ANTIHYPERTENSIVE THERAPY IN DIABETIC-PATIENTS

Diabetes mellitus (DM)-linked metabolic alterations and hypertension concomitantly accelerate or precipitate cerebrovascular and coronary heart disease, nephropathy, retinopathy and widespread macroangiopathy, thereby conferring to diabetic patients a very high risk of morbidity, disability and early death. Therefore, the long-term care for diabetic patients should be aimed at concomitant metabolic and blood pressure (BP) control. Dietary measures are indispensable; a high fibre, low fat, low salt diet is recommended, complemented with caloric restriction and physical exercise when body weight is above the ideal. Antidiabetic pharmacotherapy involves an unresolved dilemma. The desired achievement of euglycemia necessitates effective levels of insulin, but hyperinsulinemia (due to parenteral [over]treatment in insulin-dependent DM) is suspected to promote atherogenesis and represents a coronary risk factor and perhaps even facilitates hypertension. Considering antihypertensive pharmacotherapy, thiazide-type or loop diuretics are problematic drugs in DM because they can aggravate metabolic alterations. These agents also seem to exert only a limited preventive or regressive effect on left ventricular hypertrophy (LVH); beta-blockers are also not considered ideal, since they decrease the awareness of hypoglycemia and tend to promote glucose intolerance. Unselective beta-blockers in particular promote peripheral ischemia and insulin-induced hypoglycemia, while beta-blockers without intrinsic sympathomimetic activity lower serum HDL-cholesterol. Calcium antagonists and ACE inhibitors have equivalent antihypertensive efficacy, do not impair carbohydrate and lipid homeostasis or peripheral perfusion and can effectively improve LVH. Certain ACE inhibitors may even slightly ameliorate abnormal insulin sensitivity and plasma glucose levels. While alpha-blockers share most of these desirable properties, these agents are more prone to precipitate orthostatic hypotension in the diabetic patient. The non-thiazide diuretic indapamide and the serotonin2-antagonist ketanserin also combine antihypertensive efficacy with metabolic neutrality. The ultimate goal of therapy is to improve life prognosis. In essential hypertension, conventional drug treatment based on diuretics in high dosage satisfactorily reduced cerebrovascular but not coronary complications or sudden death. In diabetic patients, the influence of antihypertensive therapy on prognosis has not been assessed prospectively. Based on retrospective analyses, Warram et al reported a 3.8 times higher mortality in diabetics treated with diuretics alone, than in diabetics with untreated hypertension (Arch Intern Med. 1991;151:1350). H.H. Parving calculated that effective BP control in patients with diabetic nephropathy might reduce 10 year-mortality from about 65 to 20 percent (J Hypertension. 1990; 8[Suppl 7]:187). Considering the course of diabetic nephropathy, antihypertensive treatment with different types of drugs. mostly in type 1 diabetics, was noted to decrease microalbuminuria or clinical proteinuria, retard a progression from incipient to clinical nephropathy and slow the decline in glomerular filtration rate (GFR) in initially non-azotemic or mildly azotemic patients with clinical nephropathy. ACE inhibitors are efficacious, and at least some calcium antagonists may also decrease proteinuria. Whether certain antihypertensive drugs differ in their effect on the natural course of human diabetic nephropathy requires further investigation. Based on their pharmacological profile, ACE inhibitors and calcium antagonists have emerged as the preferred drugs for treating hypertension in DM. Monotherapy with, or a combination of these drug types allow effective BP control in the majority of hypertensive diabetics. Administration of such agents to diabetic patients necessitates monitoring of serum creatinine, potassium (ACE inhibitors) and proteinuria (particularly calcium antagonists). Ketanserin may be a potential alternative, and if the addition of a diuretic is needed, the metabolically neutral indapamide would seem a reasonable choice. If these agents do not allow satisfactory BP control, highly selective beta-blockers or alpha-blockers may be introduced as a second choice. Unless diuretics are needed for reasons other than hypertension, treatment of diabetics with thiazides or loop diuretics in conventional dosage should probably be avoided until clarification of the influence of these agents on prognosis is determined. Nevertheless. whether and to what extent other agents and non-pharmacological measures can modify prognosis in diabetic patients is also unclear and the approach to antihypertensive therapy is, therefore, still largely empirical.