Treatment of hypertension in patients with diabetes mellitus

• This topic will review the pathogenesis of hypertension in patients with diabetes mellitus and the three major treatment issues: • The evidence supporting benefit from the treatment of hypertension • The choice of antihypertensive drugs • The goal blood pressure

INTRODUCTION AND PREVALENCE • Hypertension is a common problem in pts with both type 1 and type 2 diabetes

PATHOGENESIS • 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 • Increased arterial stiffness

Hyperinsulinemia • This hypertensive response, although noted in all studies, may be mediated by concurrent weight gain and by the prohypertensive effect of insulin. • Hyperinsulinemia may be a link to explain the association between obesity and hypertension both in nondiabetic patients and those with type 2 diabetes, since insulin can increase sympathetic activity and promote renal sodium retention.

Volume expansion • Sodium retention and volume expansion may be induced both by insulin and the hyperglycemiainduced increase in the filtered glucose load • The excess filtered glucose is reabsorbed (as long as there is only moderate hyperglycemia) in the proximal tubule via a sodium-glucose cotransporter, resulting in a parallel rise in sodium reabsorption • Thus, salt loading tends to raise the blood pressure, an effect that can be reversed by salt restriction

Increased arterial stiffness • Patients with diabetes have increased vascular stiffness, which is thought to be a consequence of increased protein glycation and, at a later stage, atheromatous diseas • The reduction in arterial distensibility, which is seen with both impaired glucose tolerance and overt diabetes, can contribute to the rise in systolic pressure and is associated with mortality risk

BENEFIT OF TREATMENT • 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

• nitial 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. • Among patients with a SBP of 130 to 139 mm. Hg, or a diastolic pressure of 80 to 89 mm. Hg, initial therapy should consist of nonpharmacologic methods • If target blood pressure is not achieved after three months, treatment with pharmacological agents should be initiated.

• Since hypertension places diabetic patients at high risk for cardiovascular complications, all diabetic patients with persistent blood pressures above 140/90 mm. Hg should be started on antihypertensive drug therapy

CHOICE OF ANTIHYPERTENSIVE DRUGS • ACE inhibitors — When antihypertensive drugs are used, angiotensin converting enzyme (ACE) inhibitors offer a number of advantages: • 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. • A possible effect of ACE inhibitors in reducing the incidence of new onset type 2 diabetes is discussed elsewhere. • They protect against the progression of moderately increased albuminuria (formerly "microalbuminuria") and severely increased albuminuria (formerly "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.

Angiotensin II receptor blockers • ARBs appear to have the same benefits as ACE inhibitors described in the preceding section. • major trials, demonstrated a clear benefit in terms of renoprotection with ARBs in patients with nephropathy due to type 2 disease • This was also seen in early type 2 diabetes with normal kidney function and normoalbuminuria or moderately increased albuminuria in whom an ACE inhibitor was at least as effective as an ARB

ACE inhibitor plus ARB • A separate issue is whether an ARB should be given with an ACE inhibitor. • In the CALM trial of 199 hypertensive patients with type 2 diabetes with moderately increased albuminuria (formerly "microalbuminuria"), lisinopril (20 mg/day) and ca ndesartan (16 mg/day) produced equivalent reductions in blood pressure that were significantly less than the response seen with combination therapy (14. 1/10. 7 and 16. 7/10. 4 versus 25. 3/16. 3 ) • However, combination therapy was not compared to higher doses of either agent alone.

• • • 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 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 • Similar results in terms of safety and efficacy were reported in a 2004 meta-analysis of 14 studies that evaluated calcium channel blockers in hypertensive diabetic patients [ • • A separate question is the role of calcium channel blockers in combination therapy Amlodipine may provide better protection against cardiovascular events than lowdose hydrochlorothiazidewhen both are used in combination with an ACE inhibitor

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 • 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 • The Atherosclerosis Risk In Communities study (ARIC) study found that, among hypertensive patients who did not have diabetes, beta blocker therapy (but not carvedilol ) was associated with a 28 percent increased risk of developing type 2 diabetes compared to no antihypertensive therapy; this relationship was not seen with thiazides, calcium channel blockers, or ACE inhibitors

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

SUMMARY AND RECOMMENDATIONS • The prevalence and time of development of hypertension in patients with diabetes mellitus varies with the type of diabetes. • Among patients with type 1 diabetes, the incidence of hypertension rises from 5 percent at 10 years' duration, to 33 percent at 20 years, and 70 percent at 40 years. • The blood pressure typically begins to rise within the normal range at or within a few years after the onset of moderately increased albuminuria (formerly "microalbuminuria") and increases progressively as the renal disease progresses. • Among patients with type 2 diabetes, as many as 40 percent are hypertensive at the time of diagnosis and, in approximately onehalf of these patients, the elevation in blood pressure occurred before the onset of moderately increased albuminuria.

Choice of antihypertensive agents • An ACE inhibitor or ARB is clearly preferred as initial therapy in any hypertensive diabetic patient who has moderately increased albuminuria (formerly "microalbuminuria") or severely increased albuminuria (formerly "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. This is unlikely to occur in patients with type 1 diabetes in whom moderately increased albuminuria typically precedes hypertension

Goal blood pressure • • Major guidelines, published before the ACCORD BP trial, suggested that the goal blood pressure in patients with diabetes mellitus is less than 130/80 mm. Hg. However, there are no convincing data supporting this approach, with the possible exception of patients with diabetic nephropathy and proteinuria in whom weak evidence suggests that such a goal may slow the rate of progression of the nephropathy We recommend a goal blood pressure of less than 140/90 mm. Hg compared with higher pressures in all patients ( Grade 1 B ). We suggest (a weaker recommendation) an attempt to lower the systolic pressure below 130 to 135 mm. Hg (preferably less than 130 mm. Hg) if it can be achieved without producing significant side effects ( Grade 2 B ). We recommend a goal blood pressure of less than 130/80 mm. Hg compared with higher pressures in patients with diabetic nephropathy and proteinuria (500 mg/day or more) ( Grade 1 B ). For patients who fulfill the entry criteria in ACCORD BP (type 2 diabetes plus either cardiovascular disease or at least two additional risk factors for cardiovascular disease), the authors and reviewers of this topic suggest that the risks and burdens of aiming for a goal systolic pressure of less than 120 mm. Hg (more side effects, extra patient visits, and increased cost) plus the lack of experience of almost all physicians in attaining such a goal may be too great a burden to achieve the small reduction in stroke that may be attained (absolute benefit 1 in 89 patients at five years). However, such a goal may be considered in highly motivated patients who would accept more aggressive antihypertensive therapy to further reduce their risk of stroke.