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For our next Quick Take study, let’s look at a paper on liraglutide. This is a medication used in the treatment of diabetes, and we’ll look at it for its potential to cause weight loss in patients who are being treated with some of our second-generation antipsychotics—in this study, olanzapine and clozapine.
You may not be familiar with liraglutide. It’s one of the relatively newer medications used for diabetes. It is a glucagon-like peptide-1 receptor agonist. I think the diabetes specialists call these compounds glips. This was recently approved by the US Food and Drug Administration as a treatment for weight loss. That’s new! We certainly need medications that could cause weight loss given that our medications are causing weight gain so often, and 2 of them in particular, which are examined in this study, are olanzapine and clozapine.
So, we’re looking at a 2017 paper by Larsen and colleagues published in *JAMA Psychiatry*. Relatively briefly, the bottom line is, liraglutide does cause weight loss in patients who are taking olanzapine and clozapine. The effect size is not huge, on the order of 5 kg. That’s 5 kg more than the patients who lost weight on placebo, which was not zero. Interestingly, the dose that was used in this study was the lower of the 2 doses that have been approved. This was 1.8 mg per day; the higher dose of 3 mg per day is used in some weight-loss studies.
Tolerability becomes more of a problem. In fact, tolerability is probably the big issue, that and cost, in that this is a subcutaneous daily injection. So, that’s a huge barrier for regular use. And dose-related gastrointestinal tolerability is a problem. Vomiting and abdominal pain are common. So, even though the data are very tantalizing in that we have a potential new way to help people tolerate important medications like olanzapine and clozapine, unfortunately two-thirds of the patients on liraglutide had nausea. That was a limiting factor, and then there’s daily subcutaneous administration. People with diabetes get used to this but perhaps not so many of our patients. So, there are some limiting factors there. We can wait for some more data on how effective this is in replication and how tolerable this is for our general patient population. It is nice to know that, in addition to metformin, which clearly has data supporting its efficacy (but you have got to get it up to 1500 mg or 2000 mg, and it takes a while to get there), we have a new potential tool.
In summary, we can conclude that liraglutide is indeed associated with more weight loss than placebo in patients taking medications that we know are highly likely to cause very large weight gain, like olanzapine and clozapine. The catch is that it’s an expensive medication that requires daily subcutaneous injections and has an incidence of abdominal pain, nausea, and vomiting, even at its lower dose. So, its efficacy in routine clinical practice is still a wide-open question.
Abstract
Effect of Liraglutide Treatment on Prediabetes and Overweight or Obesity in Clozapine- or Olanzapine-Treated Patients With Schizophrenia Spectrum Disorder. A Randomized Clinical Trial
Julie R. Larsen, MD; Louise Vedtofte, PhD; Mathilde S. L. Jakobsen, MD; Hans R. Jespersen, MD; Michelle I. Jakobsen, MD; Camilla K. Svensson, MB; Kamuran Koyuncu, MD; Ole Schjerning, MD; Peter S. Oturai, MD; Andreas Kjaer, DMSc; Jimmi Nielsen, DMSc; Jens J. Holst, DMSc; Claus T. Ekstrøm, PhD; Christoph U. Correll, MD; Tina Vilsbøll, DMSc; Anders Fink-Jensen, DMSc
IMPORTANCE: Compared with the general population, patients with schizophrenia have a 2- to 3-fold higher mortality rate primarily caused by cardiovascular disease. Previous interventions designed to counteract antipsychotic-induced weight gain and cardiometabolic disturbances reported limited effects.
OBJECTIVES: To determine the effects of the glucagon-like peptide-1 receptor agonist liraglutide added to clozapine or olanzapine treatment of schizophrenia spectrum disorders.
DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical double-blind trial enrolled participants at 2 clinical sites in Denmark. Of 214 eligible participants with a schizophrenia spectrum disorder, 103 were randomized to liraglutide or placebo. Participants received stable treatment with clozapine or olanzapine, were overweight or obese, and had prediabetes. Data were collected from May 1, 2013, through February 25, 2016.
INTERVENTIONS: Treatment for 16 weeks with once-daily subcutaneous injection of liraglutide or placebo. Trial drug therapy was titrated during the first 2 weeks of the study.
MAIN OUTCOMES AND MEASURES: The primary end point was change in glucose tolerance estimated by a 75-g oral glucose tolerance test result. Secondary end points included change in body weight and cardiometabolic parameters.
RESULTS: Of the 103 patients undergoing randomization (60 men [58.3%] and 43 women [41.7%]), 97 were included in the efficacy analysis, with a mean (SD) age of 42.5 (10.5) years and mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) of 33.8 (5.9). The liraglutide and placebo groups had comparable characteristics (mean [SD] age, 42.1 [10.7] vs 43.0 [10.5] years; 30 men in each group; mean [SD] body mass index, 33.7 [5.1] vs 33.9 [6.6]). A total of 96 randomized participants (93.2%) completed the trial. Glucose tolerance improved in the liraglutide group compared with the placebo group (P< .001). Altogether, 30 liraglutide-treated participants (63.8%) developed normal glucose tolerance compared with 8 placebo-treated participants (16.0%) (P < .001; number needed to treat, 2). Body weight decreased with liraglutide compared with placebo (−5.3 kg; 95% CI, −7.0 to −3.7 kg). Reductions in waist circumference (−4.1 cm; 95% CI, −6.0 to−2.3 cm), systolic blood pressure (−4.9 mm Hg; 95% CI, −9.5 to −0.3 mm Hg), visceral fat (−250.19 g; 95% CI, −459.9 to −40.5 g), and low-density lipoprotein levels (−15.4 mg/dL; 95% CI, −23.2 to −7.7 mg/dL) occurred with liraglutide compared with placebo. Adverse events with liraglutide affected mainly the gastrointestinal tract.
CONCLUSIONS AND RELEVANCE: Liraglutide significantly improved glucose tolerance, body weight, and cardiometabolic disturbances in patients with schizophrenia spectrum disorders treated with clozapine or olanzapine.
TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01845259
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Reference
Larsen, J. R., Vedtofte, L., Jakobsen, M. S., Jespersen, H. R., Jakobsen, M. I., Svensson, C. K., Koyuncu, K., Schjerning, O., Oturai, P. S., Kjaer, A., Nielsen, J., Holst, J. J., Ekstrøm, C. T., Correll, C. U., Vilsbøll, T., & Fink-Jensen, A. (2017). Effect of Liraglutide treatment on prediabetes and overweight or obesity in clozapine- or olanzapine-treated patients with schizophrenia spectrum disorder. JAMA Psychiatry, 74(7), 719.
