Treatment of Hypertension in Diabetes

What Is the Best Therapeutic Option?

Tonje A Aksnes; Sigrid N Skårn; Sverre E Kjeldsen

Disclosures

Expert Rev Cardiovasc Ther. 2012;10(6):727-734. 

In This Article

Antihypertensive Treatment in Diabetic Patients

Nonpharmacological treatment regimens, such as low salt diet, weight loss, exercise and alcohol restriction, have been shown in meta-analyses to lower BP.[18,19] However, antihypertensive drugs often have to be used to reach the BP target of below 140/90 mmHg (or lower if high-risk patients). In the guidelines from ESH/European Society of Cardiology,[9] thiazide diuretics, β-blockers, calcium channel blockers (CCBs), ACEis and angiotensin II receptor blockers (ARBs) are recommended as suitable for initiation and maintenance of antihypertensive treatment either as monotherapy or in suitable combinations (Figure 2). β-blockers have been downgraded in the British recommendation,[102] and Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure reports[10] have given thiazide diuretics a prominent role based mainly on the results from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack (ALLHAT) study.[20] In a large meta-analysis of 27 randomized trials with 33,395 hypertensive diabetic patients, the results showed similar efficacy to prevent major cardiovascular events with ACEis, ARBs, CCBs and diuretics/β-blockers.[21] However, most patients require multiple drugs (often three to four different drugs) to achieve BP targets, and unfortunately, many patients still remain untreated or undertreated, particularly among women and minority populations.[22] In the USA, it has been calculated that only 30% of the diabetic population reach the BP target (<130/80 mmHg).[23]

Figure 2.

Antihypertensive drug treatment recommended, according to the 2007 European Society of Hypertension/European Society of Cardiology guidelines. The preferred combinations in the general hypertensive population are represented as solid lines. The boxes indicate classes of agents proven to be beneficial in controlled intervention trials. ACE: Angiotensin-converting enzyme. Reproduced with permission from [9].

All antihypertensive drugs lower (by definition) BP, and the main benefit based on a large number of randomized trials is due to lowering of BP per se and is largely independent of the drugs employed. However, differences between drugs exist with respect to target-organ damage and prevention of cardiovascular events. Treatment should be individualized according to concomitant risk factors and diseases, and depend on age, biochemical and hemodynamic measurements of the patients.

There are also known differences in diabetogenic effect between the different drug regimens.[24] A network meta-analysis has calculated the odds ratio for new-onset diabetes to be 0.62 (0.51–0.77) for ARBs, 0.67 (0.57–0.79) for ACEis, 0.75 (0.63–0.89) for placebo, 0.79 (0.67–0.92) for CCBs and 0.93 (0.78–1.11) for β-blockers compared with treatment with diuretics (reference drug = 1).[24] There is no doubt that β-blockers and diuretics, especially when combined, have adverse metabolic effects and increase the risk of new-onset diabetes in predisposed patients. The ESH guidelines therefore argue against the combination of diuretics and β-blockers in primary prevention among people with a high risk of developing diabetes.[9]

RAS Blockers (ACEis & ARBs)

ACEis block the conversion of angiotensin I into angiotensin II by inhibition of ACE. The reduced levels of angiotensin II lead not only to vasodilatation and a fall in BP but also to a reduction of potential harmful effects of angiotensin II on the cardiorenovascular system, such as structural damage to the heart, blood vessels and kidneys. ACEis also increase bradykinin levels through inhibition of degradation with potential effects and side effects (cough). The ARBs block angiotensin II Type I receptors leading to vasodilatation, but owing to their angiotensin II type I receptor selectivity, they lack the effect of potentiation of bradykinin and possibly other vasoactive peptides.

In diabetic patients, combination treatment is commonly needed to effectively lower BP, so the discussion of which medication to be used first is not always important. However, a blocker of the renin–angiotensin system (RAS) should almost invariably be included because of the evidence of its superior protective effects. Especially, in proteinuric diabetic nephropathy, RAS blockade is clearly indicated. Large hypertension and heart failure trials have also reported an impact on diabetes development in favor of RAS blockade (Figure 3). So for persons with cardiovascular or kidney disease, including microalbuminuria, or with cardiovascular risk factors in addition to diabetes and hypertension, an ACEi or ARB should be started.

Figure 3.

New-onset diabetes mellitus in hypertension and heart failure trials with renin–angiotensin system blockers. *p < 0.05; ***p < 0.001. ACEi: Angiotensin-converting enzyme inhibitor; ARB: Angiotensin II receptor blocker; BB: b-blocker; CCB: Calcium channel blocker; D: Diuretic; DM: Diabetes mellitus.

In a substudy of diabetic patients (1195 patients) included in the LIFE study, treatment with a strategy based on an ARB (losartan) significantly reduced cardiovascular morbidity and mortality compared with treatment with a β-blocker (atenolol) with a relative risk reduction of 24% (2–42%), despite almost similar BP reduction.[25] The benefit of the losartan-based strategy may have been a consequence of the greater regression in left ventricular hypertrophy.

The VALUE trial compared the effect of an ARB (valsartan) with a CCB (amlodipine), both in the whole cohort as well as in the diabetic subgroup. No significant difference in the composite cardiac end point was found despite a greater BP decrease in the CCB group.[26]

A subgroup analysis of the ONTARGET compared an ARB (telmisartan) with an ACEi; (ramipril) in 6391 patients with diabetes and found no difference in cardiovascular morbidity and mortality between the groups.[27] The patients receiving both ARBs and ACEis (whole ONTARGET cohort) had an increased risk of adverse side effects,[27] and the ARB/ACEi combination is usually not recommended.

Calcium Channel Blockers

CCBs are a chemical heterogeneous group that inhibit the transfer of calcium ions across cell membranes, thereby reducing intracellular calcium. The dihydropyridine CCBs (e.g., nifedipine and amlodipine) are more selective in blocking L-type calcium channels in vascular smooth muscle cells, inducing vascular relaxation and reduced BP, whereas nondihydropyridine CCBs (e.g., diltiazem and verapamil) at therapeutic doses block calcium channels in cardiac myocytes, thereby reducing cardiac output as well as having antiarrhythmic by effects on the atrioventricular node.

CCBs are efficient antihypertensive drugs and have no adverse effects on lipid or carbohydrate metabolism. In the ALLHAT study, the CCB (amlodipine) was associated with similar rates of coronary mortality and nonfatal myocardial infarction as treatment with ACEi (lisinopril) and the diuretic chlorthalidone.[20] The authors found a higher rate of heart failure in the patients treated with CCBs compared with chlorthalidone with a relative risk of 1.42 (1.23–1.64).[20] However, this effect may have been due, at least in part, to a lower attained BP with chlorthalidone or merely been an artifact due to lack of diuretic treatment in the CCB arm following discontinuation of previous treatments (diuretics) at the time of inclusion into the study.

In the large diabetic subgroup (5137 patients) in the BP-lowering arm of the Anglo–Scandinavian Cardiac Outcomes Trial (ASCOT), a benefit of the CCB (amlodipine)-based treatment was shown.[28] Total cardiovascular events and procedures were significantly 14% (2–24%) lower than in the β-blocker (atenolol)-based treatment group.[28] This was consistent with the overall findings. However, to what extent this result is dependent on BP differences, metabolic alterations induced by the treatments or other factors are not clear.[28]

Compared with RAS blockers, CCBs are often shown to be less effective in preventing heart failure. However, CCBs are well tolerated and very effective in lowering BP, and are often needed to achieve a target value of BP in diabetic patients, especially in combination treatment.

Diuretics

Thiazid and thiazide-like diuretics lower BP by a complex series of mechanisms, such as blocking renal tubular reabsorption of sodium. Potassium-retaining diuretics (e.g., amiloride and spironolactone) block the sodium/potassium exchange in the renal distal tubules and limit potassium loss in hypertensive patients treated with thiazide/thiazide-like diuretics. Loop diuretics are usually not used as routine antihypertensive treatment, except in patients with impaired renal function and/or heart failure.

Thiazide diuretics reduce BP at least in part by reversing the underlying tendency to volume expansion in hypertensive diabetic patients. A combination of thiazide and a RAS blocker is particularly effective as mild fluid loss increases the antihypertensive effect of RAS blockers and as the hypovolemia-induced rise in renin and angiotensin II production is reduced.

Thiazide diuretics in high doses may worsen glycemic control by impairing insulin secretion and decreasing peripheral insulin sensitivity. They have a drug- and dose-dependent hypokalemic effect that may blunt the release of insulin from the pancreas, but potassium supplementation and a combination with ACEis or ARBs may prevent hypokalemia. Low-dose thiazides are an important supplement in hypertension treatment, and diuretics have been shown to be equally effective as ACEis in preventing cardiovascular complications.[20] If creatinine clearance is low and volume control is required, a loop diuretics should be used rather than a thiazide diuretic.

In the individuals with diabetes mellitus (13,101 patients) included in the ALLHAT, the diuretic chlorthalidone was shown to be as effective as CCBs and ACEis in reducing cardiovascular morbidity and mortality.[29] In addition, in the Hypertension in the Very Elderly Trial (HYVET), the thiazide-like diuretic indapamide reduced the rate of stroke, coronary heart disease, heart failure and all-cause mortality in very old hypertensive patients.[30]

Not all thiazides are created alike, but thiazide diuretics have been, are and will be a major component of the antihypertensive drug arsenal also in the future,[31] despite negative effects on endocrine metabolism and electrolytes. The risk of developing hyponatremia (especially common in older women) may be prevented by low-dose treatment and fluid restriction. In patients with diabetes and hypertension, low-dose treatment and combination treatment with other drugs (other than β-blockers) should be preferred to reduce metabolic unwanted effects.

β-blockers

Despite the intensive investigations, the β-adrenergic blockers' exact BP-lowering effect remains controversial and depends on the pharmacological properties (e.g., some drugs with a strong intrinsic sympathomimetic effect). However, most β-blockers reduce cardiac output by negative chronotropic and inotropic effects.

β-blockers increase the risk of developing new-onset diabetes mellitus,[24] particularly when combined with thiazide diuretics. However, β1-selective blockers with vasodilating action (β2-agonist or α-blockers) may be preferred in order to avoid metabolic interference.

As a general rule, β-blockers should not be used as first-line treatment in patients with diabetes mellitus and hypertension due to unfavorable effect on endocrine metabolism.[31] However, a β-blocker is still a useful add-on antihypertensive agent, especially in patients with coronary artery disease, tachycardia and heart failure.

Other Antihypertensives

α-blockers are not recommended as primary therapy in diabetes and are not widely used because of side effects, such as orthostatic hypotension. In the ALLHAT study, the doxazocin arm was prematurely discontinued due to an increased rate of new-onset heart failure, or more likely fluid retention due to lack of diuretic treatment, compared with chlorthalidone.[20] However, in older men with symptomatic prostatism, it may be a useful add-on therapy.

Aldosterone antagonists (e.g., spironolactone and eplerenon) can be effective antihypertensive drugs in selected patients, especially in those with low serum potassium. However, there is a potential high risk of developing hyperkalemia in diabetic patients using combination treatment with a RAS blocker.

Combination Therapy

Combination therapy using two (or three) agents may also be considered as initial treatment of severe hypertension (i.e., SBP is 20 mmHg or DBP is 10 mmHg above target) or an otherwise high cardiovascular risk. This is recommend based on the consideration that high-risk individuals may experience an event soon after treatment initiation and timely BP control is desirable. In the VALUE trial that included high-risk hypertensive patients, analyses showed that patients achieving BP control within 1 month of treatment developed less cardiovascular events than the patients who achieved BP control later.[32] In a large population-based, nested case–control study of more than 200,000 hypertensive patients, the patients who started on combination therapy and kept it along the entire period of observation had a 26% (15–35%) reduction of cardiovascular risk.[33] In addition to a more effective reduction of the BP per se, a possible additional cardiovascular protective effect may result from the interference with multifold mechanism of BP control. Diabetic patients with hypertension are also more resistant to antihypertensive treatment,[31] indicating that use of combination treatment should be the first-line treatment in diabetic patients.

Many different combinations exist (Figure 1), and a RAS blocker represents the cornerstone of the antihypertensive arsenal for patients with diabetes and hypertension.[31] A combination of a RAS blocker and a thiazide diuretic or a CCB are often recommended. The relative efficacy of combination therapy was evaluated in the ACCOMPLISH trial, which included about 60% diabetic patients among the 11,508 high-risk hypertensives enrolled. The patients were randomized to ACEi (benazepril) plus hydrochlorothiazide combination or ACEi (benazepril) plus CCB (amlodipine),[34] and the trial showed superiority to the ACEi–CCB (benazepril–amlodipine) combination.[35] The patients receiving hydrochlorothiazide had more cardiovascular events, primarily driven by more myocardial infarction. The absolute risk reduction in the composite end point (myocardial infarction, stroke, cardiovascular death, hospitalization for angina, resuscitated cardiac arrest and coronary revascularization) in ACCOMPLISH was 2.2%, which gives a number needed to treat of less than 50 for the mean follow-up time of 36 months. Among the patients with diabetes, a hazard ratio of 0.79 (0.68–0.92) for the primary end point was achieved on the ACEi–CCB combination, with the greatest impact among high-risk diabetic patients.[35]

The Action in Diabetes and Vascular Disease: Preteraxe and Diamicron-MR Controlled Evaluation (ADVANCE) trial[36] used the combination of a diuretic (indapamide) and an ACEi (perindopril) on top of pre-existing antihypertensive agents to produce further BP decrease compared with placebo in more than 11,000 diabetic patients. The fixed-dose combination therapy reduced the incidence of major macrovascular or microvascular events by 9% (16.8 vs 15.5%) and all-cause mortality by 14% (4.6 vs 3.8%).[36] The reduction in BP during this trial was 5.6/2.2 mmHg in the active treatment group (active group 136/73 vs placebo group 140/73 mmHg).[36]

In light of the ACCOMPLISH trial results, a combination of an RAS blocker and CCB should probably be used as first-line combination treatment. Accordingly, the new National Institute for Health and Clinical Excellence guidelines from the UK introduce initial combination therapy with a blocker of RAS and a CCB, relegating diuretics to third-line treatment.[102]

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