Long term GLP-1 agonist treatment provides health benefits for prediabetics
3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial
Literature - le Roux CW, Astrup A, Fujioka K, et al. - The Lancet 2017; published online ahead of printBackground
Liraglutide 3 mg administered subcutaneously once-daily leads to weight loss through reduced appetite and energy intake. It is approved as adjunctive therapy on top of a reduced-calorie diet and increased physical activity program [1,2]. The effects of liraglutide were assessed in obese and overweight individuals with prediabetes and other comorbidities, for the duration of 56 weeks (SCALE Obesity and Prediabetes study) [3].
In this 3-year study extension, the effect of liraglutide 3 mg therapy on the onset of type 2 diabetes mellitus (T2DM), weight loss and safety was evaluated in 2 254 individuals with prediabetes. Patients were randomised 2:1 to either liraglutide or placebo. Those who completed 56 weeks of treatment continued for an additional 104 weeks, allowing for a total of 160 weeks of treatment. Subsequently, there was a 12-week off-treatment follow-up period (until week 172). At week 160, the mean of all continuous variables at multiple time points was calculated.
Main results
- At week 160, 2% of individuals in the liraglutide group were diagnosed with T2DM while on treatment compared with 6% in the placebo group.
- Taking the different diagnosis frequencies between the treatment groups into account, the time-to-onset of T2DM among all randomised individuals, while on treatment, was 2.7 times longer with liraglutide compared with placebo (95% CI 1.9–3.9, P<0.0001), with an HR of 0.21 (95% CI 0.13–0.34, P<0.0001).
- At week 160, 66% of individuals in the liraglutide group had regressed from prediabetes to normoglycaemia while on treatment, compared with 36% in the placebo group (OR 3.6, 95% CI 3.0–4.4, P<0.0001, NNT 3).
- After 12 weeks treatment cessation (week 172), 50% of individuals who had been treated with liraglutide still had normoglycaemia compared with 36% in the placebo group (OR 1.9, 95% CI 1.6–2.3, P<0.0001).
- At week 160, measures of insulin resistance and β-cell function were improved while on liraglutide treatment compared with placebo and glycated haemoglobin, fasting glucose and fasting insulin concentrations were lower with liraglutide than with placebo.
- Liraglutide induced greater weight loss compared with placebo at week 160 (liraglutide –6.1%, SD 7.3 and placebo –1.9%, SD 6.3; estimated treatment difference –4.3%, 95% CI –4.9 to –3.7, P<0.0001). Weight loss with liraglutide treatment was sustained over 3 years.
- After treatment cessation at week 160, some weight was regained in the liraglutide group, although the treatment difference was still significant at week 172 (–3.2%, 95% CI –4.3 to –2.2, P<0.0001).
- Systolic blood pressure (SBP) was statistically significantly decreased with liraglutide compared with placebo at week 160, but diastolic blood pressure (DBP) was not. The effects on fasting lipids and CV biomarkers were modest and levels of high-sensitivity c-reactive protein were substantially lower with liraglutide compared with placebo.
- Liraglutide 3 mg was generally well tolerated.
Conclusion
3 years of treatment with once-daily subcutaneous liraglutide 3 mg on top of a reduced-calorie diet and increased physical activity, reduced the risk of T2DM in overweight or obese individuals with prediabetes and led to greater weight loss and improvements in glycaemic control and CV risk factors compared with placebo. This data support the hypothesis that long term liraglutide therapy provides additional health benefits to a specific group of high-risk individuals.
Editorial comment
In their editorial article [4], Farr and Mantzoros comment that the important finding of the le Roux et al study is the normalisation of glucose values in prediabetes patients treated with liraglutide. However, they note that this may not be the most cost-effective way for the management of prediabetes, since lifestyle modification is less expensive, non-interventional and appears to be equally effective.
The authors conclude: ‘Whether liraglutide is more effective in the longer term (e.g. 10 years) or whether other GLP-1 analogues are more effective than lifestyle modification alone also remains to be seen. These considerations should be weighed carefully in terms of future recommendations for the treatment of patients with prediabetes in the clinic.’
References
1. van Can J, Sloth B, Jensen CB, et al. Effects of the once-daily GLP-1 analog liraglutide on gastric emptying, glycemic parameters, appetite, and energy metabolism in obese, non-diabetic adults. Int J Obes (Lond) 2013; 38: 784–93.
2. Pi-Sunyer X, Astrup A, Fujioka K, et al. A randomized, controlled trial of 3 mg of liraglutide in weight management. N Engl J Med 2015; 373: 11–22.
3. American Diabetes Association. Diagnosis and classification of Diabetes Mellitus. Diabetes Care 2010; 33: S62–69.
4. Farr OM, Mantzoros CS. Treating prediabetes in the obese: are GLP-1 analogues the answer? The Lancet 2017; published online ahead of print.
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