Endocannabinoid Blockade for Improving Glycemic Control and Lipids in Patients with Type 2 Diabetes Mellitus

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Abstract

Rimonabant significantly reduces weight and waist circumference and improves dyslipidemias in overweight and obese patients without diabetes mellitus. Numerous other metabolic changes, including reduced prevalence of the metabolic syndrome and associated cardiovascular disease (CVD) risk factors, reduced fasting glucose, and elevated adiponectin, have been demonstrated with the administration of rimonabant. The Rimonabant-in-Obesity (RIO)–Diabetes trial studied the safety and efficacy of rimonabant in overweight and obese patients with type 2 diabetes who were treated with metformin or sulfonylureas. RIO-Diabetes was a 1-year, randomized, double-blind, placebo-controlled, parallel-group study of 1,047 overweight/obese patients with type 2 diabetes in 151 centers in 11 countries. The body mass index of participants ranged from 27 to 40. Glycosylated hemoglobin (HbA1c) at screening ranged from 6.5% to 10.0%. All patients were receiving either metformin or sulfonylurea therapy and were asked to follow a hypocaloric diet (600 kcal/day deficit [1 kcal = 4.2 kJ]) for the duration of the trial. After a 4-week placebo plus diet run-in period, patients were randomized to receive placebo or rimonabant 5 mg or 20 mg once daily. At 1 year, absolute change in weight from baseline in the intention-to-treat, last observation carried forward analysis of the rimonabant 5 mg and 20 mg groups, respectively, was loss of 2.3 kg and 5.3 kg compared with 1.4 kg in the placebo group (P = 0.013 and P <0.001, respectively). Waist circumference was significantly decreased in the rimonabant 5-mg and 20-mg groups by 2.9 cm and 5.2 cm compared with 1.9 cm in the placebo group (P = 0.034 and P <0.001, respectively). HbA1c reductions of 0.1% and 0.6% were significant in the rimonabant 5-mg and 20-mg groups (P = 0.034 and P <0.001, respectively). Some 57% of the improvements in HbA1c and high-density lipoprotein cholesterol could not be attributed to observed weight loss. Compared with placebo, rimonabant 20 mg also demonstrated significant improvements in the prevalence of metabolic syndrome and improvement in its constituents, as well as systolic blood pressure and C-reactive protein levels (assay by ICON Laboratories, Farmingdale, NY and Dublin, Ireland). Rimonabant is the first selective cannabinoid1 blocker studied for type 2 diabetes and associated CVD risk factor therapy. Its ability to improve the numerous metabolic pathologies associated with diabetes and CVD risk and concomitantly to reduce weight and waist circumference introduces a strongly positive new dynamic in type 2 diabetes treatment. Its multifactorial mechanisms warrant further investigation and may provide insights into other pathologies.

Section snippets

CVD Risk, Type 2 Diabetes, and the Metabolic Syndrome

The extent to which diabetes increases CVD risk underscores the importance of optimal diabetes management. There has been debate over whether patients with diabetes should be managed as aggressively for CVD risk factors as patients who have had a previous myocardial infarction (MI). A 7-year MI incidence study was done to address this issue (Figure 1).10 A Finnish population of patients with (n = 1,059) and without (n = 1,373) diabetes, both with and without prior MI, were compared. As

The Therapeutic Gap in Type 2 Diabetes Treatment

As stated earlier, aggressive, multimodal CVD risk management has become the standard of care because, to date, it has demonstrated the highest degree of success. As demonstrated in the Steno-2 study, through aggressive, multimodal therapy it is possible to reduce cardio- and microvascular event rates by about 50% (Figure 2).8 In the Steno-2 study these therapies comprised a stepwise implementation of behavior modification and pharmacologic therapy (not including aspirin for secondary CVD risk

Rimonabant in the Management of Multiple Cardiometabolic Risk Factors

Rimonabant is a selective cannabinoid-1 (CB1) blocker that has demonstrated efficacy in the treatment of overweight and obesity, dyslipidemia, and CVD risk factors (Figure 3).23, 24 The newly discovered endocannabinoid (EC) and CB1 receptor system modulates food intake, energy balance, and body composition through both central and peripheral effects that improve glucose and lipid metabolism.16, 25, 26, 27, 28 CB1 receptors are expressed centrally in several areas of the brain and peripherally

Study Design

RIO-Diabetes was a 12-month, international, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Rimonabant 5 mg and 20 mg, in combination with a 600-kcal/day [1 kcal = 4.2 kJ] deficit diet and advice regarding physical exercise, was tested against placebo in overweight/obese patients with type 2 diabetes receiving metformin or sulfonylurea monotherapy. It was conducted in 159 center locations in 11 countries and randomized 1,045 patients, 35% of whom were in the

Efficacy Outcomes

Weight loss with rimonabant 5 mg and 20 mg was significantly greater than that with placebo after 1 year (Figure 4 and Table 3). Weight change from baseline in the rimonabant 5-mg and 20-mg groups was loss of 2.3 and 5.3 kg, respectively, compared with 1.4 kg in the placebo (intention-to-treat [ITT], last observation carried forward [LOCF]) group (P = .013 and P <0.001, respectively, vs. placebo). Weight loss in the 20-mg group began to plateau at about 38 weeks, and was maintained through the

Discussion

Results of the RIO-Diabetes study clearly demonstrate that through 1 year, rimonabant 20 mg significantly reduced weight, waist circumference, HbA1c, and a constellation of related pathometabolic CVD risk factors in obese or overweight patients with type 2 diabetes. These patients are resistant to weight loss and susceptible to weight gain, not only because of the pathometabolic nature of type 2 diabetes but also because weight gain is a side effect of several antidiabetes medications used to

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