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

Abstract

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 AdipositydLiraglutide 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 5 198) or placebo (n 5 198), combined with intensive behavioral therapy (IBT). At 56 weeks, mean weight change was 25.8% for liraglutide 3.0 mg versus 21.5% with placebo (estimated treatment difference 24.3% [95% CI 25.5; 23.2]; 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 HbA 1c 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.

Effect of Bimagrumab vs Placebo on Body Fat Mass Among Adults With Type 2 Diabetes and Obesity

“…35,36 Moreover, the distribution of body fat loss in patients treated with bimagrumab was highly favorable, with reduction of abdominal visceral adipose tissue and waist circumference that was nearly twice that observed in a recently published study of patients with type 2 diabetes treated with an intensive lifestyle program and the glucagon-like peptide 1 agonist liraglutide. 37 These observations highlight the importance of moving away from body weight as a primary efficacy marker of drugs to more metabolically relevant end points, such as total body FM.…”

Estimating and reporting treatment effects in clinical trials for weight management: using estimands to interpret effects of intercurrent events and missing data

“…While estimands do not solve all problems of trial design and interpretation, this new concept will enable trials to be designed more appropriately to obtain relevant information to address the clinical question(s) of interest. The SCALE phase 3b clinical trials have been reported [ 7 , 8 ], building on the existing evidence for the efficacy and safety of liraglutide 3.0 mg in weight management, and are some of the first clinical trials in weight management to report results using estimands.…”

“…In the recent SCALE Intensive Behavioral Therapy phase 3b trial, participants were encouraged to attend scheduled visits and thus have their weight measurements recorded regardless of discontinuing treatment [ 8 ]. To promote participant retention, the SCALE Insulin phase 3b trial permitted individuals to stop and restart liraglutide 3.0 mg without re-escalating the dose, or with re-escalation if three consecutive doses had been missed [ 7 ].…”

“…With the increasing computational awareness and capacity to develop statistical methods that provide more useful interpretations of the treatment effect, MI methods have become dominant for the reporting of recent weight management clinical trials (e.g., semaglutide obesity phase 2 trial [ 34 ] and the SCALE phase 3b trials [ 7 , 8 ]). MI is a computationally intensive method that can replace missing weight measurements for participants lost to follow up with the most plausible value that would have been expected if the participants had been available for the end-of-trial weight assessment.…”

“…In line with the EMA and FDA regulatory guidelines [5,6], ongoing and newly initiated weight management trials will be required to report results using estimands. The SCALE (Satiety and Clinical Adiposity-Liraglutide Evidence in individuals with and without diabetes) phase 3b trials investigating efficacy and safety of liraglutide 3.0 mg as an adjunct to diet and lifestyle advice for weight management have recently been published with two estimands [7,8]. Similarly, clinical trial programs for weight management drugs in development, such as the semaglutide 2.4 mg once-weekly STEP (Semaglutide Treatment Effect in People with obesity) trial program [9][10][11][12][13][14][15][16] are planned to report results utilizing estimands.…”