Diabetes and Hypertension
Diabetic people are more prone to hypertension than those without this metabolic disorder. More than 3 million people in the United States have both type II diabetes and hypertension. Cardiovascular disease is the largest cause of morbidity and mortality in diabetic persons with coexistent hypertension. Accordingly, a major focus of hypertension therapy for these persons should be the reduction of Cardiovascular disease morbidity and mortality, while reducing the complications of diabetic nephropathy. The causation of this comorbidity in Westernized societies may be attributed to populations getting older, more obese, and more sedentary. Up to 80% of the premature mortality in persons with this diabetes is due to Cardiovascular disease. Hypertension plays a key role in promoting Cardiovascular disease in diabetic persons. These observations have contributed to the recommendations of more aggressive lowering of blood pressure (blood pressure) (i.e., to <130/85 mmHg) in people with both diabetes and hypertension. However, it appears that most of such persons are inadequately controlled at this desired blood pressure. New strategies are being reviewed to improve our ability to reach blood pressures in this high-risk population.
Hypertension and diabetes both increase with advancing age in industrialized societies. As in the United States, diabetes mellitus affects more than 15 million people, 90% of whom have the noninsulin-dependent, or type II, diabetes.
Table Lipids, Coagulation, and Fibrinolysis in Hypertension and Diabetes
| 1. Increased plasma levels of very low-density lipoprotein, low-density lipoprotein, and Lp (a) |
| 2. Decreased plasma high-density lipoprotein cholesterol |
| 3. Elevated plasma levels of factor VII and VIII |
| 4. Increased flbrinogen and PAI-1 levels |
| 5. Elevated thrombin-antithrombin complexes |
| 6. Decreased antithrombin III, protein C, and S levels |
| 7. Decreased plasminogen activators and flbrinolytic activity |
| 8. Increased endofhelial expression of adhesion molecules |
Almost 20% of Caucasians over 65 yr of age have diabetes; the prevalence is even higher in African Americans and Hispanics. Whereas Cardiovascular disease accounts for 40% of overall mortality in the United States, nearly 80% of deaths in elderly diabetic persons is secondary to Cardiovascular disease complications, consisting of sudden death, myocardial congestive heart failure, and cerebrovascular and peripheral vascular disease.
People with clinical diabetes and hypertension, or with impaired glucose tolerance and hypertension, manifest a characteristic dyslipide-mia, with low high-density lipoprotein, high very low-density lipoprotein and aphenotypically small, dense, and more atherogenic low-density lipoprotein. Hypertension and coexistent diabetes are often associated with coagulation abnormalities as well as lipid disturbances. Furthermore, disturbances of the flbrinolytic system have been reported in people with hypertension, especially in those with concomitant lipid glucose abnormalities and vascular disease. Circulating levels of lipoprotein (a) [Lp(a)] are often in association with diabetes mellitus. By inhibiting fibrinolysis, increased levels of Lp (a) delay thrombolysis and predispose to plaque progression. Elevated levels of plasminogen activation inhibitor-1 (PAI-1) have been reported both in untreated patients with essential hypertension and in men with prior myocardial infarctions with increased risk for reinfarction. Elevated PAI-1 levels are associated with abdominal obesity, insulin resistance/hyperinsulinemia, and associated dyslipidemia. Platelet aggregation, activation, and adhesion are often enhanced in hypertension and associated diabetes mellitus.
Table Alterations in Platelet Function in Hypertension and Diabetes
| 1. Increased platelet adhesiveness and aggregation |
| 2. Increased platelet generation of vasoconstrictor prostanoids |
| 3. Reduced platelet generation of prostacyclin and other vasodilator prostanoids |
| 4. Increased nonenzymatic glycosylation of platelet proteins |
| 5. Decreased platelet production of nitric oxide |
| 6. Increased platelet myosin light chain phosphorylation/contraction |
Table Alterations in Cardiovascular Endothelium Associated with Hypertension and Diabetes
| 1. Increased plasma levels of von Willebrand factor |
| 2. Elevated expression, synthesis, and plasma levels of endofhelin-1 |
| 3. Diminished prostacyclin release |
| 4. Increased destruction of endothelium-derived relaxing factor (nitric oxide) and reduced responsiveness to nitric oxide |
| 5. Impaired flbrinolytic activity |
| 6. Increased endothelial cell procoagulant activity |
| 7. Increased endothelial cell-surface thrombomodulin |
| 8. Increased superoxide anion generation |
| 9. Increased expression of adhesion molecules |
Endothelial dysfunction in diabetes and hypertension
Dysfunction of the vascular endothelium appears to play a major role in the pathogenesis of Cardiovascular disease in people with hypertension and diabetes, with hyperglycemia and dyslipidemia as major contributors. Hyperglycemia results in increased destruction of endothelial cell nitric oxide, which predisposes to increased production of vasoconstrictor prostaglandins, endothelin, glycated proteins, endothelium adhesion molecules, and growth factors, which cumulatively enhance vasomotor tone, vascular growth, and remodeling. Hyperglycemia and dyslipidemia also delay endothelial cell replication and increase cell death, in part by enhancing oxidation and glycation (glycooxidation), and altering vascular nitric oxide metabolism.
Evaluation and treatment of hypertension in association with diabetes mellitus
The goal of lowering blood pressure in people with coexistent diabetes and hypertension is to prevent hypertension-associated death and disability. Those with diabetes and hypertension, partly because of reduced baroreceptor sensitivity, often have more labile blood pressures, and are more susceptible to postural hypotension. These symptoms are often associated with a lack of a normal nocturnal “dip” in blood pressures. Thus, the level of blood pressure and the diagnosis of hypertension should be based on multiple blood pressure measurements obtained in a standardized fashion on at least three occasions. Because of the propensity for orthostatic hypotension, standing blood pressures should be measured during office visits. Furthermore, because of the increased variability in blood pressure of these patients, ambulatory blood pressure measurements or home blood pressure monitoring may be particularly valuable. The consensus blood pressure goal in diabetic people with hypertension is <130/85 mmHg .
The purpose of this clinical advisory update is to alert clinicians about new information to be used in their clinical practice. Therapy in patients with hypertension and diabetes begins with weight reduction, increased physical activity, and moderation of salt and alcohol intake. The goal blood pressure is 130/85 mmHg. If it is not reached, then pharmaco-logic intervention is indicated. Based on clinical trial results, four classes of drugs have been found to be effective first-line therapy in these patients. Most hypertensive diabetic patients will require the use of more than one agent to achieve a therapeutic goal of 130/85 mmHg.
Because proteinuria is a harbinger for Cardiovascular disease and renal disease, angiotensin-converting enzyme (angiotensin-converting enzyme) inhibitors may afford unique benefits in preventing Cardiovascular disease as well as diabetic nephropathy. The Appropriate Blood Pressure Control in Diabetes trial showed a cardioprotective effect of angiotensin-converting enzyme inhibitors. Recently, the United Kingdom Prospective Diabetes Study Group reported that blood pressure lowering with an atenolol-based program was just as effective as a captopril-based regimen in reducing the incidence of diabetic complications (both microvascular and macro vascular). Many required these drugs plus a diuretic to achieve “tight control of 144/82 mmHg.” In patients assigned to less tight control (154/87 mmHg), there was less use of multiple antihypertensive agents. Risk reductions in the group assigned to tight blood pressure control were 24% in diabetes-related end points, 32% in deaths related to diabetes, 44% in strokes, and 37% in microvascular end points, predominantly diabetic retinopathy. These results suggest that combination therapy with either an angiotensin-converting enzyme inhibitor or a β-blocker are very effective in reducing macrovascular and microvascular events provided that blood pressure is adequately lowered.
Low-dose thiazide diuretics (i.e., 25 mg or less of hydrochlorothia-zide or chlorthialidone daily) are effective and safe antihypertensive agents in type II diabetic patients. In the Systolic Hypertension in the Elderly Program study, elderly type II diabetic men had reductions in stroke and coronary heart disease similar to those without diabetes. Low-dose diuretics (i.e., hydrochlorothiazide at 25 mg or lower) are not associated with significant metabolic abnormalities. Lower-dose diuretics in conjunction with angiotensin-converting enzyme inhibitors usually produces substantial synergism in reducing blood pressure, and the use of these agents together further minimizes potential metabolic problems. Diuretics are important because of the salt sensitivity and expanded plasma volume that is often present in diabetic patients, particularly in those requiring several drugs to control blood pressure levels of <130/85 mmHg.
Results from the subset analysis of type II diabetics in the Hypertension Optimal Treatment trial and a recent subanalysis of this cohort in the Systolic Hypertension in Europe (Syst-EUR) trial suggest that further reduction in diastolic blood pressure below 85 mmHg is beneficial. Hypertension Optimal Treatment also confirmed that multiple drug regimes are required to reach goal for most hypertensive diabetics. In the Syst-EUR trial, systolic blood pressure was reduced by a comparable amount in each group (-22 ±16 mmHg for nondiabetic subjects vs -22.1 ± 14 mmHg for the diabetic group), and the risk reduction in mortality from Cardiovascular disease was 13% for the nondiabetic subjects and 76% for the diabetic patients. Thus, the benefit conferred per millimeter of mercury blood pressure reduction appears to be greater in people with type II diabetes than in those with hypertension but no coexistent diabetes mellitus.
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