Efficacy and Safety of Liraglutide Added to Capped Insulin Treatment in Subjects With Type 1 Diabetes: The ADJUNCT TWO Randomized Trial

Abstract

OBJECTIVETo investigate the efficacy and safety of liraglutide added to capped insulin doses in subjects with type 1 diabetes. RESEARCH DESIGN AND METHODSA 26-week, placebo-controlled, double-blind, parallel-group trial enrolling 835 subjects randomized 3:1 receiving once-daily subcutaneous liraglutide (1.8, 1.2, and 0.6 mg) or placebo added to an individually capped total daily dose of insulin. (-5.1, -4.0, and -2.5 kg for 1.8, 1.2, and 0.6 mg, respectively) versus placebo (-0.2 kg). Significant reductions in daily insulin dose and increases in quality of life were seen with liraglutide versus placebo. There were higher rates of symptomatic hypoglycemia (21.3 vs. 16.6 events/patient/year; P = 0.03) with liraglutide 1.2 mg vs. placebo and of hyperglycemia with ketosis >1.5 mmol/L with liraglutide 1.8 mg vs. placebo (0.5 vs. 0.1 events/patient/year; P = 0.01). RESULTS Mean CONCLUSIONSIn a broad population of subjects with long-standing type 1 diabetes, liraglutide added to capped insulin reduced HbA 1c , body weight, and insulin requirements but with higher rates of hypoglycemia for liraglutide 1.2 mg and hyperglycemia with ketosis for liraglutide 1.8 mg.Most people with type 1 diabetes do not currently reach glycemic targets (1), as both patients and providers are often reluctant to intensify glycemic therapy because of reasons such as concern about hypoglycemia and/or weight gain (2). Moreover, a recent study using electronic health records from the U.S. reported that 47.8% of people with type 1 diabetes are obese (3). Therefore, noninsulin adjunctive treatments with a low intrinsic risk of hypoglycemia and weight gain offer a potential means of complementing intensive insulin therapy in people

Non‐insulin treatments for Type 1 diabetes: critical appraisal of the available evidence and insight into future directions

“…There was a higher rate of hyperglycaemic episodes with ketosis with liraglutide 1.8 mg compared with placebo, but there was no significant difference for the 1.2-and 0.6-mg groups compared with placebo (Table 3) [34]. Compared with the placebo group, the liraglutide 1.2 mg group had a higher rate of symptomatic and documented symptomatic hypoglycaemia but no significant difference in rate of severe or nocturnal hypoglycaemia.…”

“…There were reductions in insulin doses in the liraglutide treatment groups, mainly through lower requirements of prandial insulin [34]. The HbA 1c reduction with liraglutide 1.8 mg was accompanied by improvements in 1, 5-anhydroglucitol, a postprandial hyperglycaemia surrogate, compared with placebo, and by reductions in post-breakfast, post-lunch, and bedtime glucose levels.…”

Liraglutide acutely suppresses glucagon, lipolysis and ketogenesis in type 1 diabetes

“…15,19 This is intriguing and may be related to inappropriately high reduction in insulin doses. 15,19 This is intriguing and may be related to inappropriately high reduction in insulin doses.…”

Type 1 Diabetes: Disease Stratification

“…However, CGM use and data interpretation requires training and experience, has had slow adoption, and its potential remains to be fully realized. Likewise, use of therapies currently approved for the treatment of type 2 diabetes have improved outcomes in T1D such as body weight and insulin dose reductions, insulin sensitization, lowering HbA1c, increasing time in desired glucose range and even reducing glycemic variability; however, most studies have shown responses span the gamut from nonresponders to super-responders [135][136][137][138][139] , thus emphasizing the need for strat-ified, precision medicine approaches. The novel class of SGLT inhibitors, both mono SGLT2 and dual SGLT1/2, are currently in pivotal T1D label expansion studies by manufacturers.…”