hypertension in patients with diabetes mellitus .

1. IN THE NAME OF GOD hypertension in patients with diabetes mellitus.

5. ACUTE STROKE

6. — Hypertension is a common problem in patients with both type 1 and type 2 diabetes but the time course in relation to the duration of diabetes is different .Among those with type 1 diabetes, the incidence of hypertension rises from 5 percent at 10 years, to 33 percent at 20 years, and 70 percent at 40 years . There is a close relation between the prevalence of hypertension and increasing albuminuria.

7. The findings are different in patients with type 2 diabetes. In a series of over 3500 newly diagnosed patients, 39 percent were already hypertensive. In approximately one-half of these patients, the elevation in blood pressure (BP) occurred before the onset of moderately increased albuminuria.

8. PATHOGENESIS

10. Diabetes Complications Macrovascular Microvascular Cerebrovascular disease Diabetic eye disease (retinopathy, cataracts macular edema) Heart disease and hypertension Autonomic Neuropathy Erectile dysfunction Renal disease Peripheral vascular disease Peripheral Neuropathy Ulcers and amputation Foot problems

11. In addition to the development of diabetic nephropathy, at least three other factors have been proposed to contribute to hypertension in diabetes: hyperinsulinemia, extracellular fluid volume expansion, and increased arterial stiffness.

12. — Early treatment of hypertension is particularly important in diabetic patients both to prevent cardiovascular disease and to minimize progression of renal disease and diabetic retinopathy . Among patients with type 2 diabetes, the benefits of tight blood pressure control may be as great or greater than the benefit of strict glycemic control .

13. Initial therapy should include nonpharmacologic methods, such as weight reduction, increased consumption of fresh fruits, vegetables, and low-fat dairy products, exercise, salt restriction, and avoidance of smoking and excess alcohol ingestion.

14. Since hypertension places diabetic patients at high risk for cardiovascular complications, all diabetic patients with persistent blood pressures above 140/90 mmHg should be started on antihypertensive drug therapy . Successful implementation of nonpharmacologic therapy may permit later reduction in the dose or number of antihypertensive agents.

15. UKPDS trial — In the UKPDS, 1148 patients with type 2 diabetes captopril or atenolol as primary therapy; the achieved blood pressures in the two groups were 144/82 and 154/87 mmHg, respectively. At eight to nine years, patients with the lower blood pressures had a 24 percent reduction in diabetes-related end points, including microvascular disease (37 versus 49 percent, a 32 percent reduction in deaths related to diabetes (24 versus 35 percent), 44 percent fewer strokes, and a 34 and 47 percent reduction in significant deterioration in retinopathy and visual acuity, respectively.

16. ADVANCEstudy

17. After a mean of 4.3 years, the following significant differences were observed in the group assigned to active treatment compared with placebo: • A decrease in mean blood pressure by 5.6/2.2 mmHg. The mean attained blood pressures were approximately 134.5/74 and 140/76 mmHg. • A lower rate of major macrovascular or microvascular events (15.5 versus 16.8 percent). • A lower rate of cardiovascular mortality (3.8 versus 4.6 percent) and all-cause mortality (7.3 versus 8.5 percent).

18. A meta-analysis of the ACCORD BP, ABCD, and HOT trial suggested that intensive blood pressure lowering in patients with diabetes significantly lowers the incidence of stroke (2.0 versus 3.1 percent) but does not significantly lower the risk of mortality (5.5 versus 6.3 percent) or myocardial infarction (7.9 versus 8.5 percent).

19. . Intensive blood pressure control was associated with significant reductions in some secondary end points, such as progression of retinopathy (34 versus 46 percent), of normoalbuminuria to "microalbuminuria"), and of moderately increased albuminuria to "macroalbuminuria").

20. There was no reduction in the rate of all cardiovascular events with intensive antihypertensive therapy (myocardial infarction, stroke, heart failure, and cardiovascular death; 20.2 versus 19.8 percent), although there was a significant reduction in stroke.

21. ACCORD BP trial — The Action to Control Cardiovascular Risk in Diabetes blood pressure trial (ACCORD BP) randomly assigned 4733 patients with type 2 diabetes who had cardiovascular disease or at least two additional risk factors for cardiovascular disease to either intensive therapy (goal systolic blood pressure less than 120 mmHg) or standard therapy (goal systolic blood pressure less than 140 mmHg).

22. At a mean follow-up of 4.7 years, the following findings were noted: • There was no significant difference in the annual rate of the primary composite outcome of nonfatal myocardial infarction, nonfatal stroke or death from cardiovascular causes between the intensive versus standard therapy groups (1.87 versus 2.09 percent, hazard ratio 0.88, 95% CI 0.73-1.06). • There was no difference in the annual all-cause mortality rate between intensive and standard therapy groups (1.28 versus 1.19 percent) or in the rate of death from cardiovascular causes between groups (0.52 versus 0.49 percent).

23. Intensive therapy was associated with significant reductions in the annual rates of total stroke and nonfatal stroke (0.32 versus 0.53 percent, hazard ratio 0.59, 95% CI 0.39-0.89, for total stroke and 0.30 versus 0.47 percent, HR 0.63, 95% CI 0.41-0.96, for nonfatal stroke). Serious adverse events attributable to antihypertensive drugs (eg, hypotension, syncope, bradycardia or arrhythmia, hyperkalemia, angioedema, and renal failure) occurred significantly more frequently in the intensive versus standard therapy group (3.3 versus 1.3 percent).

24. treatment of hypertension in diabetic patients was associated with significant clinical benefits in three major randomized trials: UKPDS (mean attained blood pressure 144/82 versus 154/87 mmHg with less aggressive therapy), in HOT (140/81 versus 144/85 mmHg with less aggressive therapy), and in ADVANCE (mean attained blood pressure 134.5/74 versus 140/76 mmHg with placebo). These observations support a goal blood pressure for diabetic patients of less than 140/90 mmHg, as recommended in most other patients with hypertension.

25. The ACCORD BP trial of patients with type 2 diabetes at increased cardiovascular risk found no significant cardiovascular benefit and more drug side effects at a mean attained systolic pressure of 119.3 compared to 133.5 mmHg, with the exception of a reduction in stroke

26. We recommend that all patients with diabetes mellitus have a goal blood pressure less than 140/90 mmHg. We recommend a goal blood pressure of less than 130/80 mmHg in patients with diabetic nephropathy and proteinuria (500 mg/day or more).

27. CHOICE OF ANTIHYPERTENSIVE DRUGS ACE inhibitors

28. They lower the blood pressure, although no drug is likely to be sufficient as monotherapy. • They have no specific toxicity, except for cough and raising the plasma potassium concentration in patients with underlying hyperkalemia or renal insufficiency. • They have no adverse effects on lipid metabolism. • They may lower the plasma glucose concentration by increasing responsiveness to insulin. In one study, for example, 130 patients with type 2 diabetes were stabilized for three months; the subsequent administration of captopril for four months led to a reduction in hemoglobin A1C values from 8.6 to 6.5 percent with no change in insulin dose, dietary intake, or body weight . A possible effect of ACE inhibitors in reducing the incidence of new onset type 2 diabetes .

29. They protect against the progression of "microalbuminuria") to"macroalbuminuria") due to type 1 and 2 diabetes and have been evaluated for primary prevention of diabetic nephropathy. • They may slow the progression of retinopathy.

30. Angiotensin II receptor blockers (ARBs) appear to have the same benefits as ACE inhibitors . renoprotection is reported with ARBs in patients with nephropathy in type 2 disease .

31. Calcium channel blockers — Somewhat similar considerations (efficacy and lack of adverse effects of lipid or carbohydrate metabolism) apply to the nondihydropyridine calcium channel blockers (diltiazem and verapamil) . However, an ACE inhibitor is still preferred as initial therapy, in part because it appears to be superior to verapamil for the primary prevention of diabetic nephropathy among hypertensive patients with type 2 diabetes

32. Two relatively small initial trials suggested increased cardiovascular complications with nisoldipine or amlodipine compared to an ACE inhibitor .However, two major hypertension trials, HOT and Syst-Eur, found no evidence of a deleterious effect from a long-acting dihydropyridine in diabetic patients .In addition, amlodipine was associated with similar rates of coronary mortality and nonfatal myocardial infarction as chlorthalidone and lisinopril in the much larger ALLHAT trial of patients with hypertension and risk factors for cardiovascular disease .However, a higher rate of heart failure among diabetic patients was observed with amlodipine compared with chlorthalidone (relative risk 1.42, 95% CI 1.23-1.64), a finding also observed among patients without diabetes.

33. Beta blockers — Although there are concerns about masking of hypoglycemic symptoms and possible exacerbation of peripheral artery disease, beta blockers are effective therapy for hypertension in diabetic patients. In the UKPDS study of patients with type 2 diabetes, atenolol was as effective as captopril in terms of both blood pressure lowering and protection against microvascular disease . however, losartan provided significantly more protection from adverse cardiovascular outcomes than atenolol.

34. Carvedilol is a combined nonselective beta- and alpha-1 adrenergic antagonist that improves survival in patients with heart failure and may have certain advantages compared to other beta blockers in patients with diabetes.

35. Alpha blockers — Although not widely used as primary therapy in diabetes because of side effects such as orthostatic hypotension, peripheral alpha blockers (such as doxazosin) are as effective in lowering blood pressure as ACE inhibitors and calcium channel blockers and have a more favorable metabolic profile.

36. alpha blockers should not be used as primary therapy for hypertension. However, they may prove useful as add-on therapy, particularly in older men with symptomatic prostatism.

37.  The choice of antihypertensive agents in diabetic patients is based upon their ability to prevent adverse cardiovascular events and to slow progression of renal disease, if present.

38. An ACE inhibitor or ARB is clearly preferred as initial therapy in any hypertensive diabetic patient who has moderately increased albuminuria"microalbuminuria" or "macroalbuminuria" in an attempt to slow renal disease progression. Most experts will also begin with an ACE inhibitor or ARB in hypertensive diabetic patients without proteinuria.

39. Monotherapy can attain goal blood pressure in some patients with diabetes and hypertension. This is most likely to occur in those with blood pressures that are only modestly above goal. However, combination therapy is eventually required in most patients. We suggest adding a long-acting dihydropyridine to the ACE inhibitor or ARB .

40. If a beta blocker is given, carvedilol may be the drug of choice , A loop diuretic is likely to be necessary in patients with renal disease or heart failure.

41. We recommend a goal blood pressure of less than 140/90 mmHg compared with higher pressures in all patients.

42. We recommend a goal blood pressure of less than 130/80 mmHg compared with higher pressures in patients with diabetic nephropathy and proteinuria (500 mg/day or more).