Liraglutide reverses pronounced insulin-associated weight gain, improves glycaemic control and decreases insulin dose in patients with type 2 diabetes: a 26 week, randomised clinical trial (ELEGANT)

de Wit HM, Vervoort GM, Jansen HJ et al.,
Diabetologia. 2014 Jun 20. [Epub ahead of print]

Background

Although insulin therapy is safe and efficacious in improving glycaemic control, it may induce weight gain. Interindividual differences in weight changes are large, even including weight loss in some [1].
This undesirable effect occurs within the first 9-12 months of insulin therapy [1-3], thus a therapy that limits weight gain within this time frame is desirable.
Glucagon-like peptide-1 (GLP-1) analogues stimulate insulin secretion, suppress glucagon release, and reduce food intake, thereby improving glycaemic control and weight loss in type 2 diabetes (T2DM) [9-15]. Addition of GLP-1 analogues to insulin therapy may thus have advantages to reverse insulin-induced weight gain. It is, however, important to select the patients that will likely benefit most, due to the price and gastrointestinal side-effects of GLP-1 analogues. Long-term safety and efficacy data are not yet available and clinically relevant treatment strategies have not been sufficiently compared yet.
This study therefore compared addition of a GLP-1 analogue (liraglutide) to insulin therapy with the standard approach (continuation and intensification of insulin), in its ability to reverse pronounced insulin-induced weight gain, while maintaining glycaemic control in T2DM patients. 47 Patients were randomised to liraglutide or standard therapy. Most participants were obese (mean BMI: 33 kg/m2), with fair glucose regulation (mean HbA1c: 7.4%). On average, they had gained 7.1 kg while on insulin treatment.

Main results

• After 26 weeks of treatment with liraglutide, body weight had decreased by 4.5+0.5 kg, while it had increased by 0.9+0.6 kg with standard therapy (maximum likelihood mean difference: -5.2, 95%CI: -6.7 to -3.6 kg, P<0.001), corresponding to a between-group difference in BMI of -1.7+0.3 kg/m2.
• HbA1c decreased by 0.77+0.11% with liraglutide, while it increased by 0.01+0.12% with standard therapy (maximum likelihood mean difference: -0.74%, 95%CI: -1.08% to -0.41%, P<0.001).
• 19 patients (73%) in the liraglutide group vs. 7 (29%) in the standard therapy group reached HbA1c > 7.0% (p<0.004).
• Insulin dose was lowered by 29+3 U/day (-55.7+4.1%) with liraglutide, while it increased by 5+3 U/day (+11.8+4.4%) with insulin (maximum likelihood mean difference: -33u/day, 95%CI: -41 to -25 U/day, P<0.001).
• Adverse gastrointestinal events (decreased appetite, dyspepsia, constipation and nausea) were common, but mild-to-moderate in severity, and they often resolved after the first 4-8 weeks. At week 26, only 9 (35%) liraglutide-treated patients reported any gastrointestinal complaints. No serious adverse events were reported. 5 patients (19%) in the liraglutide  group could discontinue insulin therapy.
• No changes in average total energy expenditure and physical activity, or quality of life were observed between the two treatment groups.

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Conclusion

The results of the ELEGANT study show that addition of the GLP-1 analogue liraglutide to insulin, in fairly well-regulated patients with pronounced insulin-induced weight gain, yields reversal of weight gain, while continuation and intensification of insulin therapy led to further weight gain. Although it was not the aim of this study to alter glycaemic control, HbA1c decreased. Thus, glycaemic control was maintained or improved, while weight loss was induced.
Adverse gastrointestinal events were mild-to-moderate and temporary for most patients, thus addition of liraglutide seems an attractive strategy to reverse weight gain in T2DM patients with pronounced insulin-induced weight gain.
Not all patients responded to therapy, but those who did, showed an effect within 12-16 weeks. Thus, a trial period of 3 months may be a suitable approach to test the efficacy of liraglutide in an individual patient.

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