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Classical and emerging risk factors increase cardiometabolic risk

We have understood for decades the roles of ‘classical’ risk factors – elevated
LDL-C, hypertension, dysglycaemia and smoking – in the pathogenesis of cardiovascular disease. More recent research is continuing to define the contribution of emerging risk factors to the risk of developing type 2 diabetes and cardiovascular disease, particularly in the setting of insulin resistance. Abdominal obesity is associated with multiple cardiometabolic risk factors such as atherogenic dyslipidaemia (hypertriglyceridaemia and low HDL-C), dysglycaemia and inflammation, which are major drivers of cardiovascular disease and type 2 diabetes. In addition, atherosclerosis is increasingly regarded as an inflammatory condition.

Gelfand EV et al. Rimonabant: a cannabinoid receptor type 1 blocker for management of multiple cardiometabolic risk factors. J Am Coll Cardiol 2006: 47(10): 1919-26

Vasudevan AR, Ballantyne C et al, Cardiometabolic risk assessment: an approach to the prevention of cardiovascular disease and diabetes mellitus. Clin Cornerstone 2005; 7(2-3): 7-16.

Intra-abdominal adiposity (IAA) is a major contributor to increased cardiometabolic risk

This slide summarises the relationships between intra-abdominal adiposity (IAA) and increased cardiometabolic risk. Intra-abdominal adiposity drives the progression of multiple risk factors directly, through the secretion of excess free fatty acids and inflammatory adipokines, and decreased secretion of adiponectin. The important contributions of IAA to dyslipidaemia and insulin resistance provide an indirect, though clinically important, link to the genesis and progression of atherosclerosis and cardiovascular disease.

The location of excess IAA is an important determinant of cardiometabolic risk. IAA is associated with insulin resistance, hyperglycaemia, dyslipidaemia, hypertension, and prothrombotic/proinflammatory states. Excess IAA typically is accompanied by elevated levels of C-reactive protein (CRP) and free fatty acids (FFAs), as well as decreased levels of adiponectin. Elevated CRP is an indicator of inflammation. Abdominal obesity has been shown to be associated with the inflammation cascade, with adipose tissue expressing a number of inflammatory cytokines. Inflammation is now believed to play a role in the development of atherosclerosis and type 2 diabetes. Elevated levels of CRP are considered to be predictive of cardiovascular disease and insulin resistance.

Elevated FFA levels appear to play a significant role in the cause of insulin resistance. It has been suggested that elevated FFAs and intracellular lipids inhibit the insulin signaling mechanism, leading to decreased glucose transport to muscle. FFAs also play a mediating role between insulin resistance and B-cell dysfunction, indicating that a reduction in FFA level could be a desirable therapeutic target.

Adiponectin is an adipose tissue-specific circulating protein which is involved in the regulation of lipid and glucose metabolism. Adiponectin has been shown to be reduced in adults with obesity and type 2 diabetes. In non-diabetics, hypertriglyceridaemia and low HDL-C have been shown to be associated with low plasma adiponectin concentrations.

All of these components help to explain why excess abdominal adiposity is considered a great threat to cardiovascular and metabolic health.

Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 2004;89:2548–2556.

Lee YH, Pratley RE. The evolving role of inflammation in obesity and the metabolic syndrome. Curr Diab Rep 2005;5:70–75.

Boden G, Shulman GI. Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and beta-cell dysfunction. Eur J Clin Invest 2002;32:14–23.

Central and peripheral targets of ECS and effects of overactivity

CB1 receptors have been shown to play an important role in energy balance and are directly implicated in lipid and glucose metabolism. CB1 receptors are located centrally in the brain, and peripherally in adipose tissue, liver, skeletal muscle and the gastrointestinal tract.

In the brain, the hypothalamus plays a principal role in the control of feeding and regulation of body weight, and CB1 receptor stimulation leads to dopamine release in the nucleus accumbens shell, which increases motivation to eat. These effects result in increased food intake and fat accumulation.

Peripherally, ECS promotes lipogenesis at the level of adipose tissue and the liver. ECS activity in the gastrointestinal tract interferes with feelings of satiety, and CB1 receptor stimulation of skeletal muscle decreases glucose uptake. All of these central and peripheral effects indicate that an overactivated ECS could contribute to the increased risk of atherogenic dyslipidaemia (low HDL-C, high triglycerides), insulin resistance, glucose intolerance and increased cardiometabolic risk.

Bensaid M, Gary-Bobo M, Esclangon A, et al. 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;63:908–14.

Pagotto U, Vicennati V, Pasquali R. The endocannabinoid system and the treatment of obesity. Ann Med 2005;37:270–275.

Osei-Hyiaman D, DePetrillo M, Pacher P, et al. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest 2005;115:1298–1305.

Di Marzo V, Matias I. Endocannabinoid control of food intake and energy balance. Nature Neurosci 2005;8:585–589.

Liu YL, Connoley IP, Wilson CA, Stock MJ. Effects of the cannabinoid CB1 receptor antagonist SR141716 on oxygen consumption and soleus muscle glucose uptake in Lep(ob)/Lep(ob) mice. Int J Obes Relat Metab Disord 2005;29:183–187.

Sites of CB1 receptors and potential effects of CB1 receptor blockade

CB1 receptor expression is widespread centrally and peripherally in brain, adipose tissue, muscle, liver and the gastrointestinal tract (Di Marzo V, 2001; Ravinet Trillou C, 2003; Cota D, 2003; Pagotto U, 2005; Van Gaal L, 2005; Liu Y 2005; Osei-Hyiaman D 2005; Massa F, 2005 ). The ECS acts centrally in the hypothalamus to influence orexigenic drive and has been shown to interact with other hypothalamic neuropeptides known to be involved in the regulation of energy balance and lipid and glucose metabolism (Di Marzo V, 2001; Cota D, 2003).

The ECS also acts peripherally to enhance lipoprotein lipase activity in adipose tissue7, increasing glucose uptake in skeletal muscle6. Emerging evidence that CB1 receptors are also present in liver and skeletal muscle and contribute to the peripheral metabolic activity of the ECS.

Clinical trials have demonstrated the potential of selective CB1 blockade* to address the unmet clinical needs of the next decade in addressing multiple cardiometabolic risk factors. (*in vitro and animal data may not necessarily correlate with clinical results).

Di Marzo M et al. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 2001;410:822-5.

Ravinet Trillou C, Arnone M, Delgorge C et al. Anti-obesity effect of SR141716, a CB1 receptor antagonist, in diet-induced obese mice. Am J Physiol Regul Integr Comp Physiol 2003;284:R345–53.

Cota D, Marsicano G, Lutz B et al. Endogenous cannabinoid system as a modulator of food intake. Int J Obes Relat Metab Disord 2003;27:289–301.

Pagotto U, Pasquali R. Fighting obesity and associated risk factors by antagonising cannabinoid type 1 receptors. Lancet 2005;365:1363–4.

Van Gaal L et al. 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; 365:1389–97.

Liu YL et al. Effects of the cannabinoid CB1 receptor antagonist SR141716 on oxygen consumption and soleus muscle glucose uptake in Lepob/Lepob mice. Int J Obes Relat Metab Disord. 2005;29:183–187;

Osei-Hyiaman D, DePetrillo M, Pacher P et al. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest 2005;115:1298–1305

Massa F et al. The endocannabinoid system in the physiology and pathophysiology of the gastrointestinal tract. J Mol Med 2005 [e-pub ahead of print]

Rimonabant in overweight/obesity

Four studies including over 6,600 patients:

RIO North America and RIO Europe included patients with BMI ≥30, or BMI >27 with comorbidity (i.e. treated or untreated hypertension and/or treated or untreated dyslipidaemia)

•Within the RIO North America trial, patients were re-randomized at 1 year to remain on the same dose, or switch to placebo

•RIO North America assessed weight change at 1-year, and prevention of weight regain at year 2. Waist circumference, dyslipidaemia and insulin resistance (HOMA) were also evaluated

•RIO Europe assessed the same parameters as RIO North America except weight maintenance instead of prevention of weight regain at year 2 in addition to the same parameters as RIO North America

In addition to the described parameters, RIO Lipids assessed, specific atherogenic parameters such as adiponectin levels, LDL particle size and density and CRP

RIO Diabetes was conducted in overweight/obese patients with type 2 diabetes receiving oral antidiabetic drug monotherapy, either metformin or sulphonylureas. Primary end points are the same as for other RIO studies. Other parameters were evaluated such as HbA1c, fasting and post prandial glucose and insulin sensitivity, dose of antidiabetic agents and lipid parameters

Van Gaal L et al. Effects of the cannabinoid-1-receptor blocker rimonabant on weight from the RIO-Europe study. Lancet 2005;365:1389-97

Despres J-P et al. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 2005;353: 2121-2134.

Pi-Sunyer FX et al. Effects of rimonabant, a cannabinoid-1 receptor blocker on weight and cardiometabolic risk factors in overweight or obese patients RIO-North America: A randomized controlled trial. J Am Med Assoc 2006:295: 761-775

Weight and waist: the consistency of RIO results

Overall the results for weight and waist are consistent in the four studies, when examining the placebo-subtracted effect of rimonabant 20 mg. Rimonabant clearly shows a benefit on weight management and treatment of abdominal obesity.

Van Gaal L. et al Effects of the cannabinoid-1-receptor blocker rimonabant on weight from the RIO-Europe study. Lancet 2005;365:1389-97

Despres J-P et al. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidaemia. N Eng J Med 2005;353: 2121-2134

RIO North America and RIO Europe weight loss: observed cases and LOCF

These plots are observed cases by visit. The data are reported with standard error bars representing the standard error of the mean. The analysis at LOCF was the primary analysis and results are reported below the figure. Note that there are two lines; the orange colour is 20 mg rimonabant and blue is placebo. The baseline mean and standard deviation is shown at the top of the slide.

The results from RIO North America are shown on the left-hand side of this slide. Subjects lost 2 kg during the diet run-in period and had a baseline weight of 104 kg. With lifestyle changes and placebo alone patients lost an additional 2.8 kg during the first year of treatment.

In the 20 mg group the weight loss is more pronounced. Those who completed 1 year lost 8.7 kg, and so their total loss from their initial screening value was above 10 kg.

In the LOCF analysis the difference versus placebo was 4.7 kg for the 20 mg dose.

The results obtained in RIO Europe (shown here on the right-hand side) replicated the results of RIO North America nicely, with exactly the same difference of 4.7 kg between rimonabant 20 mg and placebo at 1year in the LOCF analysis.

Van Gaal L et al. Effects of the cannabinoid-1-receptor blocker rimonabant on weight from the RIO-Europe study. Lancet 2005;365:1389-97

Data on file

RIO Europe: durable weight loss at 2 years

Obtaining an initial weight loss is relatively easy but the most difficult part of weight management is to maintain the reduction over a long period of time.

In RIO Europe patients showed maintained weight loss at 2 years of about 4.2 kg placebo subtracted for placebo, compared to 4.7 kg at 1 year.

Van Gaal L. et al. Effects of the cannabinoid-1-receptor blocker rimonabant on weight from the RIO-Europe study. Lancet 2005;365:1389-97

Van Gaal L. 2-year data from the RIO-Europe study: metabolic effects of rimonabant in overweight/obese patients. J Am Coll Cardiol 2005;45(3 suppl A): 1A-446A

RIO Lipids and RIO Diabetes weight loss: observed cases and LOCF

RIO Lipids shows nearly identical results when compared to RIO North America and RIO Europe with a placebo-subtracted weight loss of 5.4 kg.

It has been known for some years now that diabetic subjects find it more difficult to lose weight than non-diabetic subjects (Wing RR, 1987; Norris SL, 2004; Hensrud DD, 2001; Campbell L, 2001), largely due to the metabolic disturbances associated with their disease. Therefore, it is not surprising that the type 2 diabetic population of RIO Diabetes have lost slightly less weight than the non-diabetic population of other RIO trials. In addition, it is notoriously difficult to achieve any significant weight loss in patients who are on an antidiabetic drug. In this difficult population of metformin- or sulphonylurea-treated diabetics in the RIO Diabetes study, a significant weight loss of 3.9 kg net of placebo was achieved. The average weight loss in the rimonabant 20 mg group of the RIO Diabetes study was 5.3 kg, vs. 1.4 kg for placebo (p<0.001 vs placebo, ITT LOCF). For those patients who completed the study, the mean weight loss was 6.1 kg compared to 1.9 kg for placebo (p<0.001).

The placebo-subtracted effect is a very relevant comparison. A modest weight loss has been seen in the placebo group of RIO Diabetes, which illustrates the difficulty of losing weight with diabetes.

Despres J-P et al. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 2005;353: 2121-2134.

Wing RR, Marcus MD, Epstein LH, Salata R. Type II diabetic subjects lose less weight than their overweight nondiabetic spouses. Diabetes Care 1987;10:563-6.

Norris SL, Zhang X, Avenell A, Gregg E, Schmid CH, Kim C, Lau J. Efficacy of pharmacotherapy for weight loss in adults with type 2 diabetes mellitus: a meta-analysis. Arch Intern Med 164(13):1395-404, 2004

Hensrud DD. Dietary treatment and long-term weight loss and maintenance in type 2 diabetes. Obesity Res 2001;9 Suppl 4:348S-353S.

Campbell L, Rossner S. Management of obesity in patients with Type 2 diabetes. Diabetic Med 2001;18:345-54.

Reductions in waist circumference observed cases by visit and LOCF

The results for waist circumference paralleled the results for weight in RIO North America and RIO Europe as shown here. Results for the two other studies, though not shown, were similar.

Van Gaal L et al. Effects of the cannabinoid-1-receptor blocker rimonabant on weight from the RIO-Europe study. Lancet 2005;365:1389-97

Glucose metabolism

Let’s now examine the results on glucose control.

RIO Diabetes randomized over 1,000 patients. About two-thirds were already on metformin and one-third who were on a sulphonylurea, but who were still not able to achieve adequate control, defined as Hb1Ac < 6.5%.

RIO North America, RIO Europe and RIO Lipids provide supportive data in pre-diabetic patients.

•

RIO Diabetes: lower weight, HbA1c and FPG

RIO Diabetes studied patients with A1c between 6.5 and 10%. At screening over 70% of patients had an A1c over 7%.

The lifestyle changes prescribed by the dieticians induced a transient decease in A1c by 0.2% during the run-in period that preceded baseline. Therefore a relatively low mean A1C of 7.3% was observed at baseline.

In terms of fasting glucose, the effects of lifestyle changes were transient in the placebo group, whereas there was a continuous decrease in the 20 mg group. This improved glucose control is confirmed by a reduction of almost 1 mM of the fasting glucose.

In terms of weight, when rimonabant was added, weight decreased with both background therapies, metformin and sulphonylurea. As most oral antidiabetic agents are known to be associated with weight gain and given the fact that weight control is an essential part of the management of patients with type 2 diabetes, this is a remarkable finding.

Scheen A et al. Rimonabant improves multiple cardiometabolic risk factors in diabetic and non diabetic overweight/obese patients. WWC 2006

RIO Diabetes: metformin and sulphonylurea subgroups change in weight and HbA1c

Patients in this trial were stratified according to their oral antidiabetic medication. As a reminder, two-thirds of patients were on a stable dose of metformin and one-third on a stable dose of sulphonylurea.

Rimonabant was equally effective in both strata for weight loss, with the metformin group losing about 4.5 kg and the sulphonylurea group losing about 3.5 kg – both findings highly significant. These findings were expected as sulphonylurea is often associated with weight gain.

There was comparable improvement in A1c in the rimonabant 20 mg groups, with both showing a highly significant -0.7 point reduction.

Similar findings in terms of significant improvement in lipid parameters, HDL-C significantly increased and triglycerides significantly decreased were found.

Scheen A et al. Rimonabant improves cardiometablic risk factors in overweight, obese patients with type 2 diabetes irrespective of background oral antidiabetic therapy (metformin or sulfonylureas) (ADA 2006)

Rimonabant increases adiponectin

Adiponectin is an important adipocytokine involved in the regulation of insulin sensitivity and lipid metabolism, especially HDL.

In addition to lipids and glycaemic control, RIO Lipids showed that rimonabant increases adiponectin levels. This confirms the pre-clinical data in animals, and may explain in part the improved insulin sensitivity observed in the RIO studies and the improved glycaemic control seen in RIO Diabetes.

As we will see in a few slides, approximately half of this effect was above and beyond what was expected based on the amount of weight lost.

Despres J-P et al. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidaemia. N Engl J Med 2005;353: 2121-2134.

RIO Lipids: HDL-C and triglycerides change

In RIO Lipids in patients treated for 1 year, rimonabant 20 mg significantly increased HDL by more than 23%, an effect of 8% over placebo and decreased triglycerides by 16%, a net 12% versus the effects seen in the placebo group (p<0.001 for both).

Despres J-P et al. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidaemia. N Engl J Med 2005;353: 2121-2134.

RIO Europe: HDL-C and triglyceride changes after 2 years

These improvements in lipids are durable. The favourable effects on HDL-C and triglycerides were maintained over time for 2 years as shown in the RIO Europe trial. This was also true in RIO North America for patients who were on the same treatment groups for 2 years.

Van Gaal L. et al. Effects of the cannabinoid-1-receptor blocker rimonabant on weight from the RIO-Europe study. Lancet 2005;365:1389-97

Van Gaal L. 2-year data from the RIO-Europe Study: metabolic effects of rimonabant in overweight/obese patients. J Am Coll Cardiol 2005;45(3 suppl A): 1A-446A

Pi-Sunyer FX et al. Effects of rimonabant, a cannabinoid-1 receptor blocker on weight and cardiometabolic risk factors in overweight or obese patients RIO-North America: a randomized controlled trial. J Am Med Assoc 2006:295: 761-775

Changes in HDL-C and triglycerides at 1 year: patients on concomitant statin therapy

In the presence or in absence of statin therapy, rimonabant 20 mg had the same benefits on HDL and triglycerides.

Subanalysis preformed in the pooled RIO studies of all patients on statin treatment included in the four studies.

Després JP et al. Rimonabant improves cardiometabolic risk factors in overweight / obese patients irrespective or treatment with statins: pooled data from the Rio Program (IAS 2006)

All RIO studies: supine SBP placebo-subtracted difference

Effects on supine systolic blood pressure across the four RIO studies, mean change from baseline

Van Gaal L et al. Effects of the cannabinoid-1-receptor blocker rimonabant on weight from the RIO-Europe study. Lancet 2005;365:1389-97

Despres J-P et al. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. NEJM 2005;353: 2121-2134.

Van Gaal L et al. Effect of rimonabant on systolic and diastolic blood pressure in overweight /obese patients with/without co-morbidities (ESH,2006)

All RIO studies: supine diastolic blood pressure placebo-subtracted difference

Effects on supine diastolic blood pressure across the four RIO studies, mean change from baseline

Van Gaal L et al. Effects of the cannabinoid-1-receptor blocker rimonabant on weight from the RIO-Europe study. Lancet 2005;365:1389-97

Despres J-P et al. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. NEJM 2005;353: 2121-2134.

Van Gaal L et al. Effect of rimonabant on systolic and diastolic blood pressure in overweight /obese patients with/without co-morbidities (ESH,2006)

Pooled RIO studies: change in blood pressure at 1 year

High blood pressure at baseline defined as: ≥140/90 for RIO Lipids, RIO North America and RIO Europe, BP ≥ 130/85 for RIO Diabetes

Van Gaal L et al. Effect of rimonabant on systolic and diastolic blood pressure in overweight /obese patients with/without co-morbidities (ESH,2006)

C-reactive protein: RIO Lipids

Chronic, low-grade inflammation is increasingly being implicated in the pathophysiology of atherogenesis in the setting of abdominal obesity (Lee YH, 2005). C-reactive protein (CRP) is a systemic marker of inflammation. Thus, interventions that reduce CRP levels are potentially antiatherogenic (Lee YH, 2005).

Data from RIO Lipids (ITT population) show that 1 year of treatment with rimonabant 20 mg reduced levels of CRP significantly relative to placebo.

The anti-inflammatory effects of rimonabant on CRP, and other parameters, such as adiponectin, lipids and insulin resistance, highlight the efficacy of this new approach to reducing multiple metabolic and cardiovascular risk factors.

Despres J-P et al. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. NEJM 2005;353: 2121-2134.

Lee YH, Pratley RE. The evolving role of inflammation in obesity and the metabolic syndrome. Curr Diab Rep 2005; 5(1):70-5

RIO programme: placebo-subtracted change for CMR factors

The prevalence of individual diagnostic criteria for the metabolic syndrome was also evaluated before and after treatment in a pooled analysis from the four RIO trials. A consistent significant improvement in waist circumference, HDL-C and triglycerides was seen vs. placebo (p<0.001 in all cases) in the four trials. The effects of rimonabant on systolic blood pressure were significant vs placebo in the RIO Diabetes and RIO Lipids trials (p<0.05).

The differences in the effect of rimonabant on blood pressure between the trials likely reflects differences in the hypertensive status of the trial populations at baseline. In general, rimonabant exerted larger effects on blood pressure in populations with high pressure at baseline factors (BP >140/90).

Overall, these data show that rimonabant consistently improved multiple of cardiometabolic risk associated.

Van Gaal L et al. 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;365:1389-97.

Després JP et al. Rimonabant in Obesity-Lipids Study Group. Effects on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 2005;353(20):2121-34

Pi-Sunyer FX. Effect of rimonabant on weight reduction and weight maintenance: RIO North America (RIO-NA) trial. Circulation 2005:111;1727.

Després JP et al. Rimonabant improves multiple risk factors in diabetic and non diabetic overweight / obese patients (WCC, 2006)

Type 2 Diabetes Program: General Safety Profile (AEs in ³ 2%* of Rimonabant-treated Patients)

Rimonabant 20 mg was evaluated specifically in patients with type 2 diabetes in the RIO Diabetes study (a 1-year study in overweight or obese type 2 diabetes patients already receiving oral antidiabetic medication) and in the SERENADE study (drug-naïve type 2 diabetes patients recruited irrespective of weight status and randomly assigned to rimonabant 20 mg or placebo for 6 months). This slide shows the tolerability and safety profile of rimonabant pooled from these two studies.

The pattern and frequency of adverse events in this type 2 diabetic population were similar to the pattern and frequency of adverse events observed in the overall pooled RIO trial population described in the previous slide.