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Abstract Context Questions remain about bariatric surgery for type 2 diabetes mellitus (T2DM) treatment. Objective Compare the remission of T2DM following surgical or nonsurgical treatments. Design, setting, and participants Randomized controlled trial at the University of Pittsburgh, in the United States. Five-year follow-up from February 2015 until June 2016. Interventions 61 participants with obesity and T2DM who were initially randomized to either bariatric surgical treatments (Roux-en-Y gastric bypass [RYGB] or laparoscopic adjustable gastric banding [LAGB]) or an intensive lifestyle weight loss intervention (LWLI) program for 1 year. Lower level lifestyle weight loss interventions (LLLIs) were then delivered for 4 years. Main Outcomes and Measures Diabetes remission assessed at 5 years. Results The mean age of the patients was 47 ± 6.6 years, 82% were women, and 21% African American. Mean hemoglobin A1c level 7.8% ± 1.9%, body mass index (BMI) 35.7 ± 3.1 kg/m2, and 26 participants (43%) had BMI < 35 kg/m2. Partial or complete T2DM remission was achieved by 30% (n = 6) of RYGB, 19% (n = 4) of LAGB, and no LWLI participants (P = .0208). At 5 years those in the RYGB group had the largest percentage of individuals (56%) not requiring any medications for T2DM compared with those in the LAGB (45%) and LWLI (0%) groups (P = .0065). Mean reductions in percent body weight at 5 years was the greatest after RYGB 25.2% ± 2.1%, followed by LAGB 12.7% ± 2.0% and lifestyle treatment 5.1% ± 2.5% (all pairwise P < .01). Conclusions Surgical treatments are more effective than lifestyle intervention alone for T2DM treatment.

Improving glucose sensitivity remains an unmet medical need in treating type 2 diabetes (T2D). Dorzagliatin is a dual-acting, orally bioavailable glucokinase activator that enhances glucokinase activity in a glucose-dependent manner, improves glucose-stimulated insulin secretion and demonstrates effects on glycemic control in patients with T2D. We report the findings of a randomized, double-blind, placebo-controlled phase 3 clinical trial to evaluate the efficacy and safety of dorzagliatin in patients with T2D. Eligible drug-naïve patients with T2D ( n  = 463) were randomly assigned to the dorzagliatin or placebo group at a ratio of 2:1 for 24 weeks of double-blind treatment, followed by 28 weeks of open-label treatment with dorzagliatin for all patients. The primary efficacy endpoint was the change in glycated hemoglobin from baseline to week 24. Safety was assessed throughout the trial. At week 24, the least-squares mean change in glycated hemoglobin from baseline (95% confidence interval) was −1.07% (−1.19%, −0.95%) in the dorzagliatin group and −0.50% (−0.68%, −0.32%) in the placebo group (estimated treatment difference, −0.57%; 95% confidence interval: −0.79%, −0.36%; P  < 0.001). The incidence of adverse events was similar between the two groups. There were no severe hypoglycemia events or drug-related serious adverse events in the dorzagliatin group. In summary, dorzagliatin improved glycemic control in drug-naïve patients with T2D and showed a good tolerability and safety profile. The SEED study is a phase 3 clinical trial demonstrating a beneficial effect on glycemic control of dorzagliatin, a glucokinase activator, in drug-naive patients with newly diagnosed type 2 diabetes.

A closed-loop system (also called an artificial pancreas) may improve glycemic outcomes in children with type 1 diabetes. In this 16-week trial, the glucose level was in the target range for a greater percentage of time with a closed-loop system than with a sensor-augmented insulin pump.

Metformin, the first-line therapy for type 2 diabetes (T2D), decreases hepatic glucose production and reduces fasting plasma glucose levels. Dorzagliatin, a dual-acting orally bioavailable glucokinase activator targeting both the pancreas and liver glucokinase, decreases postprandial glucose in patients with T2D. In this randomized, double-blind, placebo-controlled phase 3 trial, the efficacy and safety of dorzagliatin as an add-on therapy to metformin were assessed in patients with T2D who had inadequate glycemic control using metformin alone. Eligible patients with T2D ( n  = 767) were randomly assigned to receive dorzagliatin or placebo (1:1 ratio) as an add-on to metformin (1,500 mg per day) for 24 weeks of double-blind treatment, followed by 28 weeks of open-label treatment with dorzagliatin for all patients. The primary efficacy endpoint was the change in glycated hemoglobin (HbA1c) levels from baseline to week 24, and safety was assessed throughout the trial. At week 24, the least-squares mean change from baseline in HbA1c (95% confidence interval (CI)) was −1.02% (−1.11, −0.93) in the dorzagliatin group and −0.36% (−0.45, −0.26) in the placebo group (estimated treatment difference, −0.66%; 95% CI: −0.79, −0.53; P  < 0.0001). The incidence of adverse events was similar between groups. There were no severe hypoglycemia events or drug-related serious adverse events in the dorzagliatin and metformin combined therapy group. In patients with T2D who experienced inadequate glycemic control with metformin alone, dorzagliatin resulted in effective glycemic control with good tolerability and safety profile ( NCT03141073 ). The DAWN study is a phase 3 clinical trial that demonstrates effective glycemic control of dorzagliatin as an add-on therapy to metfomin in patients with type 2 diabetes.

Aims/hypothesisIntra-abdominal or visceral obesity is associated with insulin resistance and an increased risk for cardiovascular disease. This study aimed to compare the effects of semaglutide 1.0 mg and canagliflozin 300 mg on body composition in a subset of participants from the SUSTAIN 8 Phase IIIB, randomised double-blind trial who underwent whole-body dual-energy x-ray absorptiometry (DXA) scanning.MethodsAdults (age ≥18 years) with type 2 diabetes, HbA1c 53–91 mmol/mol (7.0–10.5%), on a stable daily dose of metformin (≥1500 mg or maximum tolerated dose) and with an eGFR ≥60 ml min−1 [1.73 m]−2 were randomised 1:1 to semaglutide 1.0 mg once weekly and canagliflozin placebo once daily, or canagliflozin 300 mg once daily and semaglutide placebo once weekly. Body composition was assessed using whole-body DXA scans. The study participants and investigator remained blinded throughout the trial, and quality of DXA scans was evaluated in a blinded manner. Change from baseline to week 52 in total fat mass (kg) was the confirmatory efficacy endpoint.ResultsA subset of 178 participants (semaglutide, n = 88; canagliflozin, n = 90) underwent DXA scanning at screening and were randomised into the substudy. Of these, 114 (semaglutide, n = 53; canagliflozin, n = 61) participants had observed end-of-treatment data included in the confirmatory efficacy analysis. Of the 178 participants in the substudy, numerical improvements in body composition (including fat mass, lean mass and visceral fat mass) were observed after 52 weeks with both treatments. Total fat mass (baseline 33.2 kg) was reduced by 3.4 kg and 2.6 kg with semaglutide and canagliflozin, respectively (estimated treatment difference: –0.79 [95% CI −2.10, 0.51]). Although total lean mass (baseline 51.3 kg) was also reduced by 2.3 kg and 1.5 kg with semaglutide and canagliflozin, respectively (estimated treatment difference: −0.78 [−1.61, 0.04]), the proportion of lean mass (baseline 59.4%) increased by 1.2%- and 1.1%-point, respectively (estimated treatment difference 0.14 [−0.89, 1.17]). Changes in visceral fat mass and overall changes in body composition (assessed by the fat to lean mass ratio) were comparable between the two treatment groups.Conclusions/interpretationIn individuals with uncontrolled type 2 diabetes on stable-dose metformin therapy, the changes in body composition with semaglutide and canagliflozin were not significantly different. Although numerical improvements in body composition were observed following treatment in both treatment arms, the specific impact of both treatments on body composition in the absence of a placebo arm is speculative at this stage.Trial registrationClinicalTrials.gov NCT03136484.FundingThis trial was supported by Novo Nordisk A/S, Denmark.

Impaired glucose control & Insulin resistance are reported to be risk factors for the development of cardiovascular diseases. To find the effects of a structured exercise program on insulin resistance, glycaemic control, functional capacity, and quality of life in patients with Type 2 diabetes mellitus. Randomized, controlled trial. Diabetic Foot Clinic, Department of Physiotherapy & Department of General Medicine, Kasturba Hospital in Manipal, Karnataka, India. 160 participants aged between 30-65 years with Type 2 diabetes mellitus. A set of structured exercise programs (aerobic, resistance, and combined) along with the standard hospital care was performed 3-5 times weekly for 12 weeks. Fasting Insulin Level, Homa-IR, Six-minute walk test (6MWT), and WHOQOL-BREF questionnaire at baseline and 12th week. Body composition analysis, Fasting Blood Sugar, Postprandial Blood Sugar, Glycated Haemoglobin (HbA1c), and GPAQ questionnaire at baseline and 12th week. Significant differences have been observed in Homeostasis model assessment for insulin resistance (Homa-IR) (F (1, 144) = 89.29, p < 0.001); Fasting insulin (FI) (F (1, 144) = 129.10, p < 0.001); Fasting blood sugar (FBS) (F (1, 144) = 12.193, p< 0.001); Post prandial blood sugar (PPBS) (F (1, 144) = 53.015, p< 0.001); glycated haemoglobin (HbA1c) (F (1, 144) = 80.050, p < 0.001); WHOQOL-Physical health (F (1, 144) = 20.008, p< 0.001), Psychological (F (1, 144) = 77.984, p< 0.001), Social relationship (F (1, 144) = 44.866, p< 0.001); Environmental (F (1, 144) = 69.974, p< 0.001); Six minute walk test (6MWT) (F (1, 144) = 84.135, p< 0.001) in the study group when compared with the control group from baseline to 12th week. The study reveals that a 12-week structured exercise training program effectively reduces insulin resistance, improves quality of life, enhances functional capacity, and improves glycaemic control in type 2 diabetes mellitus.

In this study of treatments for recent-onset type 2 diabetes, metformin monotherapy was associated with durable glycemic control in about 50% of patients. The addition of rosiglitazone, but not intensive lifestyle intervention, to metformin was superior to metformin alone. Increases in childhood obesity have been accompanied by an increased incidence of type 2 diabetes in youth. 1 , 2 Because the risk of microvascular and macrovascular complications in adults increases with both the duration of diabetes and lack of glycemic control, 3 , 4 it is imperative to achieve and sustain metabolic control in youth. Addressing the physiological and psychological changes that normally occur during adolescence requires a high level of family involvement and makes the achievement of stringent treatment goals especially difficult in the case of adolescents with diabetes. 5 , 6 These challenges are heightened in disadvantaged populations, which are over-represented among adolescents . . .

Hyperglucagonemia contributes to hyperglycemia in patients with type 1 diabetes (T1D); however, novel therapeutics that block glucagon action could improve glycemic control. This phase 2 study evaluated the safety and efficacy of volagidemab, an antagonistic monoclonal glucagon receptor (GCGR) antibody, as an adjunct to insulin therapy in adults with T1D. The primary endpoint was change in daily insulin use at week 12. Secondary endpoints included changes in hemoglobin A1c (HbA1c) at week 13, in average daily blood glucose concentration and time within target range as assessed by continuous blood glucose monitoring (CGM) and seven-point glucose profile at week 12, incidence of hypoglycemic events, the proportion of subjects who achieve HbA1c reduction of ≥0.4%, volagidemab drug concentrations and incidence of anti-drug antibodies. Eligible participants ( n  = 79) were randomized to receive weekly subcutaneous injections of placebo, 35 mg volagidemab or 70 mg volagidemab. Volagidemab produced a reduction in total daily insulin use at week 12 (35 mg volagidemab: −7.59 units (U) (95% confidence interval (CI) −11.79, −3.39; P  = 0.040 versus placebo); 70 mg volagidemab: −6.64 U (95% CI −10.99, −2.29; P  = 0.084 versus placebo); placebo: −1.27 U (95% CI −5.4, 2.9)) without meeting the prespecified significance level ( P  < 0.025). At week 13, the placebo-corrected reduction in HbA1c percentage was −0.53 (95% CI −0.89 to −0.17, nominal P  = 0.004) in the 35 mg volagidemab group and −0.49 (95% CI −0.85 to −0.12, nominal P  = 0.010) in the 70 mg volagidemab group. No increase in hypoglycemia was observed with volagidemab therapy; however, increases in serum transaminases, low-density lipoprotein (LDL)-cholesterol and blood pressure were observed. Although the primary endpoint did not meet the prespecified significance level, we believe that the observed reduction in HbA1c and tolerable safety profile provide a rationale for further randomized studies to define the long-term efficacy and safety of volagidemab in patients with T1D. See clinicaltrials.gov registration no. NCT03117998 . A phase 2 study testing glucagon receptor antagonist volagidemab as an adjunct to insulin therapy in patients was found to be safe and tolerable. Although the primary endpoint of reduction in daily insulin usage was not met, volagidemab therapy was associated with improved glycaemic control compared to placebo.

Aims/hypothesis The aim of this work was to evaluate the efficacy and safety of canagliflozin vs placebo and sitagliptin in patients with type 2 diabetes who were being treated with background metformin. Methods This randomised, double-blind, four-arm, parallel-group, Phase 3 study was conducted at 169 centres in 22 countries between April 2010 and August 2012. Participants ( N  = 1,284) with type 2 diabetes aged ≥18 and ≤80 years who had inadequate glycaemic control (HbA 1c ≥7.0% [53 mmol/mol] and ≤10.5% [91 mmol/mol]) on metformin therapy received canagliflozin 100 mg or 300 mg, sitagliptin 100 mg, or placebo ( n  = 368, 367, 366, 183, respectively) for a 26 week, placebo- and active-controlled period followed by a 26 week, active-controlled period (placebo group switched to sitagliptin [placebo/sitagliptin]) and were included in the modified intent-to-treat analysis set. Randomisation was performed using a computer-generated schedule; participants, study centres and the sponsor were blinded to group assignment. The primary endpoint was change from baseline in HbA 1c at week 26; secondary endpoints included changes in HbA 1c (week 52) and fasting plasma glucose (FPG), body weight, and systolic blood pressure (BP; weeks 26 and 52). Adverse events (AEs) were recorded throughout the study. Results At week 26, canagliflozin 100 mg and 300 mg reduced HbA 1c vs placebo (−0.79%, –0.94%, –0.17%, respectively; p  < 0.001). At week 52, canagliflozin 100 mg and 300 mg demonstrated non-inferiority, and canagliflozin 300 mg demonstrated statistical superiority, to sitagliptin in lowering HbA 1c (−0.73%, –0.88%,–0.73%, respectively); differences (95% CI) vs sitagliptin were 0% (−0.12, 0.12) and −0.15% (−0.27, –0.03), respectively. Canagliflozin 100 mg and 300 mg reduced body weight vs placebo (week 26: –3.7%, –4.2%, –1.2%, respectively; p  < 0.001) and sitagliptin (week 52: –3.8%, –4.2%, –1.3%, respectively; p  < 0.001). Both canagliflozin doses reduced FPG and systolic BP vs placebo (week 26) and sitagliptin (week 52) ( p  < 0.001). Overall AE and AE-related discontinuation rates were generally similar across groups, but higher with canagliflozin 100 mg. Genital mycotic infection and osmotic diuresis-related AE rates were higher with canagliflozin; few led to discontinuations. Hypoglycaemia incidence was higher with canagliflozin. Conclusions/interpretation Canagliflozin improved glycaemia and reduced body weight vs placebo (week 26) and sitagliptin (week 52) and was generally well tolerated in patients with type 2 diabetes on metformin. Clinical trial registry ClinicalTrials.gov NCT01106677 Funding This study was supported by Janssen Research & Development, LLC.

This trial assessed the efficacy and safety of the GLP-1 analogue once a week subcutaneous semaglutide 2·4 mg versus semaglutide 1·0 mg (the dose approved for diabetes treatment) and placebo for weight management in adults with overweight or obesity, and type 2 diabetes. This double-blind, double-dummy, phase 3, superiority study enrolled adults with a body-mass index of at least 27 kg/m2 and glycated haemoglobin 7–10% (53–86 mmol/mol) who had been diagnosed with type 2 diabetes at least 180 days before screening. Patients were recruited from 149 outpatient clinics in 12 countries across Europe, North America, South America, the Middle East, South Africa, and Asia. Patients were randomly allocated (1:1:1) via an interactive web-response system and stratified by background glucose-lowering medication and glycated haemoglobin, to subcutaneous injection of semaglutide 2·4 mg, or semaglutide 1·0 mg, or visually matching placebo, once a week for 68 weeks, plus a lifestyle intervention. Patients, investigators, and those assessing outcomes were masked to group assignment. Coprimary endpoints were percentage change in bodyweight and achievement of weight reduction of at least 5% at 68 weeks for semaglutide 2·4 mg versus placebo, assessed by intention to treat. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03552757 and is closed to new participants. From June 4 to Nov 14, 2018, 1595 patients were screened, of whom 1210 were randomly assigned to semaglutide 2·4 mg (n=404), semaglutide 1·0 mg (n=403), or placebo (n=403) and included in the intention-to-treat analysis. Estimated change in mean bodyweight from baseline to week 68 was −9·6% (SE 0·4) with semaglutide 2·4 mg vs −3·4% (0·4) with placebo. Estimated treatment difference for semaglutide 2·4 mg versus placebo was −6·2 percentage points (95% CI −7·3 to −5·2; p<0·0001). At week 68, more patients on semaglutide 2·4 mg than on placebo achieved weight reductions of at least 5% (267 [68·8%] of 388 vs 107 [28·5%] of 376; odds ratio 4·88, 95% CI 3·58 to 6·64; p<0·0001). Adverse events were more frequent with semaglutide 2·4 mg (in 353 [87·6%] of 403 patients) and 1·0 mg (329 [81·8%] of 402) than with placebo (309 [76·9%] of 402). Gastrointestinal adverse events, which were mostly mild to moderate, were reported in 256 (63·5%) of 403 patients with semaglutide 2·4 mg, 231 (57·5%) of 402 with semaglutide 1·0 mg, and 138 (34·3%) of 402 with placebo. In adults with overweight or obesity, and type 2 diabetes, semaglutide 2·4 mg once a week achieved a superior and clinically meaningful decrease in bodyweight compared with placebo. Novo Nordisk.