5. Hypertension in Diabetes: prevalence NEJM 2000; 342:905 Diabetes Care 2005; 28:310 Am J Kid Dis 2007; 49 (Suppl 2):S74 Type 1 (¼ are Htn) At Diagnosis: 20-40% With Microalbuminuria: 30-50% With Macroalbuminuria: 65-88% Type 2 (½ are Htn) At Diagnosis: 50% With Microalbuminuria: 80% With Macroalbuminuria: >90%
7. Hypertension in Diabetes: partners in crime DM-2 DM-1 Diabetes Hypertension 0 Cause: Cause: Mainly due insulin resistance (as a facet of MS) Mainly due insulin resistance (as a facet of MS) But may be due to underlying DN or other causes. But may be due to underlying DN or other causes. American Diabetic Association. Diab Care 2004 Onset: Onset: Usually precedes the onset of nephropathy and Usually precedes the onset of nephropathy and even the onset of type 2 diabetes by years or decade even the onset of type 2 diabetes by years or decade Ritz et al. J Int Med. 2001 ; 249: 215 Ritz et al. J Int Med. 2001 ; 249: 215 - - 223 223 Cause: Cause: Hypertension is usually Hypertension is usually renoparenchymal renoparenchymal in origin in origin caused by Or pointing to underlying diabetic nephropathy caused by Or pointing to underlying diabetic nephropathy Onset: Onset: Typically becomes manifest about the time that Typically becomes manifest about the time that patients develop patients develop microalbuminuria microalbuminuria . . American Diabetic Association. American Diabetic Association. Diab Diab Care 2004 Care 2004
48. Trials Demonstrating Risk Reduction in CVD Outcomes with Lower BP in Diabetics Crook and Velusamy, Current HTN Reports, 2003 155.1/71.1 v 151/79 SysEURO (nitrendipine) 155.1/71.1 v 144/67/7 SHEP (diuretic) 154/87 v 144/82 UKPDS (captopril & atenolol) 137/81 v 128/75 ABCD (nisoldipine & enalapril) DBP 81.1 – 85.2 HOT (felopidine) Achieved BP Study
59. ALLHAT, Diabetic Risk and Treatment of Hypertension ~9% Lisinopril ~10% Amlodipine ~16% Chlorthiadone Incidence of Diabetes over Follow-up Agent
60. Multiple Agents Usually Required to Achieve BP Goals in Diabetic Patients UKPDS ABCD MDRD HOT AASK Number of Agents Needed IDNT (<135/85) IRMA2 (<135/85) RENAAL (<140/90) Adapted, with permission, from Bakris GL, et al. Am J Kidney Dis . 2000;36:646-661.
61.
Editor's Notes
Slide 23 Insulin resistance and impaired beta-cell function are primary defects that occur early in the course of development of type 2 diabetes. Insulin resistance leads to an obligatory hyperinsulinemia in order to maintain normal glucose tolerance. In most cases of type 2 diabetes, beta-cell dysfunction develops subsequent to the development of insulin resistance, and it is not until such beta-cell dysfunction develops that any abnormality in glucose tolerance is seen. The condition that results is termed impaired glucose tolerance (IGT). In some cases beta-cell dysfunction may develop in the absence of early insulin resistance. However, exposure of tissues to hyperglycemia in the face of beta-cell dysfunction increases resistance to the effects of insulin whether or not insulin resistance was present to begin with. Ultimately, type 2 diabetes is the result of worsening beta-cell function, either in the most common situation of chronic pre-existing insulin resistance or, in the less common scenario of decreased beta-cell function without pre-existing insulin resistance. Saltiel A, Olefsky JM. Diabetes. 1996;45:1661-1669. 1
Slide 26 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. 1
Slide 32 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. 1
Physiologic changes involved in the progression of insulin resistance mimic those in the development of atherosclerosis. Adiposity plays a role in the development of insulin resistance, and fat-derived substances affect inflammatory functions involved in vascular injury. The inflammatory marker C-reactive protein is elevated in insulin resistance and predicts vascular events. Thus, the marker predicts both diabetes and cardiovascular disease. Endothelial cell dysfunction occurs with individual components of the insulin resistance syndrome, such as hypertension. It also occurs with only modest alterations in risk factors when insulin resistance is present. In the United States, the rate of metabolic syndrome—increased abdominal adiposity; elevated triglycerides; decreased high-density lipoprotein cholesterol; elevated blood pressure and uric acid; small, dense low-density lipoprotein particles; and albuminuria—is on the rise in proportion to obesity. Hsueh WA, Law R. Am J Cardiol . 2003;92(suppl):3J-9J.
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 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 100-125 mg/dL. ADA. 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. ADA. Diabetes Care . 1998;21:310-314.
Slide 7: Effect of BP on CHD Mortality: MRFIT A study by Neaton and colleagues reported the age-adjusted CHD death rates per 10,000 person-years by level of SBP and DBP for men screened in MRFIT 1 Over the 12-year average follow-up period, 19,071 deaths were identified among the 316,099 white men screened. Of these deaths, CHD accounted for 6,327 (33%) Differences in death rates due to CHD among DBP categories for each SBP category were small, particularly for those with DBP levels <90 mm Hg However, a strong risk gradient was evident for SBP for each DBP category 1. Neaton JD, Wentworth D, for the Multiple Risk Factor Intervention Trial Research Group. Serum cholesterol, blood pressure, cigarette smoking, and death from coronary heart disease. Overall findings and differences by age for 316 099 white men. Arch Intern Med. 1992;152:56-64.
In this decile analysis of the 347,978 MRFIT men, systolic BP was more strongly related to 12-year risk of stroke mortality than was diastolic BP. Thus for men in the ninth and tenth deciles of systolic BP, relative risks of fatal stroke were 4.44 and 8.21, whereas for men in these deciles of diastolic BP, relative risks were 2.85 and 4.39. Relative risk was adjusted by proportional hazards regression for age, race, serum cholesterol, cigarettes per day, use of medication for diabetes and income. SLIDE Stamler J, Stamler R, Neaton JD. Blood pressure, systolic and diastolic, and cardiovascular risks: US population data. Arch Intern Med . 1993;153:598-615.
There were no significant differences between the chlorthalidone and amlodipine groups with respect to the incidence of ESRD (RR 1.12; 95% CI, 0.89-1.40). The visionary group did not differ significantly from the chlorthalidone group with respect to ESRD (RR 1.11; 95% CI, 0.88-1.38). The ALLHAT population was selected for high CVD risk; mean baseline creatinine was 1.0 mg/dL; more detailed analyses of high – renal-risk subgroups will be forthcoming. SLIDE 57 The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288:2981-2997. In clinical trials, the most common side effects versus placebo were edema (8.3% vs 2.4%), headache (7.3% vs 7.8%), fatigue (4.5% vs 2.8%), and dizziness (3.2% vs 3.4%). Amlodipine besylate is indicated for the treatment of hypertension and angina. Please see full prescribing information enclosed in this slide kit.
In a review of clinical trials, Bakris and colleagues found that multiple antihypertensive agents (usually at least 3) were required before patients achieved the BP goals set by the study protocol. 1 Bakris GL, Williams M, Dworkin L, et al, for the National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis. 2000;36:646-661.
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