Prediabetes and type 2 diabetes mellitus are highly prevalent in the United States, each affecting approximately 38% and 12% of adults, respectively.¹ This high disease prevalence parallels that of obesity.² Studies show that lifestyle modification can lead to prevention or remission of diabetes, mainly through weight loss.^3,4 However, implementing lifestyle modification that results in sustainable weight loss is challenging.^5,6 Consequently, weight loss medications are a consideration as adjunctive therapy for diabetes prevention.

While a number of medications have been evaluated for diabetes prevention in clinical trials, only metformin is recommended by the American Diabetes Association (ADA) for diabetes prevention in specific patient subgroups.⁷ Hitherto, the use of weight loss medications in addition to lifestyle modification for diabetes prevention or management is not recommended, as these medications have not been formally tested in large-scale clinical trials for such an indication, and because of a lack of data on their efficacy and safety profile. Concerns for the safety of an FDA-approved drug lorcaserin as an adjunct to lifestyle changes for chronic weight management led to the establishment of the Cardiovascular and Metabolic Effects of Lorcaserin in Overweight and Obese Patients – Thrombolysis in Myocardial Infarction 61 (CAMELLIA-TIMI 61) trial.⁸ This study aimed at evaluating long-term cardiovascular and metabolic safety and efficacy of lorcaserin as part of a post-marketing requirement by the FDA.⁸ Lorcaserin is a serotonergic agonist that primarily acts on 5-hydroxytryptamine 2C receptors and inhibits appetite in part via activation of the anorexigenic pro-opiomelanocortin pathway.⁹

The CAMELLIA-TIMI 61 study involved 12,000 overweight or obese patients (body mass index ≥27 kg/m²) with atherosclerotic cardiovascular disease or multiple cardiovascular risk factors and compared lorcaserin (10 mg twice daily) with placebo. The primary efficacy outcome was incident diabetes among patients with prediabetes at baseline. The pre-specified secondary efficacy outcomes included incident diabetes in patients without diabetes, achievement of normoglycemia in individuals with prediabetes and change in glycated hemoglobin (HbA_1C) in those with diabetes. Other secondary outcomes included diabetic microvascular complications. Hypoglycemia was a pre-specified safety outcome. After 1 year of treatment compared to placebo, lorcaserin caused a significant weight loss: 2.6 kg in patients with diabetes, 2.8 kg in individuals with prediabetes and 3.3 kg in those with normoglycemia. Lorcaserin lowered the risk of developing diabetes by 19% in participants with prediabetes (p = 0.038) and by 23% in those without diabetes (p = 0.012). Among individuals with prediabetes, lorcaserin increased achievement of normoglycemia (9.2% vs. 7.6%; p = 0.093). After one year, patients with diabetes taking lorcaserin had a 0.33% lower HbA_1C (from a mean baseline of 7.0%) compared with placebo (p <0.0001). Lorcaserin reduced the risk of diabetic microvascular complications (composite of persistent microalbuminuria, diabetic retinopathy or diabetic neuropathy) by 21% among diabetic patients (p = 0.0015). Although severe hypoglycemia was rare among diabetic patients, it was more commonly observed with lorcaserin (0.4% vs. 0.1%; p = 0.054).

In summary, the CAMELLIA-TIMI 61 study showed that among overweight and obese patients, lorcaserin used as an adjunct therapy to lifestyle modification decreased the risk for incident diabetes and the related microvascular complications and induced remission of hyperglycemia. While CAMELLIA-TIMI 61 study was robust due to its large sample size and relatively long follow-up, there are important limitations. The study did not include body composition measures, which may be important outcomes as lorcaserin has been associated with greater loss of fat mass than lean mass, from visceral adiposity.¹⁰ The observed effect on microvascular outcomes (retinopathy and nephropathy) should be interpreted with caution, as in CAMELLIA-TIMI 61 there was no formal adjudication of these outcomes. Moreover, CAMELLIA-TIMI 61 does not provide any insight on the causal mechanisms that led to improvement of outcomes or high rates of hypoglycemia.⁸

From a clinical perspective, the utility of lorcaserin as an adjunctive therapy for diabetes prevention and remission appears to be limited in today's clinical practice for a number of reasons. First, the magnitude of the effects of lorcaserin on glycemic outcomes is modest. Second, its effects on the risk for cardiovascular disease are mild.¹¹ Third, in addition to its well-known side effects (headache, fatigue, dizziness, diarrhea and nausea), lorcaserin might increase the risk of hypoglycemia. Fourth, the CAMELLIA-TIMI 61 trial lacked data on patient-centered outcomes (e.g., quality of life) and on cost-effectiveness. Fifth, in terms of efficacy, compared to lorcaserin, it is likely that other weight loss drugs such as liraglutide would provide a similar or higher degree of weight loss and much lower risks of diabetes and cardiovascular disease.^12,13 It is possible that some subpopulations of obese people may benefit from the effects of lorcaserin because of an exceptional response to therapy. Such patient subpopulations remain to be defined possibly using unique genetic and phenotypic characteristics. While the results of the CAMELLIA-TIMI 61 trial are encouraging, it is unlikely that these findings would lead the routine use of lorcaserin for treating diabetes by providers, especially as the long-term effects this drug in the treatment of obesity remain uncertain.¹⁴

References

1. Menke A, Casagrande S, Geiss L, Cowie CC. Prevalence of and trends in diabetes among adults in the United States, 1988-2012. JAMA 2015;314:1021-9.
2. Flegal KM, Kruszon-Moran , Carroll MD, Fryar CD, Ogden CL. Trends in obesity among adults in the United States, 2005 to 2014. JAMA 2016;315:2248-91.
3. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393-403.
4. Gregg EW, Chen H, Wagenknecht LE, et al. Association of an intensive lifesytle intervention with remission of type 2 diabetes. JAMA 2012;308:2489-96.
5. Ali MK, Echouffo-Tcheugui J, Williamson DF. How effective were lifestyle interventions in real-world settings that were modeled on the Diabetes Prevention Program? Health Aff 2012;31:67-75.
6. Lean ME, Leslie WS, Barnes AC, et al. Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial. Lancet 2018;391:541-51.
7. American Diabetes Association. Prevention or delay of type 2 diabetes: standards of medical care in diabetes-2019. Diabetes Care 2019;42:S29-33.
8. Bohula EA, Scirica BM, Inzucchi SE, et al. Effect of lorcaserin on prevention and remission of type 2 diabetes in overweight and obese patients (CAMELLIA-TIMI 61): a randomised, placebo-controlled trial. Lancet 2018;392:2269-79.
9. D'Agostino G, Lyons D, Cristiano C, et al. Nucleus of the solitary tract serotonin 5-HT2C receptors modulate food intake. Cell Metab 2018;28:619-30.
10. Apovian C, Palmer K, Fain R, Perdomo C, Rubino D. Effects of lorcaserin on fat and lean mass loss in obese and overweight patients without and with type 2 diabetes mellitus: the BLOSSOM and BLOOM-DM studies. Diabetes Obes Metab 2016;18:945-8.
11. Bohula EA, Wiviott SD, McGuire DK, et al. Cardiovascular safety of lorcaserin in overweight or obese patients. N Engl J Med 2018;379:1107-17.
12. le Roux CW, Astrup A, Fujioka K, et al. 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in indivduals with prediabetes: a randomised, double-blind trial. Lancet 2017;389:1399-1409.
13. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311-22.
14. Yanovski SZ, Yanovski JA. Long-term drug treatment for obseity: a systematic and clincial review. JAMA 2014;311:74-86.

Clinical Topics: Cardiovascular Care Team, Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Vascular Medicine, Statins

Keywords: Glycated Hemoglobin A, Weight Loss, Anti-Obesity Agents, Prediabetic State, Body Mass Index, Diabetes Mellitus, Type 2, Pro-Opiomelanocortin, Serotonin, Metformin, Diabetic Neuropathies, Appetite, Diabetic Retinopathy, Cardiovascular Diseases, Dizziness, Cost-Benefit Analysis, Prevalence, Quality of Life, Sample Size, Camellia, Diabetic Angiopathies, Adiposity, Follow-Up Studies, Risk Factors, Obesity, Overweight, Benzazepines, Blood Glucose, Hyperglycemia, Hypoglycemia, Serotonin Receptor Agonists, Headache, Life Style, Diarrhea, Myocardial Infarction, Nausea, Metabolic Syndrome

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