Liraglutide in people treated for type 2 diabetes with multiple daily insulin injections: randomised clinical trial (MDI Liraglutide trial)

Abstract

Study question: What are the effects of liraglutide, an incretin based treatment, on glycaemic control in people with type 2 diabetes treated with multiple daily insulin injections?

Methods: The study was a randomised, double blind, placebo controlled trial with a parallel group design carried out at 13 hospital based outpatient clinics and one primary care unit in Sweden. Patients were considered eligible for inclusion if they had type 2 diabetes and inadequate glycaemic control (HbA1c concentrations ≥ 58 mmol/mol (7.5%) and ≤ 102 mmol/mol (11.5%)), a body mass index of 27.5-45 kg/m(2), and required multiple daily insulin injections. Overall, 124 participants were randomised 1:1 to subcutaneous liraglutide or placebo by minimisation allocation. The main outcome measure was change in HbA1c level from baseline to week 24.

Study answer and limitations: Liraglutide was associated with a significant reduction of 16.9 mmol/mol (1.5%) in HbA1c versus 4.6 mmol/mol (0.4%) for placebo, difference -12.3 mmol/mol (95% confidence interval -15.8 to -8.8 mmol/mol; -1.13%, -1.45 to -0.81 mmol/mol). Body weight was significantly reduced in participants in the liraglutide compared with placebo group (3.8 v 0.0 kg, difference -3.8, -4.9 to -2.8 kg), and total daily insulin doses were significantly reduced, by 18.1 units and 2.3 units (difference -15.8, -23.1 to -8.5 units). Reductions in mean and standard deviation of glucose levels estimated by masked continuous glucose monitoring were significantly greater in the liraglutide group than placebo group (-1.9 and -0.5 mmol/L). Neither group experienced severe hypoglycaemic events nor were there any significant differences in symptomatic or asymptomatic non-severe hypoglycaemia (<4.0 or <3.0 mmol/L). The mean number of non-severe symptomatic hypoglycaemic events (<4.0 mmol/L) during follow-up was 1.29 in the liraglutide group and 1.24 in the placebo group (P=0.96). One of the study's limitations was its relatively short duration. Sustained effects of liraglutide have, however, been found over lengthier periods in connection with other treatment regimens. Cardiovascular safety and potential adverse events during longer exposure to liraglutide need to be evaluated. Nausea was experienced by 21 (32.8%) participants in the liraglutide group and 5 (7.8%) in the placebo group and 3 (5%) and 4 (7%) participants in these groups, respectively, had any serious adverse event.

What this study adds: Adding liraglutide to multiple daily insulin injections in people with type 2 diabetes improves glycaemic control without an increased risk of hypoglycaemia, reduces body weight, and enables patients to lower their insulin doses.

Funding, competing interests, data sharing: This study was an investigator initiated trial, supported in part by Novo Nordisk and InfuCare. Potential competing interests have been reported and are available on the bmj.com.

Study registration: EudraCT 2012-001941-42.

Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: ML and SD had support from Novo Nordisk for the submitted work; outside of the submitted work, authors have relations to the following companies that may take interest in the submitted work. ML has received research grants from AstraZeneca, Dexcom, and Novo Nordisk, been a consultant or received honorariums from Medtronic, Eli Lilly, Pfizer, Abbot Scandinavia, Bayer, Novo Nordisk, and Rubin Medical, and has participated in advisory boards for Novo Nordisk. IBH has received research grants from Sanofi-US, Novo Nordisk, and Halozyme, and has been a consultant for Abbott Diabetes Care, Valeritas, Roche Diagnostics, and Becton Dickinson. JT has received research support from Bayer, Boehringer Ingelheim, Merck Sharp & Dohme, Novartis, Sanofi Aventis, and Servier, and has acted as a consultant, advisory board member, or speaker for Impeto Medical, Novartis, Novo Nordisk, Sanofi -Aventis, Eli Lilly, Merck Serono, Merck Sharp & Dohme, Bayer, and Boehringer Ingelheim. BA has consulted for Novartis, GlaxoSmithKline, Merck, Sanofi, Novo Nordisk, Boehringer Ingelheim, and Takeda, and has received lecture fees from Novartis, Merck, Novo Nordisk, Sanofi, AstraZeneca, and GlaxoSmithKline. OT has been a consultant to Eli Lilly and Novo Nordisk. ME has been a consultant or received honorariums from Novartis, Merck Sharp & Dohme, GlaxoSmithKline, Sanofi, Eli Lilly, and Rubin Medical, and has participated in advisory boards for Sanofi. KF has consulted for Novo Nordisk. BOT has participated in advisory boards for Novo Nordisk and Boehringer Ingelheim and has received lecture fees from Novo Nordisk, Eli Lilly, Sanofi, Boehringer Ingelheim, AstraZeneca, and Bristol-Myers Squibb. SS has occasionally been a consultant and received honorariums from Eli Lilly, Sanofi-Aventis, Novo Nordisk, Abbot Scandinavia, AstraZeneca, and Merck, Sharp & Dohme and has participated in advisory boards for Sanofi-Aventis, AstraZeneca, and Eli Lilly. SD, SA, and N-GP has no such conflicts of interest to declare. Authors’ spouses, partners, or children have no financial relationships that may be relevant to the submitted work; and no authors have non-financial interests that may be relevant to the submitted work.

© Lind et al 2015.

Figures

Fig 1 Flow of participants through trial

Fig 2 Change in HbA1c concentration, weight, and daily insulin dose by treatment group over time (mean and 95% confidence interval). IFCC= International Federation of Clinical Chemistry; LOCF=last observation carried forward

Fig 3 Incidence of nausea (%) by treatment group over time (safety population)