Blood pressure control in diabetes

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  • 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.
  • Blood pressure control in diabetes

    1. 1. Blood Pressure Control in Diabetes Dr. B. K. Iyer
    2. 2. Hypertension & Diabetes: Facts <ul><li>HTN is the leading cause of morbidity and mortality worldwide, affecting 20–60% of diabetics. </li></ul><ul><li>Hypertensive Diabetics vs Hypertensive non diabetics </li></ul><ul><ul><li>Twice the risk of CVD </li></ul></ul><ul><ul><li>1 in every 4 diabetic individuals in US has HTN. ADA 2005 </li></ul></ul><ul><li>The greatest reduction in cardiovascular mortality occurs at achieving a diastolic blood pressure of ~80 mmHg and systolic blood pressure to <130 mmHg </li></ul>
    3. 3. Hypertension in Diabetes: Facts <ul><li>The Third National Health and Nutrition Evaluation Survey (NHANES III) </li></ul><ul><li>29% of diabetic individuals with hypertension were unaware of the diagnosis. </li></ul><ul><li>43% of diabetic individuals with hypertension were untreated. </li></ul><ul><li>55% of diabetic individuals on treatment had a blood pressure ≥140/90. </li></ul><ul><li>12% of diabetic individuals on treatment had a blood pressure <130/85. </li></ul>Am J Prev Med 22:42–48, 2002
    4. 4. Hypertension in Diabetes: types <ul><li>1. Essential hypertension </li></ul><ul><li>2. Hypertension consequent to nephropathy </li></ul><ul><li>3. Isolated systolic hypertension </li></ul><ul><li>4. Supine hypertension with orthostatic fall </li></ul>About 20% of patients with hypertension will develop type 2 diabetes in a 3 year period. Bosch J et al. N Engl J Med 2006, 355(15):1551-1562. Fasting glucose levels increase in older adults with hypertension regardless of treatment type. BarzilayJ I et al. Arch Intern Med. 2006;166:2191-2201
    5. 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%
    6. 6. Hypertension in Diabetes: partners in crime NEJM 2000; 342:905 Diabetes Care 2005; 28:310
    7. 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
    8. 8. Hypertension in Diabetes: partners in crime <ul><li>The RAS itself plays imp. role in the development of diabetes. </li></ul><ul><li>Over activity of RAS appears to be linked to reduced insulin and glucose delivery to the peripheral skeletal muscle and impaired glucose transport and response to insulin signalling pathways, thus increasing insulin resistance. </li></ul><ul><ul><ul><li>Jandeleit-Dahm KA et al. J Hypertens 2005, 23(3):463-473. </li></ul></ul></ul><ul><li>Activation of a local pancreatic RAS, in particular within the islets, may represent an independent mechanism for the progression of islet cell damage in diabetes. </li></ul><ul><li>Ferrannini E et al. Diabetologia 2003, 46(9):1211-1219 </li></ul>Diabetes Hypertension Hypertensive patients without diabetes tend to be resistant to insulin and are hyperinsulinaemic compared with normotensive controls. Pollare T et al. Metabolism 1990, 39(2):167-174. <ul><li>The RAS itself plays imp. role in the development of diabetes. </li></ul><ul><li>Over activity of RAS appears to be linked to reduced insulin and glucose delivery to the peripheral skeletal muscle and impaired glucose transport and response to insulin signalling pathways, thus increasing insulin resistance. </li></ul><ul><li>Jandeleit-Dahm KA et al. J Hypertens 2005, 23(3):463-473. </li></ul><ul><li>Activation of a local pancreatic RAS, in particular within the islets, may represent an independent mechanism for the progression of islet cell damage in diabetes. </li></ul><ul><li>Ferrannini E et al. Diabetologia 2003, 46(9):1211-1219. </li></ul>
    9. 9. Hypertension in Diabetes: questions <ul><li>Which measurement of arterial blood pressure should be considered? </li></ul><ul><li>Which arterial pressure target value should be considered? </li></ul><ul><li>Which treatment modalities should be proposed as an optimal strategy? </li></ul>
    10. 10. Hypertension in Diabetes: unique points <ul><li>Supine, sitting, and standing blood pressure should be measured in all diabetic subjects. </li></ul><ul><li>This is an important issue in diabetic patients where autonomic neuropathy often leads to supine HTN with postural fall of blood pressure. </li></ul><ul><li>Arterial blood pressure measured in the sitting position should be considered as ideal. </li></ul>
    11. 11. Hypertension in Diabetes: targets for control
    12. 12. Hypertension in Diabetes: drugs for control <ul><li>In diabetic patients, particularly those with mild to moderate HTN, the first line of treatment includes lifestyle modification, i.e., </li></ul><ul><ul><li>weight control, </li></ul></ul><ul><ul><li>low fat </li></ul></ul><ul><ul><li>anti-atherogenic diet, </li></ul></ul><ul><ul><li>salt restriction, </li></ul></ul><ul><ul><li>reduction in alcohol intake, </li></ul></ul><ul><ul><li>discontinuation of smoking, and </li></ul></ul><ul><ul><li>supervised regimens of physical activity. </li></ul></ul><ul><li>The next step would be administration of antihypertensive drugs. </li></ul>
    13. 13. Hypertension in Diabetes: drugs for control <ul><li>Antihypertensive medications should not adversely affect carbohydrate and lipid metabolism. </li></ul><ul><li>Keeping in view the likely reason for HTN in a diabetic, any of the group of drugs can be used. </li></ul><ul><li>However, the therapeutic implications have to take into consideration the existence/ absence of </li></ul><ul><ul><li>concurrent disease/complication viz., IHD, CHF, Nephropathy, PVD. </li></ul></ul><ul><ul><li>Then the issue to be considered is the efficacy, tolerance, safety and cost effectiveness. </li></ul></ul>
    14. 14. Hypertension in Diabetes: drugs for control <ul><li>6 classes of drugs are considered to be effective for monotherapy. </li></ul><ul><ul><li>Diuretics </li></ul></ul><ul><ul><ul><li>In diabetics with isolated systolic HTN, diuretics are of greater benefit. </li></ul></ul></ul><ul><ul><li>beta-blockers, </li></ul></ul><ul><ul><li>calcium channel blocker </li></ul></ul><ul><ul><ul><li>Natriuretic CCBs like nitrendipine may be more suitable for diabetics with systolic HTN and mild diastolic HTN. </li></ul></ul></ul><ul><ul><li>alpha 1 adrenergic blockers </li></ul></ul><ul><ul><ul><li>their potentially favourable effects on the lipid profile makes them the first line therapy in the ADA statement </li></ul></ul></ul><ul><ul><li>ACE-inhibitors </li></ul></ul><ul><ul><ul><li>diabetics with rising azotaemia, i.e., serum creatinine value above 2.5 mg/dl should not be given ACE-inhibitor as it may lead to hyperkalaemia and complications. </li></ul></ul></ul><ul><ul><li>Angiotensin-receptor antagonists </li></ul></ul>
    15. 15. Development of Type 2 Diabetes
    16. 16. Hyperglycemia in Type 2 Diabetes <ul><li>Results due to 3 major metabolic defects </li></ul>
    17. 17. Insulin Resistance: Associated Conditions
    18. 18. Association of insulin resistance, Type 2 DM & CVD
    19. 19. The Continuum of CV Risk in Type 2 Diabetes
    20. 20. Factors affecting prevalence rates of hypertension <ul><li>Age </li></ul><ul><ul><li>Mean SBP and DBP increases with age </li></ul></ul><ul><ul><li>90% lifetime risk of hypertension in adults 55 years or older </li></ul></ul><ul><li>Risk factor constellation </li></ul><ul><ul><li>Obesity (particularly upper body) </li></ul></ul><ul><ul><li>Insulin resistance </li></ul></ul><ul><ul><li>Dyslipidemia (low HDL, high TG’s) </li></ul></ul><ul><ul><li>Diabetes </li></ul></ul><ul><ul><li>Salt Sensitivity </li></ul></ul><ul><ul><li>Microalbuminuria (vascular dysfunction) </li></ul></ul><ul><ul><li>Prothrombotic coagulation </li></ul></ul><ul><li>Gender </li></ul><ul><ul><li>BP higher in men until age 70 </li></ul></ul><ul><li>Obesity </li></ul><ul><li>Diabetes </li></ul><ul><li>Kidney Disease </li></ul><ul><ul><li>Prevalence of hypertension increases as renal function decreases. </li></ul></ul>
    21. 21. Hypertension in Patients with Diabetes <ul><li>Hypertension is very common in T2DM with at least 40% having elevated BP at the time their diabetes is diagnosed. </li></ul><ul><li>Over 80 % of T2DMs with nephropathy have hypertension and as renal function declines this number may increase. </li></ul>
    22. 22. Classification and Management of Blood Pressure for Adults – JNC 7 JNC 7 JAMA (2003) 289, 2560 yes yes Or > 100 > 160 Stage 2 yes yes Or 90-99 140 - 159 Stage 1 If indications yes Or 80-89 120-139 Prehypertension Encourage & < 80 < 120 Normal Initial Drug Therapy Lifestyle Modification DBP (mm Hg) SBP (mm Hg) BP Class
    23. 23. Chronic Kidney Disease (CKD) Epidemiology <ul><li>Patients may have normal serum creatinine but have normal / reduced renal function with kidney damage (proteinuria). </li></ul>GFR < 15 ml/min (ESRD) Stage 5 GFR between 15 –29 ml/min Stage 4 GFR between 30 – 59 ml/min Stage 3 GFR between 60- 89 ml/min Stage 2 GFR > 90 ml/min with presence of proteinuria or microalbuminuria Stage 1
    24. 24. Prevalence of CKD by Stage of Disease <ul><li>NHANES III (1988 – 1994, USRDS 1998 </li></ul>% of population # in millions Definition Stage .3 .4 7.6 5.3 ~ 6.0 GFR < 15 ml/min (ESRD) GFR between 15 –29 ml/min GFR between 30 – 59 ml/min GFR between 60- 89 ml/min GFR > 90 ml/min with presence of proteinuria or microalbuminuria 0.1 5 0.2 4 4.3 3 3.0 2 3.3 1
    25. 25. Hypertension Prevalence by GFR
    26. 26. Effect of BP on CHD Mortality: MRFIT 100+ 90–99 80–89 75–79 70–74 <70 <120 120–139 140–159 160+ DBP (mm Hg) SBP (mm Hg) Adapted with permission from Neaton JD et al. Arch Intern Med. 1992;152:56 CHD death rate per 10,000 person-years 9 9 9 12 10 21 24 17 14 13 13 12 25 25 25 26 25 31 48 37 35 44 38 81
    27. 27. Risk of stroke death according to Systolic & Diastolic BP in MRFIT Stamler, Stamler, Neaton. Arch Intern Med . 1993;153:598-615. 9 0 1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 8 9 10 Systolic Diastolic (Lowest 10%) (Highest 10%) Adjusted Relative Risk Decile <112 112- 118- 121- 125- 129- 132- 137- 142-  151 Systolic BP (mm Hg) <71 71- 76- 79- 81- 84- 86- 89- 92-  98 Diastolic BP (mm Hg)
    28. 28. Reasons to be aggressive in treatment of hypertension in CKD <ul><li>The adverse outcomes of CKD (kidney failure, cardiovascular disease, premature death) can be prevented or delayed </li></ul><ul><li>Treatment of earlier stages of CKD is effective in retarding progression to kidney failure and in preventing the systemic complications that develop during the course of progressive CKD. </li></ul><ul><li>Initiation of therapy for cardiovascular risk factors at earlier stages of CKD can be effective in reducing the very high cardiovascular morbidity and mortality of these patients. </li></ul>
    29. 29. The scope of cardiovascular complications in renal disease patients <ul><li>Renal disease –elevations in creatinine, proteinuria, and microalbuminuria- is associated with significant increases in cardiovascular disease (CVD). </li></ul><ul><li>Even mild increases in serum creatinine and a creatinine at the high end of normal are associated with increased CVD. </li></ul><ul><li>Renal disease is as strong a risk factor for CVD as smoking and diabetes. </li></ul>
    30. 30. Diabetes and Cardiovascular Disease <ul><li>Diabetics have similar risk of CVD as non-diabetic with existing CVD. </li></ul><ul><li>Diabetics with renal disease has CVD risk that is 6-7 fold that of diabetic without renal disease. </li></ul>
    31. 31. Is Proteinuria/Microalbuminuria associated with CVD risk in diabetes?
    32. 32. CVD risk factors that are strongly associated with diabetes and renal disease. <ul><li>Hypertension </li></ul><ul><li>Obesity </li></ul><ul><li>Lipid abnormalities (esp. proteinuria) </li></ul><ul><li>Insulin Resistance </li></ul><ul><li>CHF </li></ul><ul><li>LVH </li></ul><ul><li>Elevated Uric Acid </li></ul><ul><li>Albuminuria/Proteinuria </li></ul><ul><li>Age </li></ul><ul><li>Family History </li></ul>
    33. 33. CVD risk factors that have strong impact on vasculature
    34. 34. Studies Supporting BP Recommendations in Diabetics <ul><li>HOT </li></ul><ul><li>HOPE </li></ul><ul><li>LIFE </li></ul><ul><li>UKPDS </li></ul><ul><li>MDRD </li></ul><ul><li>ABCD </li></ul><ul><li>Collaborative Study Group </li></ul><ul><li>CAPPP </li></ul>
    35. 35. Flowchart supporting BP management in Diabetics
    36. 36. Flowchart supporting BP management in Diabetics
    37. 37. Flowchart supporting BP management in Diabetics
    38. 38. Support of BP Recommendations in Diabetic Nephropathy <ul><li>Hypertension Optimal Treatment Trial (HOT) </li></ul><ul><ul><li>Intensive lowering of BP in over 18,000 hypertensives (50 -80 yrs of age). 1501 diabetics at study entry. </li></ul></ul><ul><ul><li>Treated with Felodipine with addition of other agents as needed. </li></ul></ul><ul><ul><li>In diabetics CVD and CVD mortality was significantly lower in the group with target DBP < 80 mm HG compared < 85 or 90 mm Hg. </li></ul></ul>
    39. 39. Support of BP Recommendations in Diabetic Nephropathy <ul><li>United Kingdom Prospective Diabetes Study (UKPDS) </li></ul><ul><ul><li>Usual BP group vs. Low BP group ( 140-150/80-90 ) . </li></ul></ul><ul><ul><li>Low BP group tended to have better outcomes with regards to microvascular and macrovascular complications. </li></ul></ul><ul><ul><li>No difference between atenolol vs. captopril </li></ul></ul>
    40. 40. Systolic Hypertension in the Elderly Program (SHEP) <ul><li>Patients: > 60 yrs with isolated systolic hypertension (SBP 160-219) </li></ul><ul><li>Stepped care with chlorthalidone. Atenolol added as second step. </li></ul><ul><li>Chlorthalidone decreased incidence of heart failure by 49%. If there was previous evidence of MI by EKG the reduction was 80%. </li></ul><ul><ul><li>Kostis et al; JAMA 278: 212 </li></ul></ul>
    41. 41. Systolic Hypertension in the Elderly Program (SHEP) <ul><li>Patients: > 60 yrs with isolated systolic hypertension (SBP 160-219) </li></ul><ul><li>Stepped care with chlorthalidone. Atenolol added as second step. </li></ul><ul><li>Active therapy decreased CVD events in both diabetics and non-diabetics. </li></ul><ul><ul><li>JAMA (1996) vol. 276 </li></ul></ul>
    42. 42. Appropriate Blood Pressure Control in Diabetes (ABCD) Trial (Estacio et al., NEJM 338: 645) <ul><ul><li>Compared nisoldipine (CCB) to enalapril (ACE I) in type 2 diabetics </li></ul></ul><ul><li>Aim: Determine target BP in type 2 DM </li></ul><ul><li>Patients: Type 2 DM, age 40-74, DBP > 80 mmHg, not on antihypertensives </li></ul><ul><li>Endpoint: Primary- Cr clearance; Secondary- CV events, retinopathy, urinary albumin </li></ul><ul><li>Result : Among hypertensive, ACE I decreased rate of MI (5 fatal and non-fatal MI’s in ACE I group vs. 25 in CCB group). </li></ul>
    43. 43. Hypertension Treatment and CVD in Diabetics With Renal Disease <ul><li>ABCD (Hypertensives) (Estacio et. al. Diabetes Care 23 (suppl 2): B54-64, 2000 </li></ul><ul><li>2 BP groups (Intensive: 132/78; moderate138/86) </li></ul><ul><li>Nisoldipine vs. Enalapril as initial therapy (470 pts with 5.3 yrs follow-up). </li></ul><ul><li>Intensive therapy had lower overall incidence of death (5.5 vs. 10.7%, p=0.037) </li></ul><ul><li>No difference on progression of retinopathy and neuropathy and no difference on in progression of renal disease </li></ul>
    44. 44. Hypertension Treatment and CVD in Diabetics With Renal Disease <ul><li>ABCD (Normotensive) (Schrier et. al. KI 61: 1086, 2002) </li></ul><ul><li>Normotensive, Type 2’s (n=480, 5.3 yrs f/u) </li></ul><ul><li>Intensive (Goal: DBP decrease of 10 mm Hg, achieved 128/75) vs. moderate (Goal: DBP 80-89, achieved 137/81) </li></ul><ul><li>Intensive group randomized to nisoldipine vs. enalapril </li></ul><ul><li>Lower blood pressure group (128/75) had less progression of retinopathy and lower rates of stroke </li></ul>
    45. 45. Reduction in Endpoints in NIDDM with the Angiotensin II Antagonist Losartan Study (RENAAL) <ul><li>International, multicenter, double-blind, randomized, placebo controlled study sponsored by MERCK </li></ul><ul><li>Type 2 Diabetics ages 31-70. </li></ul><ul><li>Urine albumin/ Cr > 300,Serum Cr 1.3 – 3.0 mg/dl. </li></ul><ul><li>Losartan (50mg / dy) or placebo. </li></ul><ul><li>Losartan lowered first time admits for CHF </li></ul><ul><li>20% risk reduction in ESRD or death (p=.01) </li></ul>
    46. 46. Irbesartan Diabetic Nephropathy Trial (IDNT) <ul><li>Goal: Irbesartan vs. Amlopidine or placebo on progression of diabetic nephropathy, secondary CVD endpoints (13.3% Black) </li></ul><ul><li>Irbesartan group had 23% lower rate of CHF hospitalization compared to placebo. </li></ul><ul><li>Amlopidine group had 41% lower rate of nonfatal myocardial infarction. </li></ul><ul><li>Higher rate of CHF in amlodipine group vs. other groups (?). </li></ul><ul><li>Trend for lower rate of stroke with amlopidine. </li></ul>
    47. 47. Other Studies Examining CVD Outcomes in Diabetics <ul><li>Losartan Intervention for Endpoint Reduction (LIFE) (Lancet 359:1004) </li></ul><ul><ul><li>Essential hypertension and LVH: Losartan vs. atenolol </li></ul></ul><ul><li>Captopril Prevention Project (CAPPP) (Diabetes Care 24:253) </li></ul><ul><ul><li>Essential Hypertension: Captopril vs. conventional BP Rx (diuretics, b-blockers or both) </li></ul></ul><ul><li>Both favor RAAS blockade in reduction of CVD events in diabetics. </li></ul>
    48. 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
    49. 49. Hypertension in Diabetics with Renal Disease
    50. 50. Recommendations for Treatment of Blood Pressure in Patients with Diabetic Kidney Disease <ul><li>Target level of Blood pressure is < 130 / 80 mm Hg </li></ul><ul><li>Diabetic renal disease and BP > 130 / 80 mm Hg initiate ACE inhibitor or ARB </li></ul><ul><li>Diabetic renal disease and BP < 130 / 80 mm Hg initiate ACE inhibitor. </li></ul>
    51. 51. Blood Pressure Control and Rate of Renal Decline in Diabetic Nephropathy <ul><li>Parving et al. (1983 Lancet) </li></ul><ul><li>Ten Type 1 Diabetics followed before (mean of 29 months) and after initiation of antihypertensives (mean 39 months) </li></ul><ul><li>Antihypertensive agents were metoprolol, hydralazine, furosemide or thiazide </li></ul><ul><li>BP fell from 144/97 mmHg before treatment to 128/84 mmHg with treatment </li></ul><ul><li>Albumin excretion rate decreased from 977 mg/min before treatment to 433 mg/min with treatment </li></ul>
    52. 52. ACE Inhibition in Diabetic Nephropathy <ul><li>Blood pressure determines risk of progression of renal disease. Captopril lowers risk among those with hypertension . </li></ul><ul><ul><li># With Doubling of Serum Creatinine </li></ul></ul>Lewis et. al. 58.2 7/49 3/52 Normal BP 47.7 * 36/153 22/ 155 High BP % Risk Reduction Placebo (n=202) Captopril (n= 207) BP Baseline
    53. 53. Lewis et. al. Relationship Between BP and Diabetic Nephropathy
    54. 54. ARB’s and Diabetic Renal Disease Valsartan lowered albuminuria while amlodipine increase. Equally effect at BP control. Albuminuria, BP Type 2 DM, hypertension and Normotension Valsartan (MARVAL) <ul><ul><li>Irbesartan lowered relative risk of reaching primary endpoint compared to placebo and amlodipine respectively. Resulted in a 24% and 21% slower rise in Cr than placebo and amlodipine respectively. No effect on CVD </li></ul></ul>Mortality, doubling of Cr, ESRD Type 2 DM, urinary protein excretion of 900 mg/ 24 hours. Cr 1.0 -3.0 mg/dl in women and 1.2 – 3.0 mg/dl in men. Irbesartan (IDNT) Losartan was better than placebo at reducing albuminuria, preserving renal function and reduced 1 st time CHF hospitalizations Mortality, doubling of Cr, ESRD Type 2 DM, Urine Alb/Cr > 300, Cr 1.3-3 mg/dl Losartan (RENAAL) Outcome Endpoint(s) Patient characteristics Drug
    55. 55. Bakris et. al. (2000) 36: 646
    56. 56. Level of BP and Vascular Complications in Diabetes UKPDS. BMJ (2000) 321: 412
    57. 57. ALLHAT: Secondary Endpoints: ESRD ALLHAT Collaborative Research Group. JAMA . 2002;288:2981-2997. 1.12 (0.89-1.40) Relative Risk (95% CI) Favors Amlodipine Favors Lisinopril 1.11 (0.88-1.38) Favors Chlorthalidone Amlodipine Lisinopril
    58. 58. Antihypertensive Agents and Risk of Diabetes <ul><li>Data from ARIC (Gress, et al. NEJM 342:905) </li></ul><ul><ul><li>ACE inhibitors an Calcium did not increase risk for Type 2 diabetes mellitus. </li></ul></ul><ul><ul><li>Thiazides: No increased risk for Type 2 DM </li></ul></ul><ul><ul><li> -Blockers: 28 % increased risk for development of type 2 DM compared to those not on medications. </li></ul></ul><ul><li>HOPE: Ramipril lowered diabetic risk </li></ul><ul><li>LIFE: Losartan lowered diabetic risk compared to atenolol </li></ul>
    59. 59. ALLHAT, Diabetic Risk and Treatment of Hypertension ~9% Lisinopril ~10% Amlodipine ~16% Chlorthiadone Incidence of Diabetes over Follow-up Agent
    60. 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. 61. Other Complications of Diabetic Nephropathy <ul><li>Retinopathy </li></ul><ul><ul><li>BP control, consider RAAS inhibition </li></ul></ul><ul><li>Neuropathy </li></ul><ul><ul><li>BP control, consider RAAS inhibition </li></ul></ul><ul><li>Anemia </li></ul><ul><ul><li>Highly prevalent in diabetics </li></ul></ul><ul><ul><li>May be seen at even moderate reductions in renal function </li></ul></ul>

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