Immunogenicity, efficacy, and safety of biosimilar insulin glargine (Gan & Lee glargine) compared with originator insulin glargine (Lantus®) in patients with type 2 diabetes after 26 weeks' treatment: A randomized open label study.

AIM: To evaluate the equivalence of immunogenicity, safety and efficacy of Gan & Lee (GL) Glargine (Basalin®; Gan & Lee Pharmaceutical) with that of the reference product (Lantus®) in adult participants with type 2 diabetes mellitus. METHODS: This was a phase 3, multicenter, open-label, equivalence trial conducted across 57 sites. In total, 567 participants with type 2 diabetes mellitus were randomized in a 1:1 ratio to undergo treatment with either GL Glargine or Lantus® for 26 weeks. The primary endpoint was the proportion of participants in each treatment arm who manifested treatment-induced anti-insulin antibodies (AIA). Secondary endpoints included efficacy and safety metrics, changes in glycated haemoglobin levels, and a comparative assessment of adverse events. Results were analysed using an equivalence test comparing the limits of the 90% confidence interval (CI) for treatment-induced AIA development to the prespecified margins. RESULTS: The percentages of participants positive for treatment-induced glycated haemoglobin by week 26 were similar between the GL Glargine (19.2%) and Lantus® (21.3%) treatment groups, with a treatment difference of -2.1 percentage points and a 90% CI (-7.6%, 3.5%) (predefined similarity margins: -10.7%, 10.7%). The difference in glycated haemoglobin was -0.08% (90% CI, -0.23, 0.06). The overall percentage of participants with any treatment-emergent adverse events was similar between the GL Glargine (80.1%) and Lantus® (81.6%) treatment groups. CONCLUSIONS: GL Glargine was similar to Lantus® in terms of immunogenicity, efficacy, and safety, based on the current study.

Cardiometabolic risk factors efficacy of semaglutide in the STEP program.

People with overweight or obesity often suffer from associated cardiometabolic diseases and comorbidities. Current therapies for obesity include lifestyle intervention, bariatric surgery, and pharmacotherapy. The magnitude of weight loss achieved with these therapies can determine the level of improvement in various comorbidities. Once-weekly subcutaneous semaglutide 2.4 mg is a glucagon-like peptide-1 receptor agonist recently approved by the US Food and Drug Administration for the treatment of obesity. This article reviews data from the global phase 3 Semaglutide Treatment Effect in People with obesity (STEP) program, comparing the efficacy of once-weekly subcutaneous semaglutide 2.4 mg versus placebo for weight loss and improvements in cardiometabolic parameters across the STEP 1 to 5 trials. In STEP 1 to 3 and STEP 5, semaglutide led to greater reductions from baseline versus placebo in body weight, waist circumference, body mass index, systolic blood pressure (SBP), and diastolic blood pressure, as well as positive changes in glycated hemoglobin (HbA1c), C-reactive protein, and lipid levels. In STEP 4, all participants had a 20-week run-in period on semaglutide before either continuing on semaglutide or switching to placebo at week 20 in a 2:1 ratio for 48 weeks. At week 68, continued semaglutide led to further reductions from week 20 in HbA1c, improvements in lipid profile, and stabilization of SBP. Overall, across the STEP trials, treatment with semaglutide 2.4 mg versus placebo improved cardiometabolic risk factors associated with obesity, illustrating an effective treatment option for people with overweight (and associated comorbidities) or obesity.

Efficacy and safety of semaglutide for weight management: evidence from the STEP program.

Obesity is a global health challenge. It is a multifactorial, complex, and progressive disease associated with various health complications and increased mortality. Lifestyle modifications are central to weight management but may be insufficient to maintain clinically meaningful weight loss. Pharmacotherapies are recommended as an adjunct to lifestyle interventions to induce and sustain clinically meaningful weight loss and reduce the risk of comorbidities in appropriate patients. Glucagon-like peptide-1 is an incretin metabolic hormone responsible for a range of physiological effects, including glucose and appetite regulation. Several glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been approved for the treatment of type 2 diabetes since 2005 including exenatide (short- and extended-release), lixisenatide, liraglutide, dulaglutide, albiglutide, and semaglutide. Of these, semaglutide (subcutaneous) and liraglutide are currently US Food and Drug Administration (FDA)-approved for chronic weight management in patients with or without diabetes. The phase 3 Semaglutide Treatment Effect in People with obesity (STEP) program was designed to investigate the effect of semaglutide versus placebo on weight loss, safety, and tolerability in adults with overweight or obesity. Following the submission of the results of the STEP 1-4 trials, the FDA approved once-weekly subcutaneous semaglutide 2.4 mg for chronic weight management in people with overweight or obesity in April 2021. Data from the program demonstrated that semaglutide (2.4 mg once weekly) achieved significant and sustained weight loss, together with improvements in cardiometabolic risk factors compared with placebo, and was generally well tolerated, with a safety profile consistent with other GLP-1RAs. The most common adverse events reported in STEP 1-5 were gastrointestinal events, which were transient, mild-to-moderate in severity, and typically resolved without permanent treatment discontinuation. This article reviews the data from STEP 1-5 and highlights clinically relevant findings for primary care providers.

Effects of Dietary Self-Monitoring, Physical Activity, Liraglutide 3.0 mg, and Placebo on Weight Loss in the SCALE IBT Trial.

INTRODUCTION: Individuals who enroll in intensive behavioral therapy (IBT) programs are asked to make several lifestyle changes simultaneously. However, few studies have examined the relative effects of adherence to different treatment components on weight loss. OBJECTIVE: This secondary analysis of the SCALE IBT trial assessed adherence to the medication regimen, dietary self-monitoring, and physical activity recommendations and their relative contributions to weight change in individuals with obesity who were provided with IBT combined with either liraglutide 3.0 mg or placebo. METHODS: SCALE IBT was a double-blinded, multicenter, randomized controlled trial comparing 56-week weight losses in individuals with obesity who received liraglutide 3.0 mg (n = 142) or placebo (n = 140), as an adjunct to IBT. Adherence to dietary self-monitoring, physical activity, and medication usage (liraglutide or placebo) were measured during the 56-week treatment period. A regression model was used to estimate the relative contribution of adherence to each treatment component to weight loss at week 56. RESULTS: The proportion of individuals who adhered to each intervention component decreased over time. Compared with non-adherence, complete adherence to dietary self-monitoring and physical activity recommendations were associated with estimated weight changes of -7.2% (95% CI -10.4 to -4.0; p < 0.0001) and -2.0% (95% CI -3.2 to -0.8; p = 0.0009), respectively. Complete adherence to liraglutide predicted an additional weight loss of -6.5% (95% CI -10.2 to -2.9; p = 0.0005) relative to individuals who did not adhere to the medication regimen, while adherence to placebo did not have a statistically significant effect on weight loss (p = 0.33). CONCLUSIONS: High adherence to dietary self-monitoring and use of liraglutide 3.0 mg was associated with clinically relevant weight loss with IBT and adjunctive pharmacotherapy. The effect of adherence to physical activity was significant but smaller.

Efficacy and Safety of Liraglutide 3.0 mg in Individuals With Overweight or Obesity and Type 2 Diabetes Treated With Basal Insulin: The SCALE Insulin Randomized Controlled Trial.

OBJECTIVE: Most individuals with type 2 diabetes also have obesity, and treatment with some diabetes medications, including insulin, can cause further weight gain. No approved chronic weight management medications have been prospectively investigated in individuals with overweight or obesity and insulin-treated type 2 diabetes. The primary objective of this study was to assess the effect of liraglutide 3.0 mg versus placebo on weight loss in this population. RESEARCH DESIGN AND METHODS: Satiety and Clinical Adiposity-Liraglutide Evidence (SCALE) Insulin was a 56-week, randomized, double-blind, placebo-controlled, multinational, multicenter trial in individuals with overweight or obesity and type 2 diabetes treated with basal insulin and ≤2 oral antidiabetic drugs. RESULTS: Individuals were randomized to liraglutide 3.0 mg (n = 198) or placebo (n = 198), combined with intensive behavioral therapy (IBT). At 56 weeks, mean weight change was -5.8% for liraglutide 3.0 mg versus -1.5% with placebo (estimated treatment difference -4.3% [95% CI -5.5; -3.2]; P < 0.0001). With liraglutide 3.0 mg, 51.8% of individuals achieved ≥5% weight loss versus 24.0% with placebo (odds ratio 3.41 [95% CI 2.19; 5.31]; P < 0.0001). Liraglutide 3.0 mg was associated with significantly greater reductions in mean HbA1c and mean daytime glucose values and less need for insulin versus placebo, despite a treat-to-glycemic-target protocol. More hypoglycemic events were observed with placebo than liraglutide 3.0 mg. No new safety or tolerability issues were observed. CONCLUSIONS: In individuals with overweight or obesity and insulin-treated type 2 diabetes, liraglutide 3.0 mg as an adjunct to IBT was superior to placebo regarding weight loss and improved glycemic control despite lower doses of basal insulin and without increases in hypoglycemic events.

Liraglutide 3.0 mg and Intensive Behavioral Therapy (IBT) for Obesity in Primary Care: The SCALE IBT Randomized Controlled Trial.

OBJECTIVE: Previous studies have shown additive weight loss when intensive behavioral therapy (IBT) was combined with weight-loss medication. The present multisite study provides the first evaluation, in primary care, of the effect of the Centers for Medicare and Medicaid Services-based IBT benefit, delivered alone (with placebo) or in combination with liraglutide 3.0 mg. METHODS: The Satiety and Clinical Adiposity-Liraglutide Evidence in individuals with and without diabetes (SCALE) IBT was a 56-week, randomized, double-blind, placebo-controlled, multicenter trial in individuals with obesity who received liraglutide 3.0 mg (n = 142) or placebo (n = 140) as an adjunct to IBT. RESULTS: At week 56, mean weight loss with liraglutide 3.0 mg plus IBT was 7.5% and 4.0% with placebo combined with IBT (estimated treatment difference [95% CI]-3.4% [-5.3% to -1.6%], P = 0.0003). Significantly more individuals on liraglutide 3.0 mg than placebo achieved ≥ 5% weight loss (61.5% vs. 38.8%; odds ratio [OR] 2.5% [1.5% to 4.1%], P = 0.0003), > 10% weight loss (30.5% vs. 19.8%; OR 1.8% [1.0% to 3.1%], P = 0.0469), and > 15% weight loss (18.1% vs. 8.9%; OR 2.3% [1.1% to 4.7%], P = 0.0311). Liraglutide 3.0 mg in combination with IBT was well tolerated, with no new safety signals identified. CONCLUSIONS: In a primary care setting, Centers for Medicare and Medicaid Services-based IBT produced clinically meaningful weight loss at 56 weeks, enhanced by the addition of liraglutide 3.0 mg.

IDegLira improves patient-reported outcomes while using a simple regimen with fewer injections and dose adjustments compared with basal-bolus therapy.

AIMS: Basal-bolus therapy is associated with greater treatment burden and lower adherence compared with more simplified regimens. This post hoc analysis studied the difference between insulin degludec/liraglutide (IDegLira) and basal-bolus therapy on number of injections, dose adjustments and patient outcomes in the DUAL VII trial. MATERIALS AND METHODS: DUAL VII was a 26-week, open-label trial in which patients with uncontrolled type 2 diabetes who were using metformin and insulin glargine 100 units/mL (20-50 U) were randomized 1:1 to IDegLira (N = 252) or basal-bolus (insulin glargine U100 + insulin aspart ≤4 times/day) (N = 254). This post hoc analysis reports the observed mean number of injections and cumulative dose adjustments during 26 weeks of treatment. Patient-reported outcomes (Treatment-Related Impact Measure - Diabetes [TRIM-D] and Short Form-36 Health Survey version 2 [SF-36v2]) were collected at scheduled visits and change from baseline scores calculated. RESULTS: The clinical benefits (non-inferior HbA1c reductions, weight benefit, less hypoglycaemia) of IDegLira vs basal-bolus therapy were achieved with fewer cumulative dose adjustments (16.6 vs 217.2, respectively) and fewer injections (1 vs ≥3 per day, respectively). Patients treated with IDegLira experienced significant improvements across all TRIM-D domains compared with those undergoing basal-bolus therapy. The SF-36v2 showed improvements in both treatment arms with no significant difference between arms in the physical component summary, but there was a significant improvement in patients treated with IDegLira in the mental component summary (P = .0228). CONCLUSIONS: These findings, combined with the DUAL VII results, suggest that IDegLira, through a more simplified regimen versus basal-bolus therapy, may help improve patient adherence and improve patient outcomes related to diabetes management, treatment burden and mental health, which in turn may assist in the timely achievement of glycaemic control in clinical practice.

Efficacy of iGlarLixi, a fixed-ratio combination of insulin glargine and lixisenatide, in patients with type 2 diabetes stratified as at high or low risk according to HEDIS measurements.

The Healthcare Effectiveness Data and Information Set (HEDIS) measurements assess glycaemic goal attainment in patients with type 2 diabetes, incorporating factors including age and health status. Healthier patients are assigned a glycated haemoglobin (HbA1c) goal of <7% (low-risk [LR]) and individuals aged >65 years or with comorbidities are assigned a goal of <8% (high-risk [HR]). This post-hoc analysis assessed the safety and efficacy of iGlarLixi, a fixed-ratio combination of insulin glargine 100 U/mL (iGlar) and lixisenatide, in 1898 patients from the phase 3 LixiLan-L and LixiLan-O clinical trials, retrospectively classified as LR (n = 1181) or HR (n = 717). iGlarLixi was more effective in reducing HbA1c than comparators in both LR and HR patients across the LixiLan-L trial (change from baseline, 1.1% vs -0.6% for iGlar in both groups; P < 0.001) and the LixiLan-O trial (change from baseline, LR/HR -1.6%/-1.4% vs -1.3%/-1.2% for iGlar and -0.8%/-0.9% for lixisenatide; P < 0.01). iGlarLixi treatment significantly reduced postprandial glucose in both LR and HR patients (P < 0.001). The incidence of hypoglycaemia did not differ between risk categories in any treatment group.

Semaglutide Added to Basal Insulin in Type 2 Diabetes (SUSTAIN 5): A Randomized, Controlled Trial.

Context: Combination therapy with insulin and glucagon-like peptide-1 receptor agonists (GLP-1RAs) is important for treating type 2 diabetes (T2D). This trial assesses the efficacy and safety of semaglutide, a GLP-1RA, as an add-on to basal insulin. Objective: To demonstrate the superiority of semaglutide vs placebo on glycemic control as an add-on to basal insulin in patients with T2D. Design: Phase 3a, double-blind, placebo-controlled, 30-week trial. Setting: This study included 90 sites in five countries. Patients: We studied 397 patients with uncontrolled T2D receiving stable therapy with basal insulin with or without metformin. Interventions: Subcutaneous semaglutide 0.5 or 1.0 mg once weekly or volume-matched placebo. Main Outcome Measures: Primary endpoint was change in glycated Hb (HbA1c) from baseline to week 30. Confirmatory secondary endpoint was change in body weight from baseline to week 30. Results: At week 30, mean HbA1c reductions [mean baseline value, 8.4% (67.9 mmol/mol)] with semaglutide 0.5 and 1.0 mg were 1.4% (15.8 mmol/mol) and 1.8% (20.2 mmol/mol) vs 0.1% (1.0 mmol/mol) with placebo [estimated treatment difference (ETD) vs placebo, -1.35 (14.8 mmol/mol); 95% CI, -1.61 to -1.10 and ETD, -1.75% (19.2 mmol/mol); 95% CI, -2.01 to -1.50; both P < 0.0001]. Severe or blood glucose-confirmed hypoglycemic episodes were reported in 11 patients (17 events) and 14 patients (25 events) with semaglutide 0.5 and 1.0 mg, respectively, vs seven patients (13 events) with placebo (estimated rate ratio vs placebo, 2.08; 95% CI, 0.67 to 6.51 and estimated rate ratio vs placebo, 2.41; 95% CI, 0.84 to 6.96 for 0.5 and 1.0 mg; both P = nonsignificant). Mean body weight decreased with semaglutide 0.5 and 1.0 mg vs placebo from baseline to end of treatment: 3.7, 6.4, and 1.4 kg (ETD, -2.31; 95% CI, -3.33 to -1.29 and ETD, -5.06; 95% CI, -6.08 to -4.04 kg; both P < 0.0001). Premature treatment discontinuation due to adverse events was higher for semaglutide 0.5 and 1.0 mg vs placebo (4.5%, 6.1%, and 0.8%), mainly due to gastrointestinal disorders. Conclusions: Semaglutide, added to basal insulin, significantly reduced HbA1c and body weight in patients with uncontrolled T2D vs placebo.

Combination therapy with insulin glargine plus metformin but not insulin glargine plus sulfonylurea provides similar glycemic control to triple oral combination therapy in patients with type 2 diabetes uncontrolled with dual oral agent therapy.

AIMS: Evaluate substituting insulin glargine (GLAR) for a thiazolidinedione (TZD) versus adding a third oral antidiabetes drug (OAD) in patients with uncontrolled type 2 diabetes mellitus (T2DM) on TZD+metformin or TZD+sulfonylurea. METHODS: In this multicenter, open-label study, 337 T2DM patients with a glycated hemoglobin A1c (A1C) of 7.5-12.0% despite≥3months of treatment with a TZD plus metformin or a sulfonylurea were randomized to a third OAD (3OAD; metformin or glyburide) or GLAR+1 OAD (metformin or sulfonylurea) with TZD cessation, titrated to a fasting blood glucose≤94mg/dL. RESULTS: Substitution of GLAR for a TZD led to an adjusted mean A1C change from baseline of-1.66% versus-1.86% in the 3OAD arm (adjusted mean difference 0.20 [95% confidence interval, - 0.11, 0.51], not meeting the noninferiority criteria). This difference was driven by the GLAR+sulfonylurea stratum. GLAR+metformin was as effective as 3OAD in achieving glycemic control but with greater improvements in lipid parameters, less weight gain, and lower hypoglycemia rates. CONCLUSIONS: These findings favor substitution of GLAR for a TZD in T2DM patients not controlled on TZD+metformin. GLAR+sulfonylurea was less effective at lowering A1C than 3OAD and not associated with the benefits observed with GLAR+metformin.

The TRINITY Study: distribution of systolic blood pressure reductions.

BACKGROUND: Elevated systolic blood pressure is more difficult to control than elevated diastolic blood pressure. The objective of this prespecified analysis of the Triple Therapy with Olmesartan Medoxomil, Amlodipine, and Hydrochlorothiazide in Hypertensive Patients Study (TRINITY) was to compare the efficacy of olmesartan medoxomil (OM) 40 mg, amlodipine besylate (AML) 10 mg, and hydrochlorothiazide (HCTZ) 25 mg triple-combination treatment with the component dual-combination treatments in reducing elevated seated systolic blood pressure (SeSBP). METHODS: The 12-week TRINITY study randomized participants to either one of the three component dual-combination treatments (OM 40 mg/AML 10 mg, OM 40 mg/HCTZ 25 mg, or AML 10 mg/HCTZ 25 mg) or the triple-combination treatment. The primary outcome of this analysis was the categorical distribution of SeSBP reductions at week 12 from baseline with OM 40 mg/AML 10 mg/HCTZ 25 mg versus the dual-combination treatments. RESULTS: SeSBP reductions >50 mmHg were seen in 24.4% of participants receiving triple-combination treatment versus 8.1%-15.8% receiving dual-combination treatment. More participants receiving triple-combination treatment achieved the SeSBP target of <140 mmHg (73.6% versus 51.3%-58.8%; P < 0.001) and the seated blood pressure target of <140/90 mmHg (69.9% versus 41.1%-53.4%; P < 0.001). Prevalence and severity of adverse events were similar in all treatment groups. CONCLUSION: Treatment with OM 40 mg/AML 10 mg/HCTZ 25 mg was well tolerated and more effective in reducing SeSBP than the dual-combination treatments.

Triple therapy in type 2 diabetes: insulin glargine or rosiglitazone added to combination therapy of sulfonylurea plus metformin in insulin-naive patients.

OBJECTIVE: To evaluate the efficacy and safety of add-on insulin glargine versus rosiglitazone in insulin-naïve patients with type 2 diabetes inadequately controlled on dual oral therapy with sulfonylurea plus metformin. RESEARCH DESIGN AND METHODS: In this 24-week multicenter, randomized, open-label, parallel trial, 217 patients (HbA(1c) [A1C] 7.5-11%, BMI >25 kg/m(2)) on > or =50% of maximal-dose sulfonylurea and metformin received add-on insulin glargine 10 units/day or rosiglitazone 4 mg/day. Insulin glargine was forced-titrated to target fasting plasma glucose (FPG) < or =5.5-6.7 mmol/l (< or =100-120 mg/dl), and rosiglitazone was increased to 8 mg/day any time after 6 weeks if FPG was >5.5 mmol/l. RESULTS: A1C improvements from baseline were similar in both groups (-1.7 vs. -1.5% for insulin glargine vs. rosiglitazone, respectively); however, when baseline A1C was >9.5%, the reduction of A1C with insulin glargine was greater than with rosiglitazone (P < 0.05). Insulin glargine yielded better FPG values than rosiglitazone (-3.6 +/- 0.23 vs. -2.6 +/- 0.22 mmol/l; P = 0.001). Insulin glargine final dose per day was 38 +/- 26 IU vs. 7.1 +/- 2 mg for rosiglitazone. Confirmed hypoglycemic events at plasma glucose <3.9 mmol/l (<70 mg/dl) were slightly greater for the insulin glargine group (n = 57) than for the rosiglitazone group (n = 47) (P = 0.0528). The calculated average rate per patient-year of a confirmed hypoglycemic event (<70 mg/dl), after adjusting for BMI, was 7.7 (95% CI 5.4-10.8) and 3.4 (2.3-5.0) for the insulin glargine and rosiglitazone groups, respectively (P = 0.0073). More patients in the insulin glargine group had confirmed nocturnal hypoglycemia of <3.9 mmol/l (P = 0.02) and <2.8 mmol/l (P < 0.05) than in the rosiglitazone group. Effects on total cholesterol, LDL cholesterol, and triglyceride levels from baseline to end point with insulin glargine (-4.4, -1.4, and -19.0%, respectively) contrasted with those of rosiglitazone (+10.1, +13.1, and +4.6%, respectively; P < 0.002). HDL cholesterol was unchanged with insulin glargine but increased with rosiglitazone by 4.4% (P < 0.05). Insulin glargine had less weight gain than rosiglitazone (1.6 +/- 0.4 vs. 3.0 +/- 0.4 kg; P = 0.02), fewer adverse events (7 vs. 29%; P = 0.0001), and no peripheral edema (0 vs. 12.5%). Insulin glargine saved $235/patient over 24 weeks compared with rosiglitazone. CONCLUSIONS: Low-dose insulin glargine combined with a sulfonylurea and metformin resulted in similar A1C improvements except for greater reductions in A1C when baseline was > or =9.5% compared with add-on maximum-dose rosiglitazone. Further, insulin glargine was associated with more hypoglycemia but less weight gain, no edema, and salutary lipid changes at a lower cost of therapy.