Diabetes mellitus, which is characterized by high concentrations of blood glucose resulting from defects in insulin secretion and/or insulin action, is one of the most common chronic illnesses in the United States. This disease affects 15.7 million people, or 5.9% of the population. Of these, it is estimated that one out of every three has not been medically diagnosed. Nearly 800,000 individuals are diagnosed each year with diabetes. By the year 2025, it is estimated that nearly 22 million adults in the United States will have diabetes. Similarly, the number of patients with diabetes worldwide is predicted to increase substantially over this period. The most common form—type 2 diabetes—accounts for 90% to 95% of all diagnosed cases, whereas type 1 diabetes accounts for 5% to 10% of all diagnosed cases. Other forms of diabetes may result from specific genetic syndromes, surgery, drugs, malnutrition, infections, or other illnesses; these account for 1% to 2% of all diagnosed cases. Finally, gestational diabetes occurs in 2% to 5% of all pregnancies but resolves once the pregnancy is completed. In some studies, in nearly 40% of women who had gestational diabetes, diabetes later developed. NIDDK. Diabetes Statistics . NIH Publication No. 99-3892. March 1999 (e-text posted September 1999). Available at: http://www.niddk.nih.gov/health/diabetes/pubs/ dmstats/dmstats.htm. Accessed July 19, 2000. King H, et al. Diabetes Care . 1998;21:1414-1431.
Results of a study that used telephone surveys in 43 states and that participated in the Behavioral Risk Factor Surveillance System between the years 1990 and 1998 revealed that the prevalence of diabetes increased from 4.9% in 1990 to 6.5% in 1998—an increase of 33%. The 6.5% represents 12 million people in the participating states and 13 million in all 50 states and the District of Columbia. With respect to men and women, prevalence of diabetes among men was 5.5% and for women it was 7.4%. After adjustments for age and race, the percentages were 7.8% and 9% for men and women, respectively. The age-sex-race standardized prevalence of diabetes was reported to be 4.9% in 1990 and, according to this study, it increased by 20%, to 5.9%, in 1998. Weight also increased in both sexes during the study period. Other findings included a 76% increase in the prevalence of diabetes in people aged 30 to 39 years; a 64% increase in people with some college education; a 52% increase in former smokers; and a 47% increase in people with at least a college degree. In addition, increases in prevalence were observed in 35 of the 43 participating states. Finally, there was an approximately 9% increase in diabetes for every self-reported kilogram of weight gained. The investigators speculate that “this large difference in added risk [for diabetes] imparted by an increase in weight of 1 kg may be explained by the rapid increase in obesity prevalence in the United States.” Mokdad AH, et al. Diabetes Care . 2000;23:1278-1283.
Before the manifestation of the metabolic defects that lead to type 2 diabetes, fasting and postprandial insulin levels are similar and constant. In the majority of patients in whom type 2 diabetes develops, increasing insulin resistance leads to compensatory increases in circulating insulin, which prevents an increase in glucose levels. As time progresses, the insulin resistance reaches a peak and stabilizes, while the compensatory increase in insulin continues to prevent fasting glucose levels from becoming abnormal. However, at some point, either because of early beta-cell dysfunction or because of a natural limit of beta-cell capacity, challenge of this delicate balance with a glucose load may demonstrate that, although fasting glucose levels remain normal, postprandial glucose levels become abnormal as a limitation in insulin response is reached. Following the onset of beta-cell dysfunction, insulin levels can no longer keep up in overcoming the insulin resistance, and fasting and postprandial glucose levels increase progressively over time. Goldstein BJ. Am J Cardiol. 2002;90(suppl):3G-10G. Bergenstal RM, et al. In: DeGroot LJ, Jameson JL, eds. Endocrinology. Vol 1, 4th ed. 2001:821-835.
Patients with type 2 diabetes are at high risk for atherosclerosis and other cardiovascular disease (CVD). Insulin resistance is related to the elevated risk of CVD. Evidence suggests that hyperglycemia may contribute to endothelial dysfunction and ultimately lead to accelerated atherogenesis. Many individuals with type 2 diabetes are not diagnosed until they have experienced a cardiovascular event. People with impaired glucose tolerance or IGT (considered “prediabetes”) who do not have chronic hyperglycemia have a twofold increase in the risk of coronary artery disease (CAD) compared with normal subjects. Patients with type 2 diabetes have a threefold increased risk of CAD. In an effort to decrease the high level of morbidity and mortality associated with type 2 diabetes and to facilitate early diagnosis, the American Diabetes Association (ADA) guidelines now include a lower fasting plasma glucose (FPG) level for diagnosis of diabetes: >=126 mg/dL, reduced from the previous level of 140 mg/dL. The ADA also recently reduced the cutpoint for impaired fasting glucose (IFG) to 100 mg/dL, and redefined IFG as an FPG of 100 to 125 mg/dL. American Diabetes Association. Diabetes Care. 2003;26:3160-3167. Tsao PS, et al. Arterioscler Thromb Vasc Biol. 1998;18:947-953. Hsueh WA, et al. Am J Med. 1998;105(1A):4S-14S. American Diabetes Association. Diabetes Care. 1998;21:310-314.
This study evaluated the incidence of coronary heart disease (CHD) mortality and all CHD events during a 3.5-year period in 1,069 elderly patients without diabetes and 229 patients with type 2 diabetes. Overall, incidence of fatal CHD and nonfatal myocardial infarction (MI) was 3.4% among those without diabetes and 14.8% among those with diabetes. The odds ratios (95% CI) for CHD death and nonfatal MI were 11.7 and 4.7 for women with diabetes compared with those without diabetes. In men, corresponding odds ratios were 0.43 and 1.4. This slide demonstrates the incidence of death from CHD and of all CHD events over 3.5 years in patients with diabetes according to tertiles of A1C. The highest tertile of A1C was >7.9%, middle tertile included A1C between 6.0% and 7.9%, and lowest tertile included A1C <6%. Patients in the highest A1C tertile had a significantly (P<0.01) higher incidence of CHD mortality than did patients in the lowest tertile. Furthermore, incidence of all CHD events was significantly (P<0.05) greater in the highest A1C tertile relative to the lowest tertile. The investigators concluded that poor metabolic control and the duration of type 2 diabetes are important predictors of CHD risk in elderly subjects, especially women. Those patients with poor metabolic control are at highest risk of CHD. Kuusisto J, et al. Diabetes. 1994;43:960-967.
Insulin resistance is a primary defect in type 2 diabetes. As reported in a recent study by Haffner and colleagues, 92% of patients with type 2 diabetes have insulin resistance. It can be defined as an impaired response to the physiological effects of insulin, including those on glucose, lipid, and protein metabolism, and the effects on vascular endothelial function. Haffner SM, et al. Diabetes Care . 1999;22:562-568. Consensus Development Conference of the American Diabetes Association. Diabetes Care. 1998;21:310-314.
Three major metabolic defects contribute to hyperglycemia in patients with type 2 diabetes: increased hepatic glucose production, impaired pancreatic insulin secretion, and peripheral tissue insulin resistance. After eating a meal or ingesting glucose, insulin is secreted, hepatic glucose output is suppressed, and insulin-dependent glucose uptake by peripheral tissues is stimulated. In type 2 diabetes, insulin resistance and impaired insulin secretion inhibit normal suppression of hepatic glucose output. As a consequence, the liver continues to release glucose into the circulation. Moreover, peripheral insulin resistance coupled with insufficient insulin results in decreased uptake of glucose by insulin-dependent target tissues, notably skeletal muscle and adipose tissue. These mechanisms contribute to postprandial hyperglycemia in type 2 diabetes. In type 2 diabetes, increased hepatic glucose production is the primary factor responsible for the fasting hyperglycemia. Moreover, in patients with type 2 diabetes, fasting blood glucose levels correlate strongly with rates of hepatic glucose output. In the setting of peripheral insulin resistance, insulin-mediated glucose uptake cannot accommodate the increased hepatic glucose output and rise in fasting glucose levels. Kruszynska YT, et al. J Invest Med. 1996;44:413-428. Henry RR. Ann Intern Med. 1996;124:97-103.
Central obesity is associated with insulin resistance and elevated levels of FFAs. As illustrated in slide 23, FFAs can reduce insulin-mediated glucose disposal under experimental conditions. However, it remains to be determined whether increased FFAs cause insulin resistance or vice versa in obese subjects. In either case, insulin resistance and elevated FFAs stimulate hepatic apolipoprotein B secretion and increase hepatic lipase activity. This enzyme catalyzes the removal of lipids from LDL and HDL, which makes them smaller and more dense. In turn, these effects lead to hypertriglyceridemia, production of small, dense LDL particles, and reduced HDL 2 -cholesterol levels. This dyslipidemic pattern, which has been termed the atherogenic lipoprotein phenotype, is also characteristic of that found in type 2 diabetes. Brunzell JD, et al. Diabetes Care. 1999;22(suppl 3):C10-C13.
In addition to type 2 diabetes, insulin resistance is associated with the development of a broad spectrum of clinical conditions. These include hypertension, atherosclerosis, dyslipidemia, decreased fibrinolytic activity, impaired glucose tolerance, acanthosis nigricans, hyperuricemia, polycystic ovary disease, and obesity. Adapted from Consensus Development Conference of the American Diabetes Association. Diabetes Care . 1998;21:310-314.
The number of new cases of ESRD has been on the rise, with diabetes accounting for a growing percentage of these new cases. Of the 86,438 new cases of ESRD in 1998, diabetes was the primary cause in 34,874 (40.3%) cases. USRDS 2000 Annual Data Report . 2000:251.
Diabetes was the most frequently reported primary cause of ESRD in 1998, accounting for almost one half of all new cases. In comparison, hypertension, the second leading cause, accounted for slightly more than one fifth of new cases. Hypertension is listed as a composite category that includes several distinct entities, such as renal disease due to hypertension, renal artery stenosis/occlusion, and atheroembolic disease. The remaining new cases were attributed to glomerulonephritis, cystic kidney disease, and other causes. Whites accounted for the majority (62.6%) of new ESRD cases in 1998, but, notably, African Americans (12.8% of the population in general) accounted for a disproportionately large percentage (30.1%) of these cases. This finding is consistent with the higher incidence of diabetes in the African American population. Asians/Pacific Islanders and Alaska Natives/Native Americans accounted for small proportions of the new ESRD cases, 3.4% and 1.6%, respectively. USRDS 2000 Annual Data Report . 2000:251.
In addition to being the earliest manifestation of nephropathy, albuminuria is also a marker of increased cardiovascular morbidity and mortality for patients with diabetes. The presence of microalbuminuria is an indicator for screening for possible vascular disease and aggressive intervention to reduce all cardiovascular risk factors—elevated LDL, hypertension, smoking, and physical inactivity. Preliminary evidence suggests that cholesterol lowering may also reduce urinary protein levels. American Diabetes Association. Diabetes Care . 2001;24 (suppl 1):S69-S72.
CVD is the primary cause of death among 55% of patients with diabetes compared with 31% of deaths in the general population. Ischemic heart disease (IHD) accounts for about 40% of deaths in patients with diabetes. The risk of mortality due to diseases of the heart is 2 to 4 times higher among patients with diabetes than in persons without diabetes. Data from a 10-year period show a 37% increase in the number of hospitalizations that listed major CVD as the primary diagnosis and diabetes as a secondary diagnosis. Geiss LS, et al. In Diabetes in America , 2nd ed. NIH Publication No. 95-1468.1995:243,558. Centers for Disease Control and Prevention. National Vital Statistics Reports. 2000;48:5.
This population-based study compared the 7-year incidence of fatal and nonfatal MI among subjects with and without type 2 diabetes. A history of MI at baseline in either group was significantly associated with an increased incidence of fatal and nonfatal MI ( P <0.001). Subjects with neither diabetes nor prior MI had the best prognosis (3.5% incidence of MI); subjects with both diabetes and prior MI had the worst prognosis (45% incidence of MI). Those patients with type 2 diabetes and no prior history of MI had intermediate survival rates, similar to patients without diabetes but with a history of MI (20.2% and 18.8%, respectively, after adjustments for age and sex). Coronary disease incidence rates were also similar between these two groups. These findings suggest that all patients with diabetes should be treated as if they had prior MI, ie, should be treated aggressively. Haffner SM, et al. N Engl J Med . 1998;339:229–234.
Insulin resistance is a precursor to a variety of metabolic abnormalities, including systemic inflammation, visceral obesity, and type 2 diabetes. Insulin resistance is also a risk factor for cardiovascular abnormalities, including hypertension, dyslipidemia (increased triglycerides and LDL and decreased HDL), disordered fibrinolysis, and endothelial dysfunction. All of these aberrations contribute to the atherosclerotic process. Consensus Development Conference of the American Diabetes Association. Diabetes Care. 1998;21:310-314. Pradhan AD et al. JAMA. 2001;286:327-334.
Circling back to the discussion of abdominal adiposity, data regarding waist circumference and diabetes illustrate its health impact. These are age-adjusted data from the Nurses’ Health Study, analyzing responses from 43,581 subjects who provided information on weight and body measurements in 1986. These subjects had no history of cancer, heart disease, stroke, or any type of diabetes. An 8-year follow-up in this population showed a strong positive association between waist circumference and the incidence of diabetes. At the far end of the spectrum, women with a waist circumference >38 inches had a diabetes risk of 22.4, relative to women in the normal waist circumference range of <28 inches. Other obesity measures studied included body mass index and waist-to-hip ratio; both of these were also found to be independent determinants of type 2 diabetes in this population. The sharpest risk gradient was documented with waist circumference, indicating that it is a powerful independent predictor of type 2 diabetes in women. (WC was measured at the high point of the iliac crest at minimal respiration to the nearest 0.1 cm.) Carey VJ, Walters EE, Colditz GA, et al. Body fat distribution and risk of non-insulin-dependent diabetes mellitus in women: the Nurses’ Health Study. Am J Epidemiol. 1997;145:614-619.
The risks of high waist circumference are not unique to women, nor to persons without a history of heart disease. Data from Dagenais and colleagues demonstrate that the risk of CVD death, MI, and all-cause death increase along with waist circumference in 6,620 men and 2,182 women with stable CVD but no congestive heart failure (CHF). The mean age of subjects was 66 years; they were participants in the Heart Outcomes Prevention Evaluation (HOPE) study. The primary outcomes of interest were CVD death, MI, stroke, hospitalization for CHF, and all-cause mortality. The green bars in this graph represent women and men in the normal waist circumference range (<87 cm for women, <95 cm for men), the orange bars represent subjects in the second tertile, or first level of increased waist circumference. The aqua bars represent individuals in the third tertile, or group with the highest waist circumferences. The 3 outcomes for which the increase in relative risk was significant are shown here. The risk of CVD mortality, MI, and all-cause mortality all rose with the increased waist circumference. In all-cause mortality, for example, women and men in the third tertile were found to have a risk of 1.35 relative to individuals in the normal waist circumference range. The authors concluded that abdominal adiposity worsens the prognosis for individuals with existing CVD; they recommended that weight reduction be added as a component to the therapeutic regimen. Dagenais GR, Yi Q, Mann JF, Bosch J, Pogue J, Yusuf S. Prognostic impact of body weight and abdominal obesity in women and men with cardiovascular disease. Am Heart J . 2005;149:54-60.
According to the International Diabetes Foundation (IDF) definition of the metabolic syndrome, central obesity (defined by waist circumference) is an essential component for diagnosis of the syndrome. The IDF definition recognizes ethnic-specific values for waist circumference, as shown on this slide. The IDF consensus group acknowledged that these are pragmatic cut-points taken from various different data sources, and that better data will be needed to link these to risk. The IDF points out that although a higher cut-point is currently used for all ethnic groups in the United States for clinical diagnosis, it is strongly recommended that for epidemiological studies and, wherever possible, for case detection, ethnic group-specific cut-points should be used for people of the same ethnic group wherever they are found. Thus the criteria recommended for Japan would also be used in expatriate Japanese communities, as would those for South Asian males and females regardless of place and country of residence. International Diabetes Federation. The IDF consensus worldwide definition of the metabolic syndrome. 2005. Tan CE, Ma S, Wai D, et al. Can we apply the National Cholesterol Education Program Adult Treatment Panel definition of the metabolic syndrome to Asians? Diabetes Care . 2004;27:1182-1186.
To measure waist circumference, 1) locate the upper hip bone and the top of the right iliac crest, 2) place the measuring tape in a horizontal plane around the abdomen at the iliac crest, 3) ensure that the tape is snug but does not compress the skin, 4) the tape should be parallel to floor, and 5) record the measurement at the end of a normal expiration. Men are at increased relative risk if they have a waist circumference greater than 40 inches (102 cm); women are at an increased relative risk if they have a waist circumference greater than 35 inches (88 cm). There are ethnic- and age-related differences in body fat distribution that may affect the predictive validity of waist circumference as a surrogate for abdominal fat. Heterogeneity of composition of abdominal tissues, in particular adipose tissue and skeletal muscle, and their location-specific and changing relations with metabolic factors and CV risk factors in different ethnic groups do not allow a simple definition of abdominal obesity that could be applied uniformly. In particular, Asians appear to have higher morbidity at lower cutoff points for waist circumference than do white Caucasians. National Institutes of Health, National Heart, Lung, and Blood Institute, NHLBI Obesity Education Initiative, North American Association for the Study of Obesity. The practical guide to the identification, evaluation, and treatment of overweight and obesity in adults. NIH Publication Number 00-4084. October 2000. Misra A, Wasir JS, Vikram NK. Waist circumference criteria for the diagnosis of abdominal obesity are not applicable uniformly to all populations and ethnic groups. Nutrition . 2005;21:969-976.
A key concept of cardiometabolic risk is that the risk factors tend to cluster, as illustrated in this diagram. The cardiovascular and metabolic variables are often associated with each other and therefore can occur simultaneously. In recent years, the clustering of cardiometabolic risk factors has received increasing attention, leading groups such as the World Health Organization, International Diabetes Federation, and the Adult Treatment Panel III (ATP III) (National Cholesterol Education Program) to issue clinical guidelines for identifying this particular group of risk factors as the metabolic syndrome. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-2497.
Which of the metabolic syndrome risk factors are we most likely to find in US adults who do not yet have T2DM? Wong and colleagues extrapolated the incidence of individual risk factors. In men, high WC, high BP, high TG, and low HDL-C were all very common, with high LDL-C occurring in just over one half of the study population. In women, high WC and low HDL-C were the most common risk factors noted, with high BP and high TG in the 70% range, and high LDL-C just above 60%. Prediabetes glucose levels were documented in 22% of the men and 17% of the women. Wong ND, Pio JR, Franklin SS, L’Italien GJ, Kamath TV, Williams GR. Preventing coronary events by optimal control of blood pressure and lipids in patients with the metabolic syndrome. Am J Cardiol . 2003;91:1421-1426.
Age-Specific Prevalence of the Metabolic Syndrome Among 8814 US Adults aged at least 20 years, by Sex, National Health and Nutrition Examination Survey III, 1988-1994
Prevalence of the NCEP metabolic syndrome: NHANES III by sex and race/ethnicity This slide shows the prevalence of the metabolic syndrome as defined by NCEP in NHANES III participants by sex and ethnicity. The prevalence of the metabolic syndrome is highest in Mexican American women and lowest in African American men. The prevalence of the metabolic syndrome (using the NCEP definition) is low in African Americans because African Americans have low triglycerides and high HDL-C levels and also because NCEP has separate criteria for triglycerides and HDL-C. Thus, the reports of the low prevalence of the metabolic syndrome in African Americans should be taken with caution since this ethnic group is known to have high rates of glucose intolerance and hypertension. Reference: Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002;287:356-359.
Malik and colleagues demonstrated that the cardiometabolic risk factors associated with metabolic syndrome increase the CVD mortality rate. Relative to an individual with no metabolic syndrome risk factors, having 1 to 2 risk factors increased a patient’s hazard ratio by more than 70%. Persons with metabolic syndrome (having ≥3 of the 5 risk factors) were found to have a hazard ratio of 2.71. The ratio increased with the onset of type 2 diabetes, CVD, and was greatest in persons with existing CVD and T2DM. Malik S, Wong ND, Franklin SS, et al. Impact of the metabolic syndrome on mortality from coronary heart disease, cardiovascular disease, and all causes in United States adults. Circulation . 2004;110:1245-1250.
The role of hyperglycemia in the development and progression of microvascular and macrovascular complications of type 2 diabetes has been amply substantiated in the literature. So too has the need to aggressively treat hyperglycemia, dyslipidemia, and hypertension in order to prevent or delay the progression of these complications. The following series of slides based on the results of landmark trials provide substantial evidence to support aggressive treatment.
Essential components of treatment for patients with type 2 diabetes are nutrition therapy and regular physical activity. Weight loss frequently is a primary goal of nutrition therapy in obese patients with type 2 diabetes. When 3 months of dietary modification and exercise alone do not result in near-normalization of blood glucose levels, oral antidiabetic agents should be initiated as adjunctive therapy. In the United States, there are currently five classes of oral pharmacologic agents that have been approved for the treatment of type 2 diabetes. These include sulfonylureas, biguanides, thiazolidinediones, meglitinides, and alpha-glucosidase inhibitors. Edelman SV, Henry RR. Diagnosis and Management of Type 2 Diabetes . 3rd ed. Caddo, Okla: Professional Communications, Inc; 1999:45-102.
The major metabolic defects present in type 2 diabetes mellitus that lead to glucose elevation are: decreased glucose transport and utilization at the level of muscle and adipose tissue, increased glucose production by the liver, and relatively insufficient insulin secretion by the pancreas. Added to this abnormal flux is any dietary carbohydrate that is absorbed as glucose or converted to glucose during the absorptive or postabsorptive process. Sulfonylureas, the oldest oral agents used to treat type 2 diabetes, stimulate pancreatic insulin secretion. More recently, repaglinide, a meglitinide, has been added to the available agents that stimulate increased pancreatic insulin secretion. Insulin administration, the oldest pharmacologic therapy for diabetes, is also a choice to increase circulating insulin levels in response to failing beta-cell function and increased insulin resistance. Biguanides increase the sensitivity of the liver to circulating insulin, thereby reducing the level of glucose produced by the liver in type 2 diabetes. Thiazolidinediones, peroxisome proliferator-activated receptors, act at a number of sites to lower blood glucose levels. They also improve insulin sensitivity at the level of the liver, thereby decreasing the excess glucose production by that organ. They are more commonly recognized for their action in increasing peripheral insulin sensitivity in muscle and adipose tissue. By improving this sensitivity, they allow for improvement in the utilization of glucose by the muscle and adipose tissue. It should be noted that biguanides, in high doses, also have some mild effect on increasing peripheral glucose utilization. Alpha-glucosidase inhibitors decrease the rapid influx of carbohydrate from ingested food and slow the digestion of starches and the absorption of glucose and several other sugars. Sonnenberg GE, Kotchen TA. Curr Opin Nephrol Hypertens . 1998;7:551-555.
The Diabetes Control and Complications Trial (DCCT) asked the question, “Do efforts to control blood glucose impact the development or progression of the long-term complications of diabetes?” In this prospective, randomized, multicenter study involving 1,441 patients with type 1 diabetes followed for 6½ years, the effects of intensive insulin therapy vs conventional insulin therapy on early microvascular and neurologic complications were compared. Intensively treated patients received either insulin pump therapy or three or more injections of insulin daily. Adjustments in treatment were determined by the results of frequent home blood glucose monitoring. A 1c levels reached a nadir in the intensively treated group in 6 months. The difference in the average A 1c between the two groups was statistically significant ( P <0.001) and was maintained after baseline (average, 9.1% and 7.2% for the conventional and intensive therapy groups, respectively). This slide summarizes the effects of improved blood glucose control on retinopathy, nephropathy, and neuropathy. Intensive therapy reduced the risk for: development of retinopathy by 63% ( P<= 0.002; 95% confidence interval [CI], 52% to 71%) nephropathy, determined by albuminuria (excretion rate >=300 mg/24 hr), by 54% ( P <0.04; 95% CI, 19% to 74%) clinical neuropathy by 60% ( P<= 0.002; 95% CI, 38% to 74%). Diabetes Control and Complications Trial Research Group. N Engl J Med . 1993;329:977-986. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. N Engl J Med . 2000;342:381-389.
This multicenter, randomized, controlled trial sought to determine whether: intensive glycemic control (study goal: fasting plasma glucose [FPG] <108 mg/dL) reduces the risk of microvascular and macrovascular complications of type 2 diabetes sulfonylurea, metformin (in obese patients), or insulin has specific advantages or disadvantages tight blood pressure control (<150/85 mm Hg) reduces the risk of complications tight blood pressure control with an ACE inhibitor or a beta-blocker has specific advantages in preventing the microvascular and macrovascular complications of diabetes. Of the 7,616 patients referred to the UKPDS, 5,102 were enrolled in a 3-month dietary run-in phase during which they followed a diet that was low in saturated fats, was of moderately high fiber, and that derived 50% of calories from carbohydrates. The other 2,514 patients were excluded from the study. After completion of the dietary phase, 744 patients were excluded because their FPG was >270 mg/dL and an additional 149 were excluded because of FPG levels that were <=108 mg/dL. The remaining patients (4,209) were stratified by ideal body weight and randomized to conventional or intensive treatment. Conventional treatment consisted of initial dietary therapy only, with a goal FPG of <270 mg/dL. If the goal was not met, subjects were randomized to receive a sulfonylurea, insulin, or metformin. The FPG goal remained the same. Intensive treatment consisted of a sulfonylurea (either chlorpropamide, glibenclamide, or glipizide) or insulin, with a goal of maintaining FPG <108 mg/dL. Intensive metformin therapy was an additional treatment option for overweight patients. In the intensive treatment group, combination therapy was initiated when glycemic goals were not achieved with monotherapy. For those patients who had been receiving a sulfonylurea, metformin or insulin was added; metformin-treated patients had a sulfonylurea added if the glycemic goal was not met; and insulin was substituted for a sulfonylurea if necessary to achieve the glycemic goal. Aggregate endpoints included: any diabetes-related clinical endpoint (sudden death, death from hyperglycemia or hypoglycemia, fatal or nonfatal MI, angina, heart failure, stroke, renal failure, amputation of at least one digit, vitreous hemorrhage, retinal photocoagulation, blindness in an eye, or cataract extraction) diabetes-related death (death from an MI, stroke, peripheral vascular disease (PVD), renal disease, hyperglycemia or hypoglycemia, or sudden death) all-cause mortality. UK Prospective Diabetes Study (UKPDS) Group. Lancet . 1998;352:837-853.
Patients were followed for 10 years and median A 1c levels were 7% in the intensively treated patients vs 7.9% in those who received conventional treatment. No differences in A 1c levels were observed in individual therapies. Significant reductions were observed in diabetes complications in the intensively treated groups compared with the conventionally treated group. There was a reduction of 16% in MI in the intensive treatment group, which approached statistical significance ( P =0.052). Analysis of the data revealed that any reduction in A 1c level is predictive of benefit to patients with type 2 diabetes. American Diabetes Association. Diabetes Care . 1999;22(suppl 1):S27-S31. UK Prospective Diabetes Study (UKPDS) Group. Lancet . 1998;352:837-853.
Of the 1,704 overweight patients in the study, 342 were randomized to intensive therapy with metformin. Patients in whom glycemic goals were not met with intensive monotherapy received combination therapy. In sulfonylurea-treated patients either metformin or insulin was added and in metformin-treated patients a sulfonylurea was added; if the glycemic goal was still not met, insulin was substituted for the sulfonylurea. The aggregate endpoints for metformin-treated patients were: any diabetes-related clinical endpoint (sudden death, death from hyperglycemia or hypoglycemia, fatal or nonfatal MI, angina, heart failure, stroke, renal failure, amputation of at least one digit, vitreous hemorrhage, retinopathy requiring photocoagulation, blindness in an eye, or cataract extraction) diabetes-related mortality (death from MI, stroke, PVD, renal disease, hyperglycemia or hypoglycemia, or sudden death) all-cause mortality. To determine the effect of intensive treatment on vascular disease, secondary outcomes analysis included: MI (both fatal and nonfatal and sudden death) stroke (both fatal and nonfatal) amputation of at least one digit or death from PVD microvascular complications (retinopathy necessitating photocoagulation, vitreous hemorrhage, fatal and nonfatal renal failure). Intensive metformin therapy significantly reduced any diabetes-related endpoint by 32% ( P =0.0023); diabetes-related mortality by 42% ( P =0.017); all-cause mortality by 36% ( P =0.011); and MI by 39% ( P =0.01). UK Prospective Diabetes Study (UKPDS) Group. Lancet . 1998;352:854-865. American Diabetes Association. Diabetes Care . 1999;22(suppl 1):S27-S31.
The relationship between exposure to glycemia over time and incidence of microvascular and macrovascular complications was evaluated in a prospective observational study of 4,585 patients with type 2 diabetes. These patients had been recruited for the UKPDS clinical trial and had A 1c measured 3 months after the diagnosis of diabetes. Glycemia exposure over time for each individual was determined from the updated mean of annual A 1c measurements made each year during follow-up. Subjects were grouped according to their updated mean A 1c concentrations into the following categories: <6%; 6% to <7%; 7% to <8%; 8% to <9%; 9% to <10%; and >=10%. After adjusting for age, sex, ethnicity, and duration of diabetes, the incidence of microvascular and macrovascular complications increased with each higher category of updated A 1c . This slide shows the adjusted incidence of any diabetes-related endpoint relative to the updated mean A 1c for white men aged 50 to 54 years at diagnosis with a mean duration of diabetes of 10 years. Diabetes-related complications increased threefold over the range of A 1c from <6% to >=10%. Notably, there was no evidence of a threshold for A 1c with respect to incidence of diabetes-related complications. Stratton IM, et al. BMJ . 2000;321:405-412.
Glycemic exposure over time for each individual was determined from the updated mean of measurements of A 1c made each year during follow-up. For each 1% decline in updated A 1c , the reduction in risk for microvascular complications and amputation or death from peripheral vascular disease was the greatest. Risk for microvascular disease declined by 37% (95% CI, 33% to 41%; P <0.0001), and risk for amputation or death from peripheral vascular disease decreased by 43% (95% CI, 31% to 53%; P <0.0001). In comparison, risk for MI declined by 14% (95% CI, 8% to 21%; P <0.0001); risk for stroke decreased by 12% (95% CI, 1% to 21%; P =0.035); and risk for heart failure decreased by 16% (95% CI, 3% to 26%; P =0.016). In addition, risk for cataract extraction decreased by 19% (95% CI, 11% to 26%; P <0.0001) for each 1% reduction in updated A 1c . Notably, there was no indication of an updated A 1c threshold for any complication below which risk no longer decreased or a level above which risk no longer increased. This prospective observational study demonstrates that risk for diabetic complications is strongly associated with previous hyperglycemia. Moreover, the results show that any reduction in A 1c is likely to reduce the risk for both microvascular and macrovascular complications. The lowest risk is associated with A 1c values in the normal range (<6%). Stratton IM, et al. BMJ . 2000;321:405-412.
Study participants were randomized to one of three groups: treatment with metformin, intensive lifestyle intervention, or placebo. Randomization to placebo and metformin was double-blinded. Subjects assigned to the metformin arm received 850 mg a day for 1 month, which was titrated to 850 mg bid thereafter. Those assigned to lifestyle intervention were expected to engage in moderate exercise (eg, brisk walking) for at least 150 minutes a week and to achieve and maintain a weight loss of at least 7%. A 16-lesson curriculum that covered diet, exercise, and behavior modification was taught by case managers on a 1-to-1 basis during the first 24 weeks after study enrollment. The average follow-up was 2.8 years with a range of 1.8 to 4.6 years. Diabetes Prevention Program Research Group. N Engl J Med . 2002;346:393-403.
Lifestyle reduced the incidence of diabetes by 58% (95% CI, 48%-66%) and metformin reduced the incidence by 31% (95% CI, 17%-43%). The incidence of diabetes was 39% lower (95% CI, 24%-51%) in the lifestyle group than in the metformin group. Treatment effects did not differ significantly according to sex or to race or ethnic group. The lifestyle intervention was highly effective in all subgroups. Its effect was significantly greater among persons with lower base-line glucose concentrations two hours after a glucose load than among those with higher base-line glucose values. The advantage of lifestyle intervention over metformin was greater in older persons and those with a lower body-mass-index than in younger persons and those with a higher body-mass-index. The effect of metformin was less with a lower body-mass-index or a lower fasting glucose concentration than with higher values for those variables. The investigators concluded that, compared with placebo, 1 case of diabetes can be prevented for every 7 persons treated with lifestyle changes for 3 years and for every 14 persons treated with metformin for 3 years. Diabetes Prevention Program Research Group. N Engl J Med . 2002;346:393-403.
The structures of the thiazolidinedione agents pioglitazone HCI (ACTOS ® ), rosiglitazone maleate (Avandia ® ), and troglitazone (Rezulin ® ) have the same thiazolidine-2-4-dione basic structure but differ in their terminal structure.
Thiazolidinediones cross the plasma membrane and pass through the cytoplasm to the nucleus, where they bind with peroxisome proliferator-activated receptors, which are in conformation with retinoic X receptors. This activated complex integrates with the ribosomal moieties. Once insulin binds to its receptor, it has immediate postreceptor actions; but of importance, it also sends a transnuclear signal into the nucleus to activate transcription factors in the ribosomal matrix. The activated thiazolidinedione–peroxisome proliferator-activated receptor/retinoic X receptor complex augments the function and efficiency of the transcription factor process that insulin has initiated. This augmentation increases the nuclear-based actions of insulin, which include the signal for formation of proteins involved in enzymatic processes, cell growth, regulation of insulin receptor activity, and glucose transport into the cell itself. Saltiel AR, Olefsky JM. Diabetes . 1996;45:1661-1669.
The thiazolidinediones offer a rational approach to the management of type 2 diabetes. They are known to target insulin resistance, a primary defect in this condition, and to improve glycemic control without causing hypoglycemia. ACTOS has demonstrated improvement in lipid profiles in patients with diabetes who are treated with these agents. Potential benefits of thiazolidinedione treatment, which have been suggested in preclinical studies, include further improvements in the cardiovascular risk profile (endothelial cell function, smooth muscle reactivity and effects on the fibrinolytic pathway) and preservation of pancreatic beta-cell function. This latter effect has prompted the use of thiazolidinediones in several studies of the prevention of progression of impaired glucose tolerance to type 2 diabetes. Saltiel AR, Olefsky JM. Diabetes . 1996;45:1661-1669. Sonnenberg GE, Kotchen TA. Curr Opin Nephrol Hypertens . 1998;7:551-555.
The action of ACTOS results in enhancement of insulin action and subsequent reductions in insulin secretion. ACTOS helps normalize glucose levels by increasing peripheral glucose utilization and decreasing hepatic glucose production. These effects are mediated by regulating the transcription of genes that encode polypeptides involved in carbohydrate, lipid, and protein metabolism. ACTOS Package Insert, February 2000. Sonnenberg GE, Kotchen TA. Curr Opin Nephrol Hypertens . 1998;7:551-555.
The above slide summarizes the calculated percentage changes from baseline in insulin resistance at the conclusion of three 16-week, double-blind studies, using homeostasis model assessment (HOMA). The HOMA models followed standardized mathematical calculations designed to estimate beta-cell function and insulin resistance values. For an individual patient, a decrease in values for insulin resistance and an increase in values for beta-cell function indicate a positive effect on these parameters. HOMA IR = fasting plasma insulin ( lU/mL) x fasting plasma glucose (mmol/L) 22.5 Compared with baseline, insulin resistance significantly decreased in the pioglitazone 30 mg, the sulfonylurea + pioglitazone 30 mg, and the metformin + pioglitazone 30 mg treatment groups by 12.5% ( P =0.045), 30.1% ( P <0.001), and 18.2% ( P =0.039), respectively. In the placebo, the sulfonylurea + placebo, and the metformin + placebo treatment groups, insulin resistance increased 30.3% ( P =0.002), 20.1% ( P =0.001), and 17.6% ( P =0.100), respectively, compared with baseline. Rosenstock J, for the Pioglitazone HCl Study Group. Diabetologia . 2000;43(suppl 1):A192. Matthews DR, et al. Diabetologia . 1985;28:412-419.
The above slide summarizes the calculated percentage changes from baseline in beta-cell function at the conclusion of three 16-week, double-blind studies, using homeostasis model assessment (HOMA). The HOMA models followed standardized mathematical calculations designed to estimate beta-cell function and insulin resistance values. For an individual patient, a decrease in values for insulin resistance and an increase in values for beta-cell function indicate a positive effect on these parameters. HOMA BCF = 20 x fasting plasma insulin ( lU/mL) fasting plasma glucose (mmol/L) – 3.5 The pioglitazone 30 mg, the sulfonylurea + pioglitazone 30 mg, and the metformin + pioglitazone 30 mg treatment groups showed significant ( P <0.001) improvements in beta-cell function, as calculated by HOMA-BCF, with changes of 41.4%, 38.0%, and 37.6%, respectively. Compared with baseline, the placebo, the sulfonylurea + placebo, and the metformin + placebo treatment groups also showed improvements in beta-cell function, with changes of 23.4% ( P =0.027), 8.2% ( P =0.07), and 36.8% ( P =0.051), respectively. Rosenstock J, for the Pioglitazone HCl Study Group. Diabetologia . 2000;43(suppl 1):A192. Matthews DR, et al. Diabetologia . 1985;28:412-419.
Based on LOCF analysis of data from all treated subjects, those receiving placebo demonstrated statistically significant ( P <=0.05) mean increases from baseline in A 1c . In patients receiving ACTOS, the mean decrease in A 1c from baseline was statistically significant ( P <=0.05), with the exception of the 7.5-mg group, at most timepoints. The difference in mean A 1c at endpoint for the 45-mg once-daily dose group vs placebo was 1.6 percentage points. Aronoff S, et al. Diabetes Care . 2000;23:1605-1611.
There is consistent effectiveness in a subset analysis of patients with a baseline FPG <280 mg/dL. In this subgroup of patients, the mean A 1c at baseline was 9.0% and the mean FPG level was 211.1 mg/dL. ACTOS compared with placebo achieved significant ( P <=0.05) mean A 1c reductions of 1.2 percentage points at 15 mg once daily and 2.0 percentage points at 45 mg once daily. The data are from Study 001, a 26-week, double-blind, placebo-controlled, multicenter study. The subanalysis included 217 patients. Aronoff S, et al. Diabetes Care . 2000;23:1605-1611.
When the secondary efficacy analysis of mean change from baseline in FPG was assessed, it was found that patients receiving placebo showed a mean increase in FPG at all timepoints. In contrast, for the ACTOS groups taking 15-, 30-, or 45-mg once-daily doses, there were statistically significant ( P <=0.05) mean decreases from baseline at each visit. At endpoint, the difference in FPG for the 45-mg/day group vs the placebo-treated group was 65.3 mg/dL. Aronoff S, et al. Diabetes Care . 2000;23:1605-1611.
At the study endpoint, favorable effects on lipid profile were observed in the groups treated with ACTOS. In this monotherapy study, the group taking 45 mg once daily showed a statistically significant ( P <=0.05) increase in HDL-C vs placebo. The change from baseline was 19.1%. Aronoff S, et al. Diabetes Care . 2000;23:1605-1611.
CHICAGO (Carotid intima-media tHICkness in Atherosclerosis using pioGlitazOne) is an 18-month, double-blind, randomized, multicentered, comparator-controlled study in subjects with type 2 diabetes mellitus that evaluated the effects of ACTOS® (pioglitazone HCl) versus glimepiride on the rate of progression of coronary atherosclerotic disease. The primary objective was to evaluate ACTOS compared with glimepiride on carotid artery atherosclerosis as measured by carotid intima-media thickness. The secondary objectives included the comparison of ACTOS and glimepiride on: The percent change in coronary calcium score* using electron beam computed tomography (EBCT) Cardiovascular events including heart failure Other objectives of this study included the effect of ACTOS versus glimepiride on the following biochemical markers: Glucose metabolism Lipids Inflammation *The presence of coronary artery calcification provides substantial, cost-effective, independent prognostic value in predicting incident coronary heart disease that is incremental to measured coronary risk factors. Takeda Pharmaceuticals North America, Inc. Data on file.
Evaluable baseline and follow-up IVUS examinations were available in 360 patients (66%), 181 in the glimepiride group and 179 in the pioglitazone group. This slide shows the results for the primary efficacy parameter, the change in percent atheroma volume. The glimepiride group (shown in orange) had highly significant progression, 0.73%, p<.001, compared with baseline. Pioglitazone treated patients had a reduction of -0.16%, which was statistically unchanged from baseline. The between groups P value was 0.002. These data demonstrate that, after 18 months of treatment, patients assigned to glimepiride had unequivocal progression of coronary atherosclerosis, whereas pioglitazone-treated patients had no progression. To our knowledge, this is the first study in which a diabetes therapy has been shown to slow or prevent progression of coronary atherosclerosis.
Several secondary IVUS endpoints were pre-specified in the study protocol. These included the mean maximum atheroma thickness, the total atheroma volume, and the atheroma volume in the most diseased 10 mm sub-segment. For these three endpoints, the most significant difference was observed for the maximum atheroma thickness, p=0.006. There were no statistical differences in the 10 mm most diseased sub-segment.
Both regimens were well tolerated, but revealed a different pattern of adverse effects. Hypoglycemia was more common with glimepiride, 37% versus 15%, p<.001. Peripheral edema was more common with pioglitazone, 17.8% compared with 11% for glimepiride, p=0.02. Angina was more common in the glimepiride group. Bone fractures occurred exclusively in the pioglitazone group, affecting 3% of patients. There was approximately a 2 kg greater weight gain in the pioglitazone group.
The UKPDS also investigated the effects of blood pressure control on the prevention of complications of diabetes. One thousand one hundred forty-eight (1,148) of the randomized (4,297) patients had hypertension (mean BP160/94 mm Hg). Patients were randomized to either an ACE inhibitor or a beta-blocker to achieve either tight BP control (<150/85 mm Hg) or less tight control (180/105 mm Hg), with avoidance of treatment with ACE inhibitors or beta-blockers. However, medications were permitted in each group if required to achieve or maintain goals. Mean BP was reduced significantly during the follow-up period (median 8.4 years) in the tight control group compared with the less tight control group, with mean BP of 144/82 mm Hg and 154/87 mm Hg, respectively. However, after 9 years of follow-up, three or more medications were required in the tight control group to sustain goal BP. Statistically significant reductions in both microvascular and macrovascular complications were observed in the tight control group vs the less tight control group. These reductions are illustrated on this slide. It should be noted that a reduction (not shown here) in all-cause mortality did not reach statistical significance. The investigators also found that the studied ACE inhibitor and beta-blocker were equally safe and effective. UK Prospective Diabetes Study Group. BMJ . 1998;317:703-713. UK Prospective Diabetes Study Group. BMJ . 1998;317:713-720.
This graphs shows the second order relationship of LDL+HDL and cardiovascular event risk reduction, using data from major clinical trials of lipid-lowering therapy. The percent change from baseline (or placebo) for LDL+HDL is added using absolute values. This is plotted against the relative risk reduction in composite endpoints from each of the trials. The trend line indicates that these variables are highly correlated. In fact, it appears that the percent absolute change in LDL+HDL during treatment in these clinical trials accounts for 76% of the effect on cardiovascular event relative risk reduction vs placebo in this crude analysis.
The Hypertension Optimal Treatment (HOT) study was designed to determine if major cardiovascular outcomes are associated with target diastolic blood pressure (DBP) levels <=90 mm Hg, <=85 mm Hg, and <=80 mm Hg. More than 18,000 patients aged 50 to 80 years with hypertension and DBP between 100 and 115 mm Hg were randomized to achieve one of the three target DBP levels mentioned above. Antihypertensive therapy was started with the calcium blocker felodipine, and then additional treatment was given according to a 5-step regimen until the target DBP was achieved. In this study, patients were also randomized to receive low-dose aspirin (75 mg daily) or placebo. Patients were followed for an average of 3.8 years. A total of 1,501 patients had diabetes at baseline, including 8% of patients in each of the three target DBP groups. In this subgroup of patients, the rate of major cardiovascular events (fatal and nonfatal myocardial infarction or stroke or all other cardiovascular deaths) declined in relation to the target DBP group ( P =0.005 for trend). Notably, risk for these events in the <=80-mm Hg group was reduced by 51% relative to the <=90-mm Hg group. Risk for MI ( P =0.11 for trend) and stroke ( P =0.34 for trend) was also reduced with lower target DBP levels. Risk for these events in the <=80-mm Hg group was reduced by 50% and 30%, respectively, relative to the <=90-mm Hg group. However, these risk reductions did not achieve statistical significance. Finally, cardiovascular mortality in the <=80-mm Hg groups was significantly reduced by 67% relative to the other DBP target groups ( P =0.016 for trend). These results demonstrate that lowering DBP to a target level <=85 mm Hg is associated with significant reductions in cardiovascular morbidity and mortality. Hansson L, et al for the HOT Study Group. Lancet . 1998;351:1755-1762.
There are 2 known endogenous cannabinoid receptors — CB1 and CB2. Endogenous ligands shown to bind to these receptors have also been identified. These ligands include anandamide and 2-arachidonyl glycerol (2-AG). Levels of 2-AG are much higher than anandamide, and 2-AG is thought to be involved in several other metabolic pathways. Anandamide and 2-AG exert their actions by binding to and activating the cannabinoid receptors. CB 1 -R and CB 2 -R activation leads to: Inhibition of adenylate cyclase Stimulation of mitogen-activated protein kinase Inhibition of voltage gated Ca 2+ channels (CB 1 -R only) Cannabinoid receptors are G-protein coupled receptors consisting of 7 transmembrane-spanning domains Pertwee RG. Pharmacology of cannabinoid CB1 and CB2 receptor. Pharmacol Ther. 1997;74:129-180. De Petrocellis L, Cascio MG, Di Marzo V . The endocannabinoid system: a general view and latest additions. Br J Pharmacol. 2004;141:765-774. Sugiura T, Kondo S, Sukagawa A, et al . 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Commun. 1995;215:89-97. Devane WA, Hanus L, Breuer A, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 1992;258:1946-1949. Ameri A. The effects of cannabinoids on the brain. Prog Neurobiol. 1999;58:315-348. Devane WA, Dysarz FA, Johnson MR, Melvin LS, Howlett AC. Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol . 1988;34:605-613.
This table offers a comprehensive summary illustration of how many cardiometabolic risk factors may be affected by the ECS. In the brain, the hypothalamus receives and integrates signals regarding the status of body-fat stores from adipose tissue and other peripheral tissues. CB1-R overactivity in the hypothalamus is associated with excess adiposity. CB1-R activation in the hypothalamus also sustains overeating in obese animals. Endocannabinoids have been documented in adipose tissue, with CB1-R having been shown to be active in stimulating lipogenesis. Ongoing investigation in animals indicates that, in skeletal muscle, CB1-R stimulation reduces insulin-mediated glucose uptake. In the liver, it has been demonstrated that endocannabinoid-mediated increase in de novo lipogenesis in the liver is a critical component in diet-induced obesity. In the gastrointestinal tract, it is known that CB1-R activation by anandamide increases food intake. A surge in intestinal anandamide levels serves as a short-range hunger signal to promote feeding. Badman MK, Flier JS. The gut and energy balance: visceral allies in the obesity wars. Science . 2005;307:1909-1914. Schwartz GJ. The role of gastrointestinal vagal afferents in the control of food intake: Current Prospects. Nutrition . 2000;16:866-873. 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. 2 003;63:908-914. Di Marzo V, Goparaju SK, Wang L, et al. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature. 2001;410:822-825. Cota D, Marsicano G, Tschöp M, et al. The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J Clin Invest . 2003;112:423-431. Pagotto U, Vicennati V, Pasquali R. The endocannabinoid system and the treatment of obesity. Ann Med . 2005;37:270-275. 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 (Lond) . 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. Gomez RG, Navarro M, Ferrer B, et al. A peripheral mechanism for CB1 cannabinoid receptor-dependent modulation of feeding. J. Neurosci. 2002;22:9612-9617.
The ECS is upregulated in the brain, liver, and adipose tissue in chronic obesity. In the brain, the hypothalamus plays a principal role in the control of feeding and regulation of body weight, and excessive cannabinoid expression in the hypothalamus is associated with obesity. CB1-R 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. In the peripheral arena, ECS overactivation promotes lipogenesis at the level of adipose tissue and the liver. ECS activity in the GI tract interferes with feelings of satiety, and CB1-R stimulation of skeletal muscle decreases glucose uptake. All of these central and peripheral effects contribute to the increased risk of dyslipidemia, 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;63:908-914. 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. Nat 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 (Lond) . 2005;29:183-187.
It has become well accepted that moderate weight loss improves cardiovascular and metabolic risk factors. In a study by Case and colleagues of obese individuals enrolled in a medically supervised rapid weight loss program study, 1 year of consecutive patients’ charts was reviewed to determine the response to diet-induced weight loss. Out of 185 individuals, 125 (68%) met the NCEP definition of the metabolic syndrome. At 4 weeks, a moderate decrease in weight (6.5%) induced by a very low calorie diet resulted in substantial reductions of systolic (11.1 mm Hg) and diastolic (5.8 mm Hg) blood pressure, glucose (17 mg/dL), triglycerides (94 mg/dL) and total cholesterol (37 mg/dL) (all P <0.001). These improvements were sustained at the end of active weight loss (average 16.7 weeks; total weight loss 15.1%), with further significant reductions in blood pressure and triglycerides. Weight loss was related to the changes in each criterion of the metabolic syndrome. The authors concluded that moderate weight loss markedly improved all aspects of the metabolic syndrome. Case CC, Jones PH, Nelson K, O’Brian Smith E, Ballantyne CM. Impact of weight loss on the metabolic syndrome. Diabetes Obes Metab . 2002;4:407-414.
Metabolic Syndrome, Diabetes, and Cardiovascular Disease ...
Metabolic Syndrome, Diabetes, and Cardiovascular Disease: Implications for Preventive Cardiology <ul><li>Nathan D. Wong, PhD, FACC, FAHA </li></ul><ul><li>Professor and Director </li></ul><ul><li>Heart Disease Prevention Program </li></ul><ul><li>Division of Cardiology </li></ul><ul><li>University of California, Irvine </li></ul>
Probability of Death From CHD in Patients With Type 2 Diabetes With or Without Previous MI
Framingham Heart Study 30-Year Follow-Up: CVD Events in Patients With Diabetes (Ages 35-64) 10 9 20 11 9 6 38 19 3* 30 0 2 4 6 8 10 Age-adjusted annual rate/1,000 Men Women Total CVD CHD Cardiac failure Intermittent claudication Stroke Risk ratio P <0.001 for all values except * P <0.05. Wilson PWF, Kannel WB. In: Hyperglycemia, Diabetes and Vascular Disease. Ruderman N et al, eds. Oxford; 1992.
The Metabolic Syndrome Insulin Resistance Hypertension Type 2 Diabetes Disordered Fibrinolysis Complex Dyslipidemia TG, LDL HDL Endothelial Dysfunction Systemic Inflammation Athero- sclerosis Visceral Obesity Adapted from the ADA. Diabetes Care. 1998;21:310-314; Pradhan AD et al. JAMA. 2001;286:327-334.
Revised ATP III Metabolic Syndrome Oct 2005 *Diagnosis is established when 3 of these risk factors are present. † Abdominal obesity is more highly correlated with metabolic risk factors than is BMI. ‡ Some men develop metabolic risk factors when circumference is only marginally increased. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA . 2001;285:2486-2497; Updated AHA/NHLBI Statement Oct 18, 2005: Grundy et al. Circulation 2005; 112 (epub). <40 mg/dL <50 mg/dL or Rx for ↓ HDL Men Women > 102 cm (>40 in) > 88 cm (>35 in) Men Women 100 mg/dL or Rx for ↑ glucose Fasting glucose 130/ 85 mm Hg or on HTN Rx Blood pressure HDL-C 150 mg/dL or Rx for ↑ TG TG Abdominal obesity † (Waist circumference ‡ ) Defining Level Risk Factor
International Diabetes Federation Definition: Abdominal obesity plus two other components: elevated BP, low HDL, elevated TG, or impaired fasting glucose
Intra-abdominal (Visceral) Fat The dangerous inner fat! Back Visceral AT Subcutaneous AT Front
Relationship Between Visceral Adipose Tissue and Insulin Action Banerji M, et al. Am J Physiol. 1997;273(2 pt 1):E425-E432. 18 16 14 12 10 8 6 4 2 0 1,000 2,000 3,000 4,000 5,000 Visceral adipose tissue volume per unit surface area (mL/m 2 ) Glucose disposal (mg/kg LBM/min) Women Men
Prevalence of the Metabolic Syndrome Among US Adults NHANES 1988-1994 Age (years) Ford E et al. JAMA . 2002(287):356. 1999-2002 Prevalence by IDF vs. NCEP Definitions (Ford ES, Diabetes Care 2005; 28: 2745-9) (unadjusted, age 20+) NCEP : 33.7% in men and 35.4% in women IDF: 39.9% in men and 38.1% in women Prevalence (%) 0 5 10 15 20 25 30 35 40 45 20-29 30-39 40-49 50-59 60-69 > 70 Men Women
Prevalence of the NCEP Metabolic Syndrome: NHANES III by Sex and Race/Ethnicity Prevalence, % Men Ford ES et al. JAMA 2002;287:356-359. Women 25% 16% 28% 21% 23% 26% 36% 20% White African American Mexican American Other
Cardiovascular Disease (CVD) and Total Mortality: US Men and Women Ages 30-74 (age, gender, and risk-factor adjusted Cox regression) NHANES II Follow-Up (n=6255)(Malik and Wong, et al., Circulation 2004; 110: 1245-1250 ) * p<.05, ** p<.01, **** p<.0001 compared to none * *** *** *** ** *** *** *** *** *** ***
Metabolic Syndrome, CVD Events, and Mortality <ul><li>European cohort studies (6156 men and 5356 women): Modified WHO definition of MetS associated with all-cause mortality (RR=1.44 [1.17-1.84] in men and 1.38 [1.02-1.87] in women) and CVD mortality (RR=2.26 [1.61-3.17] in men and 2.78 [1.57-4.94 in women) (Hu et al. Arch Intern Med 2004; 164: 1066-76) </li></ul><ul><li>Atherosclerosis Risk in Communities (ARIC) study (12,089 men and women): 11 year follow-up, ATP III MetS associated with 1.5-2-fold greater likelihood of developing CHD and stroke, but MetS did not improve prediction over FRS (McNeill et al. Diab Care 2005; 28: 385-90) </li></ul><ul><li>Cardiovascular Health Study (CHS) (2,175 elderly subjects): ATP III definition associated with 38% increased risk (p<0.01) of coronary/cerebrovascular events (Scuteri et al., Diab Care 2005; 28: 882-7) </li></ul>
Evidence Supporting Aggressive Glycemic Control
Thiazolidinediones: Mechanism of Insulin Sensitization
PPAR α vs. gamma <ul><li>PPAR α (fibrates) work mostly in the liver and lower VLDL triglycerides and increase HDL-C but do not affect FFA, glucose, or insulin sensitivity </li></ul><ul><li>PPAR gammas (TZDs such as rosiglitazone or pioglitazone) promote new fat cells in subcutaneous tissue and decrease intramuscular and visceral fat. </li></ul>
Thiazolidinediones: Rationale for Type 2 Diabetes Therapy
Reduced Insulin Resistance Suggested by HOMA Analysis of Pioglitazone Therapy
Improved β-Cell Response Suggested by HOMA Analysis of Pioglitazone Therapy
Changes in A 1c From Baseline in All Treated Patients
Endpoint Changes in Patients With Lower Baseline A 1c (Mean 9.0%)*
Change in FPG From Baseline in All Treated Patients
Change in Lipid Profile at Endpoint: ACTOS 26-Week Monotherapy
DREAM Study for Prevention of Diabetes <ul><li>5,269 persons with pre-diabetes randomized to rosiglitazone (8 mg daily) vs. placebo and ramipril vs. placebo for median of 3 years </li></ul><ul><li>10.6% of those on rosiglitazone progressed to type 2 diabetes vs. 25% on placebo, a 62% risk reduction (p<0.0001). </li></ul><ul><li>Primary endpoint of development of diabetes or death from any cause reduced by 60% </li></ul><ul><li>51% of those on rosiglitazone vs. 30% on placebo returned to normal blood sugar </li></ul><ul><li>No significant difference in future cardiovascular events, but higher rate of new heart failure in those on rosiglitazone (0.5%) vs. placebo (0.1%). Body weight increased 2.2kg more in the rosiglitazone vs. placebo group. </li></ul>The DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) investigators. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 2006;368:1096-105.
PERISCOPE: Comparison of Pioglitazone vs. Glimepiride on Progression of Coronary Atherosclerosis in Patients with Type 2 Diabetes Steve E. Nissen, MD Cleveland Clinic Foundation Cleveland, Ohio ACC Scientific Sessions, Late Breaker Monday March 31, 2008 Chicago, Illinois
PERISCOPE Background <ul><li>Background </li></ul><ul><li>Cardiovascular disease is the leading cause of death in patients with diabetes </li></ul><ul><li>Few studies have compared outcomes for diabetes medications beyond their glucose lowering efficacy </li></ul><ul><li>Sought to compare coronary disease progression measured by intravascular ultrasound for two alternative treatment strategies: </li></ul><ul><ul><li>Glimepiride (an insulin secretagogue) </li></ul></ul><ul><ul><li>Pioglitazone (an insulin sensitizer) </li></ul></ul><ul><li>Hypothesis </li></ul><ul><li>To directly compare the effectiveness of these 2 alternative approaches, an insulin-providing vs an insulin-sensitizing strategy, in reducing progression of atherosclerosis in patients with type 2 diabetes and coexisting coronary artery disease </li></ul>Nissen S. JAMA .2008;299(13):1561-1573
543 patients with type 2 diabetes undergoing angiography for clinical indications Glimepiride 1-4mg (titrated to maximally tolerated dose) Repeat Intravascular Ultrasonography Examination at 16 weeks Primary Outcome Measure: Change in percent atheroma volume (PAV) from baseline to study completion Pioglitazone 15-45mg ( titrated to maximally tolerated dose ) PERISCOPE Study Design Nissen S. JAMA .2008;299(13):1561-1573
Pioglitazone PERISCOPE Primary Efficacy Parameter Change in Percent Atheroma Volume (%) P<0.001 P=0.44 Change in PAV(%) 0.73 -0.16 Difference between groups P=0.002 Nissen S. JAMA .2008;299(13):1561-1573
PERISCOPE Other Adverse Events Nissen S. JAMA .2008;299(13):1561-1573 <0.001 +3.6kg +1.6kg Change in Body Weight 0.004 3.0% 0% Bone Fractures 0.07 4.8% 8.8% Hypertension 0.69 1.1% 0.7% Creatinine > 2.0 mg/dL 0.01 10.7% 4.8% BUN >30 mg/dL 0.05 7.0% 12.1% Angina 0.02 17.8% 11.0% Edema <0.001 15.2% 37.0% Hypoglycemia P Value Pioglitazone (n=270) Glimepiride (n=273)
UKPDS: Effects of Tight vs Less-Tight Blood Pressure Control
ACCORD: Is too aggressive lowering of HbA1c harmful? <ul><li>NHLBI-sponsored ACCORD study of approx. 10,000 T2DM pts with CHD or 2+ risk factors tested control of HbA1c to <6% vs. standard strategy for HbA1c 7-7.9%. </li></ul><ul><li>Median HbA1c achieved 6.4% vs. 7.5% </li></ul><ul><li>The trial was stopped early (Feb 6, 2008) due to more deaths in intensive arm (257, or 14/1000 person years) vs. standard arm (203, or 11/1000 person years). </li></ul><ul><li>There were, however, 10% fewer MIs in intensive arm and no link to any particular medication causing increases in deaths was noted. </li></ul><ul><li>No change in general recommendation by ADA to achieve for HbA1c <7% in most diabetics; in older diabetics with prior CHD or other risk factors like in ACCORD population, less stringent goals of around 7% might be appropriate. </li></ul>
ADVANCE and VADT <ul><li>In light of ACCORD, a larger study, ADVANCE, in progress of 11,140 pts with T2DM also did an interim analysis reported February 14 but did not find any evidence of increased risks. </li></ul><ul><li>These pts achieved the same HbA1c of 6.4% as achieved in the ACCORD intensive therapy arm, but ADVANCE pts had less severe diabetes--duration shorter (8 vs. 10 years) and somewhat lower HbA1c at baseline. </li></ul><ul><li>It is possible that it is the intensity of treatment or rather than the HbA1c achieved which is the problem but that will need to be examined further. </li></ul><ul><li>The U.S. VA Diabetes Trial, also examining the relation of intensive glycemic control to cardiovascular outcomes will report its results soon. </li></ul><ul><li>The ADA plans to evaluate the results from all these studies before making further recommendations. </li></ul>
Collaborative Atorvastatin Diabetes Study (CARDS) <ul><li>2838 patients aged 40-75 with type 2 diabetes, no prior CVD, but at least 1 of the following: retinopathy, albuminuria, smoking, or hypertension </li></ul><ul><li>Randomization to 10 mg atorvastatin or placebo </li></ul><ul><li>Mean follow-up 3.9 years </li></ul><ul><li>Reduction in all CVD events of 37% (p=0.001), all cause mortality 27% (p=0.059). CHD events reduced 36% and stroke 48%. </li></ul>Colhoun HM et al., The Lancet 2004; 364: 685-696
Relative Risk of Events in 4S Study Adapted from Haffner et al. Arch Intern Med . 1999;159:2661. NFG IFG DM NFG IFG DM NFG IFG DM Patients (%) CAD Events Revascularization Total Mortality 16.6 16.7 0 5 10 15 20 25 Patients (%) 26.2 0 10 20 30 40 Patients (%) Placebo Simvastatin n = 1631/1606 P <0.001 95% CI = 0.59-0.79 RR = 0.68 n = 335/343 P <0.003 95% CI = 0.46-0.85 RR = 0.62 n = 232/251 P <0.001 95% CI = 0.41-0.80 RR = 0.58 n = 1631/1606 P <0.001 95% CI = 0.55-0.80 RR = 0.67 n = 335/343 P <0.01 95% CI = 0.37-.87 RR = .57 n = 232/251 P <0.005 95% CI = 0.32-0.82 RR = 0.52 n = 1631/1606 P <0.005 0.57-0.90 95% CI = RR = 0.72 n = 335/343 P <0.02 0.35-0.93 95% CI = RR = 0.57 n = 232/251 P <0.34 95% CI = 0.49-1.27 RR = 0.79 21.1 11.5 10.2 11.6 30.4 37.5 18.6 19.5 23.5
Reduction in CHD Event Rates With Statin Treatment (WOSCOPS) Sattar N, et al. Circulation . 2003;108:414-419 10.4 6.2 7.7 4.4 0 2 4 6 8 10 12 CHD event rate (%) Patients With Metabolic Syndrome Patients Without Metabolic Syndrome Placebo Pravastatin
Are LDL and HDL Effects Additive? R2 = 0.8512 0 20 40 60 80 100 0 10 20 30 40 50 60 70 80 % Absolute Change in LDL+HDL % CV Event RRR 4S VA HIT DAIS BIP AFCAPS/ TexCAPS WOSCOPS LIPID CARE, HPS HHS CDP ASCOT ALLHAT PROSPER 2 nd Order Relationship HATS FATS FATS F/U
Hypertension Optimal Treatment (HOT): Outcomes in Patients With Diabetes
Most CHD Events May be Preventable by Control of Blood Pressure, HDL-C, LDL-C to “Optimal” Levels in Persons with the Metabolic Syndrome (Wong et al., Am J Cardiol 2003; 91: 1421-26) ** * * p<0.05, ** p<0.01 compared to men
The endocannabinoid system <ul><li>An endogenous signaling system which contributes to physiologic regulation of energy balance, food intake, and lipid and glucose metabolism through both central and peripheral effects </li></ul>
Effects of cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors over 1 year: RIO Europe Study <ul><li>1,507 pts with BMI >=30 or >27 with dyslipidemia and/or hypertension randomized to placebo, 5mg or 20 mg rimonabant, w/hypocaloric diet </li></ul><ul><li>Weight loss at 1 year: -3.4 kg w/5mg, -6.6 kg w/10 mg rimonabant vs. placebo (-1.8 kg) </li></ul><ul><li>Rimonabant 20 mg produced greater improvements in waist circumference, HDL-C, triglycerides, LDL-C, insulin, and prevalence of metabolic syndrome (reduced by 34% w/placebo vs. 64.8% with rimonabant) </li></ul>Van Gaal LF, et al. Lancet 2005; 365: 1389-97
Metabolic Syndrome: Lifestyle Management <ul><li>Obesity / weight management: low fat – high fiber diet resulting in 500-1000 calorie reduction per day to provide a 7-10% reduction on body weight over 6-12 mos, ideal goal BMI <25 </li></ul><ul><li>Physical activity: at least 30, pref. 60 min moderate intensity on most or all days of the week as appropriate to individual </li></ul><ul><li>Nutritional recommendations per ATP III guidelines: low intake of saturated fats, trans fats, and cholesterol, reduced consumption of simple sugars, and increased intakes of fruits, vegetables, and whole grains are reasonable </li></ul>Grundy SM, Hansen B, Smith SC, et al. Clinical management of metabolic syndrome. Report of the American Heart Association / National Heart, Lung, and Blood Institute / American Diabetes Association Conference on Scientific Issues Related to Management. Circulation 2004; 109: 551-556
Therapeutic Lifestyle Changes Nutrient Composition of TLC Diet <ul><li>Nutrient Recommended Intake </li></ul><ul><li>Saturated fat Less than 7% of total calories </li></ul><ul><li>Polyunsaturated fat Up to 10% of total calories </li></ul><ul><li>Monounsaturated fat Up to 20% of total calories </li></ul><ul><li>Total fat 25–35% of total calories </li></ul><ul><li>Carbohydrate 50–60% of total calories </li></ul><ul><li>Fiber 20–30 grams per day </li></ul><ul><li>Protein Approximately 15% of total calories </li></ul><ul><li>Cholesterol Less than 200 mg/day </li></ul><ul><li>Total calories (energy) Balance energy intake and expenditure to maintain desirable body weight/ prevent weight gain </li></ul>
Effect of Mediterranean-style diet in the metabolic syndrome <ul><li>180 pts with metabolic syndrome randomized to Mediterranean-style vs. prudent diet for 2 years </li></ul><ul><li>Those in intervention group lost more weight (-4kg) than those in the control group (+0.6kg) (p<0.01), and significant reductions in CRP and Il-6. </li></ul><ul><li>After 2 years, 40 pts in intervention group still had features of metabolic syndrome compared to 78 pts in the control group </li></ul>Esposito K et al. JAMA 2004; 292(12): 1440-6.
Therapeutic Goals and Recommendations for Clinical Management of Metabolic Syndrome (Grundy et al. Circulation 2005; 112 (epub) Oct 18) Dyslipidemia LDL-C, HDL-C, TG, non-HDL-C Elevated Blood Pressure Elevated Glucose Prothrombotic and Proinflammatory States
ABC’s of Metabolic Syndrome Management Aim for BP <130/85 mm Hg, or <130/80 mm Hg for type 2 diabetes . Consider ACE-I or ARBs and low dose diuretics in combination rx. BP Control B Treat all high-risk patients with low-dose aspirin (or clopidogrel in those with CVD if aspirin is contraindicated) and consider low-dose aspirin in moderately high-risk patients. Antiplatelet agent A Goals / Treatment Intervention
ABC’s of Metabolic Syndrome Management Long term smoking cessation Cigarette Smoking <ul><li>LDL-C targets, ATP III guidelines </li></ul><ul><ul><li>– High Risk : CHD, CHD risk equivalents (incl. >20% 10-year risk): <100 mg/dL (option <70 mg/dl if CVD present) </li></ul></ul><ul><ul><li>– Moderately High Risk (10-20% risk or subclinical disease) 2 RF: <130 mg/dL, option <100 mg/dL </li></ul></ul><ul><ul><li>– Moderate Risk (2+ RF, <10%) <130 mg/dL </li></ul></ul><ul><ul><li>-- Low Risk : 0-1 RF: <160 mg/dL </li></ul></ul><ul><li>Non-HDL-C targets 30 mg/dL higher </li></ul><ul><li>HDL-C: >40 mg/dL (men) </li></ul><ul><ul><ul><li>>50 mg/dL (women) </li></ul></ul></ul><ul><li>TG: <150 mg/dL </li></ul>Cholesterol Management C Goals Intervention
Goals for Elevated Glucose <ul><li>For IFG delay progression to type 2 diabetes; for diabetes, HgbA1c <7.0% </li></ul><ul><li>For IFG encourage weight reduction and increased physical activity </li></ul><ul><li>For type 2 diabetes, lifestyle therapy and if necessary, pharmacologic therapy to achieve near normal HgbA1c <7%; modify other risk factors and behaviors. </li></ul><ul><li>Limited clinical trial data on treatment to reduce CVD events; neither metformin or thiazolidinediones recommended just for prevention of diabetes because cost-effectiveness and long-term safety not yet documented. </li></ul>Grundy et al. AHA/NHLBI scientific statement on diagnosis and management of metabolic syndrome. Circulation Oct 18, 2005; 112 (e pub)