Drug Therapy to Control Hypertension in Patients With Diabetes
David S.H. Bell, MD, FACE

Cardiovascular Disease and Myocardial Infarction in Patients with Diabetes

Patients with diabetes are at especially high risk for cardiovascular disease, including myocardial infarction (MI) and heart failure. According to the American Heart Association 75% of people with diabetes mellitus die of some form of heart or blood vessel disease.¹ This figure is supported by results of the Diabetes Mellitus Insulin-Glucose Infusion in Acute MI (DIGAMI) trial, in which 66% of total mortality among diabetic patients was due to heart failure.² Data have been widely disseminated showing that in Finland, patients with diabetes who have had diabetes for 8 years with no history of MI are at as great a risk of experiencing an MI as are nondiabetic people who have already suffered an event.³ However, data on new onset patients from a Scotland study show that the risk in this group is not as great.⁴ In the past decade, nondiabetic patients have experienced a significant decrease in mortality from ischemic heart disease (men, 43.8% and women, 27%).⁵ During the same period, men with diabetes have experienced only a 16.6% decrease in mortality from ischemic heart disease, while women with diabetes have experienced a 23% increase in mortality from heart disease.⁵ Clearly the cardiovascular risk factors in the diabetes patient, including hypertension, are not being treated intensively enough.

Etiology of Hypertension in the Patient With Diabetes

Patients with type 1 diabetes are at high risk of hypertension due to nephropathy.⁶ In addition, there is a direct correlation between the risk of complications of diabetes and systolic blood pressure over time.⁷ The increased frequency of hypertension in patients with diabetes is independent of age and obesity.

There are several causes for the increased hypertension in patients with diabetes. Hyperglycemia plays a part. For every molecule of glucose filtered and reabsorbed, one molecule of sodium is reabsorbed. Hyperglycemia also glycosylates proteins, resulting in cross-linking of collagen and premature stiffening of major vessels. Furthermore, people with diabetes are more prone to atherosclerosis, and calcified atheromatous plaques also leads to decreased elasticity of major vessels. Therefore, the subject with diabetes has a higher incidence of systolic hypertension due to this stiffening.

Insulin resistance also directly contributes to hypertension. High insulin levels result in:

Decreased sodium excretion
Stimulation of the sympathetic nervous system
Proliferation of vascular smooth muscle cells, which also have a high sodium and calcium content. This leads to remodeling of the vessel wall which results in left ventricular hypertrophy and more concentric left ventricular geometry, associated with decreased myocardial function, and is possibly why so many patients with diabetes suffer congestive heart failure⁸
Stimulation of the AT₁ receptor

Hypertension is part of the insulin resistance syndrome, and occurs independently of age, gender, weight, or blood pressure.

The Effect of Blood Pressure Control on the Risk of Complications

The United Kingdom Prospective Diabetes Study (UKPDS) contained a Blood Pressure Control Study that produced very compelling data with regard to hypertension in patients with diabetes. Tighter control of blood pressure (144/82) versus less tight control of blood pressure (154/87) resulted in substantial risk reductions, particularly for microvascular disease (37%) (Figure 1).⁷ The 47% risk reduction in visual deterioration is especially noteworthy. Impressive risk reductions are also clearly visible for every 10 mm Hg reduction in systolic blood pressure (Figures 2-4).⁸

Figure 1. Blood pressure control study in type 2 diabetes.

Figure 2. UKPDS. Epidemiological Study.

Figure 3. UKPSD Epidemiological Study (cont.).

Figure 4. UKPSD Epidemiological Study (cont.).

The results of the UKPDS Blood Pressure Control Study illustrated that by controlling blood pressure in patients with diabetes, the risk of complications decreased.⁸

The Hypertension Optimum Treatment (HOT) study showed that tight blood pressure control is far more important and beneficial for patients with diabetes than for nondiabetic subjects. The study randomized 18,790 patients with diastolic blood pressures of between 100 and 115 mm Hg to groups with goals of ≤90, ≤85, or ≤80.⁹ A comparison of patients in the 90 mm Hg and 80 mm Hg groups showed that those with the lower diastolic blood pressure experienced a 10% reduction in cardiac events.⁹ However, the same comparison resulted in a 51% reduction in cardiac events in patients with diabetes.⁹

The data from these and other trials resulted in the blood pressure goals for patients with diabetes currently recommended by the National Kidney Foundation, American Diabetes Association, and the Seventh Report of the Joint National Committee on the Prevention, Detection, and Evaluation of High Blood Pressure (Figure 5).^10-12

Figure 5. Blood pressure guideline comparison.

Achieving Tight Blood Pressure Control

In order to achieve the above goals, most patients with diabetes will require between 3 and 5 anithypertensive medications.¹³ The antihypertensive of choice for the diabetes patient is the ACE inhibitor. The effectiveness of ACE inhibitors was shown in the Heart Outcomes Prevention (HOPE) Study. Diabetes patients receiving 10 mg of the ACE inhibitor ramapril per day experienced significant risk reductions in the areas of all-cause mortality, stroke, myocardial infarction, and cardiovascular death (Figure 6).¹⁴ ACE inhibitors should be used extensively, and a case can be made that every patient with type 2 diabetes should be taking an ACE inhibitor.¹⁶

Figure 6. Kaplan-Meier Survival Curves.

Angiontensin II receptor blockers (ARBs) do not lower insulin resistance as the ACE inhibitors do, but in patients with angioneurotic cough or edema, ARBs should be substituted for ACE inhibitors. Since the effect of ACE inhibitors is amplified with the addition of a low-dose thiazide diuretic, thiazides should be taken in combination with ACE inhibitors. High doses of thiazide diuretics increase insulin resistance, but conservative doses (12.5 or 25 mg of HCTZ) have a negligible effect on it (Figure 7).

Figure 7. Emerging role of ARBs.

There has been some controversy in the use of dihydropyridine calcium channel blockers in patients with type 2 diabetes¹⁷ (Figure 8). A possible explanation of the increased risk of cardiac events or mortality in patients with type 2 diabetes is the increase in the penetration of these lipophilic drugs into the myocardium due to damage to the muscle membranes from glycosylation (Figure 9). However, it must be emphasized that the increase in mortality and cardiac events does not occur in nondiabetic patients or diabetic subjects who are also on an ACE inhibitor.

Figure 8. Dihydropyridine vs nondihydropyridine.

Figure 9. Calcium antagonists versus other antihypertensives.¹⁷

Used as monotherapy, β-blockers have been shown in older studies to decrease mortality, in both the short and the long term, more in the diabetic than the nondiabetic patients. These studies could never be ethically repeated, so the question is whether β-blockers are as effective with the availability of fibrinolytics and ACE inhibitors. β-blockers still maintain an advantage, as was clearly shown in the DIGAMI study in post-MI patients with diabetes, and in the Benzafibrate Infarction Prevention Study in diabetic subjects with chronic ischemic heart disease. Therefore, β-blockers are even more valuable in patients with diabetes than in nondiabetic patients, and should be the drug used following an ACE inhibitor and a thiazide diuretic. Unfortunately, first- and second-generation β-blockers, by their vasoconstricting properties, increase insulin resistance, triglycerides, serum glucoses, and lower HDL and worsen peripheral vascular disease. Third-generation β-blockers, by their α-1 blocking effect, vasodilate and thus lower insulin resistance, glucose, and triglyceride levels, increase HDL levels, and peripherally vasodilate. Therefore, a third-generation β-blocker such as carvedilol is the preferred drug in the insulin-resistant and diabetic patient.

To review, the first step to achieving the blood pressure goals in a patient with diabetes is to treat with the combination of an ACE inhibitor or an ARB and a thiazide diuretic. If the patient fails to achieve the blood pressure goal, a β-blocker should then be added. If the combination of ACE inhibitor, thiazide diuretic, and β-blocker fails to achieve the blood pressure goal, a nondihydropyridine calcium channel blocker should be added in addition to whichever antihypertensives are needed to achieve a goal of 130/80 or below, or 120/75 in the presence of significant proteinuria.

Figure 10. Choice of antihypertensive in patients with diabetes.

Drug Therapy to Control Hypertension in Patients With DiabetesDavid S.H. Bell, MD, FACE

Cardiovascular Disease and Myocardial Infarction in Patients with Diabetes

Etiology of Hypertension in the Patient With Diabetes

The Effect of Blood Pressure Control on the Risk of Complications

Achieving Tight Blood Pressure Control

References

Drug Therapy to Control Hypertension in Patients With Diabetes
David S.H. Bell, MD, FACE