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Levels of circulating semaglutide determine reductions in HbA1c and body weight in people with type 2 diabetes.

ABSTRACT: Glucagon-like peptide-1 receptor agonists (GLP-1RA) are used for the treatment of type 2 diabetes. Whether clinically important responses and adverse events (AEs) are dependent on the route of administration has not been determined. We demonstrate that nearly identical exposure-response pharmacodynamic relationships are determined by plasma semaglutide levels achieved through oral versus injectable administration for changes in HbA_1c, body weight, biomarkers of cardiovascular risk, and AEs such as nausea and vomiting. At typical exposure levels for oral semaglutide, the estimated response is 1.58% (oral) versus -1.62% (subcutaneous) for HbA_1c and 3.77% (oral) versus 3.48% (subcutaneous) reduction in body weight relative to baseline after 6 months. Increased body weight is the most important variable associated with reduced semaglutide exposure for both formulations. Hence, interindividual variation in GLP-1R responsivity or route of administration are not major determinants of GLP-1RA effectiveness in the clinic.

SUBMITTER: Overgaard RV

PROVIDER: S-EPMC8484505 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Levels of circulating semaglutide determine reductions in HbA1c and body weight in people with type 2 diabetes.

Overgaard Rune V RV Hertz Christin L CL Ingwersen Steen H SH Navarria Andrea A Drucker Daniel J DJ

Cell reports. Medicine 20210903 9

Glucagon-like peptide-1 receptor agonists (GLP-1RA) are used for the treatment of type 2 diabetes. Whether clinically important responses and adverse events (AEs) are dependent on the route of administration has not been determined. We demonstrate that nearly identical exposure-response pharmacodynamic relationships are determined by plasma semaglutide levels achieved through oral versus injectable administration for changes in HbA<sub>1c</sub>, body weight, biomarkers of cardiovascular risk, an ...[more]

PMID: 34622228

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Project description:INTRODUCTION:Despite treatment with oral antidiabetic drugs (OADs), achieving effective glycaemic control in type 2 diabetes (T2D) remains a challenge. The objective of this post hoc analysis of data from the SUSTAIN 2, 3, 4 and 10 active-controlled trials was to assess the efficacy and safety of the once-weekly glucagon-like peptide 1 receptor agonist (GLP-1RA) semaglutide in patients on background treatment with metformin (MET), with or without a sulphonylurea (SU). METHODS:Data from the randomised phase 3 trials SUSTAIN 2, 3, 4 and 10 for subjects who received background MET alone or MET + SU were analysed. Change from baseline in HbA1c and body weight at the end of treatment visit (week 30 in SUSTAIN 4 and 10, week 56 in SUSTAIN 2 and 3), and rates of hypoglycaemia and adverse events leading to premature treatment discontinuation were assessed. RESULTS:In total, 3411 subjects were included in the full analysis set (3410 in the safety analysis set). Across the four trials, semaglutide significantly reduced HbA1c (estimated treatment difference [ETD] - 0.32 to - 0.79%-points for semaglutide 0.5 mg, and - 0.38 to - 1.07%-points for semaglutide 1.0 mg vs comparators; p < 0.01) in subjects receiving both MET and MET + SU. Regardless of background OAD, semaglutide significantly reduced body weight (ETD - 2.35 to - 4.72 kg for semaglutide 0.5 mg, and - 2.96 to - 6.76 kg for semaglutide 1.0 mg vs comparators; p < 0.0001). Across the trials, hypoglycaemic events were more common with background MET + SU than MET alone, in subjects receiving either semaglutide or a comparator. The rate of adverse events (AEs) leading to premature treatment discontinuations in subjects treated with semaglutide were generally consistent regardless of background therapy. CONCLUSION:Semaglutide 0.5 mg and 1.0 mg significantly improve glycaemic control (HbA1c) and body weight in subjects with T2D, with a similar tolerability profile, regardless of whether they receive background MET or MET + SU. TRIAL REGISTRATION:Clinicaltrials.gov: NCT01930188 (SUSTAIN 2), NCT01885208 (SUSTAIN 3), NCT02128932 (SUSTAIN 4) and NCT03191396 (SUSTAIN 10).

Project description:INTRODUCTION:Dapagliflozin is an orally active inhibitor of sodium-glucose co-transporter 2 (SGLT2) that is indicated for use in adults with type 1 diabetes (T1DM) (with a body mass index (BMI) of at least 27 kg/m2 in Europe, no such BMI limit in Japan), when insulin alone does not provide adequate glycaemic control. The aim of this study was to evaluate changes in glycated haemoglobin (HbA1c), body weight and insulin dose following discontinuation of dapagliflozin for the management of T1DM in the DEPICT clinical trial programme. METHODS:The interrelationship between treatment discontinuation, insulin requirement and outcomes post-discontinuation was evaluated using descriptive summary statistics and linear regression modelling. Data were analysed from individuals with T1DM discontinuing dapagliflozin in DEPICT-1 or DEPICT-2 (unplanned or end of study). HbA1c and body weight were measured over the 56-week study period (consisting of a 52-week treatment period and a 4-week follow-up period) at 4-8 weekly intervals. Following discontinuation of dapagliflozin, 1-year change in HbA1c (%) and weight (kg) following discontinuation of dapagliflozin was estimated; total daily insulin doses were descriptively summarised. RESULTS:Of the 1059 individuals that received dapagliflozin during the DEPICT trials 91 met the eligibility criteria and were included in the analyses of HbA1c and body weight. The mean duration of follow-up was 209 days in both analyses. Following dapagliflozin discontinuation, estimated annualised changes in HbA1c and body weight were + 0.99% (95% CI 0.39, 1.59) and + 3.75 kg (1.65, 5.86), respectively. An increase in insulin dose was observed around the time of discontinuation; insulin dose in the 2-week post-discontinuation was + 3.6 IU and + 4.4 IU higher with dapagliflozin 5 mg and 10 mg than 2 weeks pre-discontinuation, respectively. CONCLUSION:Discontinuation of dapagliflozin is predicted to lead to clinically meaningful increases in HbA1c and body weight, in addition to higher insulin doses. These findings are important in the management of people with T1DM among whom insulin is the only existing pharmacological treatment option.

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Levels of circulating semaglutide determine reductions in HbA1c and body weight in people with type 2 diabetes.

Publications

Levels of circulating semaglutide determine reductions in HbA1c and body weight in people with type 2 diabetes.

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