- Email: [email protected]
Cannabinoid-1 Receptor Blockade in Cardiometabolic Risk Reduction: Safety, Tolerability, and Therapeutic Potential
Cannabinoid-1 Receptor Blockade in Cardiometabolic Risk Reduction: Safety, Tolerability, and Therapeutic Potential Benjamin A. Steinberg, MD,a and Christopher P. Cannon, MDb,* Rimonabant is the first selective blocker of the cannabinoid-1 receptor in development for the treatment of obesity, diabetes mellitus, and cardiometabolic risk factors. (Recently, an FDA Advisory Committee recommended a delay in the approval of rimonabant because of safety issues that need to be addressed in further studies.) Although it is associated with favorable effects on weight, waist circumference, serum lipids, C-reactive protein, and an improvement in glycemic control in type 2 diabetes, there are concerns about side effects. Generally, rimonabant has been well tolerated, with a primary side effect of nausea. Other side effects seen in trials have been anxiety and depressive symptoms, as well as neurologic events, albeit at low rates. When rimonabant becomes clinically available, physicians should be vigilant regarding the expected side effects and use alternative therapies if needed. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100[suppl]:27P–32P)
With the growing worldwide epidemic of both obesity and diabetes mellitus (sometimes called diobesity), efforts have intensified to find novel therapies to help patients lose weight and either prevent or control diabetes and its associated cardiovascular sequelae. Weight loss is associated with favorable changes in lipid profiles and C-reactive protein, as well as with improved glycemic control and decreased mortality.1,2 However, success with behavior modification and currently available medications in achieving and sustaining even mild weight loss is limited. Manipulation of the endocannabinoid (EC) system via blockade of the cannabinoid-1 (CB1) receptor is an intriguing new approach that addresses obesity and diabetes. Rimonabant, the first such agent to act through this mechanism, has been approved in Europe and is currently under review in the United States. Its therapeutic effects are discussed elsewhere in this supplement.3 As with any medication, side effects do occur; some are related to the drug and others are part of the condition being treated. This review briefly discusses some of those side effects. Safety of Current Therapies for Obesity Although diet and exercise are the mainstays of treatment for obesity, patients frequently need additional therapies to assist in achieving or maintaining weight loss. There are several a Department of Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA; and bCardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, Massachusetts, USA. Statement of author disclosure: Please see the Author Disclosures section at the end of this article. *Address for reprints: Christopher P. Cannon, MD, Brigham and Women’s Hospital, The Thrombolysis in Myocardial Infarction (TIMI) Study, 1st Floor, 350 Longwood Avenue, Boston, Massachusetts 02115. E-mail address: [email protected].
0002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2007.10.011
approved pharmacotherapies including phentermine, which promotes satiety; sibutramine, which acts by inhibiting reuptake of norepinephrine and serotonin; and orlistat, which alters fat absorption. Phentermine and sibutramine mimic the actions of norepinephrine and effect weight loss by causing early satiety. Cardiovascular adverse effects, such as hypertension and tachycardia, limit the use of these agents, especially in patients with cardiac comorbidities. Surgical procedures, such as gastric banding or gastric bypass, are effective for sustained weight loss but are clearly invasive and associated with a significant rate of complications.4 They are generally reserved for patients with morbid obesity (body mass index ⬎40) and those with obesity-related complications.5 All current therapies appear to have some risks associated with them. Rimonabant: a Cannabinoid-1 Receptor Blocker ECs, such as arachidonoyl ethanolamine (anandamide) and 2-arachidonoyl glycerol, interact with specific G-protein– coupled receptors, CB1 and CB2 (cannabinoid-2).6,7 Rimonabant† is an antagonist of the CB1 receptor at the typical doses. The CB1 receptors are overwhelmingly distributed to the brain8 and adipose tissue,9 but they are also found in the myocardium,10 vascular endothelium,11 liver, muscle, and sympathetic nerve terminals.12 With this distribution, gastrointestinal and central nervous system side effects might be anticipated. Rimonabant in Patients with Obesity There have been 4 randomized trials in obesity, including a study specifically in overweight or obese individuals with †
Recently, an FDA Advisory Committee recommended a delay in the approval of rimonabant because of safety issues that need to be addressed in further studies. www.AJConline.org
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diabetes. The Rimonabant in Obesity (RIO) program trials were all double-blind, placebo-controlled trials that randomized patients to receive rimonabant 20 mg/day, 5 mg/ day, or a matching placebo, in addition to counseling on following a hypocaloric diet. Efficacy results are summarized elsewhere in this supplement.3 In the RIO-Lipids trial, after a 4-week placebo run-in period, obese patients with untreated hyperlipidemia were randomized to rimonabant or placebo as discussed above and observed for 1 year.13 Patients in the rimonabant group lost significantly more weight than those in the placebo group. With rimonabant 20 mg/day, 33% of patients lost ⱖ10% of their initial body weight compared with 7% of patients receiving placebo. A similarly-sized RIO-Europe trial14,15 running concurrently with RIO-Lipids enrolled obese subjects with either hypertension or hyperlipidemia. Patients were advised to follow a hypocaloric diet and were randomized to rimonabant 20 mg/day, rimonabant 5 mg/day, or placebo. The study included a 4-week run-in period, similar to the RIOLipids trial. The on-treatment analysis of its results showed that after a full year of therapy, treatment with rimonabant 5 mg/day or 20 mg/day was associated with significantly greater waist circumference reduction than placebo (reductions of 6.5 cm for the 20-mg dose, 3.9 cm for the 5-mg dose, and 2.4 cm for placebo). There were favorable changes in the lipid profile of subjects in both rimonabant groups: triglyceride levels decreased and high-density lipoprotein (HDL) levels increased, which may have been mediated by increased levels of adiponectin. The 2-year results from RIO-Europe demonstrate a substantial decrease in the proportion of subjects with metabolic syndrome with the combination of a hypocaloric diet and rimonabant 20 mg/day: 42.2% at baseline, 19.6% at 1 year,14 and 21.5% at 2 years.15 The RIO–North America trial16 used criteria similar to those in the other RIO trials, but after 1 year of treatment with rimonabant or placebo the trial randomized its subjects to another year of therapy or to matching placebo. Whereas the first-year outcomes were similar to those in other RIO trials, subjects who completed only 1 year of rimonabant treatment and were then randomized to placebo regained much of the lost weight during the period in which they were not taking the drug. Average weight loss for patients receiving rimonabant for the full 2 years was 7.4 kg; those taking placebo for 2 years lost 2.3 kg; and those taking rimonabant for 1 year followed by placebo lost 3.2 kg. Consistent with the other RIO trials, rimonabant therapy at the 20-mg/day dose was associated with an increase in HDL of 25%.
standard oral hypoglycemic regimen was continued throughout the study. At the end of 1 year of therapy, subjects in the high-dose rimonabant group lost significantly more weight than those in the placebo group (5.3 kg vs 1.5 kg, respectively). Average HbA1c levels decreased by 0.6% in the high-dose rimonabant group but increased in the placebo group by 0.1%. By the end of the study, 43% of all subjects treated with rimonabant were able to achieve an optimal HbA1c level of ⬍6.5% compared with 21% of those receiving placebo. Adverse Effects in Clinical Trials of Rimonabant Clinical experience with rimonabant in the setting of phase 3 clinical trials involves approximately 6,500 obese patients to date and is rapidly growing. It suggests that the drug is generally well tolerated. In the RIO phase 3 program, the 1-year dropout rates were consistently in the 36%– 49% range13,15–17 but did not differ from placebo. Relatively high dropout rates are characteristic of weight loss trials. The most common adverse effects were mild nausea (11.2%– 12.9%) and diarrhea (5.3%–7.2%) in the high-dose (20 mg) rimonabant groups. The rates of discontinuation attributable to adverse effects were 12.8%–15% for rimonabant compared with 5%–9.2% for placebo. Because of the EC physiology, potential neuropsychiatric adverse effects of rimonabant have been carefully assessed in clinical trials conducted to date. In each of the RIO trials, the incidence of psychiatric adverse events was higher in the rimonabant groups compared with placebo, and it increased with higher doses of rimonabant. However, the absolute incidence of the most common psychiatric side effects was 1.2%– 5.2% for depressed mood, 5.0%– 8.7% for anxiety, 5.8%– 6.4% for insomnia, and 5.6%–10.4% for dizziness (at the highest studied dose of rimonabant, 20 mg). Also of particular interest are the rates of adverse cardiovascular events in the treatment groups. The RIO-Lipids trial reported 1 patient in the placebo group with an adverse vascular event and 3 patients in the rimonabant groups with adverse cardiac events (5 mg: n ⫽ 2; 20 mg: n ⫽ 1).13 In the RIO-Diabetes trial, 2 patients in the rimonabant 20-mg group discontinued study medication because of chest pain.17 The RIO–North America trial noted no differences in change in the corrected QT interval over time and did not report any adverse cardiovascular events.16 In RIO-Europe, no patients in the placebo group had serious vascular or cardiac adverse events, whereas 2 patients each in the rimonabant 5-mg and 20-mg groups experienced cardiac events, and 2 patients in the 5-mg and 3 in the 20-mg rimonabant groups experienced vascular adverse events.14
Rimonabant in Patients with Diabetes The latest component of the RIO program was the RIO-Diabetes trial,17 which examined the effects of rimonabant on glucose control in obese subjects with type 2 diabetes with an average baseline glycosylated hemoglobin (HbA1c) of 7.3%. A
Pooled Safety Data from the Rimonabant in Obesity Program Overall, although study drug discontinuation rates were 32%– 49% for both the placebo and rimonabant groups in
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Table 1 Psychiatric events reported by patients randomized to rimonabant 20 mg without crossover
Total patients reporting symptom, n (%) Adverse events, n (%)* Anxiety Insomnia Depressed mood Depression Stress Nervousness Depressive symptom Sleep disorder Nightmare Panic attack Mood alteration Major depression Mood swings Agitation Affect lability Aggression Abnormal dreams Affective disorder Decreased libido
Placebo (n ⫽ 1,602)
Rimonabant 5 mg (n ⫽ 2,220)
Rimonabant 20 mg (n ⫽ 2,176)
226 (14.1)
356 (16.0)
569 (26.2)
40 (2.50) 53 (3.31) 45 (2.81) 23 (1.44) 28 (1.75) 5 (0.31) 12 (0.75) 7 (0.44) 3 (0.19) 1 (0.06) 4 (0.25) 5 (0.31) 2 (0.12) 2 (0.12) 1 (0.06) 1 (0.06) 2 (0.12) 3 (0.19) 6 (0.37)
68 (3.06) 66 (2.97) 66 (2.97) 55 (2.48) 35 (1.58) 14 (0.63) 15 (0.68) 13 (0.59) 4 (0.18) 3 (0.14) 5 (0.23) 5 (0.23) 11 (0.50) 5 (0.23) 7 (0.32) 6 (0.27) 1 (0.045) 1 (0.04) 4 (0.18)
131 (6.02) 118 (5.42) 83 (3.81) 74 (3.40) 38 (1.75) 31 (1.42) 23 (1.06) 21 (0.97) 21 (0.97) 18 (0.83) 15 (0.69) 15 (0.69) 10 (0.46) 10 (0.46) 10 (0.46) 9 (0.41) 8 (0.37) 7 (0.32) 6 (0.28)
*Data are shown in decreasing order of frequency. Adapted from US Food and Drug Administration Briefing Document.18
Figure 1. Relative risks (RR) of depressive and anxiety disorder symptoms in Rimonabant in Obesity (RIO) trial subjects receiving both rimonabant 20 mg and placebo. CI ⫽ confidence interval; OBE(DB) ⫽ RIO-Diabetes; OBE(EU) ⫽ RIO-Europe; OBE(LP) ⫽ RIO-Lipids; OBE(NA) ⫽RIO–North America. (Adapted from US Food and Drug Administration Briefing Document.18)
the RIO program, they were attributed to adverse events in ⬍33% of cases. Because of the known potential of rimonabant for neuropsychiatric effects, specific attention has been focused on the detection of these disorders. Recently, the US Food and Drug Administration (FDA) performed a safety review of the RIO program.18 It pooled the adverse events reported in each of the RIO studies to summarize the current data. For patients not randomized to any crossover within the studies, 26% in the rimonabant 20-mg groups, compared with 14% in the placebo groups, experienced and reported psychiatric effects. Such symptoms and disorders are gauged on a standardized self-assessment scale, the Hospital Anxiety and Depression Scale (HADS).19 Summarized data on psychiatric events reported by patients randomized to rimonabant 20 mg without crossover are shown in Table 1.
A more in-depth review of trial source documentation by the manufacturer of rimonabant, sanofi-aventis, yielded additional symptoms of both depressive disorders and anxiety disorders in trial subjects receiving both rimonabant 20 mg and placebo. Using these more comprehensive rates of psychiatric side effects, the relative risks of such symptoms (for rimonabant 20 mg vs placebo) were calculated by the FDA (Figure 1). Based on these pooled analyses, the relative risk for reported psychiatric adverse events was significantly higher for patients taking 20 mg rimonabant compared with those taking placebo (relative risk, 1.9; 95% confidence interval [CI], 1.5–2.3). Although the increased risk for such symptoms is of concern, an effort was also made to identify further the severity of such symptoms. In response to such a request from the FDA, the manufacturer enlisted the help of Kelly
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Table 2 Summary of patients and suicidality based on Columbia University report for the US Food and Drug Administration (FDA) Classification
Placebo (n ⫽ 2,909)
Rimonabant 5 mg (n ⫽ 5,121)
Rimonabant 20 mg (n ⫽ 6,802)
Complete suicide Suicide attempt Preparatory acts toward suicide Suicidal ideation Self-injurious behavior, intent unknown Not enough information (fatal) Not enough information (nonfatal)
— 7 — 13 — — —
— — 1 6 — 1 —
— 4 — 39 — — 3
Adapted from FDA Briefing Document.18
Figure 2. Columbia University analysis of suicidality events. Odds ratios (OR) are shown for the occurrence of a suicide attempt in all available clinical trial data, including rimonabant trials for treatment of obesity. *Rimonabant 20 mg was compared with active comparator (5 mg) for analysis because there was no placebo (Plb) arm in the first randomization. ACT4855 ⫽ ACTOL; CI ⫽ confidence interval; EFC4474 ⫽ Studies with Rimonabant and Tobacco (STRATUS)–Europe; EFC4796 ⫽ Studies with Rimonabant and Tobacco (STRATUS)–WW; EFC4964 ⫽ Studies with Rimonabant and Tobacco (STRATUS)–US; EFC5794 ⫽ Studies with Rimonabant and Tobacco (STRATUS)–META; NA ⫽ not available; OBE ⫽ obese; OBE(BED) ACT3801 ⫽ CRAVING; OBE(CRA) EFC5031 ⫽ REBA; OBE(DIA) EFC4736 ⫽ Rimonabant in Obesity (RIO)–Diabetes; OBE(DIA) EFC5825 ⫽ Study Evaluating Rimonabant Efficacy in Drug-Naive Diabetic Patients (SERENADE); OBE(EUR) EFC4733 ⫽ Rimonabant in Obesity (RIO)–EUROPE; OBE(LIP) EFC4735 ⫽ Rimonabant in Obesity (RIO)–LIPIDS; OBE(N.A.) EFC4743 ⫽ Rimonabant in Obesity (RIO)–North America; OBE(Ph2) DRI3388 ⫽; SCHIZOPH ⫽ schizophrenia; METATRI ⫽ METATRIAL. (Adapted from US Food and Drug Administration Briefing Document.18)
Posner and colleagues18 at Columbia University. They were able to identify a subset of patients with advanced psychiatric symptoms, including suicidal ideation and even suicide attempts (although no completed suicides), as shown in Table 2. Although suicidal ideation was more common in the rimonabant groups (20 mg: n ⫽ 39; 5 mg: n ⫽ 6; placebo: n ⫽ 13), more suicide attempts were made in the placebo group. Once again, in an effort to quantify the risk of such serious events for patients taking rimonabant, odds ratios (ORs) were calculated for the occurrence of a suicide attempt, not only in the obesity trials of rimonabant but also in all available clinical trial data. Results from the Columbia University analysis are shown in Figure 2. Importantly, the overall OR for incidence of suicidality in the rimonabant 20-mg group compared with the placebo group was 1.9 (95% CI, 1.1–3.1). However, this included
data from trials of patients with schizophrenia as well as those abusing alcohol (2 groups with known suicidality rates higher than those of the general population), and when the analysis was restricted to only the 7 trials of obese patients, the overall OR was 1.8 (95% CI, 0.8 –3.8). To add perspective to these rates, the FDA obtained prescription rates for both weight loss medications and antidepressants. Of the ⬎500,000 patients who received a prescription for a weight loss agent in 2004 –2006, approximately 30% also received concurrent prescriptions for antidepressants, indicating a potential source of confounding in these data.18 With regard to neurologic effects, the distribution of CB1 receptors throughout the brain may place patients at risk not only for psychiatric effects but also potentially for neurologic adverse events. A similar pooled analysis of neurologic adverse events in the RIO trials was performed by the FDA (Table 3).18
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Table 3 Neurologic adverse events in the Rimonabant in Obesity trials, based on pooled data analysis by the US Food and Drug Administration (FDA) Characteristic
Placebo (n ⫽ 1,602)
Rimonabant 5 mg (n ⫽ 2,220)
Rimonabant 20 mg (n ⫽ 2,176)
Total subjects reporting symptoms, n (%)* Neurologic adverse events, n (%)* ● Neurologic disorders NEC Dizziness Paresthesia Hypoesthesia ● Headaches Headache Migraine ● Mental impairment disorders —Memory impairment —Disturbance in attention —Amnesia ● Spinal cord and nerve root disorders —Sciatica ● Movement disorders (including parkinsonism) —Tremor ● Peripheral neuropathies
391 (24.4)
535 (24.1)
596 (27.4)
151 (9.4) 89 (5.56) 17 (1.06) 14 (0.87) 247 (15.4) 203 (12.67) 31 (1.94) 21 (1.3) 7 (0.44) 10 (0.62) 8 (0.50) 15 (0.94) 10 (0.62) 1 (0.06) 0 19 (1.19)
227 (10.2) 138 (6.22) 23 (1.04) 32 (1.44) 287 (12.9) 225 (10.14) 43 (1.94) 26 (1.2) 14 (0.63) 2 (0.09) 8 (0.36) 29 (1.3) 23 (1.04) 8 (0.36) 6 (0.27) 29 (1.31)
311 (14.3) 186 (8.55) 37 (1.70) 31 (1.42) 266 (12.2) 220 (10.11) 36 (1.65) 45 (2.1) 16 (0.74) 15 (0.69) 14 (0.64) 31 (1.4) 27 (1.24) 24 (1.1) 21 (0.97) 21 (0.97)
NEC ⫽ not elsewhere classified. *Data are for subjects receiving the same treatment during the entire study. Adapted from FDA Briefing Document.18
Although the absolute event rates are similar across treatment arms, the pooled relative risk of neurologic symptoms for patients receiving rimonabant 20 mg compared with placebo was 1.7 (95% CI, 1.1–2.7).18 Special attention has also been paid to the incidence of seizures in patients taking rimonabant, particularly because cannabinoids (agonists) have been known to have antiepileptic properties, although thus far no apparent increase has been seen in the individual trials.
Preliminary Postmarketing Surveillance Safety Data Rimonabant has been approved in 42 countries and marketed in 20. The manufacturer estimates that ⬎78,000 patients have been exposed to rimonabant as of November 30, 2006.18 During the first postapproval surveillance summary of data from June 19, 2006, to December 18, 2006, sanofi-aventis reported receiving 918 cases totaling 2,362 adverse events. Nearly half of the reported events were gastrointestinal, consisting of nausea (47.4%), diarrhea (16.8%), and vomiting (10.2%). Approximately 1 in 10 were psychiatric events: anxiety (10.7%), depressed mood (10.7%), depression (10.3%), and insomnia (7.3%). Neurologic adverse events were also reported, including dizziness (27.6%), headache (17.8%), paresthesia (5.7%), tremor (5.1%), somnolence (4.4%), amnesia (4.0%), and attention disturbance (3.7%).
Future Potential Therapeutic Applications Therapy with rimonabant induces significant, favorable changes in an individual’s cardiometabolic risk profile as ev-
idenced by weight loss, higher serum HDL and lower triglyceride levels, and improved glycemic control. It is not yet known, however, whether these alterations have any effect on the progression of atherosclerosis. This question is being directly addressed by the Strategy to Reduce Atherosclerosis Development Involving Administration of Rimonabant—the Intravascular Ultrasound Study (STRADIVARIUS),20 which will enroll obese subjects with 20%–50% coronary artery stenosis diagnosed during clinically relevant coronary angiography. Subjects will be randomized to rimonabant or placebo and will undergo repeat angiography after 18 months of treatment, with the primary end point being change in the volume of the index atheroma as measured by intravascular ultrasound. A large clinical end points trial—the Comprehensive Rimonabant Evaluation Study of Cardiovascular Endpoints and Outcomes (CRESCENDO)—is also being conducted to determine whether long-term treatment with rimonabant could reduce the risk for cardiovascular events.21 Animal experiments demonstrated that CB1 receptor blockade attenuates cue reactivity and reduces drug-seeking behavior across the wide spectrum of addictive substances.22 Subsequently, the National Institutes of Health (NIH) are sponsoring a phase 2 trial that will test whether therapy with rimonabant would be a useful adjunct in reducing alcohol consumption.23 Animal experiments that show that CB1 receptor blockade with rimonabant attenuates shock caused by extreme hemorrhage,24 endotoxemia,25 or myocardial infarction26 may prompt human clinical trials in the near future. CB1 receptor blockade may also be useful in the treatment of the vasodilatory state and chronic hypotension in patients with advanced liver disease.27
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Conclusion Rimonabant represents the first agent in a novel class of cannabinoid receptor antagonists, with potential therapeutic applications ranging from weight loss to treatment of advanced atherosclerotic disease. However, the FDA still has not approved this agent for weight loss or any other indication. Because of the extensive distribution of cannabinoid receptors throughout the adipose, gastrointestinal, and nervous systems, patients taking rimonabant may experience a variety of side effects. Most of these side effects appear not to be life threatening. However, certain populations may be at increased risk for serious adverse events, particularly psychiatric and neurologic events. Thus, there is a need for a clinical trial specifically designed to clarify this issue. Safety data from postmarketing surveillance and ongoing clinical trials may also provide insight into the risks/benefits of CB1 receptor blockade. Author Disclosures The authors who contributed to this article have disclosed the following industry relationships: Christopher P. Cannon, MD has received grant/research support from Accumetrics, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Merck & Co., Inc., sanofiaventis, and Schering-Plough Corporation. Benjamin A. Steinberg, MD, has no financial arrangement or affiliation with a corporate organization or a manufacturer of a product discussed in this supplement. 1. Eriksson KF, Lindgarde F. No excess 12-year mortality in men with impaired glucose tolerance who participated in the Mälmo Preventive Trial with diet and exercise. Diabetologia 1998;41:1010 –1016. 2. Wadden TA, Anderson DA, Foster GD. Two-year changes in lipids and lipoproteins associated with the maintenance of a 5% to 10% reduction in initial weight: some findings and some questions. Obes Res 1999;7:170 –178. 3. Aronne LJ, Isoldi KK. Cannabinoid-1 receptor blockade in cardiometabolic risk reduction: efficacy. Am J Cardiol 2007;100 (Suppl 12A): 18P–26P. 4. Flum DR, Salem L, Elrod JA, Dellinger EP, Cheadle A, Chan L. Early mortality among Medicare beneficiaries undergoing bariatric surgical procedures. JAMA 2005;294:1903–1908. 5. Buchwald H, Avidor Y, Braunwald E, Jensen MD, Pories W, Fahrbach K, Schoelles K. Bariatric surgery: a systematic review and metaanalysis. JAMA 2004;292:1724 –1737. 6. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 1990;346:561–564. 7. Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature 1993;365:61– 65. 8. Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS, de Costa BR, Rice KC. Cannabinoid receptor localization in brain. Proc Natl Acad Sci U S A 1990;87:1932–1936. 9. Bensaid M, Gary-Bobo M, Esclangon A, Maffrand JP, Le Fur G, Oury-Donat F, Soubrie P. The cannabinoid CB1 receptor antagonist SR141716 increases Acrp30 mRNA expression in adipose tissue of obese fa/fa rats and in cultured adipocyte cells. Mol Pharmacol 2003; 63:908 –914.
10. Bonz A, Laser M, Kullmer S, Kniesch S, Babin-Ebell J, Popp V, Ertl G, Wagner JA. Cannabinoids acting on CB1 receptors decrease contractile performance in human atrial muscle. J Cardiovasc Pharmacol 2003;41:657– 664. 11. Liu J, Gao B, Mirshahi F, Sanyal AJ, Khanolkar AD, Makriyannis A, Kunos G. Functional CB1 cannabinoid receptors in human vascular endothelial cells. Biochem J 2000;346:835– 840. 12. Ishac EJ, Jiang L, Lake KD, Varga K, Abood ME, Kunos G. Inhibition of exocytotic noradrenaline release by presynaptic cannabinoid CB1 receptors on peripheral sympathetic nerves. Br J Pharmacol 1996;118: 2023–2028. 13. Despres JP, Golay A, Sjostrom L. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 2005;353:2121–2134. 14. Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rossner S. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 2005;365:1389 –1397. 15. Van Gaal LF. 2-Year data from the RIO-Europe study: metabolic effects of rimonabant in overweight/obese patients. Presented at the American College of Cardiology 2005 Annual Scientific Sessions; March 6 –9, 2005; Orlando, Florida. 16. Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIONorth America: a randomized controlled trial. JAMA 2006;295:761– 775. 17. Scheen AJ, Finer N, Hollander P, Jensen MD, Van Gaal LF. Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. Lancet 2006;368: 1660 –1672. 18. US Food and Drug Administration Briefing Document, NDA 21-888. Zimulti (rimonabant) tablets, 20 mg; sanofi-aventis, Advisory Committee; June 13, 2007. Available at: www.fda.gov/ohrms/dockets/AC/ 07/briefing/2007-4306b1-fda-backgrounder.pdf. Accessed. 19. Zigmond AS, Snaith RP. The Hospital Anxiety and Depression Scale. Acta Psychiatr Scand 1983;67:361–370. 20. Strategy to Reduce Atherosclerosis Development Involving Administration of Rimonabant - The Ultrasound Study (STRADIVARIUS). Available at http://www.clinicaltrials.gov/ct/show/NCT00124332. Accessed November 15, 2007. 21. Comprehensive Rimonabant Evaluation Study of Cardiovascular Endpoints and Outcomes (CRESCENDO). Available at http://www. clinicaltrials.gov/ct/show/NCT00263042. Accessed November 15, 2007. 22. Fattore L, Spano MS, Deiana S, Melis V, Cossu G, Fadda P, Fratta W. An endocannabinoid mechanism in replapse to drug seeking: a review of animal studies and clinical perspectives. Brain Res Rev 2007;53:1– 16. Epub 2006 July 12. 23. Pacher P, Batkai S, Kunos G. The endocannabinoid system as an emerging target of pharmactherapy. Pharmacol Rev 2006;58:389 – 462. 24. Wagner JA, Varga K, Ellis EF, Rzigalinski BA, Martin BR, Kunos G. Activation of peripheral CB1 cannabinoid receptors in haemorrhagic shock. Nature 1997;390:518 –521. 25. Varga K, Wagner JA, Bridgen DT, Kunos G. Platelet- and macrophage-derived endogenous cannabinoids are involved in endotoxininduced hypotension. FASEB J 1998;12:1035–1044. 26. Wagner JA, Hu K, Bauersachs J, Karcher J, Wiesler M, Goparaju SK, Kunos G, Ertl G. Endogenous cannabinoids mediate hypotension after experimental myocardial infarction. J Am Coll Cardiol 2001;38:2048 – 2054. 27. Batkai S, Jarai Z, Wagner JA, Goparaju SK, Varga K, Liu J, Wang L, Mirshahi F, Khanolkar AD, Makriyannis A, et al. Endocannabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis. Nat Med 2001;7:827– 832.
With the growing worldwide epidemic of both obesity and diabetes mellitus (sometimes called diobesity), efforts have intensified to find novel therapies to help patients lose weight and either prevent or control diabetes and its associated cardiovascular sequelae. Weight loss is associated with favorable changes in lipid profiles and C-reactive protein, as well as with improved glycemic control and decreased mortality.1,2 However, success with behavior modification and currently available medications in achieving and sustaining even mild weight loss is limited. Manipulation of the endocannabinoid (EC) system via blockade of the cannabinoid-1 (CB1) receptor is an intriguing new approach that addresses obesity and diabetes. Rimonabant, the first such agent to act through this mechanism, has been approved in Europe and is currently under review in the United States. Its therapeutic effects are discussed elsewhere in this supplement.3 As with any medication, side effects do occur; some are related to the drug and others are part of the condition being treated. This review briefly discusses some of those side effects. Safety of Current Therapies for Obesity Although diet and exercise are the mainstays of treatment for obesity, patients frequently need additional therapies to assist in achieving or maintaining weight loss. There are several a Department of Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA; and bCardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, Massachusetts, USA. Statement of author disclosure: Please see the Author Disclosures section at the end of this article. *Address for reprints: Christopher P. Cannon, MD, Brigham and Women’s Hospital, The Thrombolysis in Myocardial Infarction (TIMI) Study, 1st Floor, 350 Longwood Avenue, Boston, Massachusetts 02115. E-mail address: [email protected].
0002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2007.10.011
approved pharmacotherapies including phentermine, which promotes satiety; sibutramine, which acts by inhibiting reuptake of norepinephrine and serotonin; and orlistat, which alters fat absorption. Phentermine and sibutramine mimic the actions of norepinephrine and effect weight loss by causing early satiety. Cardiovascular adverse effects, such as hypertension and tachycardia, limit the use of these agents, especially in patients with cardiac comorbidities. Surgical procedures, such as gastric banding or gastric bypass, are effective for sustained weight loss but are clearly invasive and associated with a significant rate of complications.4 They are generally reserved for patients with morbid obesity (body mass index ⬎40) and those with obesity-related complications.5 All current therapies appear to have some risks associated with them. Rimonabant: a Cannabinoid-1 Receptor Blocker ECs, such as arachidonoyl ethanolamine (anandamide) and 2-arachidonoyl glycerol, interact with specific G-protein– coupled receptors, CB1 and CB2 (cannabinoid-2).6,7 Rimonabant† is an antagonist of the CB1 receptor at the typical doses. The CB1 receptors are overwhelmingly distributed to the brain8 and adipose tissue,9 but they are also found in the myocardium,10 vascular endothelium,11 liver, muscle, and sympathetic nerve terminals.12 With this distribution, gastrointestinal and central nervous system side effects might be anticipated. Rimonabant in Patients with Obesity There have been 4 randomized trials in obesity, including a study specifically in overweight or obese individuals with †
Recently, an FDA Advisory Committee recommended a delay in the approval of rimonabant because of safety issues that need to be addressed in further studies. www.AJConline.org
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diabetes. The Rimonabant in Obesity (RIO) program trials were all double-blind, placebo-controlled trials that randomized patients to receive rimonabant 20 mg/day, 5 mg/ day, or a matching placebo, in addition to counseling on following a hypocaloric diet. Efficacy results are summarized elsewhere in this supplement.3 In the RIO-Lipids trial, after a 4-week placebo run-in period, obese patients with untreated hyperlipidemia were randomized to rimonabant or placebo as discussed above and observed for 1 year.13 Patients in the rimonabant group lost significantly more weight than those in the placebo group. With rimonabant 20 mg/day, 33% of patients lost ⱖ10% of their initial body weight compared with 7% of patients receiving placebo. A similarly-sized RIO-Europe trial14,15 running concurrently with RIO-Lipids enrolled obese subjects with either hypertension or hyperlipidemia. Patients were advised to follow a hypocaloric diet and were randomized to rimonabant 20 mg/day, rimonabant 5 mg/day, or placebo. The study included a 4-week run-in period, similar to the RIOLipids trial. The on-treatment analysis of its results showed that after a full year of therapy, treatment with rimonabant 5 mg/day or 20 mg/day was associated with significantly greater waist circumference reduction than placebo (reductions of 6.5 cm for the 20-mg dose, 3.9 cm for the 5-mg dose, and 2.4 cm for placebo). There were favorable changes in the lipid profile of subjects in both rimonabant groups: triglyceride levels decreased and high-density lipoprotein (HDL) levels increased, which may have been mediated by increased levels of adiponectin. The 2-year results from RIO-Europe demonstrate a substantial decrease in the proportion of subjects with metabolic syndrome with the combination of a hypocaloric diet and rimonabant 20 mg/day: 42.2% at baseline, 19.6% at 1 year,14 and 21.5% at 2 years.15 The RIO–North America trial16 used criteria similar to those in the other RIO trials, but after 1 year of treatment with rimonabant or placebo the trial randomized its subjects to another year of therapy or to matching placebo. Whereas the first-year outcomes were similar to those in other RIO trials, subjects who completed only 1 year of rimonabant treatment and were then randomized to placebo regained much of the lost weight during the period in which they were not taking the drug. Average weight loss for patients receiving rimonabant for the full 2 years was 7.4 kg; those taking placebo for 2 years lost 2.3 kg; and those taking rimonabant for 1 year followed by placebo lost 3.2 kg. Consistent with the other RIO trials, rimonabant therapy at the 20-mg/day dose was associated with an increase in HDL of 25%.
standard oral hypoglycemic regimen was continued throughout the study. At the end of 1 year of therapy, subjects in the high-dose rimonabant group lost significantly more weight than those in the placebo group (5.3 kg vs 1.5 kg, respectively). Average HbA1c levels decreased by 0.6% in the high-dose rimonabant group but increased in the placebo group by 0.1%. By the end of the study, 43% of all subjects treated with rimonabant were able to achieve an optimal HbA1c level of ⬍6.5% compared with 21% of those receiving placebo. Adverse Effects in Clinical Trials of Rimonabant Clinical experience with rimonabant in the setting of phase 3 clinical trials involves approximately 6,500 obese patients to date and is rapidly growing. It suggests that the drug is generally well tolerated. In the RIO phase 3 program, the 1-year dropout rates were consistently in the 36%– 49% range13,15–17 but did not differ from placebo. Relatively high dropout rates are characteristic of weight loss trials. The most common adverse effects were mild nausea (11.2%– 12.9%) and diarrhea (5.3%–7.2%) in the high-dose (20 mg) rimonabant groups. The rates of discontinuation attributable to adverse effects were 12.8%–15% for rimonabant compared with 5%–9.2% for placebo. Because of the EC physiology, potential neuropsychiatric adverse effects of rimonabant have been carefully assessed in clinical trials conducted to date. In each of the RIO trials, the incidence of psychiatric adverse events was higher in the rimonabant groups compared with placebo, and it increased with higher doses of rimonabant. However, the absolute incidence of the most common psychiatric side effects was 1.2%– 5.2% for depressed mood, 5.0%– 8.7% for anxiety, 5.8%– 6.4% for insomnia, and 5.6%–10.4% for dizziness (at the highest studied dose of rimonabant, 20 mg). Also of particular interest are the rates of adverse cardiovascular events in the treatment groups. The RIO-Lipids trial reported 1 patient in the placebo group with an adverse vascular event and 3 patients in the rimonabant groups with adverse cardiac events (5 mg: n ⫽ 2; 20 mg: n ⫽ 1).13 In the RIO-Diabetes trial, 2 patients in the rimonabant 20-mg group discontinued study medication because of chest pain.17 The RIO–North America trial noted no differences in change in the corrected QT interval over time and did not report any adverse cardiovascular events.16 In RIO-Europe, no patients in the placebo group had serious vascular or cardiac adverse events, whereas 2 patients each in the rimonabant 5-mg and 20-mg groups experienced cardiac events, and 2 patients in the 5-mg and 3 in the 20-mg rimonabant groups experienced vascular adverse events.14
Rimonabant in Patients with Diabetes The latest component of the RIO program was the RIO-Diabetes trial,17 which examined the effects of rimonabant on glucose control in obese subjects with type 2 diabetes with an average baseline glycosylated hemoglobin (HbA1c) of 7.3%. A
Pooled Safety Data from the Rimonabant in Obesity Program Overall, although study drug discontinuation rates were 32%– 49% for both the placebo and rimonabant groups in
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Table 1 Psychiatric events reported by patients randomized to rimonabant 20 mg without crossover
Total patients reporting symptom, n (%) Adverse events, n (%)* Anxiety Insomnia Depressed mood Depression Stress Nervousness Depressive symptom Sleep disorder Nightmare Panic attack Mood alteration Major depression Mood swings Agitation Affect lability Aggression Abnormal dreams Affective disorder Decreased libido
Placebo (n ⫽ 1,602)
Rimonabant 5 mg (n ⫽ 2,220)
Rimonabant 20 mg (n ⫽ 2,176)
226 (14.1)
356 (16.0)
569 (26.2)
40 (2.50) 53 (3.31) 45 (2.81) 23 (1.44) 28 (1.75) 5 (0.31) 12 (0.75) 7 (0.44) 3 (0.19) 1 (0.06) 4 (0.25) 5 (0.31) 2 (0.12) 2 (0.12) 1 (0.06) 1 (0.06) 2 (0.12) 3 (0.19) 6 (0.37)
68 (3.06) 66 (2.97) 66 (2.97) 55 (2.48) 35 (1.58) 14 (0.63) 15 (0.68) 13 (0.59) 4 (0.18) 3 (0.14) 5 (0.23) 5 (0.23) 11 (0.50) 5 (0.23) 7 (0.32) 6 (0.27) 1 (0.045) 1 (0.04) 4 (0.18)
131 (6.02) 118 (5.42) 83 (3.81) 74 (3.40) 38 (1.75) 31 (1.42) 23 (1.06) 21 (0.97) 21 (0.97) 18 (0.83) 15 (0.69) 15 (0.69) 10 (0.46) 10 (0.46) 10 (0.46) 9 (0.41) 8 (0.37) 7 (0.32) 6 (0.28)
*Data are shown in decreasing order of frequency. Adapted from US Food and Drug Administration Briefing Document.18
Figure 1. Relative risks (RR) of depressive and anxiety disorder symptoms in Rimonabant in Obesity (RIO) trial subjects receiving both rimonabant 20 mg and placebo. CI ⫽ confidence interval; OBE(DB) ⫽ RIO-Diabetes; OBE(EU) ⫽ RIO-Europe; OBE(LP) ⫽ RIO-Lipids; OBE(NA) ⫽RIO–North America. (Adapted from US Food and Drug Administration Briefing Document.18)
the RIO program, they were attributed to adverse events in ⬍33% of cases. Because of the known potential of rimonabant for neuropsychiatric effects, specific attention has been focused on the detection of these disorders. Recently, the US Food and Drug Administration (FDA) performed a safety review of the RIO program.18 It pooled the adverse events reported in each of the RIO studies to summarize the current data. For patients not randomized to any crossover within the studies, 26% in the rimonabant 20-mg groups, compared with 14% in the placebo groups, experienced and reported psychiatric effects. Such symptoms and disorders are gauged on a standardized self-assessment scale, the Hospital Anxiety and Depression Scale (HADS).19 Summarized data on psychiatric events reported by patients randomized to rimonabant 20 mg without crossover are shown in Table 1.
A more in-depth review of trial source documentation by the manufacturer of rimonabant, sanofi-aventis, yielded additional symptoms of both depressive disorders and anxiety disorders in trial subjects receiving both rimonabant 20 mg and placebo. Using these more comprehensive rates of psychiatric side effects, the relative risks of such symptoms (for rimonabant 20 mg vs placebo) were calculated by the FDA (Figure 1). Based on these pooled analyses, the relative risk for reported psychiatric adverse events was significantly higher for patients taking 20 mg rimonabant compared with those taking placebo (relative risk, 1.9; 95% confidence interval [CI], 1.5–2.3). Although the increased risk for such symptoms is of concern, an effort was also made to identify further the severity of such symptoms. In response to such a request from the FDA, the manufacturer enlisted the help of Kelly
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Table 2 Summary of patients and suicidality based on Columbia University report for the US Food and Drug Administration (FDA) Classification
Placebo (n ⫽ 2,909)
Rimonabant 5 mg (n ⫽ 5,121)
Rimonabant 20 mg (n ⫽ 6,802)
Complete suicide Suicide attempt Preparatory acts toward suicide Suicidal ideation Self-injurious behavior, intent unknown Not enough information (fatal) Not enough information (nonfatal)
— 7 — 13 — — —
— — 1 6 — 1 —
— 4 — 39 — — 3
Adapted from FDA Briefing Document.18
Figure 2. Columbia University analysis of suicidality events. Odds ratios (OR) are shown for the occurrence of a suicide attempt in all available clinical trial data, including rimonabant trials for treatment of obesity. *Rimonabant 20 mg was compared with active comparator (5 mg) for analysis because there was no placebo (Plb) arm in the first randomization. ACT4855 ⫽ ACTOL; CI ⫽ confidence interval; EFC4474 ⫽ Studies with Rimonabant and Tobacco (STRATUS)–Europe; EFC4796 ⫽ Studies with Rimonabant and Tobacco (STRATUS)–WW; EFC4964 ⫽ Studies with Rimonabant and Tobacco (STRATUS)–US; EFC5794 ⫽ Studies with Rimonabant and Tobacco (STRATUS)–META; NA ⫽ not available; OBE ⫽ obese; OBE(BED) ACT3801 ⫽ CRAVING; OBE(CRA) EFC5031 ⫽ REBA; OBE(DIA) EFC4736 ⫽ Rimonabant in Obesity (RIO)–Diabetes; OBE(DIA) EFC5825 ⫽ Study Evaluating Rimonabant Efficacy in Drug-Naive Diabetic Patients (SERENADE); OBE(EUR) EFC4733 ⫽ Rimonabant in Obesity (RIO)–EUROPE; OBE(LIP) EFC4735 ⫽ Rimonabant in Obesity (RIO)–LIPIDS; OBE(N.A.) EFC4743 ⫽ Rimonabant in Obesity (RIO)–North America; OBE(Ph2) DRI3388 ⫽; SCHIZOPH ⫽ schizophrenia; METATRI ⫽ METATRIAL. (Adapted from US Food and Drug Administration Briefing Document.18)
Posner and colleagues18 at Columbia University. They were able to identify a subset of patients with advanced psychiatric symptoms, including suicidal ideation and even suicide attempts (although no completed suicides), as shown in Table 2. Although suicidal ideation was more common in the rimonabant groups (20 mg: n ⫽ 39; 5 mg: n ⫽ 6; placebo: n ⫽ 13), more suicide attempts were made in the placebo group. Once again, in an effort to quantify the risk of such serious events for patients taking rimonabant, odds ratios (ORs) were calculated for the occurrence of a suicide attempt, not only in the obesity trials of rimonabant but also in all available clinical trial data. Results from the Columbia University analysis are shown in Figure 2. Importantly, the overall OR for incidence of suicidality in the rimonabant 20-mg group compared with the placebo group was 1.9 (95% CI, 1.1–3.1). However, this included
data from trials of patients with schizophrenia as well as those abusing alcohol (2 groups with known suicidality rates higher than those of the general population), and when the analysis was restricted to only the 7 trials of obese patients, the overall OR was 1.8 (95% CI, 0.8 –3.8). To add perspective to these rates, the FDA obtained prescription rates for both weight loss medications and antidepressants. Of the ⬎500,000 patients who received a prescription for a weight loss agent in 2004 –2006, approximately 30% also received concurrent prescriptions for antidepressants, indicating a potential source of confounding in these data.18 With regard to neurologic effects, the distribution of CB1 receptors throughout the brain may place patients at risk not only for psychiatric effects but also potentially for neurologic adverse events. A similar pooled analysis of neurologic adverse events in the RIO trials was performed by the FDA (Table 3).18
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Table 3 Neurologic adverse events in the Rimonabant in Obesity trials, based on pooled data analysis by the US Food and Drug Administration (FDA) Characteristic
Placebo (n ⫽ 1,602)
Rimonabant 5 mg (n ⫽ 2,220)
Rimonabant 20 mg (n ⫽ 2,176)
Total subjects reporting symptoms, n (%)* Neurologic adverse events, n (%)* ● Neurologic disorders NEC Dizziness Paresthesia Hypoesthesia ● Headaches Headache Migraine ● Mental impairment disorders —Memory impairment —Disturbance in attention —Amnesia ● Spinal cord and nerve root disorders —Sciatica ● Movement disorders (including parkinsonism) —Tremor ● Peripheral neuropathies
391 (24.4)
535 (24.1)
596 (27.4)
151 (9.4) 89 (5.56) 17 (1.06) 14 (0.87) 247 (15.4) 203 (12.67) 31 (1.94) 21 (1.3) 7 (0.44) 10 (0.62) 8 (0.50) 15 (0.94) 10 (0.62) 1 (0.06) 0 19 (1.19)
227 (10.2) 138 (6.22) 23 (1.04) 32 (1.44) 287 (12.9) 225 (10.14) 43 (1.94) 26 (1.2) 14 (0.63) 2 (0.09) 8 (0.36) 29 (1.3) 23 (1.04) 8 (0.36) 6 (0.27) 29 (1.31)
311 (14.3) 186 (8.55) 37 (1.70) 31 (1.42) 266 (12.2) 220 (10.11) 36 (1.65) 45 (2.1) 16 (0.74) 15 (0.69) 14 (0.64) 31 (1.4) 27 (1.24) 24 (1.1) 21 (0.97) 21 (0.97)
NEC ⫽ not elsewhere classified. *Data are for subjects receiving the same treatment during the entire study. Adapted from FDA Briefing Document.18
Although the absolute event rates are similar across treatment arms, the pooled relative risk of neurologic symptoms for patients receiving rimonabant 20 mg compared with placebo was 1.7 (95% CI, 1.1–2.7).18 Special attention has also been paid to the incidence of seizures in patients taking rimonabant, particularly because cannabinoids (agonists) have been known to have antiepileptic properties, although thus far no apparent increase has been seen in the individual trials.
Preliminary Postmarketing Surveillance Safety Data Rimonabant has been approved in 42 countries and marketed in 20. The manufacturer estimates that ⬎78,000 patients have been exposed to rimonabant as of November 30, 2006.18 During the first postapproval surveillance summary of data from June 19, 2006, to December 18, 2006, sanofi-aventis reported receiving 918 cases totaling 2,362 adverse events. Nearly half of the reported events were gastrointestinal, consisting of nausea (47.4%), diarrhea (16.8%), and vomiting (10.2%). Approximately 1 in 10 were psychiatric events: anxiety (10.7%), depressed mood (10.7%), depression (10.3%), and insomnia (7.3%). Neurologic adverse events were also reported, including dizziness (27.6%), headache (17.8%), paresthesia (5.7%), tremor (5.1%), somnolence (4.4%), amnesia (4.0%), and attention disturbance (3.7%).
Future Potential Therapeutic Applications Therapy with rimonabant induces significant, favorable changes in an individual’s cardiometabolic risk profile as ev-
idenced by weight loss, higher serum HDL and lower triglyceride levels, and improved glycemic control. It is not yet known, however, whether these alterations have any effect on the progression of atherosclerosis. This question is being directly addressed by the Strategy to Reduce Atherosclerosis Development Involving Administration of Rimonabant—the Intravascular Ultrasound Study (STRADIVARIUS),20 which will enroll obese subjects with 20%–50% coronary artery stenosis diagnosed during clinically relevant coronary angiography. Subjects will be randomized to rimonabant or placebo and will undergo repeat angiography after 18 months of treatment, with the primary end point being change in the volume of the index atheroma as measured by intravascular ultrasound. A large clinical end points trial—the Comprehensive Rimonabant Evaluation Study of Cardiovascular Endpoints and Outcomes (CRESCENDO)—is also being conducted to determine whether long-term treatment with rimonabant could reduce the risk for cardiovascular events.21 Animal experiments demonstrated that CB1 receptor blockade attenuates cue reactivity and reduces drug-seeking behavior across the wide spectrum of addictive substances.22 Subsequently, the National Institutes of Health (NIH) are sponsoring a phase 2 trial that will test whether therapy with rimonabant would be a useful adjunct in reducing alcohol consumption.23 Animal experiments that show that CB1 receptor blockade with rimonabant attenuates shock caused by extreme hemorrhage,24 endotoxemia,25 or myocardial infarction26 may prompt human clinical trials in the near future. CB1 receptor blockade may also be useful in the treatment of the vasodilatory state and chronic hypotension in patients with advanced liver disease.27
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Conclusion Rimonabant represents the first agent in a novel class of cannabinoid receptor antagonists, with potential therapeutic applications ranging from weight loss to treatment of advanced atherosclerotic disease. However, the FDA still has not approved this agent for weight loss or any other indication. Because of the extensive distribution of cannabinoid receptors throughout the adipose, gastrointestinal, and nervous systems, patients taking rimonabant may experience a variety of side effects. Most of these side effects appear not to be life threatening. However, certain populations may be at increased risk for serious adverse events, particularly psychiatric and neurologic events. Thus, there is a need for a clinical trial specifically designed to clarify this issue. Safety data from postmarketing surveillance and ongoing clinical trials may also provide insight into the risks/benefits of CB1 receptor blockade. Author Disclosures The authors who contributed to this article have disclosed the following industry relationships: Christopher P. Cannon, MD has received grant/research support from Accumetrics, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Merck & Co., Inc., sanofiaventis, and Schering-Plough Corporation. Benjamin A. Steinberg, MD, has no financial arrangement or affiliation with a corporate organization or a manufacturer of a product discussed in this supplement. 1. Eriksson KF, Lindgarde F. No excess 12-year mortality in men with impaired glucose tolerance who participated in the Mälmo Preventive Trial with diet and exercise. Diabetologia 1998;41:1010 –1016. 2. Wadden TA, Anderson DA, Foster GD. Two-year changes in lipids and lipoproteins associated with the maintenance of a 5% to 10% reduction in initial weight: some findings and some questions. Obes Res 1999;7:170 –178. 3. Aronne LJ, Isoldi KK. Cannabinoid-1 receptor blockade in cardiometabolic risk reduction: efficacy. Am J Cardiol 2007;100 (Suppl 12A): 18P–26P. 4. Flum DR, Salem L, Elrod JA, Dellinger EP, Cheadle A, Chan L. Early mortality among Medicare beneficiaries undergoing bariatric surgical procedures. JAMA 2005;294:1903–1908. 5. Buchwald H, Avidor Y, Braunwald E, Jensen MD, Pories W, Fahrbach K, Schoelles K. Bariatric surgery: a systematic review and metaanalysis. JAMA 2004;292:1724 –1737. 6. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 1990;346:561–564. 7. Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature 1993;365:61– 65. 8. Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS, de Costa BR, Rice KC. Cannabinoid receptor localization in brain. Proc Natl Acad Sci U S A 1990;87:1932–1936. 9. Bensaid M, Gary-Bobo M, Esclangon A, Maffrand JP, Le Fur G, Oury-Donat F, Soubrie P. The cannabinoid CB1 receptor antagonist SR141716 increases Acrp30 mRNA expression in adipose tissue of obese fa/fa rats and in cultured adipocyte cells. Mol Pharmacol 2003; 63:908 –914.
10. Bonz A, Laser M, Kullmer S, Kniesch S, Babin-Ebell J, Popp V, Ertl G, Wagner JA. Cannabinoids acting on CB1 receptors decrease contractile performance in human atrial muscle. J Cardiovasc Pharmacol 2003;41:657– 664. 11. Liu J, Gao B, Mirshahi F, Sanyal AJ, Khanolkar AD, Makriyannis A, Kunos G. Functional CB1 cannabinoid receptors in human vascular endothelial cells. Biochem J 2000;346:835– 840. 12. Ishac EJ, Jiang L, Lake KD, Varga K, Abood ME, Kunos G. Inhibition of exocytotic noradrenaline release by presynaptic cannabinoid CB1 receptors on peripheral sympathetic nerves. Br J Pharmacol 1996;118: 2023–2028. 13. Despres JP, Golay A, Sjostrom L. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 2005;353:2121–2134. 14. Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rossner S. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 2005;365:1389 –1397. 15. Van Gaal LF. 2-Year data from the RIO-Europe study: metabolic effects of rimonabant in overweight/obese patients. Presented at the American College of Cardiology 2005 Annual Scientific Sessions; March 6 –9, 2005; Orlando, Florida. 16. Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIONorth America: a randomized controlled trial. JAMA 2006;295:761– 775. 17. Scheen AJ, Finer N, Hollander P, Jensen MD, Van Gaal LF. Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. Lancet 2006;368: 1660 –1672. 18. US Food and Drug Administration Briefing Document, NDA 21-888. Zimulti (rimonabant) tablets, 20 mg; sanofi-aventis, Advisory Committee; June 13, 2007. Available at: www.fda.gov/ohrms/dockets/AC/ 07/briefing/2007-4306b1-fda-backgrounder.pdf. Accessed. 19. Zigmond AS, Snaith RP. The Hospital Anxiety and Depression Scale. Acta Psychiatr Scand 1983;67:361–370. 20. Strategy to Reduce Atherosclerosis Development Involving Administration of Rimonabant - The Ultrasound Study (STRADIVARIUS). Available at http://www.clinicaltrials.gov/ct/show/NCT00124332. Accessed November 15, 2007. 21. Comprehensive Rimonabant Evaluation Study of Cardiovascular Endpoints and Outcomes (CRESCENDO). Available at http://www. clinicaltrials.gov/ct/show/NCT00263042. Accessed November 15, 2007. 22. Fattore L, Spano MS, Deiana S, Melis V, Cossu G, Fadda P, Fratta W. An endocannabinoid mechanism in replapse to drug seeking: a review of animal studies and clinical perspectives. Brain Res Rev 2007;53:1– 16. Epub 2006 July 12. 23. Pacher P, Batkai S, Kunos G. The endocannabinoid system as an emerging target of pharmactherapy. Pharmacol Rev 2006;58:389 – 462. 24. Wagner JA, Varga K, Ellis EF, Rzigalinski BA, Martin BR, Kunos G. Activation of peripheral CB1 cannabinoid receptors in haemorrhagic shock. Nature 1997;390:518 –521. 25. Varga K, Wagner JA, Bridgen DT, Kunos G. Platelet- and macrophage-derived endogenous cannabinoids are involved in endotoxininduced hypotension. FASEB J 1998;12:1035–1044. 26. Wagner JA, Hu K, Bauersachs J, Karcher J, Wiesler M, Goparaju SK, Kunos G, Ertl G. Endogenous cannabinoids mediate hypotension after experimental myocardial infarction. J Am Coll Cardiol 2001;38:2048 – 2054. 27. Batkai S, Jarai Z, Wagner JA, Goparaju SK, Varga K, Liu J, Wang L, Mirshahi F, Khanolkar AD, Makriyannis A, et al. Endocannabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis. Nat Med 2001;7:827– 832.