Antihypertensives and Diabetes: Is There a Connection?

Q: An increasing number of reports link antihypertensive agents to new-onset diabetes mellitus. Should this affect our treatment decisions for patients with newly diagnosed hypertension?

A: The concern is whether certain antihypertensives decrease insulin sensitivity and thus create a greater-than-expected number of new diabetes cases in a susceptible population. Keep in mind, however, that about 150 million persons worldwide and 17 million in the United States have diabetes; most have type 2 diabetes. Moreover, an additional 16 million Americans who are middle-aged or older have impaired glucose tolerance and undiagnosed diabetes. Another 10 million are considered prediabetic: they have impaired fasting glucose and are at high risk for progression to overt diabetes. Hypertension and diabetes or prediabetes both tend to occur in patients with the metabolic syndrome, which has become epidemic in the United States.

The prevalence of type 2 diabetes is expected to continue to increase rapidly, and it is not surprising that the issue of the potential effects of different classes of antihypertensive drugs on glucose metabolism and glycemic control has sparked debate.¹ Are these concerns justified?

Thiazide diuretics can impede glycemic control by impairing insulin secretion and by decreasing peripheral insulin sensitivity. Worsening glycemic control appears to be dose-dependent and significantly related to thiazide-induced hypokalemia. However, prevention of hypokalemia with potassium supplementation attenuates thiazide-induced glucose intolerance, and hypokalemia is reversible with discontinuation of thiazide treatment.

ß-Blockers inhibit pancreatic insulin release by blocking b₂-receptors. The potential mechanisms include unopposed α₂-receptor-mediated glycogenolysis and significant weight gain, which are not uncommon with β-blocker administration. β-Blockers with intrinsic sympathomimetic activity, such as acebutolol, and those with β- and α-blocking activity, such as carvedilol, exhibit minimal detrimental effects on glycemic control.²

On the other hand, agents that inhibit the renin angiotensin system--angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs)--appear to have a potentially beneficial effect on insulin resistance and on the incidence of diabetes. Animal and clinical research has suggested that angiotensin II impairs pancreatic blood flow; enhances insulin resistance; and mediates islet cell differentiation, apoptosis, oxidative stress, and cytokine release. Angiotensin II also inhibits adipocyte differentiation in vitro. Inhibition of angiotensin II has beneficial effects on these interactions.² In addition, ACE inhibitors and ARBs raise potassium levels; this counteracts the impairment of insulin secretion seen with hypokalemia.

Animal studies suggest that vasodilation and improved peripheral blood flow may help explain the potential improvement in insulin sensitivity associated with calcium channel blockers. These agents and α-blockers seem to have metabolically neutral or favorable effects compared with those of older agents.

Before we criticize the methodology or results of older clinical trials that involved diuretics and β-blockers (most of these trials were performed before some of the newer classes of agents became available), we should remember that in those trials, blood pressure (BP) was reduced significantly.¹ In addition, an almost 40% reduction in morbidity and mortality associated with stroke and a 15% reduction in coronary events were observed. The shortfall in prevention of coronary events might be attributed, in part, to the disadvantages of diuretics and β-blockers. In fact, more recent trials suggest that for a given reduction in BP, newer agents confer potential advantages, as described above, over diuretics and β-blockers.

However, the clinical significance of these findings is unclear, in part because of the design of the earlier studies. In many of these, diabetes was a secondary end point to hypertension. Failure to adjust adequately for the presence of hypertension was a confounding factor in some trials; in others, adjustment was not made for potential confounders such as age, sex, race, and concomitant medications. Carefully controlled clinical trials, with adequate numbers of patients and adequate follow-up, are necessary to determine primary diabetic end points with different classes of agents.

The bottom line. The primary goal for hypertensive patients with diabetes is the control of hypertension, which is grossly undertreated in these patients. The JNC 7 guidelines recommend a goal BP below 130/80 mm Hg in patients with diabetes.³ Rather than getting mired in decisions about which drug to use initially, recognize that most hypertensive patients with diabetes will require 2 or more agents to achieve this goal. Many of these patients have accelerated atherosclerosis and are appropriate candidates for β-blockers--the only class of agents approved for cardioprotection after myocardial infarction. β-Blockers should be considered first-line agents in these patients.

ACE inhibitors and ARBs are renoprotective in patients with diabetes and progressive renal disease, but most of these patients will also require a thiazide or loop diuretic for fluid retention and/or to achieve the lower BP goal. Calcium channel blockers can represent valuable add-on therapy in this group. The diabetogenic potential of thiazide diuretics and β-blockers can be minimized by the use of lower doses when possible, in addition to the measures mentioned above. Ongoing and future clinical trials should help clarify some of these important concerns.

References:

REFERENCES:

1.

Moser M, Sowers JR, Oparil S, Black H. New-onset diabetes in treated hypertensive patients--is it clinically significant?

J Clin Hypertens (Greenwich)

. 2005;7:90-95.

2.

Asfaha S, Padwal R. Antihypertensive drugs and incidence of type 2 diabetes: evidence and implications for clinical practice.

Curr Hypertens Rep

. 2005;7:314-322.

3.

Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report [published correction appears in

JAMA.

2003;290:197].

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2003;289:2560-2572.