Metabolic Syndrome
The metabolic syndrome is a cluster of metabolic and nonmetabolic abnormalities (abdominal obesity, dyslipidaemia, hyperglycaemia, and hypertension) that are related to insulin sensitivity and visceral obesity. These metabolic abnormalities predispose to the development of Type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD)i. The syndrome is increasing in prevalence worldwide as a consequence of increasing obesity prevalence. Metabolic syndrome is likely to have a marked impact on the prevalence of cardiovascular disease and Type 2 diabetes worldwide in the next two decades.
In September 2010 GW commenced its programme of Phase IIa exploratory clinical trials exploring cannabinoids as potential treatments in the field of type 2 diabetes and metabolic syndrome.
Disease Background
Type 2 diabetes frequently co-exists with a cluster of other cardiovascular and metabolic risk factors including abdominal obesity, low HDL-cholesterol concentrations, high triglyceride concentrations, and raised blood pressurei, and is considered to be a cardiovascular disease risk equivalentii. The treatment of multiple cardiovascular and metabolic risk factors is central to the management of type 2 diabetesiii. Being overweight or obese, in particular abdominally obese, increases the risk of Type 2 diabetes and cardiovascular disease, yet those with diabetes often have more difficulty in losing weight and experience weight gain associated with most antidiabetic medicationsiii.
Obesity has reached epidemic proportions globally, with more than 1 billion adults overweight - at least 300 million of them clinically obese - and is a major contributor to the global burden of chronic disease and disabilityiv. Often coexisting in developing countries with under-nutrition, obesity is a complex condition, with serious social and psychological dimensions, affecting virtually all ages and socioeconomic groups.
Increasingly obesity (and related disorders such as Type 2 diabetes) has become a major health problem in the developing world. In 1995, the Emerging Market Economies had the highest number of diabetics. If current trends continue, India and the Middle Eastern region will have taken over by 2025. Large increases will also be observed in China, Latin America and the Caribbean, and the rest of Asiaiv.
Hypertension is the most important single, modifiable risk factor for stroke and an important risk factor for atherosclerosis and ischaemic heart disease. Obesity, lack of physical activity and modification of diet in a “Westernised” direction are all associated with increasing blood pressure.
Insulin sensitivity is one of the major pathophysiological abnormalities inType 2 diabetes. Insulin sensitivity is the condition in which normal amounts of insulin are inadequate to produce a normal insulin response from fat, muscle and liver cells. Insulin sensitivity in fat cells reduces the effects of insulin and results in elevated hydrolysis of stored triglycerides. Increased mobilization of stored lipids in these cells elevates free fatty acids in the blood plasma. Insulin sensitivity in muscle cells reduces glucose uptake (and so local storage of glucose as glycogen), whereas insulin sensitivity in liver cells reduces storage of glycogen, making it unavailable for release into the blood when blood insulin levels fall (normally only when blood glucose levels are low). Both cause elevated blood glucose levels. High plasma levels of insulin and glucose due to insulin sensitivity often lead to metabolic syndrome and Type 2 diabetes, including its complications.
Dyslipidaemia is a disruption in the amount of lipids in the blood, and may be characterised by an elevation of plasma cholesterol and/or triglycerides or a low HDL cholesterol level that contributes to the development of atherosclerosisv. Causes may be primary (genetic) or secondary (due to a sedentary lifestyle with excessive dietary intake of saturated fat, cholesterol, and trans fatty acids (TFAs). In western societies, most dyslipidaemias are hyperlipidaemias; that is, an elevation of lipids in the blood, often due to diet and lifestyle. Prolonged elevation of insulin levels can lead to dyslipidaemia. Dyslipidaemia is generally characterised by increased total cholesterol in combination with increased levels of low density lipoprotein (LDL)-cholesterol and is associated with an increased risk of atherosclerosis and CVDv.
Type 2 diabetes generally occurs following insulin sensitivity. Diabetes is an especially significant secondary cause of dyslipidaemia because subjects tend to have an atherogenic combination of high triglycerides; high small, dense LDL fractions; and low HDLs (diabetic dyslipidemia, hypertriglyceridemic hyperapo B)v. Subjects with Type 2 diabetes are especially at risk. The combination may be a consequence of obesity and/or poor control of diabetes, which may increase circulating free fatty acids, leading to increased hepatic VLDL production. Triglyceride-rich VLDL then transfers triglycerides and cholesterol to LDL and HDL, promoting formation of triglyceride-rich, small, dense LDL and clearance of triglyceride-rich HDL. Diabetic dyslipidemia is often exacerbated by the increased caloric intake and physical inactivity that characterize the lifestyles of some subjects with Type 2 diabetesv. The likelihood of developing Type 2 diabetes and hypertension rises steeply with increasing central adiposity. Of people with Type 2 diabetes, approximately 90% are obese or overweight.
Potential Drug Targets
Potential for Cannabinoids
The mammalian endogenous cannabinoid (EC) system is a natural physiological system, which was discovered in the early 1990si. There are several EC agonists, (e.g. arachidonoylethanolamide (AEA, anandamide), 2-arachidonoylglycerol (2-AG)). Activation of the EC system promotes food ingestion, relaxation, pain reduction, and the extinction of aversive memories. The endocannabinoids exert some of their pharmacologic action through interaction with the specific receptors, CB1 and CB2, with other activity being evident through other receptor systems (e.g. TRPV1). The CB1 receptors are primarily distributed in the brain and adipose tissuexand sympathetic nerve terminals. The CB2 receptors are primarily located in the lymphoid tissue and peripheral macrophagesxi.
Under normal conditions endocannabinoids are produced on demand, act locally, and are rapidly inactivated. The putative effect of the blockade of centrally and peripherally located CB1 receptors may result in decreased motivation to eat palatable food (nucleus accumbens), anorexigenic effect (hypothalamus), stimulation of satiating signals engaging CB1 in sensory terminals (gastrointestinal tract), increased adiponectin production, inhibition of lipogenesis (adipose tissue and liver), and increased glucose uptake (muscles)xii. The EC system appears to modulate energy homeostasis in addition to lipid and glucose metabolismii,xiii.
GW's research in this area has focused on two cannabinoids - delta-9-tetrahydrocannabivarin (THCV) and cannabidiol (CBD). THCV is a neutral antagonist at the CB1 receptorvii(please click here to see an animation detailing the differences between inverse agonism and neutral antagnoism). THCV also interacts with CB1 receptors when administered in vivo, behaving either as a CB1 antagonist or, at higher doses, as a CB1 receptor agonistviii. In addition, THCV antagonizes cannabinoid receptor agonists (such as THC) in CB1-expressing tissues and does this with relatively high potency and in a manner that is both tissue and ligand dependent. THCV also behaves as a potent CB2 receptor partial agonist in vitrovii. CBD does not bind to CB1 or CB2 receptors with any great affinity, but displays unexpectedly high potency as an antagonist of CB1/CB2 receptor agonists in CB1- and CB2-expressing cells or tissuesix.
In animal models of obesity (Dietary-Induced Obese (DIO) mouse model, ob/ob genetic mouse model), low doses of THCV (0.3mg/kg) have been shown to produce fat loss (reduce body weight gain), and increase energy expenditure and reduce fasting plasma insulin levels and leptin levels. CBD) has also been shown to be effective in producing positive metabolic effects in animal models of obesity (ob/ob genetic mouse model)xiv. Four weeks treatment with CBD alone (3.0mg/kg) produced a 55% increase in plasma HDL cholesterol levels, and reduced total cholesterol levels by more than 25%. In addition, the same dose reduced liver triglyceride and increased liver glycogen levels and increased adiponectin levels. A 1:1 ratio of a combination of THCV and CBD (3.0mg/kg + 3.0mg/kg respectively) also produced positive metabolic effects in the same model: a 50% increase in plasma HDL cholesterol levels, and reduced total cholesterol levels by 19%, reduced liver triglyceride and increased liver glycogen levels, reduced fasting insulin levels and increased energy expenditure at 3 hours post dose.
This data suggests that these two cannabinoids, both alone and in combination, appear to produce multiple desirable effects which may improve at least two of the cluster of symptoms which make up the metabolic syndrome (obesity, dyslipidaemia, insulin sensitivity, hyperglycaemia, and hypertension). For this reason, GW intends to advance into clinical trials by evaluating a combination of THCV and CBD in subjects at high risk of cardiovascular disease and atherosclerosis (Type 2 diabetics with dyslipidaemia).
References
vi Pertwee RG. Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther. 1997;74(2):129-80.
xiv GW Pharma Ltd. Study Report (Protocol Number Bu07-020): The effect of tetrahydrocannabivarin and cannabidiol in ob/ob mice December 2007 – Data on file.