Oral Semaglutide versus Sitagliptin on Glycated Hemoglobin in Adults With Type 2 Diabetes

Oral Semaglutide versus Sitagliptin on Glycated Hemoglobin in Adults With Type 2 Diabetes

By Aly Becraft, MS and Kevin C Maki, PhD

 

The PIONEER3 trial was designed to compare the efficacy, long-term adverse event profile, and tolerability of an orally administered formulation of the glucagon-like peptide 1 receptor agonist (GLP-1RA), semaglutide, with the widely-used dipeptidyl peptidase-4 (DPP-4) inhibitor, sitagliptin, as an add on to metformin, with or without sulfonylurea, in patients with type 2 diabetes (T2D).1,2 This 78-week, phase 3a, randomized, double-blind, active-controlled, parallel-group trial included a total of 1864 patients with T2D and glycated hemoglobin (HbA1c) levels of 7.0% to 10.5%. Patients were randomized to receive either 3 mg/d (n = 466), 7 mg/d (n = 466), or 14 mg/d (n = 465) of semaglutide, or 100-mg/d sitagliptin (n = 467). The primary endpoint was change in HbA1c from baseline to week 26. The key secondary endpoint was change in body weight from baseline to week 26. Additional secondary endpoints included changes in HbA1c and body weight from baseline to weeks 52 and 78. The analysis evaluated both intention-to-treat and per-protocol samples.

Semaglutide at doses of 7 and 14 mg/d was found to be superior to sitagliptin for reducing HbA1c and body weight (see table, intention-to-treat results at week 26). Neither superiority nor non-inferiority with 3-mg/d semaglutide was demonstrated.

 

Estimated mean changes from baseline and estimated mean

(95% confidence interval) differences

from sitagliptin at week 26

 

Sitagliptin

Semaglutide

 

100 mg/d

3 mg/d

7 mg/d

14 mg/d

 HbA1c, %

-0.8

-0.6

-1.0

-1.3

 Difference from sitagliptin

0.2 (0.0, 0.3)

-0.3 (-0.4, -0.1)

-0.5 (-0.6, -0.4)

 Body Weight, kg

-0.6

-1.2

-2.2

-3.1

 Difference from sitagliptin

-0.6 (-1.1, -0.1)

-1.6 (-2.0, -1.1)

-2.5 (-3.0, -2.0)

 

At week 78, significantly (p<0.05) greater reductions in HbA1c were observed with the semaglutide dosage of 14 mg/d versus sitagliptin in both intention-to-treat and per protocol samples (-0.4% and -0.7%, respectively), but semaglutide 7 mg/d was greater only in the per protocol sample (-0.3%). Significantly (p<0.05) greater body weight reductions were observed with all three dosages of semaglutide versus sitagliptin at week 78 (estimated mean differences of -0.8, -1.7 and -2.1 kg for 3, 7 and 14 mg/d of semaglutide). In addition, significant reductions in fasting plasma glucose and mean self-measured whole-blood glucose were greatest in the the14-mg/d semaglutide group at weeks 26 and 78 compared with sitagliptin.

The overall proportions of patients with at least one adverse event were similar across all treatment groups. However, a greater incidence of discontinuation due to adverse events was reported with 14 mg/d of semaglutide (11.6%), while 3- and 7-mg/d dosages (5.6% and 5.8%, respectively) had comparable incidences of discontinuation to sitagliptin (5.2%).  The primary cause of discontinuation in all treatment groups was gastrointestinal adverse events; for a substantial proportion of patients in the 7- and 14-mg/d semaglutide groups, the onset of the event leading to discontinuation occurred during the dose escalation period.

Conclusion: Compared to sitagliptin, oral semaglutide at 7 and 14 mg/d further reduced HbA1c and body weight over 26 weeks.

References:

  1. Rosenstock J, Allison D, Birkenfeld AL, et al. Effect of additional oral semaglutide vs sitagliptin on glycated hemoglobin in adults with type 2 diabetes uncontrolled with metformin alone or with sulfonylurea: The PIONEER 3 randomized clinical trial. JAMA. 2019; Epub ahead of print.
  2. Hirsch IB. The future of the GLP-1 receptor agonists. JAMA. 2019;321:1457-1458.

 

Photo by David Clode

Viscous Fiber Supplements in Diabetes Control: Results from a Systematic Review and Meta-analysis of Randomized Controlled Trials

Viscous Fiber Supplements in Diabetes Control: Results from a Systematic Review and Meta-analysis of Randomized Controlled Trials

By Heather Nelson Cortes, PhD and Kevin C Maki, PhD

According to the recent 2019 American Diabetes Association (ADA) Standards of Medical Care in Diabetes, people with diabetes should increase their intake of viscous fiber from sources such as oats, legumes, and citrus to help regulate blood glucose levels and lower risk of cardiovascular disease1. Viscous fibers are described as such because they increase viscosity in the human gut, thereby reducing the rate at which carbohydrates are digested and the glucose molecules from them absorbed.  These effects occur because the viscous solution impedes the ability of digestive enzymes to reach starch molecules and slows the rate at which glucose molecules reach the brush border in the intestinal lumen, where absorption can occur.  The result is flattening of the postprandial glycemic and insulinemic responses.  While these acute effects are well established, the longer-term impacts of viscous fibers on glycemic control markers are not well known2.

 

In a systematic review and meta-analysis, Jovanovski2 investigated the effect of viscous dietary fiber supplementation on markers of glycemic control in people with type 2 diabetes (T2D).  A comprehensive literature search on MEDLINE, Embase, and Cochrane Central Register of Controlled Trials through June 15, 2018 identified 2,716 potential RCTs.  After reviewing the studies based on the inclusion/exclusion criteria, 27 studies (n = 1,394) were identified for the review and meta-analysis.  Inclusion criteria were: ≥3 weeks in duration, studied viscous fiber supplementation (β-glucan, guar gum, konjac, psyllium, pectin, xanthan gum, locust bean gum, alginate, agar) compared to an appropriate control (i.e., fiber-free supplement or one containing insoluble fiber, background diet, or placebo), and included at least one glycemic measurement (glycated hemoglobin [HbA1c], fasting glucose, fasting insulin, homeostatic model assessment of insulin resistance [HOMA-IR], or fructosamine).

 

The median age of subjects was 60 years (range 48-67) and they had a median body mass index of 27 kg/m2 (range 26-32 kg/m2).  The median dose of viscous fibers in the studies was 13.1 g/day (range 2.55-21.0 g/day) and the median study duration was 8 weeks (range 3-52 weeks).

 

Compared to control groups, inclusion of viscous fiber in the diet was associated with significant reductions in HbA1c, fasting blood glucose and HOMA- IR. 

 

  • HbA1c: mean difference (MD) -0.58% 95% confidence interval (CI) -0.88%, -0.28%; p = 0.0002;
  • Fasting blood glucose: MD -14.8 mg/dL 95% CI -23.8, -5.59; p = 0.001
  • HOMA-IR: MD -1.89 95% CI -3.45, -0.33; p = 0.02.

 

There were no differences between viscous fiber groups and controls for fasting insulin (MD -2.53 µU/mL 95% CI -5.41, 0.35; p = 0.08) or fructosamine (MD -0.12 mmol/L 95% CI -0.39, 0.14; p = 0.37).  Only 2 studies reported fructosamine, so this finding should be interpreted with caution.  There was no evidence of a significant dose-response effect.  Results for HbA1c, fasting glucose, fasting insulin, and HOMA-IR were graded moderate for certainty of evidence, while fructosamine was graded low.

 

Comment.  Viscous fiber intake, through consumption of food sources such as legumes, whole fruits (e.g., apples and pears) and whole grain oats and barley, as well as dietary supplementation with products such as psyllium (e.g., Metamucil®), methylcellulose (e.g., Citrucel®) or konjac (e.g., Lipozene®), appears to have several benefits regarding cardiometabolic health.  For those with T2D, this meta-analysis shows evidence to support favorable effects on glycemic control and insulin sensitivity.  More research is needed to establish more clearly whether all viscous fibers enhance insulin sensitivity, or whether this property is limited to those with certain characteristics, such colonic fermentability or content of specific bioactive compounds3,4.  Evidence from other sources also shows that viscous fiber lowers the circulating cholesterol level, likely by trapping cholesterol and bile acids, thus preventing their absorption/reabsorption3.  In addition, viscous fibers appear to play a role in appetite regulation, enhancing satiety after meal5.

 

The meta-analysis by Jovanovski and colleagues shows that inclusion of viscous fiber in the diet produces clinically meaningful improvements in glycemic control for patients with T2D.  Based on this, as well as evidence for other benefits (cholesterol lowering and enhanced satiety), inclusion of viscous fiber from foods and/or supplements should be considered an important component of the management plan for patients with T2D.

 

References

  1. American Diabetes Association. 10. Cardiovascular Disease and Risk Management: Standards of Medical Care in Diabetes—2019. Diabetes Care. 2019;42(Supplement 1): S103-S123.

 

  1. Jovanovski E, Khayyat R,  Zurbau A,  et al. Should viscous fiber supplements be considered in diabetes control? Results from a systematic review and meta-analysis of randomized controlled trials. Diabetes Care. 2019 Jan; doi:10.2337 [Epub ahead of print].

 

  1. Weickert MO, Pfeiffer AFH. Impact of dietary fiber consumption on insulin resistance and the prevention of type 2 diabetes. J Nutr. 2018;148:7-12.

 

  1. Kärkkäninen O, Lankinen MA, Vitale M, et al. Diets rich in whole grains increase betainized compounds associated with glucose metabolism. Am J Clin Nutr. 2018;108:971-979.

 

  1. Rebello CJ, Chu YF, Johnson WD, et al. The role of meal viscosity and oat ß–glucan characteristics in human appetite control: a randomized crossover trial. Nutr J. 2014;13:49.

 

 

Photo by Sara Dubler