Estimated Treatment Difference Research Articles

Safety and efficacy of a GLP-1 and glucagon receptor dual agonist mazdutide (IBI362) 9 mg and 10 mg in Chinese adults with overweight or obesity: A randomised, placebo-controlled, multiple-ascending-dose phase 1b trial.

SummaryBackgroundMazdutide (also known as IBI362 or LY3305677), a novel once-weekly glucagon-like peptide-1 (GLP-1) and glucagon receptor dual agonist, achieved 12-week body weight loss up to 6.4% at doses up to 6 mg in Chinese adults with overweight or obesity. We further explored the safety and efficacy of mazdutide dosed up to 9 mg and 10 mg.MethodsIn this randomised, placebo-controlled, multiple-ascending-dose phase 1b trial, we enrolled adults (aged 18-75 years, both inclusive) with overweight (body-mass index [BMI] ≥24 kg/m2) accompanied by hyperphagia and/or at least one obesity-related comorbidity or obesity (BMI ≥28 kg/m2) from five hospitals in China. Eligible participants were randomly assigned (2:1) within each cohort by using an interactive web-response system to receive once-weekly subcutaneous mazdutide or placebo for 12 weeks in the 9 mg cohort (3 mg weeks 1-4; 6 mg weeks 5-8; 9 mg weeks 9-12) and for 16 weeks in the 10 mg cohort (2.5 mg weeks 1-4; 5 mg weeks 5-8; 7.5 mg weeks 9-12; 10 mg weeks 13-16). The participants, investigators, study site personnel involved in treating and assessing participants in each cohort and sponsor personnel were masked to treatment allocation. The primary outcomes were safety and tolerability of mazdutide, assessed from baseline to end of follow-up in all participants who received at least one dose of the study treatment. The secondary outcomes included the change from baseline to week 12 or week 16 in body weight, waist circumference and BMI. This trial is registered with ClinicalTrials.gov, NCT04440345.FindingsBetween Mar. 1, 2021 and Mar. 26, 2021, a total of 24 participants were enrolled, with eight randomly assigned to mazdutide and four to placebo in each cohort. One participant receiving mazdutide and two receiving placebo in the 10 mg cohort withdrew consent and quitted the study. No serious adverse event was reported. All treatment-emergent adverse events (TEAEs) were mild or moderate in severity and most commonly-reported TEAEs were upper respiratory tract infection, diarrhoea, decreased appetite, nausea, urinary tract infection, abdominal distension and vomiting. The mean percent change from baseline to week 12 in body weight were −11.7% (SE 1.5) for participants receiving mazdutide in the 9 mg cohort and −1.8% (1.6) for participants receiving placebo (estimated treatment difference [ETD]: −9.8%; 95% confidence interval [CI]: −14.4, −5.3; P = 0.0002). The mean percent change from baseline to week 16 in body weight were −9.5% (SE 1.7) for participants receiving mazdutide in the 10 mg cohort and −3.3% (1.9) for participants receiving placebo (ETD: −6.2%; 95% CI: −11.5, −0.9; P = 0.024). In addition, compared with placebo, mazdutide achieved more profound reductions in waist circumference and BMI.InterpretationMazdutide dosed up to 9 mg and 10 mg was both well tolerated and showed a favourable safety profile. High-dose mazdutide showed promising 12-week body weight loss, holding great potential for the treatment of moderate-to-severe obesity. A larger and longer phase 2 trial will further evaluate the efficacy and safety of high-dose mazdutide in Chinese adults with obesity.FundingInnovent Biologics, Inc.

The effect of ziltivekimab on the neutrophil-lymphocyte ratio: analysis from RESCUE

Abstract Background The neutrophil-lymphocyte ratio (NLR), derived from the complete blood count, independently predicts atherosclerotic events and is a potential biomarker for residual inflammatory risk. A previous study showed that interleukin (IL)-1β inhibition reduces the NLR, but whether inhibition with IL-6, a cytokine downstream of IL-1, also lowers the NLR is unknown. Purpose To evaluate whether ziltivekimab, a monoclonal antibody targeting the IL-6 ligand, dose-dependently lowers the NLR compared to placebo. Methods The phase II RESCUE trial randomized 264 patients with moderate to severe chronic kidney disease (CKD) and high-sensitivity CRP (hsCRP) >2mg/L in a 1:1:1:1 ratio to placebo or ziltivekimab 7.5 mg, 15 mg, and 30 mg subcutaneously once every four weeks. As previously reported, the trial met its primary endpoint as demonstrated by hsCRP reductions of 4% in the placebo group as compared to 77%, 88%, and 92% at 12 weeks in the ziltivekimab 7.5, 15, and 30 mg groups, respectively. Using RESCUE trial data, we further evaluated the percent change from baseline in the NLR at 12 weeks and sought evidence of correlation between any observed changes in the NLR with changes in other measured biomarkers. Results Ziltivekimab dose-dependently reduced the NLR starting at week one and sustained through week 12 (Table). The median change in the NLR at 12 weeks, the primary pre-specified endpoint, was −13.5% in the 7.5 mg group, −14.3% in the 15 mg group, and −22.4% in the 30 mg group compared to 1.56% in the placebo group. The estimated treatment difference was −14.6% (p=0.004), −15.3% (p=0.004), and −23.6% (p<0.0001) in the ziltivekimab 7.5, 15, and 30 mg groups respectively. These changes were driven largely by reductions in the absolute neutrophil count with minimal change in lymphocyte count. The change in NLR with ziltivekimab correlated modestly with the changes in hsCRP (R=0.26, p=0.0006), fibrinogen (R=0.18, p=0.02), and haptoglobin (R=0.17, p=0.03), but not serum amyloid A, ApoA1, ApoB, ApoB/ApoA ratio, or traditional risk markers. Conclusions IL-6 inhibition with ziltivekimab lowers the NLR. The ongoing ZEUS cardiovascular (CV) outcomes trial will assess whether ziltivekimab can reduce CV event rates among individuals with stage 3 to 4 CKD, known atherosclerotic disease, and elevated hsCRP. If ziltivekimab reduces CV risk, it would provide further evidence for critical inter-relationships between bone marrow function and atherothrombosis. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Novo Nordisk

Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial

The STEP 5 trial assessed the efficacy and safety of once-weekly subcutaneous semaglutide 2.4 mg versus placebo (both plus behavioral intervention) for long-term treatment of adults with obesity, or overweight with at least one weight-related comorbidity, without diabetes. The co-primary endpoints were the percentage change in body weight and achievement of weight loss of ≥5% at week 104. Efficacy was assessed among all randomized participants regardless of treatment discontinuation or rescue intervention. From 5 October 2018 to 1 February 2019, 304 participants were randomly assigned to semaglutide 2.4 mg (n = 152) or placebo (n = 152), 92.8% of whom completed the trial (attended the end-of-trial safety visit). Most participants were female (236 (77.6%)) and white (283 (93.1%)), with a mean (s.d.) age of 47.3 (11.0) years, body mass index of 38.5 (6.9) kg m–2 and weight of 106.0 (22.0) kg. The mean change in body weight from baseline to week 104 was −15.2% in the semaglutide group (n = 152) versus −2.6% with placebo (n = 152), for an estimated treatment difference of −12.6 %-points (95% confidence interval, −15.3 to −9.8; P < 0.0001). More participants in the semaglutide group than in the placebo group achieved weight loss ≥5% from baseline at week 104 (77.1% versus 34.4%; P < 0.0001). Gastrointestinal adverse events, mostly mild-to-moderate, were reported more often with semaglutide than with placebo (82.2% versus 53.9%). In summary, in adults with overweight (with at least one weight-related comorbidity) or obesity, semaglutide treatment led to substantial, sustained weight loss over 104 weeks versus placebo. NCT03693430

The effect of curcumin on hepatic fat content in individuals with obesity.

To evaluate the effect of curcumin treatment on hepatic fat content in obese individuals. In a double-blind, parallel-group trial, 37 obese, non-diabetic individuals were randomized to placebo or curcumin treatment for 6 weeks. Curcumin was dosed as lecithin-formulated tablet; 200 mg twice daily. The primary endpoint was hepatic fat content as assessed by magnetic resonance spectroscopy (MRS). Other endpoints included anthropometric measurements, hepatic biomarkers including FibroScan measurements, metabolic variables, inflammation markers, appetite measures and ad libitum food intake. Baseline characteristics (mean ± SD) were age 46 ± 14 years, hepatic fat content 12.2% ± 8.8% points, body mass index 38.8 ± 6.1 kg/m2 and waist circumference 125.8 ± 12.3 cm. After 6 weeks of treatment with curcumin, hepatic fat content was changed by -0.86% points (95% CI-3.65; 1.94) compared with 0.71% points (95% CI - 2.08; 3.51) with placebo, thus resulting in a non-significant estimated treatment difference of -1.57% points (95% CI -5.36; 2.22, P=.412). Compared with placebo, curcumin treatment caused small reductions in fasting plasma glucose (estimated treatment difference [ETD] - 0.24 mmol/L [95% CI -0.45; -0.03]), triglycerides (ETD [percentage change] -20.22% [95% CI -33.21; -6.03]) and gamma glutamyltransferase (ETD [percentage change] -15.70% [95% CI -23.32; -7.32]), but except for gamma glutamyltransferase, none of these differences remained statistically significant after adjusting for multiple testing. Treatment was well tolerated. Compared with placebo, curcumin treatment for 6 weeks had no significant effect on MRS-assessed hepatic fat content in obese individuals with primarily mild steatosis. Curcumin was well tolerated.

High-Protein, Low-Glycaemic Meal Replacement Improves Physical Health-Related Quality of Life in High-Risk Persons for Metabolic Syndrome-A Subanalysis of the Randomised-Controlled ACOORH Trial.

While obesity impairs health-related quality of life (HRQOL), lifestyle interventions targeting weight reduction have been effective in improving HRQOL. Therefore, we hypothesised that a meal replacement-based lifestyle intervention, which has been shown to successfully reduce weight, would also improve HRQOL more effectively than a lifestyle intervention alone. In the international, multicenter, randomised-controlled ACOORH-trial (Almased-Concept-against- Overweight-and-Obesity-and-Related-Health-Risk), overweight or obese participants with elevated risk for metabolic syndrome (n = 463) were randomised into two groups. Both groups received telemonitoring devices and nutritional advice. The intervention group additionally used a protein-rich, low-glycaemic meal replacement for 6 months. HRQOL was estimated at baseline, after 3 and 12 months, using the SF-36 questionnaire, and all datasets providing HRQOL data (n = 263) were included in this predefined subanalysis. Stronger improvements in the physical component summary (PCS) were observed in the intervention compared to the control group, peaking after 3 months (estimated treatment difference 2.7 [1.2; 4.2]; p < 0.0001), but also in the long-term. Multiple regression analysis demonstrated that insulin levels and the achieved weight loss were associated with the mental component summary (MCS) after 12 months (p < 0.05). Thus, meal replacement-based lifestyle intervention is not only effective in weight reduction but, concomitantly, in enhancing HRQOL.

Comparative efficacy and safety of two insulin aspart formulations (Rapilin and NovoRapid) when combined with metformin, for patients with diabetes mellitus: a multicenter, randomized, open-label, controlled clinical trial

Objective This phase 3 confirmatory diabetes mellitus treatment study compared the safety and efficacy of Rapilin and NovoRapid insulin asparts in combination with metformin. Methods This 24-week, open-label, randomized, active-controlled, noninferiority phase 3 confirmatory study conducted across centers in China aimed to enroll patients with type 2 diabetes mellitus and blood sugar glucose inadequately controlled by oral antidiabetic drugs. Randomized patients received subcutaneous mealtime Rapilin or NovoRapid (3:1) injections, with metformin. The primary objectives were to demonstrate noninferiority (margin of 0.4%) in HbA1c change from baseline and compare safety profiles of Rapilin versus NovoRapid after 24 weeks. Secondary outcomes included 2-h postprandial plasma glucose (PPG), fasting plasma glucose (FPG), and patients achieving HbA1c <7.0% and ≤6.5%. Results 590 patients with type 2 diabetes mellitus were randomized to Rapilin (n = 441) and NovoRapid (n = 149) groups. After 24 weeks, the mean HbA1c change from baseline was −2.20% (Rapilin) and −2.32% (NovoRapid); the estimated treatment difference based on least-square means was 0.04% (95% CI: −0.17, 0.26), meeting the noninferiority criteria for Rapilin versus NovoRapid. Comparable improvements were reported for mean 2-hour PPG (6.14 and 6.29 mmol/L), FPG (2.02 and 1.70 mmol/L), and patients with HbA1c <7.0% (52.6% and 51.0%) and ≤6.5% (34.2% and 30.9%), in the Rapilin and NovoRapid groups, respectively, with no significant safety or immunogenicity outcome differences. Conclusions Rapilin demonstrated non-inferior glycemic control, and matching safety and immunogenicity to NovoRapid in patients with type 2 diabetes mellitus also receiving metformin over 24 weeks. Trial registration ChiCTR20003129041

Early and Strong Leptin Reduction Is Predictive for Long-Term Weight Loss during High-Protein, Low-Glycaemic Meal Replacement-A Subanalysis of the Randomised-Controlled ACOORH Trial.

Lifestyle interventions including meal replacement are suitable for prevention and treatment of obesity and type-2-diabetes. Since leptin is involved in weight regulation, we hypothesised that a meal replacement-based lifestyle intervention would reduce leptin levels more effectively than lifestyle intervention alone. In the international, multicentre, randomised-controlled ACOORH-trial (Almased-Concept-against-Overweight-and-Obesity-and-Related- Health-Risk), overweight or obese participants with metabolic syndrome criteria (n = 463) were randomised into two groups and received telemonitoring devices and nutritional advice. The intervention group additionally used a protein-rich, low-glycaemic meal replacement. Data were collected at baseline, after 1, 3, 6, and 12 months. All datasets providing leptin data (n = 427) were included in this predefined subanalysis. Serum leptin levels significantly correlated with sex, body mass index, weight, and fat mass at baseline (p < 0.0001). Stronger leptin reduction has been observed in the intervention compared to the control group with the lowest levels after 1 month of intervention (estimated treatment difference −3.4 µg/L [1.4; 5.4] for females; −2.2 µg/L [1.2; 3.3] for males; p < 0.001 each) and was predictive for stronger reduction of body weight and fat mass (p < 0.001 each) over 12 months. Strongest weight loss was observed after 6 months (−5.9 ± 5.1 kg in females of the intervention group vs. −2.9 ± 4.9 kg in the control group (p < 0.0001); −6.8 ± 5.3 kg vs. −4.1 ± 4.4 kg (p = 0.003) in males) and in those participants with combined leptin and insulin decrease. A meal replacement-based lifestyle intervention effectively reduces leptin which is predictive for long-term weight loss.

Efficacy of tirzepatide 5, 10 and 15 mg versus semaglutide 2mg in patients with type 2 diabetes: An adjusted indirect treatment comparison.

AimTo conduct an adjusted indirect treatment comparison (aITC) of the efficacy of tirzepatide 5/10/15 mg versus semaglutide 2 mg in patients with type 2 diabetes.Materials and MethodsThe primary analysis was a Bucher aITC of the change from baseline at week 40 in HbA1c (%) and body weight (kg). Aggregate data from the SURPASS‐2 study that met the HbA1c inclusion criterion of the SUSTAIN FORTE study and from SUSTAIN FORTE metformin‐only treated patients were used for primary analysis.ResultsThe SURPASS‐2 refined population comprised 238/245/240 and 240 participants for tirzepatide 5/10/15 mg and semaglutide 1 mg, respectively. The SUSTAIN FORTE metformin‐only population comprised 222 and 227 participants for semaglutide 1 and 2 mg, respectively. In this aITC, tirzepatide 10 and 15 mg significantly reduced HbA1c versus semaglutide 2 mg with an estimated treatment difference (ETD) of −0.36% (95% confidence interval [CI] −0.63, −0.09) and −0.4% (95% CI −0.67, −0.13), respectively. Tirzepatide 10 and 15 mg significantly reduced body weight versus semaglutide 2 mg with an ETD of −3.15 kg (95% CI −4.84, −1.46) and −5.15 kg (95% CI −6.85, −3.45), respectively. There were no significant differences between tirzepatide 5 mg and semaglutide 2 mg on change from baseline in HbA1c and body weight.ConclusionsIn this aITC, HbA1c and weight reductions were significantly greater for tirzepatide 10 and 15 mg versus semaglutide 2 mg and were similar for tirzepatide 5 mg versus semaglutide 2 mg. These findings provide comparative effectiveness insights in the absence of a head‐to‐head clinical trial.

38-OR: Glycemic Control with Ultrarapid Lispro (URLi) vs. Lispro in Children and Adolescents with T1D: PRONTO-Peds

This phase 3, treat-to-target study evaluated efficacy and safety of URLi vs. lispro in 716 pediatric patients (pts) with type 1 diabetes (T1D) . After 4-week lead-in to optimize basal insulin, pts were randomized to double-blind URLi (n=280) or lispro (n=298) injected 0-2 min prior to meals, or open-label URLi (n=138) injected up to 20 min after meals (URLi+20) . Pts remained on prestudy basal insulin (degludec, detemir, or glargine) . Primary endpoint was HbA1c change from baseline after 26 weeks. Noninferiority was shown in HbA1c change with URLi vs. lispro: estimated treatment difference (ETD) -0.02% (95% CI -0.17, 0.13) and with URLi+20 vs. lispro: ETD -0.02% (95% CI -0.20, 0.17) . Postprandial glucose (PPG) measured by self-monitored blood glucose (SMBG) was lower with URLi vs. lispro 1 h after breakfast (p&amp;lt;0.001) and dinner (p=0.006) . URLi significantly reduced 1 h postmeal glucose daily mean vs. lispro (p=0.001) . Total daily insulin dose was similar between treatments. There were no significant differences among treatments in rate or incidence of severe, nocturnal or documented hypoglycemia (&amp;lt;54 mg/dL) . With URLi vs. lispro, rate of postdose hypoglycemia (&amp;lt;54 mg/dL) was higher at ≤2 h (p=0.034) . Incidence of treatment-emergent adverse events was similar between groups. More pts reported an injection site reaction related event with URLi (7.9%) and URLi+20 (2.9%) vs. lispro (2.7%) . All injection site reactions were mild or moderate in severity. Two URLi patients discontinued the study due to injection site reactions. In children and adolescents with T1D, URLi demonstrated similar overall glycemic control and greater PPG lowering with an acceptable safety and tolerability profile compared with lispro. URLi dosed at the start of meals or up to 20 min after the start of meals showed noninferiority for HbA1c change from baseline vs. lispro. URLi dosed at the beginning of meals showed lower PPG at 1 h after breakfast and dinner and lower 1 h postmeal glucose daily mean vs. lispro. Disclosure R. Wadwa: Advisory Panel; Dompé. Consultant; Beta Bionics, Inc. Research Support; Dexcom, Inc., Eli Lilly and Company, Tandem Diabetes Care, Inc. Other Relationship; Tandem Diabetes Care, Inc. L.M. Laffel: Advisory Panel; Medtronic, Roche Diabetes Care. Consultant; Boehringer Ingelheim International GmbH, Dexcom, Inc., Dompé, Insulet Corporation, Janssen Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk, Provention Bio, Inc. D.R. Franco: Advisory Panel; Abbott Diabetes, Medtronic, Novo Nordisk, Sanofi. Research Support; Eli Lilly and Company. Speaker's Bureau; Abbott Diabetes, AstraZeneca, Medtronic, Roche Diabetes Care, Sanofi. M.A. Dellva: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. R.K. Pollom: Employee; Eli Lilly and Company. Funding Eli Lilly and Company

DUALI China: Improved glycemic control withIDegLiraversus its individual components in a randomized trial with Chinese participants with type 2 diabetes uncontrolled on oral antidiabetic drugs

BackgroundDUAL I China, one of the DUAL trials, assessed efficacy/safety of insulin degludec/liraglutide (IDegLira) in Chinese adults with type 2 diabetes (T2D) not controlled by oral antidiabetic drugs (OADs).MethodsThis phase 3a, treat‐to‐target multicenter trial randomized participants (glycated hemoglobin [HbA1c] 53.0‐85.8 mmol/mol; previous metformin ± another OAD) 2:1:1 to IDegLira (n = 361), degludec (n = 179), or liraglutide (n = 180). Primary endpoint was change in HbA1c after 26 weeks. Secondary endpoints included: HbA1c < 53.0 mmol/mol attainment, weight change, treatment‐emergent hypoglycemia, end‐of‐treatment insulin dose, and safety.ResultsAt 26 weeks, HbA1c had decreased by a mean 18.12 mmoL/moL (IDegLira), 12.37 mmoL/moL (degludec) (estimated treatment difference [ETD] −6.50 mmoL/moL; 95% confidence interval [CI] −7.96, −5.04; P < .0001), and 11.33 mmoL/moL (liraglutide) (ETD −6.87 mmoL/moL; 95% CI −8.33, −5.41; P < 0.0001), indicating noninferiority for IDegLira vs degludec and superiority vs liraglutide. HbA1c < 53.0 mmoL/moL attainment was 77.0% (IDegLira), 46.4% (degludec), and 48.3% (liraglutide). Mean weight change with IDegLira (0.1 kg) was superior to degludec (1.2 kg) (ETD −1.08 kg; 96% CI −1.55, −0.62; P < 0.0001). Severe or confirmed hypoglycemic event rates were 0.24 (IDegLira) and 0.17 (degludec) episodes/participant‐year (estimated rate ratio 1.46; 95% CI 0.71, 3.02; P = .3008, not significant). At the end of treatment, the IDegLira insulin dose was lower (24.5 U/d) vs degludec (30.3 U/d) (ETD −5.49 U; 95% CI −7.77, −3.21; P < 0.0001). No unexpected safety issues occurred.ConclusionsIDegLira is efficacious and well tolerated in Chinese adults with T2D not controlled by OADs.

Dorzagliatin in drug-naïve patients with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 3 trial

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.

Dorzagliatin add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 3 trial

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).

SURPASSing the current dogma: is our framework shifting?

In their article in The Lancet Diabetes and Endocrinology, Tadej Battelino and colleagues1 report on a dedicated substudy of the parent SURPASS-3 randomised clinical trial, in which all three groups given the dual GLP-1 and GIP, tirzepatide (5 mg, 10 mg, or 15 mg weekly doses), had significantly greater reductions in HbA1c (estimated treatment difference [ETD] –0·59% to –1·04%, p<0·0001) and bodyweight (ETD –9·8 to –15·2 kg, p<0·0001) at 52 weeks than did the insulin degludec group in participants who were insulin-naive with type 2 diabetes.

Effect of tirzepatide versus insulin degludec on liver fat content and abdominal adipose tissue in people with type 2 diabetes (SURPASS-3 MRI): a substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial

Tirzepatide is a novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 receptor agonist under development for the treatment of type 2 diabetes. The aim of this substudy was to characterise the changes in liver fat content (LFC), volume of visceral adipose tissue (VAT), and abdominal subcutaneous adipose tissue (ASAT) in response to tirzepatide or insulin degludec in a subpopulation of the SURPASS-3 study. This substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial was done at 45 medical research centres and hospitals across eight countries (Argentina, Austria, Greece, Hungary, Italy, Romania, Spain, and the USA). Eligible participants were adults with type 2 diabetes, a baseline HbA1c 7·0-10·5% (53-91 mmol/mol), a BMI of at least 25 kg/m2, stable weight, were insulin-naive, and on treatment with metformin alone or in combination with a SGLT2 inhibitor for at least 3 months before screening. In addition to the main study inclusion criteria, substudy participants had a fatty liver index of at least 60. Participants had an MRI scan and were randomised (1:1:1:1) in the main study to subcutaneous injection once per week of tirzepatide 5 mg, 10 mg, or 15 mg, or subcutaneous injection once per day of titrated insulin degludec, using an interactive web-response system, and were stratified by country, HbA1c, and concomitant oral anti-hyperglycaemic medication. The primary efficacy endpoint was the change from baseline in LFC (as measured by MRI-proton density fat fraction [MRI-PDFF]) at week 52 using pooled data from the tirzepatide 10 mg and 15 mg groups versus insulin degludec. Analyses were assessed in the enrolled MRI population, which consisted of participants in the modified intention-to-treat population of the main study who also had a valid MRI at either baseline or after baseline. This is a substudy of the trial registered with ClinicalTrials.gov, number NCT03882970, and is complete. From April 1, 2019, to Nov 15, 2019, 502 participants were assessed for eligibility to participate in this substudy, 296 (59%) of whom were included in the enrolled MRI population and randomly assigned to treatment (tirzepatide 5 mg, n=71; tirzepatide 10 mg, n=79; tirzepatide 15 mg, n=72; and insulin degludec, n=74). Baseline demographics and clinical characteristics were similar across all treatment groups. From an overall mean baseline LFC of 15·71% (SD 8·93), the absolute reduction in LFC at week 52 was significantly greater for the pooled tirzepatide 10 mg and 15 mg groups (-8·09%, SE 0·57) versus the insulin degludec group (-3·38%, 0·83). The estimated treatment difference versus insulin degludec was -4·71% (95% CI -6·72 to -2·70; p<0·0001). The reduction in LFC was significantly correlated (p≤0·0006) with baseline LFC (ρ=-0·71), reductions in VAT (ρ=0·29), reductions in ASAT (ρ=0·33), and reductions in body weight (ρ=0·34) in the tirzepatide groups. Tirzepatide showed a significant reduction in LFC and VAT and ASAT volumes compared with insulin degludec in this subpopulation of patients with type 2 diabetes in the SURPASS-3 study. These data provide additional evidence on the metabolic effects of this novel dual GIP and GLP-1 receptor agonist. Eli Lilly and Company.

Efficacy of once-weekly tirzepatide versus once-daily insulin degludec on glycaemic control measured by continuous glucose monitoring in adults with type 2 diabetes (SURPASS-3 CGM): a substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial

Tirzepatide is a novel dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist under development for the treatment of type 2 diabetes. In this study, we used continuous glucose monitoring (CGM) to compare the 24 h glucose profile for participants given tirzepatide compared with those given insulin degludec. This substudy of the open-label, parallel-group, phase 3 SURPASS-3 trial, was done at 45 sites across six countries (Hungary, Poland, Romania, Spain, Ukraine, and the USA). Eligible participants in the main study were adults with type 2 diabetes, a baseline HbA1c of 7·0-10·5% (53-91 mmol/mol), and a BMI of 25 kg/m2 or more, who were insulin-naive, and treated with metformin alone or in combination with a SGLT2 inhibitor for at least 3 months before screening. Participants in the main study were randomly assigned (1:1:1:1) to receive once-weekly subcutaneous injection of tirzepatide 5 mg, 10 mg, or 15 mg, or once-daily subcutaneous injection of titrated insulin degludec (100 U/mL), using an interactive web-response system. Participants were stratified by country, HbA1c concentration, and concomitant oral antihyperglycaemic medication. A subset of these patients with a normal wake-sleep cycle were enrolled into this substudy, and interstitial glucose values were collected by CGM for approximately 7 days at baseline, 24 weeks, and 52 weeks. The primary outcome was to compare pooled participants assigned to 10 mg and 15 mg tirzepatide versus insulin degludec for the proportion of time that CGM values were in the tight target range (71-140 mg/dL) at 52 weeks, assessed in all randomly assigned participants who received at least one dose of study drug and had an evaluable CGM session at either baseline or after baseline. The secondary outcomes were to compare tirzepatide (5 mg, 10 mg, and 15 mg) versus insulin degludec for the proportion and duration of time in tight target range at 24 and 52 weeks. This was a substudy of the trial registered with ClinicalTrials.gov, NCT03882970, and is complete. From April 1 to Nov 27, 2019, 313 participants were screened for eligibility, 243 of whom were enrolled in CGM substudy (tirzepatide 5 mg, n=64; tirzepatide 10 mg, n=51; tirzepatide 15 mg, n=73; and insulin degludec, n=55). Patients given once-weekly tirzepatide (pooled 10 mg and 15 mg groups) had a greater proportion of time in tight target range compared with patients given insulin degludec (estimated treatment difference 25% [95% CI 16-33]; p<0·0001). Participants assigned to tirzepatide spent significantly more time in tight target range at 52 weeks compared with those assigned to insulin degludec (5 mg 12% [1-22], p=0·031; 10 mg 24% [13-35], p<0·0001; and 15 mg 25% [14-35], p<0·0001). Participants assigned to tirzepatide 10 mg and 15 mg, but not to tirzepatide 5 mg, spent significantly more time in tight target range at 24 weeks compared with insulin degludec (10 mg 19% [8-30], p=0·0008; 15 mg 21% [11-31], p<0·0001). Once-weekly treatment with tirzepatide showed superior glycaemic control measured using CGM compared with insulin degludec in participants with type 2 diabetes on metformin, with or without a SGLT2 inhibitor. These new data provide additional evidence to the effect of tirzepatide and potential for achieving glycaemic targets without increase of hypoglycaemic risk compared with a basal insulin. Eli Lilly and Company.

A randomized trial to investigate the efficacy and safety of once-daily liraglutide 1.8 mg in Japanese adults with type 2 diabetes exhibiting an inadequate response to liraglutide 0.9 mg.

ABSTRACTAims/IntroductionThe present trial compared the efficacy and safety of once‐daily liraglutide 1.8 mg with liraglutide 0.9 mg in Japanese patients with type 2 diabetes to assess the incremental effects of liraglutide 1.8 mg in those who exhibited an inadequate response to 0.9 mg.Materials and MethodsThis 26‐week randomized trial (NCT02505334) enrolled Japanese adults with type 2 diabetes across 47 sites in Japan. Participants with glycated hemoglobin (HbA1c) 7.5–10.0% were included and those on insulin treatment were excluded. Participants discontinued pre‐trial oral antidiabetic drug and initiated liraglutide 0.9 mg for a 12‐week run‐in period, after which those with HbA1c ≥7.0% (466) were randomized (1:1) to two treatment arms: continuing liraglutide 0.9 mg or dose escalation to 1.8 mg. The change from baseline in HbA1c (primary endpoint) and treatment‐emergent adverse events (secondary endpoint) were measured at the end of 26 weeks.ResultsAfter 26 weeks of treatment, liraglutide 1.8 mg was more effective compared with 0.9 mg in lowering HbA1c levels, with an estimated treatment difference of −0.40% (95% confidence interval [CI] −0.55, −0.24; P < 0.0001). Liraglutide 1.8 mg was associated with significantly greater odds of participants reaching HbA1c <7.0% (estimated odds ratio [EOR] 3.87; 95% CI 2.12, 7.08; P < 0.0001) and ≤6.5% (EOR 3.78; 95% CI 1.36, 10.54; P = 0.0109) compared with 0.9 mg. Both doses were well tolerated.ConclusionsLiraglutide 1.8 mg had better efficacy in improving HbA1c levels after 26 weeks treatment vs 0.9 mg in Japanese patients, with both doses well tolerated.

IDF21-0140 Higher derived time in range with insulin degludec/insulin aspart vs insulin glargine U100 in Japanese adults with T2D

Background: Time in range (TIR) is an important metric providing reliable information on overall glycaemic control and a convenient method to differentiate between insulin therapies. Aim: We used the concept of blood-glucose monitored derived TIR (dTIR) to evaluate and compare treatment with insulin degludec/insulin aspart (IDegAsp) and insulin glargine 100 units/mL (IGlar U100) in insulin-naïve patients with type 2 diabetes (T2D). Method: Data from BOOST Japan – a phase 3, open-label, treat-to-target trial of insulin-naïve Japanese adults with T2D who were randomised to either IDegAsp (n=147) or IGlar U100 (n=149) – were evaluated post hoc. Self-monitored blood glucose profiles (weeks 0, 12, 16 and 26) were used to derive the proportion of available readings within (dTIR: 3.9–10 mmol/L [70–180 mg/dL]), below (derived time below range [dTBR]: <3.9 mmol/L [<70 mg/dL]), or above (derived time above range [dTAR]: >10 mmol/L [>180 mg/dL]) target range. Profiles with ≥6 non-missing points from the 9-point profiles for patient visits were included. The change from baseline to end of treatment (EOT; Week 26) was calculated for patients with assessments at both visits; estimated treatment differences (ETDs; IDegAsp−IGlar U100) were analysed by ANCOVA. Results: The change from baseline to EOT in dTIR was significantly greater with IDegAsp versus IGlar U100 (ETD [95% CI]: 5.28% [1.21; 9.35], p=0.0112). The ETD [95% CI] for dTBR was -0.12% [-1.54; 1.30], p=0.8678; the ETD [95% CI] for dTAR [95% CI] was -5.13% [-9.08; -1.17], p=0.0113. The proportion of patients achieving ≥70% dTIR at EOT with IDegAsp and IGlar U100, respectively, was 50.3% and 34.2%; the proportion achieving a ≥5% increase in dTIR from baseline to EOT was 71.4% and 59.7%, respectively; and the proportion achieving ≥70% dTIR without dTBR from baseline to EOT was 42.9% and 30.9%, respectively. Discussion: IDegAsp was associated with significantly greater dTIR versus IGlar U100 without an increase in dTBR in insulin-naïve patients with T2D, highlighting the clinical value of IDegAsp – a unique co-formulation that provides convenient dosing with the main meal.

Efficacy and safety of oral semaglutide in Japanese patients with type 2 diabetes: A subgroup analysis by baseline variables in the PIONEER 9 and PIONEER 10 trials.

Aims/IntroductionTo assess the impact of baseline characteristics on the efficacy and safety of oral semaglutide in Japanese patients with type 2 diabetes.Materials and MethodsIn the Peptide InnOvatioN for Early diabEtes tReatment (PIONEER) 9 and 10 trials, Japanese patients were randomized to once‐daily oral semaglutide (3, 7, or 14 mg) or a comparator (placebo or once‐daily subcutaneous liraglutide 0.9 mg in PIONEER 9; once‐weekly subcutaneous dulaglutide 0.75 mg in PIONEER 10) for 52 weeks, with 5 weeks of follow up. An exploratory analysis grouped patients in each trial according to baseline glycated hemoglobin (HbA1c; ≤8.0, >8.0–≤9.0, or >9.0%), body mass index (<25, ≥25–<30, or ≥30 kg/m2) and, for PIONEER 10 only, by background medication (sulfonylurea, glinide, thiazolidinedione, α‐glucosidase inhibitor, sodium‐glucose cotransporter 2 inhibitor). Efficacy (changes from baseline to week 26 in HbA1c and bodyweight) and safety were assessed.ResultsSeven hundred and one patients were included (PIONEER 9: N = 243; PIONEER 10: N = 458). In both trials, HbA1c reductions increased as baseline HbA1c increased; there were no other apparent patterns between the variables investigated and HbA1c or bodyweight changes. There was one statistically significant subgroup interaction between baseline HbA1c and estimated treatment differences in bodyweight change for oral semaglutide 14 mg versus placebo in PIONEER 9 (P = 0.0286). Baseline HbA1c, baseline body mass index and background medication did not appear to affect the proportions of patients reporting adverse events.ConclusionsOral semaglutide is effective across a range of baseline subgroups of Japanese patients with type 2 diabetes, with no unexpected safety findings.

Prospective Randomized Trial of Continuous Passive Motion Versus Physical Therapy After Arthroscopic Release of Elbow Contracture.

Continuous passive motion (CPM) has been used for decades, but we are not aware of any randomized controlled trials (RCTs) in which CPM has been compared with physical therapy (PT) for rehabilitation following release of elbow contracture. In this single-blinded, single-center RCT, we randomly assigned patients undergoing arthroscopic release of elbow contracture to a rehabilitation protocol involving either CPM or PT. The primary outcomes were the rate of recovery and the arc of elbow motion (range of motion) at 1 year. The rate of recovery was evaluated by measuring range of motion at 6 weeks and 3 months. The secondary outcomes included other range-of-motion-related outcomes, patient-reported outcome measures (PROMs), flexion strength and endurance, grip strength, and forearm circumference at multiple time points. A total of 24 patients were assigned to receive CPM, and 27 were assigned to receive PT. At 1 year, CPM was superior to PT with regard to the range of motion, with an estimated treatment difference of 9° (95% confidence interval [CI], 3° to 16°; p = 0.007). Similarly, the use of CPM led to a greater range of motion at 6 weeks and 3 months than PT. The percentage of lost motion recovered at 1 year was higher in the CPM group (51%) than in the PT group (36%) (p = 0.01). The probability of restoring a functional range of motion at 1 year was 62% higher in the CPM group than in the PT group (risk ratio for functional range of motion, 1.62; 95% CI, 1.01 to 2.61; p = 0.04). PROM scores were similar in the 2 groups at all time points, except for a difference in the American Shoulder and Elbow Surgeons (ASES) elbow function subscale, in favor of CPM, at 6 weeks. The use of CPM decreased swelling and reduced the loss of flexion strength, flexion endurance, and grip strength on day 3, with no between-group differences thereafter. Among patients undergoing arthroscopic release of elbow contracture, those who received CPM obtained a faster recovery and a greater range of motion at 1 year, with a higher chance of restoration of functional elbow motion than those who underwent routine PT. Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Abstract 6: Maternal efficacy, safety, and pregnancy outcomes with degludec versus detemir in the treatment of pregnant women with type 1 diabetes: An international, multicentre, randomised trial

Background and Aims:To compare the efficacy and safety of insulin degludec (degludec) versus insulin detemir (detemir) in pregnant women with type 1 diabetes (T1D).Materials and Methods:EXPECT was an open-label, randomised trial of women aged ≥18 years with T1D and previously treated with insulin, who were at 8-13 weeks’ gestation or planned to become pregnant within 52 weeks. Women were randomised to degludec once daily or detemir 1- 2 times daily, both with insulin aspart 2-4 times daily. The primary analysis aimed to demonstrate the non-inferiority (margin of 0.4%) of degludec to detemir with respect to the last planned glycated haemoglobin (HbA1c) measurement prior to delivery (>16 weeks’ gestation) using ANCOVA. Secondary endpoints were maternal efficacy, safety, and pregnancy outcomes.Results:In total, 225 women (degludec: 111; detemir: 114) were randomised including 144 who were, and 81 who planned to become pregnant. Mean (±SD) HbA1c at treatment baseline was 6.8% (±0.7%) and 6.7% (±0.8%) with degludec and detemir, respectively. Over the trial, 188 women (degludec: 92; detemir: 96) with singleton pregnancies were included and there were 171 live-born infants (degludec: 86; detemir: 85), with no perinatal deaths (between ≥20 week's gestation and and <1 week after delivery). Estimated mean HbA1c prior to delivery was 6.23% with degludec and 6.34% with detemir (estimated treatment difference: −0.11% [−0.31; 0.08]95% CI, confirming non-inferiority). See Table for supportive maternal safety and pregnancy outcomes.TableSupportive maternal safely and pregnancy outcomes in women with type 1 diabetes randomised to degijdec or detemirDegludecDetemir n/N%EventsRalen/N%EventsRaleMaternal safer/ outcomosOverall hypoglycaemia89.’9197.8543111.84591/94968598213,401Nocturnal hypoglycaemia*71/9178.0712155369/9473.47591700Adjudicated severe hypoglycaemia‡6/916.68-3:943.24-Adverse events78/9185.742993676/9480.9328735Pre-edampsia12/8814.0--7/858.2--Pregnancy outcomesfctusevinfants with major abnormalities§8/928.7--8:968.3--Pre-teim delivery (<37 vreeks’ gestation)¶29/8633.7--19/85224--Infants born large for gestabonal age55/86840--4A8550.6--Infants with neonatal hypoglycaemia††20/8623.3--19/8522.4--Maternal safety outcomos were assessed over the pregnancy period and based on all randomised women who weie pregnant during the trial and received 21 dose of trial product. Additionally, tor pre-eciampsa. only women who delvered an infant at 220 weeks’ gestation were considered. Pregnancy outcomes were based on all randomised women who delivered an infant at ≤20 weeks’ gestation, except tor major abnormalities, where all randomised women who were pregnant during the trial were considered The analyses of maternal safety and pregnancy enidpoints were pre-specified to provide a descriptive summary only†Events occurhng between 00:01 and 05:59 (both inclusive): ‡events requiring third-party assistance; §UROCAT classified; ¶affer 20 weeks’ gestation: ††defined as blood glucose t .7 mmol/l (≤31 mg/dL) and assessed over the first 24 hours after birth.%. percentage of women with ≥ event: degludec. insulin degludec. detemir. insulin detemir; EUROCAT, European Concerted Action on Congenital Abnormalities and Twins; n, number of women with ≥1 event; N, total number of women In treatment group and analysis set: rate, rate of events per 100 years of exposure.Conclusion: In pregnant women with T1D, degludec was non-inferior to detemir with respect to HbA1c prior to delivery. Hypoglycaemia rates and pregnancy outcomes were comparable between insulins.