. GLP-1 receptor antagonists have a relatively lower risk of hypoglycemia compared to other agents, and provide weight loss by reducing appetite and energy intake. This study had 2 aims: (1) to characterize the dose-response relationship of oral semaglutide, and (2) to test the effectiveness of glycemic control with once-weekly subcutaneous semaglutide. It found that all dosages of oral semaglutide, as well as subcutaneous semaglutide, led to significantly reduced mean HbA1C levels compared to placebo after 26 weeks of administration, in a dose-dependent manner. There was a significant amount of weight loss over the trial period, with the proportion of patients reaching 5% weight loss being significantly greater in the oral semaglutide dosage groups of 10 mg and higher. There was a larger proportion of patients reporting gastrointestinal adverse events in both the oral and subcutaneous semaglutide groups compared to placebo. There was no significant difference in hypoglycemic episodes between treatment and placebo groups.

There are a few limitations to the study. First, the duration of the study is relatively short. Longer-term data will provide more information regarding safety, efficacy, and durability of semaglutide for diabetes management. Second, there were no adjustments made in the statistical analyses for multiplicity, which may contribute to type 1 error. Third, the use of placebo instead of the gold standard treatment highlights changes in HbA1c levels well, but perhaps the study could be more powerful if the first line treatment (metformin) for T2DM was used as a comparison instead. Overall, this study provides evidence that both oral and subcutaneous Semaglutide improves glycemic control in patients with T2DM over a 26 week period

Click to read the study in JAMA

Relevant Reading: Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans.

In-Depth [randomized control study]: This randomized clinical trial studied the dose-response relationship for oral semaglutide in patients with T2DM and poor glycemic control. The study also included an open label study of subcutaneous injections of semaglutide in T2DM patients for glycemic control. Adult patients with T2DM and insufficient glycemic control (HbA1C level 7.0%-9.5%) on diet and exercise alone, or with a stable dose of at least 1 month of metformin, were enrolled at 100 sites across 14 countries. This 26-week, randomized, parallel group, phase 2, dosage finding trial, divided patients into multiple dose-response groups of once daily oral semaglutide, compared to placebo. As well, an open label, once-weekly subcutaneous injection of semaglutide was included in the randomization for these patients with T2DM. Primary endpoints were change in HbA1C level at week 26 compared to baseline, and secondary endpoints were the proportion of patients achieving HbA1c target level of less than 7.0%; change in baseline in fasting plasma glucose and body weight; percent of patients achieving 5% or more of body weight reductions; among other measures. Safety endpoints included the number of treatment emergent adverse events and severe hypoglycemic episodes recorded from baseline until week 31.

A total of 632 patients with T2DM meeting the enrollment criteria were randomized into the study, with 70 patients randomized into each oral semaglutide dosage group (placebo, 2.5, 5, 10, 20mg, etc.). Additionally, the 210 patients receiving the highest dose of semaglutide (70 in each group of: 40 mg, standard dose escalation; 40 mg, 8-week dose escalation; 40 mg, 2-week dose escalation); were randomized to receive a weekly 1 mg subcutaneous injection of semaglutide. All dosages of oral semaglutide reduced mean HbA1c level more than placebo by week 26 in a dose-dependent manner: ETDs for dosage-dependent oral semaglutide vs placebo were −0.4% (95%CI –0.7% to –0.1% for the 2.5-mg group; –0.9%, 95%CI –1.2% to –0.6% for the 5-mg group; –1.2%, 95%CI –1.5% to –0.9% for the 10-mg group; –1.4%, 95%CI –1.7% to –1.1% for the 20-mg group; and –1.6%, 95%CI –1.9% to –1.3% for the 40-mg standard escalation group; p = 0.007 for the 2.5-mg group, p < 0.001 for other dosages). The proportion of patients achieving 5% weight loss was significantly greater for oral semaglutide dosage groups of 10-mg and higher (p < 0.001; 10-mg group: 38 of 69 patients [56%], RR, 4.1 [95%CI 2.2 to 7.6]; 20-mg group: 45 of 70 patients [64%], RR, 5.2 [95%CI 2.8 to 9.6]; 40-mg standard escalation group: 50 of 71 patients [71%], RR, 5.4 [95%CI 9.2 to 9.9]) vs the placebo group (9 of 71 patients [13%]), and the subcutaneous semaglutide (45 of 69 patients [66%], RR, 5.2 [95%CI 2.8 to 9.6], p < 0.001). In terms of adverse events, gastrointestinal events were the most common: the proportion of patients reporting gastrointestinal events was higher with oral semaglutide (31%-77%; 255 of 490 patients) and subcutaneous semaglutide (54%; 37 of 69 patients) than with placebo (28%; 20 of 71 patients). The overall number of hypoglycemic episodes was low and similar for oral semaglutide, subcutaneous semaglutide, and placebo.

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