Choice of ACE inhibitor combinations in hypertensive patients with type 2 diabetes: update after recent clinical trials

Abstract

The diabetes epidemic continues to grow unabated, with a staggering toll in micro- and macrovascular complications, disability, and death. Diabetes causes a two- to fourfold increase in the risk of cardiovascular disease, and represents the first cause of dialysis treatment both in the UK and the US. Concomitant hypertension doubles total mortality and stroke risk, triples the risk of coronary heart disease and significantly hastens the progression of microvascular complications, including diabetic nephropathy. Therefore, blood pressure reduction is of particular importance in preventing cardiovascular and renal outcomes. Successful antihypertensive treatment will often require a combination therapy, either with separate drugs or with fixed-dose combinations. Angiotensin converting enzyme (ACE) inhibitor plus diuretic combination therapy improves blood pressure control, counterbalances renin-angiotensin system activation due to diuretic therapy and reduces the risk of electrolyte alterations, obtaining at the same time synergistic antiproteinuric effects. ACE inhibitor plus calcium channel blocker provides a significant additive effect on blood pressure reduction, may have favorable metabolic effects and synergistically reduce proteinuria and the rate of decline in glomerular filtration rate, as evidenced by the GUARD trial. Finally, the recently published ACCOMPLISH trial showed that an ACE inhibitor/calcium channel blocker combination may be particularly useful in reducing cardiovascular outcomes in high-risk patients. The present review will focus on different ACE inhibitor combinations in the treatment of patients with type 2 diabetes mellitus and hypertension, in the light of recent clinical trials, including GUARD and ACCOMPLISH.

Treatments for Hypertension in Type 2 Diabetes-Non-Pharmacological and Pharmacological Measurements

“…To this stage, the preferred antihypertensive drug classes are somewhat uncertain, and disputed, however, smaller dosage of each class of drugs might lead less side events. Currently a combination therapy with 2 or more different classes of antihypertensive drugs is recommended [1,4,168]. Use of ACEIs and ARBs as the initial treatment in hypertension in type 2 diabetes is usually advocated as these agents exert favourable effects on insulin sensitivity and provide renal protection.…”

“…Thus, management of subjects with type 2 diabetes and associated hypertension needs to be early and aggressive, and must utilize a global approach. Now, especially for hypertensive patients with diabetes and obesity, multiple-medications are common [168].…”

Emerging drug combinations to optimize renovascular protection and blood pressure goals

“…54 Moreover, in the 13,101 hypertensive patients with type 2 diabetes enrolled in the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) study, chlorthalidone, a thiazide-type diuretic, reduced cardiovascular outcomes to an extent similar to lisinopril or amlodipine. 55 However, diuretics may cause urinary electrolyte wasting and, secondary to this, hyponatremia, hypokalemia, and/or hypomagnesemia.…”

“…6 At low doses, thiazide diuretics usually do not cause changes in renal function, and they can be used when the estimated glomerular filtration rate is .30 mL/minute. 54,56 Several studies have analyzed the effects of the combination of RAS inhibitors and diuretics on renal outcomes. Thus, it has been shown that in hypertensive patients with stage 3-4 chronic kidney disease, the combination of losartan and hydrochlorothiazide significantly reduced the urinary protein-to-creatinine ratio, without significant changes in the serum creatinine levels and estimated glomerular filtration rates.…”

“…64 Although through the reduction of BP levels calcium channel blockers may reduce urinary albumin excretion, not all calcium channel blockers are equal, as they differ in their effect on glomerular hemodynamics and urinary albumin excretion. 54 Conventional dihydropyridines block only L-type calcium channels. This promotes peripheral vasodilatation, including afferent renal arterioles with little change in the efferent arteriole diameter, as the efferent arterioles lack L-type receptors.…”