Efficacy and safety of oral semaglutide monotherapy vs placebo in a predominantly Chinese population with type 2 diabetes (PIONEER 11): a double-blind, Phase IIIa, randomised trial.

AIMS/HYPOTHESIS: The aim of this study was to evaluate the efficacy and safety of oral semaglutide monotherapy vs placebo in a predominantly Chinese population with type 2 diabetes insufficiently controlled with diet and exercise alone. METHODS: The Peptide Innovation for Early Diabetes Treatment (PIONEER) 11 trial was a double-blind, randomised, Phase IIIa trial conducted across 52 sites in the China region (mainland China and Taiwan), Hungary, Serbia and Ukraine. Eligible participants were ≥18 years (≥20 years in Taiwan), had a diagnosis of type 2 diabetes with HbA1c 53-86 mmol/mol (7.0-10.0%) and were not receiving any glucose-lowering drugs. After a 4-week run-in period in which participants were treated with diet and exercise alone, those who fulfilled the randomisation criteria were randomised (1:1:1:1) using a web-based randomisation system to receive once-daily oral semaglutide 3 mg, 7 mg or 14 mg or placebo for 26 weeks (using a 4-week dose-escalation regimen for the higher doses). Randomisation was stratified according to whether participants were from the China region or elsewhere. The primary and confirmatory secondary endpoints were change from baseline to week 26 in HbA1c and body weight (kg), respectively. Safety was assessed in all participants exposed to at least one dose of the trial product. RESULTS: Between October 2019 and October 2021, a total of 774 participants were screened and 521 participants were randomised to oral semaglutide 3 mg (n=130), 7 mg (n=130), 14 mg (n=130) or placebo (n=131); most participants (92.5%, n=482) completed the trial, with 39 participants prematurely discontinuing treatment. The number of participants contributing to the trial analyses was based on the total number of participants who were randomised at the beginning of the trial. The majority of participants were male (63.7%), and the mean age of participants was 52 years. At baseline, mean HbA1c and body weight were 63 mmol/mol (8.0%) and 79.6 kg, respectively. Oral semaglutide resulted in significantly greater reductions in HbA1c than placebo at week 26 (p<0.001 for all doses). The estimated treatment differences (ETDs [95% CIs]) for oral semaglutide 3 mg, 7 mg and 14 mg vs placebo were -11 (-13, -9) mmol/mol, -16 (-18, -13) mmol/mol and -17 (-19, -15) mmol/mol, respectively. The corresponding ETDs in percentage points (95% CI) vs placebo were -1.0 (-1.2, -0.8), -1.4 (-1.6, -1.2) and -1.5 (-1.8, -1.3), respectively. Significantly greater reductions in body weight were also observed for oral semaglutide 7 mg and 14 mg than for placebo at week 26 (ETD [95% CI] -1.2 kg [-2.0 kg, -0.4 kg; p<0.01] and -2.0 kg [-2.8 kg, -1.2 kg; p<0.001], respectively), but not for oral semaglutide 3 mg (ETD [95% CI] -0.0 kg [-0.9 kg, 0.8 kg; not significant]). Similar reductions in HbA1c and body weight were observed in the Chinese subpopulation, which represented 74.9% of participants in the overall population. Adverse events (AEs) occurred in between 65.4% and 72.3% of participants receiving oral semaglutide (for all doses) and 57.3% of participants with placebo. Most AEs were mild to moderate in severity, with few serious AEs reported; the most commonly reported AEs were gastrointestinal-related and were more frequent with semaglutide (all doses) than with placebo. The proportion of AEs was slightly higher in the Chinese subpopulation. CONCLUSIONS/INTERPRETATION: Oral semaglutide resulted in significantly greater reductions in HbA1c across all doses and in significant body weight reductions for the 7 mg and 14 mg doses when compared with placebo in predominantly Chinese participants with type 2 diabetes insufficiently controlled by diet and exercise alone. Oral semaglutide was generally well tolerated, with a safety profile consistent with that seen in the global PIONEER trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT04109547. FUNDING: Novo Nordisk A/S.

Efficacy and safety of oral semaglutide vs sitagliptin in a predominantly Chinese population with type 2 diabetes uncontrolled with metformin: PIONEER 12, a double-blind, Phase IIIa, randomised trial.

AIMS/HYPOTHESIS: The aim of this study was to assess the efficacy and safety of oral semaglutide vs sitagliptin in a predominantly Chinese population with type 2 diabetes inadequately controlled with metformin treatment. METHODS: The Peptide Innovation for Early Diabetes Treatment (PIONEER) 12 trial was a randomised, double-dummy, active-controlled, parallel-group, Phase IIIa trial conducted over 26 weeks at 90 sites across the China region (including mainland China, Taiwan and Hong Kong) and five other countries. Adults aged ≥18 years (≥20 years in Taiwan) with a diagnosis of type 2 diabetes, HbA1c between 53 and 91 mmol/mol (inclusive) and treated with a stable daily dose of metformin were eligible for inclusion. Participants were randomised (1:1:1:1) using a web-based randomisation system to either once-daily oral semaglutide (3 mg, 7 mg or 14 mg) or once-daily oral sitagliptin 100 mg. Treatment allocation was masked to both participants and investigators. Randomisation was stratified according to whether participants were from the China region or elsewhere. The primary endpoint was change in HbA1c from baseline to week 26. The confirmatory secondary endpoint was change in body weight (kg) from baseline to week 26. All randomised participants were included in the full analysis set (FAS). All participants exposed to at least one dose of trial product were included in the safety analysis (SAS). RESULTS: Of 1839 participants screened, 1441 were randomly assigned to oral semaglutide 3 mg (n=361), 7 mg (n=360), 14 mg (n=361) or sitagliptin 100 mg (n=359) and included in the FAS. A total of 1438 participants were included in the SAS. In total, 75.2% of participants were from the China region. A total of 1372 (95.2%) participants completed the trial and 130 participants prematurely discontinued treatment (8.3%, 8.6% and 15.0% for oral semaglutide 3 mg, 7 mg and 14 mg, respectively; 4.2% for sitagliptin 100 mg). Significantly greater reductions in HbA1c from baseline to week 26 were reported for all doses of oral semaglutide vs sitagliptin 100 mg. For oral semaglutide 3 mg, 7 mg and 14 mg vs sitagliptin 100 mg, the estimated treatment differences (ETDs [95% CI]) were -2 (-4, -1) mmol/mol, -8 (-9, -6) mmol/mol and -11 (-12, -9) mmol/mol, respectively. The corresponding ETDs (95% CI) in percentage points vs sitagliptin 100 mg were -0.2 (-0.3, -0.1), -0.7 (-0.8, -0.6) and -1.0 (-1.1, -0.8), respectively. Reductions in body weight were significantly greater for all doses of oral semaglutide vs sitagliptin 100 mg (ETD [95% CI] -0.9 [-1.4, -0.4] kg, -2.3 [-2.8, -1.8] kg and -3.3 [-3.8, -2.8] kg for 3 mg, 7 mg and 14 mg, respectively). In the subpopulation of participants from the China region (75.2% of trial participants), reductions in HbA1c and body weight from baseline to week 26 were similar to those seen in the overall population. The most frequent adverse events in the semaglutide treatment arms were gastrointestinal, although these were mostly transient and mild/moderate in severity. CONCLUSIONS/INTERPRETATION: Significantly greater reductions in both HbA1c and body weight over 26 weeks were seen with oral semaglutide 3 mg, 7 mg and 14 mg than with sitagliptin 100 mg in a predominantly Chinese population with type 2 diabetes inadequately controlled with metformin treatment. Oral semaglutide was generally well tolerated, with a safety profile consistent with that seen in the global PIONEER trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT04017832. FUNDING: This trial was funded by Novo Nordisk A/S, Søborg, Denmark.

Dose-response effects on HbA1c and bodyweight reduction of survodutide, a dual glucagon/GLP-1 receptor agonist, compared with placebo and open-label semaglutide in people with type 2 diabetes: a randomised clinical trial.

AIMS/HYPOTHESIS: The aim of this study was to assess the dose-response effects of the subcutaneous glucagon receptor/glucagon-like peptide-1 receptor dual agonist survodutide (BI 456906) on HbA1c levels and bodyweight reduction. METHODS: This Phase II, multicentre, randomised, double-blind, parallel-group, placebo-controlled study, conducted in clinical research centres, assessed survodutide in participants aged 18-75 years with type 2 diabetes, an HbA1c level of 53-86 mmol/mol (7.0-10.0%) and a BMI of 25-50 kg/m2 on a background of metformin therapy. Participants were randomised via interactive response technology to receive survodutide (up to 0.3, 0.9, 1.8 or 2.7 mg once weekly [qw; dose group (DG) 1-4, respectively] or 1.2 or 1.8 mg twice weekly [DG 5 and 6, respectively]), placebo or semaglutide (up to 1.0 mg qw). Participants and all those involved in the trial conduct/analysis were blinded; the semaglutide arm was open-label. The primary endpoint was absolute change from baseline in HbA1c after 16 weeks' treatment. The key secondary endpoint was relative change from baseline in bodyweight after 16 weeks' treatment. RESULTS: A total of 413 participants were randomised (DG1, n=50; DG2, n=50; DG3, n=52; DG4, n=50; DG5, n=51; DG6, n=50; semaglutide, n=50; placebo, n=60). The full analysis set comprised 411 treated participants (DG6, n=49; placebo, n=59). Adjusted mean (95% CI) HbA1c decreased from baseline (mean ± SD 64.7±9.2 mmol/mol [8.07±0.84%] after 16 weeks' treatment: DG1 (n=41), -9.92 mmol/mol (-12.27, -7.56; -0.91% [-1.12, -0.69]); DG2 (n=46), -15.95 mmol/mol (-18.27, -13.63; -1.46% [-1.67, -1.25]); DG3 (n=36), -18.72 mmol/mol (-21.15, -16.29; -1.71% [-1.94, -1.49]); DG4 (n=33), -17.01 mmol/mol (-19.59, -14.43; -1.56% [-1.79, -1.32]); DG5 (n=44), -17.84 mmol/mol (-20.18, -15.51; -1.63% [-1.85, -1.42]); DG6 (n=36), -18.38 mmol/mol (-20.90, -15.87; -1.68% [-1.91, -1.45]). The mean reduction in HbA1c was similar with low-dose survodutide (DG2: -15.95 mmol/mol [-1.46%]; n=46) and semaglutide (-16.07 mmol/mol [-1.47%]; n=45). Mean (95% CI) bodyweight decreased dose-dependently up to -8.7% (-10.1, -7.3; DG6, n=37); survodutide ≥1.8 mg qw produced greater bodyweight reductions than semaglutide (-5.3% [-6.6, -4.1]; n=45). Adverse events (AEs) were reported for 77.8% of survodutide-treated participants (mainly gastrointestinal), 52.5% receiving placebo and 52.0% receiving semaglutide. CONCLUSIONS/INTERPRETATION: Survodutide reduced HbA1c levels and bodyweight after 16 weeks' treatment in participants with type 2 diabetes. Dose-related gastrointestinal AEs could be mitigated with slower dose escalations. TRIAL REGISTRATION: ClinicalTrials.gov NCT04153929 and EudraCT 2019-002390-60. FUNDING: Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.

An extended minimal model of OGTT: estimation of α- and ß-cell dysfunction, insulin resistance, and the incretin effect.

Loss of insulin sensitivity, α- and ß-cell dysfunction, and impairment in incretin effect have all been implicated in the pathophysiology of type 2 diabetes (T2D). Parsimonious mathematical models are useful in quantifying parameters related to the pathophysiology of T2D. Here, we extend the minimum model developed to describe the glucose-insulin-glucagon dynamics in the isoglycemic intravenous glucose infusion (IIGI) experiment to the oral glucose tolerance test (OGTT). The extended model describes glucose and hormone dynamics in OGTT including the contribution of the incretin hormones, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1), to insulin secretion. A new function describing glucose arrival from the gut is introduced. The model is fitted to OGTT data from eight individuals with T2D and eight weight-matched controls (CS) without diabetes to obtain parameters related to insulin sensitivity, ß- and α-cell function. The parameters, i.e., measures of insulin sensitivity, a1, suppression of glucagon secretion, k1, magnitude of glucagon secretion, γ2, and incretin-dependent insulin secretion, γ3, were found to be different between CS and T2D with P values < 0.002, <0.017, <0.009, <0.004, respectively. A new rubric for estimating the incretin effect directly from modeling the OGTT is presented. The average incretin effect correlated well with the experimentally determined incretin effect with a Spearman rank test correlation coefficient of 0.67 (P < 0.012). The average incretin effect was found to be different between CS and T2D (P < 0.032). The developed model is shown to be effective in quantifying the factors relevant to T2D pathophysiology.NEW & NOTEWORTHY A new extended model of oral glucose tolerance test (OGTT) has been developed that includes glucagon dynamics and incretin contribution to insulin secretion. The model allows the estimation of parameters related to α- and ß-cell dysfunction, insulin sensitivity, and incretin action. A new function describing the influx of glucose from the gut has been introduced. A new rubric for estimating the incretin effect directly from the OGTT experiment has been developed. The effect of glucose dose was also investigated.

Patients with autoimmune liver disease have glucose disturbances that mechanistically differ from steatotic liver disease.

Autoimmune liver diseases are associated with an increased risk of diabetes, yet the underlying mechanisms remain unknown. In this cross-sectional study, we investigated the glucose-regulatory disturbances in patients with autoimmune hepatitis (AIH, n = 19), primary biliary cholangitis (PBC, n = 15), and primary sclerosing cholangitis (PSC, n = 6). Healthy individuals (n = 24) and patients with metabolic dysfunction-associated steatotic liver disease (MASLD, n = 18) were included as controls. Blood samples were collected during a 120-min oral glucose tolerance test. We measured the concentrations of glucose, C-peptide, insulin, glucagon, and the two incretin hormones, glucose insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). We calculated the homeostasis model assessment of insulin resistance (HOMA-IR), whole body insulin resistance (Matsuda index), insulin clearance, and insulinogenic index. All patient groups had increased fasting plasma glucose and impaired glucose responses compared with healthy controls. Beta-cell secretion was increased in AIH, PBC, and MASLD but not in PSC. Patients with AIH and MASLD had hyperglucagonemia and hepatic, as well as peripheral, insulin resistance and decreased insulin clearance, resulting in hyperinsulinemia. Patients with autoimmune liver disease had an increased GIP response, and those with AIH or PBC had an increased GLP-1 response. Our data demonstrate that the mechanism underlying glucose disturbances in patients with autoimmune liver disease differs from that underlying MASLD, including compensatory incretin responses in patients with autoimmune liver disease. Our results suggest that glucose disturbances are present at an early stage of the disease.NEW & NOTEWORTHY Patients with autoimmune liver disease but without overt diabetes display glucose disturbances early on in their disease course. We identified pathophysiological traits specific to these patients including altered incretin responses.

Reduction of prevalence of patients meeting the criteria for metabolic syndrome with tirzepatide: a post hoc analysis from the SURPASS Clinical Trial Program.

BACKGROUND: Metabolic syndrome is characterized as the co-occurrence of interrelated cardiovascular risk factors, including insulin resistance, hyperinsulinemia, abdominal obesity, dyslipidemia and hypertension. Once weekly tirzepatide is approved in the US and EU for the treatment of type 2 diabetes (T2D) and obesity. In the SURPASS clinical trial program for T2D, tirzepatide demonstrated greater improvements in glycemic control, body weight reduction and other cardiometabolic risk factors versus placebo, subcutaneous semaglutide 1 mg, insulin degludec, and insulin glargine. This post hoc analysis assessed the effect of tirzepatide use on the prevalence of patients meeting the criteria for metabolic syndrome across SURPASS 1-5. METHODS: Metabolic syndrome was defined as having ≥ 3 of 5 criteria according to the US National Cholesterol Education Program: Adult Treatment Panel III. Analyses were based on on-treatment data at the primary endpoint from patients adherent to treatment (taking ≥ 75% study drug). A logistic regression model with metabolic syndrome status as the response variable, metabolic syndrome status at the baseline visit as an adjustment, and randomized treatment as fixed explanatory effect was used. The effect of tirzepatide use on the prevalence of patients meeting the criteria for metabolic syndrome by categorical weight loss, background medication and gender were assessed. RESULTS: In SURPASS, the prevalence of patients meeting the criteria for metabolic syndrome at baseline was 67-88% across treatment groups with reductions at the primary endpoint to 38-64% with tirzepatide versus 64-82% with comparators. Reductions in the prevalence of patients meeting the criteria for metabolic syndrome was significantly greater with all tirzepatide doses versus placebo, semaglutide 1 mg, insulin glargine, and insulin degludec (p < 0.001). Individual components of metabolic syndrome were also reduced to a greater extent with tirzepatide vs comparators. Greater reductions in body weight were associated with greater reductions in the prevalence of patients meeting the criteria for metabolic syndrome and its individual components. Background SGLT2i or sulfonylurea use or gender did not impact the change in prevalence of patients meeting the criteria for metabolic syndrome. CONCLUSIONS: In this post hoc analysis, tirzepatide at all doses studied was associated with a greater reduction in the prevalence of patients meeting the criteria for metabolic syndrome compared to placebo, semaglutide 1 mg, insulin degludec, and insulin glargine. Although more evidence is needed, these data would support greater potential improvement in cardiovascular risk factor profile with tirzepatide treatment in people across the continuum of T2D.

Body Fat Depletion: the Yin Paradigm for Treating Type 2 Diabetes.

PURPOSE OF REVIEW: To highlight that body fat depletion (the Yin paradigm) with glucose-lowering treatments (the Yang paradigm) are associated with metabolic benefits for patients with type 2 diabetes mellitus (T2DM). RECENT FINDINGS: The sodium-glucose cotransporter-2 inhibitor-mediated sodium/glucose deprivation can directly improve glycemic control and kidney outcome in patients with T2DM. The glucose deprivation might also promote systemic fatty acid ß-oxidation to deplete ectopic/visceral fat and thereby contribute to the prevention of cardiovascular diseases. As with metabolic surgery, bioengineered incretin-based medications with potent anorexigenic and insulinotropic efficacy can significantly reduce blood glucose as well as body weight (especially in the ectopic/visceral fat depots). The latter effects could be a key contributor to their cardiovascular-renal protective effects. In addition to a healthy diet, the newer glucose-lowering medications, with body fat reduction effects, should be prioritized when treating patients with T2DM, especially for those with established cardiovascular/renal risks or diseases.

Greater time spent with HbA1c less than 7.0% with oral semaglutide versus oral comparators: An exploratory analysis of the PIONEER studies.

AIM: To assess how long participants with type 2 diabetes spent with HbA1c less than 7.0% and how likely they were to maintain this target with oral semaglutide 7 mg versus sitagliptin 100 mg or oral semaglutide 14 mg versus empagliflozin 25 mg, sitagliptin 100 mg or subcutaneous liraglutide 1.8 mg. MATERIALS AND METHODS: Analyses used on-treatment data without rescue medication for all randomized participants (semaglutide [approved maintenance doses], n = 1880; comparators [not including placebo], n = 1412). Duration of time with HbA1c less than 7.0% was calculated using an HbA1c time curve. A binary endpoint of achieving HbA1c less than 7.0% at weeks 26 (week 24 for PIONEER 7) and 52 of each trial (and week 78 for PIONEER 3) was analysed. RESULTS: Mean duration of time with HbA1c less than 7.0% was greater with oral semaglutide 7 mg versus sitagliptin in PIONEER 3 (27 vs. 22 weeks) and with oral semaglutide 14 mg versus empagliflozin and sitagliptin (27-34 vs. 19 vs. 22 weeks, respectively), and similar versus subcutaneous liraglutide. A greater proportion of participants achieved and maintained HbA1c less than 7.0% for more than 75% of the trial with oral semaglutide 14 mg versus oral comparators. The odds of achieving HbA1c less than 7.0% at weeks 24/26 and 52/78 were significantly greater with oral semaglutide 14 mg versus oral comparators or subcutaneous liraglutide, and with oral semaglutide 7 mg versus sitagliptin. CONCLUSIONS: Oral semaglutide 7 and 14 mg resulted in greater time spent with HbA1c less than 7.0%, and a greater likelihood of achieving and maintaining HbA1c less than 7.0% versus oral comparators.

Dual glucagon-like peptide-1 and glucagon receptor agonism reduces energy intake in type 2 diabetes with obesity.

AIMS: To establish which components of energy balance mediate the clinically significant weight loss demonstrated with use of cotadutide, a glucagon-like peptide-1 (GLP-1)/glucagon receptor dual agonist, in early-phase studies. MATERIALS AND METHODS: We conducted a phase 2a, single-centre, randomized, placebo-controlled trial in overweight and obese adults with type 2 diabetes. Following a 16-day single-blind placebo run-in, participants were randomized 2:1 to double-blind 42-day subcutaneous treatment with cotadutide (100-300 µg daily) or placebo. The primary outcome was percentage weight change. Secondary outcomes included change in energy intake (EI) and energy expenditure (EE). RESULTS: A total of 12 participants (63%) in the cotadutide group and seven (78%) in the placebo group completed the study. The mean (90% confidence interval [CI]) weight change was -4.0% (-4.9%, -3.1%) and -1.4% (-2.7%, -0.1%) for the cotadutide and placebo groups, respectively (p = 0.011). EI was lower with cotadutide versus placebo (-41.3% [-66.7, -15.9]; p = 0.011). Difference in EE (per kJ/kg lean body mass) for cotadutide versus placebo was 1.0% (90% CI -8.4, 10.4; p = 0.784), assessed by doubly labelled water, and -6.5% (90% CI -9.3, -3.7; p < 0.001), assessed by indirect calorimetry. CONCLUSION: Weight loss with cotadutide is primarily driven by reduced EI, with relatively small compensatory changes in EE.

Efficacy and safety of tirzepatide in people with type 2 diabetes by baseline body mass index: An exploratory subgroup analysis of SURPASS-AP-Combo.

AIMS: To assess the efficacy and safety of tirzepatide versus insulin glargine in people with type 2 diabetes (T2D) by baseline body mass index (BMI). MATERIALS AND METHODS: Participants with T2D from the Phase 3 SURPASS-AP-Combo trial (NCT04093752) were categorized into three BMI subgroups (normal weight [<25 kg/m2 ], overweight [≥25 and <30 kg/m2 ], and obese [≥30 kg/m2 ]) according to World Health Organization criteria. Exploratory outcomes including glycaemic control, body weight, cardiometabolic risk, and safety were compared among three tirzepatide doses (5, 10 or 15 mg) and insulin glargine. RESULTS: Of 907 participants, 235 (25.9%) had a BMI <25 kg/m2 , 458 (50.5%) a BMI ≥25 to <30 kg/m2 , and 214 (23.6%) a BMI ≥30 kg/m2 at baseline. At Week 40, all tirzepatide doses led to a greater reduction in mean glycated haemoglobin (HbA1c; -2.0% to -2.8% vs. -0.8% to -1.0%, respectively) and percent change in body weight (-5.5% to -10.8% vs. 1.0% to 2.5%, respectively) versus insulin glargine, across the BMI subgroups. Compared with insulin glargine, a higher proportion of tirzepatide-treated participants achieved treatment goals for HbA1c and body weight reduction. Improvements in other cardiometabolic indicators were also observed with tirzepatide across all the BMI subgroups. The safety profile of tirzepatide was similar across all subgroups by BMI. The most frequent adverse events with tirzepatide were gastrointestinal-related events and decreased appetite, with relatively few events leading to treatment discontinuation. CONCLUSIONS: In participants with T2D, regardless of baseline BMI, treatment with tirzepatide resulted in statistically significant and clinically meaningful glycaemic reductions and body weight reductions compared with insulin glargine, with a safety profile consistent with previous reports.

Randomised comparison of intravenous and subcutaneous routes of glucagon-like peptide-1 administration for lowering plasma glucose in hyperglycaemic subjects with type 2 diabetes.

AIM: To perform a direct, double-blind, randomised, crossover comparison of subcutaneous and intravenous glucagon-like peptide-1 (GLP-1) in hyperglycaemic subjects with type 2 diabetes naïve to GLP-1-based therapy. MATERIALS AND METHODS: Ten fasted, hyperglycaemic subjects (1 female, age 63 ± 10 years [mean ± SD], glycated haemoglobin 73.5 ± 22.0 mmol/mol [8.9% ± 2.0%], both mean ± SD) received subcutaneous GLP-1 and intravenous saline, or intravenous GLP-1 and subcutaneous saline. Infusion rates were doubled every 120 min (1.2, 2.4, 4.8 and 9.6 pmol·kg-1·min-1 for subcutaneous, and 0.3, 0.6, 1.2 and 2.4 pmol·kg-1·min-1 for intravenous). Plasma glucose, total and intact GLP-1, insulin, C-peptide, glucagon and gastrointestinal symptoms were evaluated over 8 h. The results are presented as mean ± SEM. RESULTS: Plasma glucose decreased more with intravenous (by ~8.0 mmol/L [144 mg/dL]) than subcutaneous GLP-1 (by ~5.6 mmol/L [100 mg/dL]; p < 0.001). Plasma GLP-1 increased dose-dependently, but more with intravenous than subcutaneous for both total (∆max 154.2 ± 3.9 pmol/L vs. 85.1 ± 3.8 pmol/L; p < 0.001), and intact GLP-1 (∆max 44.2 ± 2.2 pmol/L vs. 12.8 ± 2.2 pmol/L; p < 0.001). Total and intact GLP-1 clearance was higher for subcutaneous than intravenous GLP-1 (p < 0.001 and p = 0.002, respectively). The increase in insulin secretion was greater, and glucagon was suppressed more with intravenous GLP-1 (p < 0.05 each). Gastrointestinal symptoms did not differ (p > 0.05 each). CONCLUSIONS: Subcutaneous GLP-1 administration is much less efficient than intravenous GLP-1 in lowering fasting plasma glucose, with less stimulation of insulin and suppression of glucagon, and much less bioavailability, even at fourfold higher infusion rates.

Liraglutide treatment for the prevention of glucose tolerance deterioration in women with prior gestational diabetes mellitus: A 52-week randomized controlled clinical trial.

AIM: We investigated the effect of 52-week treatment with liraglutide, a glucagon-like peptide 1 receptor agonist, on glucose tolerance and incretin effect in women with previous gestational diabetes mellitus (pGDM). MATERIALS AND METHODS: Women with overweight/obesity and pGDM were randomized to once daily subcutaneous liraglutide 1.8 mg or placebo for 52 weeks. Participants underwent oral glucose tolerance test (OGTT) and isoglycaemic intravenous glucose infusion at baseline and at 52 weeks, and an additional OGTT after the drug wash-out. RESULTS: In total, 104 women [age: mean ± SD, 38 ± 5 years; fasting plasma glucose (FPG): 5.5 ± 0.4 mmol/L; glycated haemoglobin (HbA1c): 33 ± 4 mmol/mol, bodyweight: 88.2 ± 14.8 kg, body mass index: 31.1 ± 4.3 kg/m2 ] were assigned to liraglutide (n = 49) or placebo (n = 55). Estimated treatment difference (ETD) for area under curve during OGTT was -173 (95% confidence interval -250 to -97) mmol/L × min, p < .0001, but after wash-out the difference disappeared [ETD 58 (-30 to 146) mmol/L × min, p = .536]. Liraglutide reduced FPG [ETD -0.2 (-0.4 to -0.1) mmol/L, p = .018], HbA1c [-2.2 (-3.5 to -0.8) mmol/mol, p = .018] and bodyweight [-3.9 (-6.2 to -1.6) kg, p = .012]. No change in the incretin effect was observed. The number of women with prediabetes was reduced from 64% to 10% with liraglutide vs. 50% with placebo [adjusted odds ratio 0.10 (0.03-0.32), p = .002]. CONCLUSIONS: Treatment with liraglutide for 52 weeks improved glucose tolerance, FPG, HbA1c and bodyweight in women with overweight/obesity and pGDM. Progression to prediabetes while on drug was markedly reduced, but after a 1-week drug wash-out, the effect was lost.

Gastrointestinal adverse events and weight reduction in people with type 2 diabetes treated with tirzepatide in the SURPASS clinical trials.

AIMS: To evaluate gastrointestinal adverse events (AEs) and the impact of nausea, vomiting or diarrhoea (N/V/D) and any gastrointestinal (GI) AEs overall on weight change with tirzepatide across the SURPASS-1 to -5 clinical trials. MATERIALS AND METHODS: Participants with type 2 diabetes were randomized to receive once-weekly tirzepatide (5, 10 or 15 mg) or comparator (placebo, semaglutide 1 mg once weekly, or titrated daily basal insulins) as monotherapy or added on to background antihyperglycaemic medication(s). This post hoc analysis subdivided participants within each trial into subgroups that self-reported (yes/no) any N/V/D or GI AEs. Change from baseline in body weight at the primary timepoint was assessed within each trial and subgroup. Mediation analyses were conducted to evaluate the contribution of direct and indirect (mediated by N/V/D or GI AEs) effects of tirzepatide on weight change versus comparators. RESULTS: Across the SURPASS-1 to -5 trials (N = 6263), nausea (12%-24%), diarrhoea (12%-22%), and vomiting (2%-13%) were the most common GI AEs reported with tirzepatide; these were transient and of mild-to-moderate severity. Mean weight reduction at the primary timepoint with tirzepatide was consistent between participants who reported N/V/D (-6.2 to -14.9 kg) and those who did not report N/V/D (-6.2 to -13.3 kg). Mean weight reduction was significantly (P < 0.01) greater with tirzepatide compared with placebo, semaglutide 1 mg, and basal insulins within the N/V/D and GI AEs subgroups. Mediation analyses suggested minimal contribution (<6%) of N/V/D and GI AEs to the overall difference in weight change between tirzepatide and comparators. CONCLUSIONS: Superior weight reduction with tirzepatide versus comparators appears to be independent of reported N/V/D or GI AEs.

Incretin Analogs for Weight Management in Adults Without Diabetes.

OBJECTIVE: This is a narrative review of incretin analogs and their effect on weight management in adult without diabetes. DATA SOURCES: Randomized controlled trials were identified by English language. PubMed/MEDLINE, Scopus, and Embase databases were searched from inception through June 2023 to identify all pertinent trials reporting outcomes on efficacy and safety search using the terms: tirzepatide, semaglutide, liraglutide, and obesity. STUDY SELECTION AND DATA EXTRACTION: Selected studies were included if the study population was composed of adults without diabetes being treated by glucagon-like peptide 1 (GLP-1) receptor agonists or glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 agonists for weight management, and weight loss was assessed as a primary outcome. DATA SYNTHESIS: Fifteen studies involving 3 pharmacotherapies (liraglutide, semaglutide, and tirzepatide) were identified. Efficacy data supporting the use of these agents for weight management were promising when compared to placebo and/or other behavioral therapies. Percent weight loss ranged from 5.7% to 11.8%, 14.9% to 17.4%, and 15% to 20.9% for liraglutide, semaglutide, and tirzepatide, respectively. Safety data were relatively similar across all trials and identified gastrointestinal adverse effects as most common. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Glucagon-like peptide 1 agonists are preferred for overweight or obese patients by the American Gastroenterological Association. Future guidelines may address tirzepatides' place in therapy as new evidence comes forth. Providers should consider patient-specific factors such as cost, adverse effects, drug interactions, and comorbidities when prescribing these agents and provide education regarding the need for concurrent diet and exercise modifications. CONCLUSIONS: All incretin analogs in this review are superior to placebo when used for weight management in adults without diabetes.

Secretion of glucagon, GLP-1 and GIP may be affected by circadian rhythm in healthy males.

BACKGROUND: Glucagon is secreted from pancreatic alpha cells in response to low blood glucose and increases hepatic glucose production. Furthermore, glucagon enhances hepatic protein and lipid metabolism during a mixed meal. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted from gut endocrine cells during meals and control glucose homeostasis by potentiating insulin secretion and inhibiting food intake. Both glucose homeostasis and food intake have been reported to be affected by circadian rhythms and vice versa. In this study, we investigated whether the secretion of glucagon, GLP-1 and GIP was affected by circadian rhythms. METHODS: A total of 24 healthy men with regular sleep schedules were examined for 24 h at the hospital ward with 15 h of wakefulness and 9 h of sleep. Food intake was standardized, and blood samples were obtained every third hour. Plasma concentrations of glucagon, GLP-1 and GIP were measured, and data were analyzed by rhythmometric statistical methods. Available data on plasma glucose and plasma C-peptide were also included. RESULTS: Plasma concentrations of glucagon, GLP-1, GIP, C-peptide and glucose fluctuated with a diurnal 24-h rhythm, with the highest levels during the day and the lowest levels during the night: glucagon (p < 0.0001, peak time 18:26 h), GLP-1 (p < 0.0001, peak time 17:28 h), GIP (p < 0.0001, peak time 18:01 h), C-peptide (p < 0.0001, peak time 17.59 h), and glucose (p < 0.0001, peak time 23:26 h). As expected, we found significant correlations between plasma concentrations of C-peptide and GLP-1 and GIP but did not find correlations between glucose concentrations and concentrations of glucagon, GLP-1 and GIP. CONCLUSIONS: Our results demonstrate that under meal conditions that are similar to that of many free-living individuals, plasma concentrations of glucagon, GLP-1 and GIP were observed to be higher during daytime and evening than overnight. These findings underpin disturbed circadian rhythm as a potential risk factor for diabetes and obesity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06166368. Registered 12 December 2023.

A Review of Incretin Therapies Approved and in Late-Stage Development for Overweight and Obesity Management.

OBJECTIVE: To review clinical trial data for incretin therapies that are approved or in late-stage development for overweight or obesity management, along with clinical implications of these therapies and future directions. METHODS: We searched for clinical trials involving incretin therapies studied specifically for overweight or obesity management in ClinicalTrials.gov and PubMed from registry inception through December 2023. RESULTS: Glucagon-like peptide-1 (GLP-1) receptor agonism, alone and in combination with glucose-dependent insulinotropic polypeptide (GIP) receptor agonism or glucagon agonism, leads to significant weight reduction in people with overweight or obesity. Newer incretin therapies have demonstrated weight reduction between 15% to 25%, far outpacing non-incretin therapies for weight management and achieving levels of weight loss that may prevent weight-related complications. However, the discontinuation of incretin therapies is associated with weight regain. The main side effects of incretin therapies are transient, mild-to-moderate gastrointestinal side effects - nausea, diarrhea, constipation, and vomiting - that commonly occur in the first 4 to 8 weeks of treatment. There is a rich late-stage pipeline of incretin therapies for weight management, consisting of oral GLP-1 receptor agonists, dual GLP-1/GIP receptor agonists, dual GLP-1/glucagon receptor agonists, triple GLP-1/GIP/glucagon receptor agonists, and combination therapies with nonincretin drugs. CONCLUSION: Newer incretin therapies for weight management have the potential to improve the treatment for overweight and obesity, the treatment and prevention of weight-related complications, and the individualization of weight management. Ensuring that these therapies are accessible - and that treatment with them is consistent and sustainable - is necessary to translate findings from trials into the real world.

Curbing the Obesity Epidemic: Should GLP-1 Receptor Agonists Be the Standard of Care for Obesity?

PURPOSE OF REVIEW: This article summarizes the medical management of obesity with an emphasis on incretin-based therapeutics that target the neuro-hormonal basis of obesity. RECENT FINDINGS: Medications that mimic the effect of incretins, a group of peptide hormones released in response to nutrient intake that regulate appetite, result in potent and durable weight loss. Glucagon-like peptide 1 (GLP-1) agonists and glucose-dependent insulinotropic polypeptide (GIP) agonists such as semaglutide and tirzepatide are approved by the United States Food and Drug Administration (FDA) for the management of obesity. The SELECT trial demonstrated that semaglutide led to a reduction in major adverse cardiovascular events in patients without diabetes who were either overweight and had preexisting cardiovascular disease or obese. SUMMARY: The treatment of obesity is critical to prevent the progression of cardiovascular-kidney-metabolic syndrome. Incretin-based therapies offer remarkable weight loss and reduce major cardiovascular adverse events.

Socioeconomic aspects of incretin-based therapy.

Incretin-based therapies, particularly glucagon-like peptide-1 receptor agonists (GLP-1 RAs), have demonstrated cardiovascular benefits in people with type 2 diabetes. However, socioeconomic disparities in their uptake may constrain the collective advantages offered by these medications to the broader population. In this review we examine the socioeconomic disparities in the utilisation of incretin-based therapies and discuss strategies to address these inequalities. Based on real-world evidence, the uptake of GLP-1 RAs is reduced in people who live in socioeconomically disadvantaged areas, have low income and education level, or belong to racial/ethnic minorities, even though these individuals have a greater burden of type 2 diabetes and cardiovascular disease. Contributing factors include suboptimal health insurance coverage, limited accessibility to incretin-based therapies, financial constraints, low health literacy and physician-patient barriers such as provider bias. Advocating for a reduction in the price of GLP-1 RAs is a pivotal initial step to enhance their affordability among lower socioeconomic groups and improve their value-for-money from a societal perspective. By implementing cost-effective strategies, healthcare systems can amplify the societal benefits of incretin-based therapies, alongside measures that include maximising treatment benefits in specific subpopulations while minimising harms in vulnerable individuals, increasing accessibility, enhancing health literacy and overcoming physician-patient barriers. A collaborative approach between governments, pharmaceutical companies, healthcare providers and people with diabetes is necessary for the effective implementation of these strategies to enhance the overall societal benefits of incretin-based therapies.

The expanding incretin universe: from basic biology to clinical translation.

Incretin hormones, principally glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1(GLP-1), potentiate meal-stimulated insulin secretion through direct (GIP + GLP-1) and indirect (GLP-1) actions on islet ß-cells. GIP and GLP-1 also regulate glucagon secretion, through direct and indirect pathways. The incretin hormone receptors (GIPR and GLP-1R) are widely distributed beyond the pancreas, principally in the brain, cardiovascular and immune systems, gut and kidney, consistent with a broad array of extrapancreatic incretin actions. Notably, the glucoregulatory and anorectic activities of GIP and GLP-1 have supported development of incretin-based therapies for the treatment of type 2 diabetes and obesity. Here we review evolving concepts of incretin action, focusing predominantly on GLP-1, from discovery, to clinical proof of concept, to therapeutic outcomes. We identify established vs uncertain mechanisms of action, highlighting biology conserved across species, while illuminating areas of active investigation and uncertainty that require additional clarification.

Genome-wide association analysis identifies ancestry-specific genetic variation associated with acute response to metformin and glipizide in SUGAR-MGH.

AIMS/HYPOTHESIS: Characterisation of genetic variation that influences the response to glucose-lowering medications is instrumental to precision medicine for treatment of type 2 diabetes. The Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH) examined the acute response to metformin and glipizide in order to identify new pharmacogenetic associations for the response to common glucose-lowering medications in individuals at risk of type 2 diabetes. METHODS: One thousand participants at risk for type 2 diabetes from diverse ancestries underwent sequential glipizide and metformin challenges. A genome-wide association study was performed using the Illumina Multi-Ethnic Genotyping Array. Imputation was performed with the TOPMed reference panel. Multiple linear regression using an additive model tested for association between genetic variants and primary endpoints of drug response. In a more focused analysis, we evaluated the influence of 804 unique type 2 diabetes- and glycaemic trait-associated variants on SUGAR-MGH outcomes and performed colocalisation analyses to identify shared genetic signals. RESULTS: Five genome-wide significant variants were associated with metformin or glipizide response. The strongest association was between an African ancestry-specific variant (minor allele frequency [MAFAfr]=0.0283) at rs149403252 and lower fasting glucose at Visit 2 following metformin (p=1.9×10-9); carriers were found to have a 0.94 mmol/l larger decrease in fasting glucose. rs111770298, another African ancestry-specific variant (MAFAfr=0.0536), was associated with a reduced response to metformin (p=2.4×10-8), where carriers had a 0.29 mmol/l increase in fasting glucose compared with non-carriers, who experienced a 0.15 mmol/l decrease. This finding was validated in the Diabetes Prevention Program, where rs111770298 was associated with a worse glycaemic response to metformin: heterozygous carriers had an increase in HbA1c of 0.08% and non-carriers had an HbA1c increase of 0.01% after 1 year of treatment (p=3.3×10-3). We also identified associations between type 2 diabetes-associated variants and glycaemic response, including the type 2 diabetes-protective C allele of rs703972 near ZMIZ1 and increased levels of active glucagon-like peptide 1 (GLP-1) (p=1.6×10-5), supporting the role of alterations in incretin levels in type 2 diabetes pathophysiology. CONCLUSIONS/INTERPRETATION: We present a well-phenotyped, densely genotyped, multi-ancestry resource to study gene-drug interactions, uncover novel variation associated with response to common glucose-lowering medications and provide insight into mechanisms of action of type 2 diabetes-related variation. DATA AVAILABILITY: The complete summary statistics from this study are available at the Common Metabolic Diseases Knowledge Portal ( https://hugeamp.org ) and the GWAS Catalog ( www.ebi.ac.uk/gwas/ , accession IDs: GCST90269867 to GCST90269899).