Risk Factors

Is “metabolic syndrome” really a syndrome, or a collection of individual risk factors?

The metabolic syndrome is more than a simple random cluster of risk factors. The conditions presented in the syndrome (dyslipidemia, glucose intolerance, insulin resistance, central obesity and hypertension) co-occur in an individual more often than might be expected by chance, suggesting the existence of a unique pathophysiologic condition. When grouped together as in the Adult Treatment Panel III (ATP III) definition of the metabolic syndrome, the individual risk factors are associated with an increased cardiometabolic risk. Specifically, the diagnosis of the metabolic syndrome is associated with an increased risk for cardiovascular disease and mortality, even after adjustment for conventional risk factors. Similarly, metabolic syndrome identifies individuals at high risk of developing type 2 diabetes.

Can insulin resistance be detected prior to an abnormal fasting blood sugar (FBS) level or glucose tolerance test (GTT)?

Increased waist circumference, one component of the metabolic syndrome, is a good predictor of insulin resistance, explaining more than 50% of the variation in insulin sensitivity in both sexes. The addition of other metabolic syndrome components (hypertension and increased triglycerides, for example, are associated with increased insulin resistance) increases our ability to identify people with insulin resistance.

Is microalbuminuria a risk factor?

Microalbuminuria is considered an important risk factor and is part of the World Health Organization (WHO) metabolic syndrome definition. The National Cholesterol Education Program (NCEP)/ATP III definition does not include microalbuminuria in the metabolic syndrome definition.

Is waist circumference the best measurement for adiposity?

Waist circumference is the best measurement of central adiposity, and central adiposity is one of the most important determinants of cardiometabolic risk.

How much does the waist circumference need to be reduced in order to reduce cardiometabolic risk factors?

Each 1-cm reduction in waist circumference reduces the risk of cardiovascular disease by 2% to 6% in both men and women.

Rimonabant Trial Results

What is the length of rimonabant therapy in the Rimonabant in Obesity (RIO) trials?

In the RIO-Lipids the length of therapy with rimonabant was 12 months. In the RIO-North America (NA) and RIO-Europe, after a run-in period of 4 weeks, the patients were treated for 1 year. After the first year of treatment, the patients were re-randomized for an additional 1 year of treatment. Therefore subjects received from 1 to 2 years of treatment, depending on the treatment allocation.

What dosages were studied?

In all RIO trials (RIO-Lipids, RIO-NA and RIO-Europe) 5-mg and 20-mg doses were used.

How long will weight loss be maintained once rimonabant therapy is discontinued?

After discontinuing rimonabant therapy, patients regained the lost weight, on average returning to their previous weight and waist circumference measurements over the next year after treatment discontinuation.

What is the maximum weight loss to be expected with rimonabant?

About 50% of the patients in the 20-mg rimonabant group lost 5% to 10% of body weight and about 25% of the  patients achieved a weight reduction of 10% or greater. The mean weight reduction was about 4 kg to 5 kg in the 20-mg group and about 1 to 2 kg in the 5-mg group. An average reduction of 3 cm to 4 cm of waist circumference can be expected in the 20-mg treatment group.

The clinical trials show that rimonabant has favorable effects on lipids and lipoprotein profiles. Are there any effects on markers of vascular inflammation such as C-reactive protein (CRP)?

CRP, a recognized cardiometabolic risk factor and marker of inflammation, was evaluated in the RIO-Lipids trial. In the RIO-Lipids trial the CRP level decreased by 0.9mg/L (baseline ~5.0mg/L) in the 20-mg rimonabant group.                              

What are the consistent findings in all the RIO trails?

Rimonabant consistently reduces body weight and waist circumference, increases high-density lipoprotein (HDL) cholesterol, decreases triglycerides and total cholesterol/HDL cholesterol ratios.  The percentage of ‘responders’ is consistently high with about 50% of the patients taking 20 mg of  rimonabant losing 5% to 10% of body weight and about 25% of the  patients achieving a weight reduction of 10% or greater.

Are there any trials that looked at rimonabant and smoking cessation?

The STRATUS (STudies with Rimonabant And Tobacco USe)-US trial looked at the effect of rimonabant in smoking cessation and weight gain control in smokers motivated to quit. By the end of the study the abstinence rates in the 20-mg rimonabant group was 36% compared with 20% in the 5-mg and  21% in the placebo group. The weight gain was significantly lower in the 20-mg group compared with placebo. These are preliminary results, as the final report has not yet been published.

Safety and Side Effects

What is the long-term safety of rimonabant 20 mg?

Most of the adverse effects (AEs) of rimonabant are transient, occurring mainly in the first months of treatment. The overall rates of AEs were lower after 2 years of treatment than after the first year, with no differences in overall rates among treated and untreated patients.

What are the major side effects observed in the clinical trials?

The most common AEs observed in the RIO-Europe trial were nausea, dizziness, arthralgia, and diarrhea; in the RIO-NA trial the most common AEs were upper respiratory tract infection, nasopharingitis, nausea, arthralgia, and influenza. 

The AEs leading to study withdrawal in both RIO-NA and RIO-Europe were depressed mood disorders, nausea, vomiting, diarrhea, headache, dizziness, and anxiety. AEs leading to discontinuation and categorized as ‘psychiatric disorders’ were more frequent in the rimonabant-treated patients—42 patients of 599 treated with 20 mg rimonabant versus 16 of 305 patients treated with placebo.

Why were the discontinuation rates so high?

To date, most phase 3 obesity pharmacotherapy studies have high drop-out rates. The drop-out rate in RIO-NA of about 50% was similar to previous phase 3 obesity pharmacotherapy studies.  Drop out rates in the orlistat pivotal trial and the sibutramine pivotal were very similar. 

What are the potential neurologic and psychiatric side effects of rimonabant?

Based on the published data (RIO-NA and RIO-Europe) potential neurologic side effects of rimonabant are headache and dizziness; the potential psychiatric disorders are depressed mood (depression, major depression, depressed mood, and depressive symptoms), anxiety, agitation, irritability, and sleep disorders.  Obviously, the final US package labeling is not yet available.

Does rimonabant cause depression?

The Hospital Anxiety and Depression (HAD) scale was used to evaluate mood in the RIO trials. No significant changes in the HAD scale subscores for depression or anxiety were noted in the rimonabant-treated patients. See the question above on AEs.