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Use of Liraglutide in Obese Patients May Reduce Risk for Type 2 Diabetes

A new finding from the SCALE trial.

Since the recognition of prediabetes as a syndrome, the prevalence of diabetes has been on the rise, with a 5-10% transition rate annually among obese patients with prediabetes. Prior to the introduction of the newer non-insulin therapies, risk reduction was mediated via weight loss through lifestyle modification techniques, regardless of the presence of pharmacological intervention.

From June 2011 to March 2015, the SCALE Obesity and Diabetes study was performed. SCALE was a 4-armed study that looked at the effects of the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide, in conjunction with modification of dietary and exercise habits, on weight loss. It was a large, multicenter, multinational, placebo-controlled trial performed over a 56-week period in obese individuals with and without prediabetes. Subjects who displayed prediabetes at enrollment screening were then continued on the regimen for an additional two years, followed by 12 weeks off-drug for further evaluation. Treatment consisted of either liraglutide 3 mg daily or placebo, along with a standardized lifestyle modification program. The primary objective of SCALE was development of type 2 diabetes with time to development being the main endpoint.

There were also four co-primary endpoints, three of which being weight loss, proportion of subjects losing at least 5% of their baseline weight, and proportion losing at least 10%, all at 56 weeks from enrollment. Secondary endpoints included change from baseline to 160 weeks in glycemic metrics, body weight, BMI, waist size, cardiometabolic markers, vital signs, and quality of life indicators. A study size of 3,600 subjects was determined sufficient for appropriate power and an alpha of 5%, using two-sided χ2 testing. There were 4,992 patients evaluated, of which 2,254 were randomized, with a distribution of liraglutide to placebo of 2 to 1. The number of subjects accounted for a projected 160-week dropout rate of 65% in both groups. Mean changes in continuous variable data were analyzed using logistic regression.

Of the 2,254 patients enrolled, 783 subjects in the liraglutide arm (52%) and 327 in the placebo arm (44%) completed the 160 weeks study period with the accompanying 12 week follow-up period. At the end of 172 weeks, 26 patients (2%) in the treatment arm and 46 patients (6%) in the placebo arm had been diagnosed with diabetes, with a hazard ratio of 0.21 (95% CI 0.13-0.34, p<0.0001). Onset of diabetes on treatment was 2.7 times longer than on placebo (95% CI 1.0-3.9, p<0.0001). Another data evaluation showed the number of patients who improved to normoglycemia by the end of the trial was 970 (66%) in the treatment arm versus 263 (36%) on placebo (OR 3.6, 95% CI 3.0-4.4, p<0.0001). Weight loss was also greater in the treatment arm (-6.1%) versus placebo (-1.9%) with an estimated treatment difference of -4.3% (95% CI -4.9 to -3.7, p<0.0001), at the end of 160 weeks. Some weight re-gain was noticed in both arms at 172 weeks, but the difference remained significant in favor of liraglutide (-3.2%, 95% CI -4.3 to -2.2, p<0.0001). With regards to the major safety concern involving liraglutide administration, there were no cases of medullary thyroid cancer or C-cell hyperplasia observed in the treatment arm. There were also no observable increases in serum calcitonin concentrations caused by liraglutide.

The authors of this study conclude that 3-year continued use of liraglutide in overweight persons with prediabetes was associated with a decreased risk of developing type 2 diabetes and an increase in sustained weight loss when compared to placebo. These findings were consistent with previous studies involving liraglutide. Reversion to normoglycemia was also associated with a lower risk of diabetes. While this seems intuitive, the means to achieve remission was more successful when liraglutide was included in the lifestyle modification regimen, versus the same with no drug treatment, a result observed in treatment with other GLP-1 agonists, suggesting a class-wide effect.  Further suggested is that return to normoglycemia is associated with a 56% reduction of risk in people with prediabetes. Key to the findings was that improvements in excess weight and cardiometabolic markers can be sustained for three years with continued use of liraglutide in combination with diet and exercise, with similar results likely across the class of GLP-1 agonists.

It is interesting to note that the degree of weight loss and blood glucose reduction (as well as the reduction in A1C) attributed to diet and exercise alone, as evidenced by the results in the placebo group, suggests that a regimen without pharmacologic intervention warrants a reasonable trial period. The high degree of success with addition of a GLP-1 agonist gives clinicians an extra tool in reserve for their patients who fail diet and exercise alone.

Practice Pearls:

  • The risk of developing diabetes has long been associated with obesity, making weight loss a primary goal in treatment of prediabetes.
  • The use of liraglutide along with lifestyle changes has been shown to reduce blood glucose, hemoglobin A1C, and weight in a sustained and favorable fashion.
  • The high cost of GLP-1 agonists supports use of a diet and exercise regimen prior to initiating one of these agents.

References:

Le Roux CW, Astrup A, Fujioka K, Greenway F, Lau DC, Van Gaal L, et al. 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial. Lancet. 2017. Epub 2017/02/22. doi: 10.1016/S0140-6736(17)30069-7.

Wadden TA, Hollander P, Klein S, Niswender K, Woo V, Hale PM, et al. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study. Int J Obes (Lond). 2013;37(11):1443-51. Epub 2013/07/01. doi: 10.1038/ijo.2013.120.

Tabák AG, Herder C, Rathmann W, Brunner EJ, Kivimäki M. Prediabetes: a high-risk state for diabetes development. Lancet. 2012;379(9833):2279-90. Epub 2012/06/09. doi: 10.1016/S0140-6736(12)60283-9.

Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393-403.

Tuomilehto J, Lindström J, Eriksson JG, Valle TT, Hämäläinen H, Ilanne-Parikka P, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344(18):1343-50.
Mark T. Lawrence, RPh, PharmD Candidate, University of Colorado-Denver, School of Pharmacy NTPD