of Hypertensive Diabetic Patients:
A Report from the ADA 2004 and JNC-VII 2003
Hypertension is an extremely common comorbidity of diabetes, affecting 20–60% of people with diabetes, and it is also a major risk factor for cardiovascular events as well as for diabetic microvascular complications, such as retinopathy nephropathy, and possibly neuropathy. Thus, the occurrence of hypertension in association with type 2 diabetes mellitus (T2DM) constitutes one of the most rapidly increasing disorders in the world. Recently, the results of adequate evidence-based studies support an aggressive approach to the diagnosis and treatment of hypertension in reducing the incidence of both diabetic macrovascular and microvascular complications.
Definition of hypertension in diabetic populations :
The standard definition of hypertension by the JNC-VII is a blood pressure (BP) ≧140/90 mmHg for the general population and they recommended a lower target (130/80 mmHg) for diabetic patients. General population with BP:120~139/80~89 mm Hg are regarded as “Prehypertensives”. Because of the high cardiovascular risk associated with BP ≧130/80 mmHg in patients with diabetes, 130/80 mmHg is considered to be the cut point for defining diabetic hypertension, rather than 140/90 mmHg, as in the general population.
Prevalence of hypertension in diabetic populations :
The prevalence of hypertension in the diabetic population is 1.5–3 times higher than that of nondiabetic age-matched groups. Hypertension ultimately affects ∼30% of individuals with type 1 DM and approximately 20–60% of patients with type 2 DM will develop hypertension, depending on age, ethnicity, and obesity.
Management of hypertension in diabetes mellitus:
1. Screening and initial evaluation:
A complete medical history with special emphasis on cardiovascular risk factors and the presence of diabetic and other cardiovascular complications should be assessed initially. Blood Pressure should be measured at every routine diabetes visit and should ideally be measured in the supine and standing position in order to detect the presence of autonomic neuropathy because the presence of postural hypotension should be taken in consideration when anti-hypertensive drugs are to be chosen. Patients found to have systolic BP≧130 or diastolic BP≧80 mmHg should have blood pressure confirmed on a separate day. Initial laboratory examination should include serum creatinine, electrolytes, HbA1c, fasting lipid profile, and urinary albumin excretion.
2. Behavioral treatments of hypertension:
Diabetic patients with a systolic BP of 130–139 mmHg (ADA opinion, and 120-139 mm Hg suggested by the JNC-VII) or a diastolic BP of 80–89 mmHg should be given lifestyle/behavioral therapy alone for a maximum of 3 months and then, if targets are not achieved, should also be treated pharmacologically with agents that block the renin-angiotensin system. Since weight reduction can reduce BP and improve blood glucose and lipid levels, it should be considered an effective measure in the initial management of mild-to-moderate hypertension. The loss of 1 kg body weight has resulted in decreases in mean arterial BP of ~1 mmHg. Moderately intense physical activity, such as 30–45 min of brisk walking most days of the week, has been shown to lower BP and is recommended in JNC VI. The ADA has recommended that diabetic patients who are 35 years of age or older and are planning to begin a vigorous exercise program should have exercise stress testing or other appropriate noninvasive testing. Smoking cessation and moderation of alcohol intake are also recommended by JNC VI to reduce BP and are clearly appropriate for all patients with diabetes. These nonpharmacological strategies may also positively affect glycemia and lipid control.
3. Drug Therapy:
There is strong evidence that pharmacologic therapy of hypertension in patients with diabetes is effective in producing substantial decreases in cardiovascular and microvascular diseases. Patients with confirmed hypertension (systolic BP ≧140 mmHg or diastolic BP ≧90 mmHg) should receive immediate pharmacological treatment in addition to lifestyle/behavioral therapy. JNC VII suggests the use of both therapies simultaneously and immediately when systolic BP ≧130 mmHg or diastolic BP ≧80 mmHg, and in order to achieve such goal, usually a combination of 2 or more drugs are required.
(a). Thiazide diuretics: Diuretics reduce total body sodium through their natriuretic action and have been shown to have vasodilatory effects as well. Hydrochlorothiazide at a daily dose of 25 mg does not significantly decrease insulin sensitivity. Recently the Systolic Hypertension in the Elderly (SHEP) study showed that low-dose thiazide treatment of systolic hypertension in older diabetic subjects was associated with a significant reduction in cardiovascular events. Thiazides may not be effective in subjects who have significantly decreased renal function (i.e., GFR ＜60 ml·min-1·1.73m-2) and in this particular case, loop diuretic (furosemide) is recommended when it is to be used in combination with other agents, though no long-term studies of the effect of loop diuretics on long-term complications of diabetes have been shown.
(b). Adrenergic blockers:
(i). centrally acting agents: These drugs effectively lower BP by decreasing central sympathetic outflow. However, their effects on the progression or development of microvascular complications or cardiovascular disease have not been studied in detail. They are associated with orthostatic hypotension, and they should be used with caution in patients with diabetic autonomic neuropathy. (ii). ß-blockers: In three randomized studies in diabetic hypertensive patients in which proteinuria was examined, atenolol (a selective ß1-blocker) produced similar reductions in proteinuria compared with an ACE inhibitor. In the UKPDS-HDS (Hypertension in Diabetes Study), the ß1-blocker atenolol and the ACE inhibitor captopril were equally effective in decreasing the risk of diabetes-related end points and microvascular events in a large group of subjects with T2DM. Although the UKPDS study did not show an increased incidence of hypoglycemic episodes in the group treated with ß-blockers, it is probably prudent to avoid the use of ß-blockers in insulin-using patients who have a history of severe hypoglycemia. In other patients with diabetes, especially patients with a recent myocardial infarction where ß-Blockers have demonstrated efficacy with relative reductions in mortality of ∼25%, the benefits of ß-blockers would appear to outweigh the potential risks.
(iii). a-adrenergic blockers: No long-term randomized clinical trials examining renal or cardiovascular outcomes have been published using this family of drugs. a-blockers have been associated with improved insulin sensitivity in patients with insulin resistance associated with essential hypertension. A slight decrease in LDL cholesterol has been reported with a-blockers in small short-term clinical studies, all involving ＜25 patients per group. The clinical significance of these findings is unclear. Initial doses of these agents, particularly prazosin, have been associated with orthostatic hypotension, so this agent should be used with caution in patients with diabetic autonomic neuropathy. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study had an arm comparing an a1-blocker, doxazosin, with a ß-blocker, a CCB, and an ACE inhibitor versus a diuretic. This part of the study was terminated because of an increased incidence of cardiovascular events, especially congestive heart failure, in patients receiving the a1-blocker versus a diuretic. Approximately one-third of the 40,000 patients randomized has diabetes. However, though the final reports of ALLHAT has been published in 2002, controversials still existed.
(c). Calcium channel blockers: The family of CCB is subdivided in three subclasses that have significant differences in their hemodynamic effects. The dihydropyridine group (DCCBs) has mainly vasodilatory effects and relatively small effects on cardiac inotropism or atrio-ventricular conduction. Reflex tachycardia can be seen, and edema is the most common side effect. There are many drugs in this group and it is difficult to assess and generalize results of clinical studies with the DCCB agents. The second group, the benzothiazepines have moderate vasodilatory effects and moderate negative inotropic and chronotropic effects. Diltiazem is the only agent available in this group, and several preparations with different pharmacokinetic profiles exist. The third group, the phenylalkylamines, has similar vascular and cardiac effects as diltiazem. Verapamil is the only agent in this group available in the U.S. The benzothiazepine diltiazem and the phenylalkylamine verapamil are referred to as NDCCBs. Conflicting evidence exists regarding the safety and efficacy of DCCBs in reducing cardiovascular end points. A recent meta-analysis suggests that DCCBs may be equivalent in protecting against stroke but less effective in reducing myocardial infarction and combined major coronary events than ACE inhibitors, ß-blockers, or diuretics. In general, DCCBs seem to have a neutral effect on metabolic parameters. Small studies of short duration using diltiazem and verapamil (NDCCBs) have been associated with decreased proteinuria in patients with overt diabetic nephropathy, but long-term studies showing a reduction in the rate of fall of GFR have not been carried out.
(d). ACE inhibitors: These drugs are useful in the management of hypertension in diabetic patients with or without diabetic nephropathy. ACE inhibitors have been extensively studied in the treatment of diabetic nephropathy and are effective in preventing progression of retinopathy. The recent HOPE (Heart Outcomes Prevention Evaluation) trial that documented decreased cardiovascular end points despite quite minor changes in BP raises the possibility that ACE inhibitors have benefits for diabetic patients that are independent of their antihypertensive effect. Postulated mechanisms include effects on the endothelium as a result of decreased vascular smooth muscle growth, decreased release of endothelin, increased fibrinolysis, and release of the vasodilating substances nitric oxide and prostacyclin mediated by bradykinin. The most common side effects of ACE inhibitors include cough and, occasionally, acute decreases in renal function. Hyperkalemia can be seen, especially in patients with renal insufficiency, bilateral renal artery stenosis, and hyporeninemic hypoaldosteronism.
(e). ARBs: The recently published RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan) and PRIME (Program for Irbesartan Mortality and Morbidity Evaluations) studies in the New England Journal of Medicine of September issue (2001) showed that ARBs are able to retard the progression of albuminuria and the development and progression of nephropathy in T2DM. However, long-term data on cardiovascular outcomes using this class of drugs are limited.
Combinations of antihypertensive agents:
In general, combination therapy may help to improve compliance, as one drug may antagonize the adverse effects of another. The superiority of one combination regime over another has not been documented. However, it is clear that intensive treatment of hypertension, with goals recommended by the ADA’s and JNC VII’s new target of ＜130/80 mmHg, will require more than two drugs in most patients and three or more in many.
Blood pressure goals in diabetic patients:
There is support from several recent randomized clinical trials for reducing systolic BP to ≦140 mmHg and for reducing diastolic BP to ≦80 mmHg. Epidemiological evidence demonstrates that BP ≧115/75 mmHg are associated with increased cardiovascular event rates and mortality in persons with diabetes. Therefore, a target BP goal of ＜130/80 mmHg is reasonable, if it can be safely achieved. Although there is no threshold value for BP, whether even more aggressive treatment would reduce the risk still further is an unanswered question. Achieving lower levels, however, would increase the cost of care as well as drug side effects and is difficult in practice.
Strategy of drug therapy in hypertensive diabetes:
The ideal strategy for treating hypertension in persons with diabetes is still not clear. Initial drugs for those with a blood pressure ≧140/90 mm Hg should be with a drug class shown to reduce CVD events in patients with diabetes which include ACE inhibitors, ARBs, low-dose thiazide diuretics, ß-blockers, and calcium channel blockers. Though there is no conclusive evidence favoring one class of drugs, as large number of studies in patients with diabetes (both type 1 and type 2) and hypertension (either mild or more severe) demonstrating improvement in a range of outcomes, including progression of nephropathy, cardiovascular events, and mortality, it is now an established practice to begin hypertensive patients with diabetes and without microalbuminuria on an ACE inhibitor. When microalbuminuria or more advanced stages of nephropathy is present, both ACE inhibitors (T1DM and T2DM patients) and ARBs (T2DM patients) are considered first-line therapy for preventing the progression of nephropathy. However, other strategies including diuretic and b-blocker-based therapy are also supported by evidence. If the target BP goal of ＜130/80 mmHg is not obtained with the initial doses of first-line drugs, increases in doses are recommended, or the addition of a second drug from a different group should be considered. Regardless of the initial treatment, it must be emphasized that most patients will require more than two drugs to achieve the recommended target of ＜130/80 mmHg, and many will require three or more. Achievement of the target BP may be more important than the particular drug regimen used. Thiazide diuretics have been shown to improve cardiovascular outcomes and may address the volume or salt-sensitive components of hypertension, complementing the mechanisms of action of other drugs, so these are appropriate choices for a second or third drug and can be used for initial therapy in patients without additional cardiovascular risk factors (e.g. dyslipidemia) or proteinuria. Actually the JNC VII suggests diuretics, either use alone or in combination, should be the initial drug to be used in patients with hypertension. NDCCBs can be used when ACE inhibitors, ARBs, or ß-blockers are not tolerated or are contraindicated or when a second or third drug is required. Actually classes of drugs for which there are no long-term data on efficacy in improving outcomes can be used when there is intolerance to other classes, when there are specific indications for their use apart from treatment of hypertension (for example, a1-blockers for patients with benign prostatic hypertrophy and diltiazem for rate control in atrial fibrillation), or when additional drugs are required to achieve the target for blood pressure.
Treatment decisions should, of course, be individualized based on the clinical characteristics of the patient, including comorbidities as well as tolerability, personal preference, and cost, and in elderly hypertensive patients, blood pressure should be lowered gradually to avoid complications.
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