Combination Therapy in Hypertension with Diabetes: Preferential Consideration for CCB and ARBs

An important factor leading to poor BP control is the limited use of combination drug treatment, despite scientific evidence of its superior ability to control BP in patients with difficult-to-treat hypertension. In addition, combination treatment allows achieving BP control more easily (and more quickly) as compared with monotherapy (3) . More than 70% of adults treated for hypertension eventually require at least two antihypertensive agents for achieving blood pressure control (4)

When hypertensive patients do not achieve target blood pressure control, the options to try and achieve required treatment goals are to increase the dose of monotherapy (which increases the risk of side effects) or to use drug combinations with minimum side effects. In order to avoid complications, it is important to start treatment as soon as possible, achieve the goals in the shortest time possible and ensure treatment adherence (5) . The mechanisms which lead to blood pressure rise in a patient vary – monotherapy acts on one or at best two of these mechanisms, while the use of a combination of drugs allows for action on multiple different hypertensive mechanisms (6). By combining two drugs with different mechanisms of action, an antihypertensive effect of two to five times greater compared to monotherapy is possible (7). Increasing the dose of monotherapy reduces coronary events by 29% and cerebrovascular events by 40%, while combining two antihypertensive agents with a different mechanism of action reduces coronary events by 40% and cerebrovascular events by 54%, respectively (8). Thus, the use of combination therapy provides greater target organ protection than increasing the dose of monotherapy. Fixed-dose single pill combinations offer additional advantages, such as improved adherence by 24% and potentially reduced cost (9) - all these benefits are of much clinical and practical value for hypertensive patients with diabetes.

Combinations of antihypertensive drugs also have actions unrelated to their effect on blood pressure that can have an impact on the prognosis of patients (10) . As per the last European Society of Cardiology (ESC) guidelines recommendations for the management of hypertension, combination treatment is recommended for most hypertensive patients as initial therapy. Preferred combinations recommended comprise a RAS blocker (either an ACE inhibitor or an ARB) with a CCB or diuretic. (11)

Drugs that inhibit the renin angiotensin system have been effective in the prevention of cardiac and renal complications. Hypertension, specifically systolic hypertension, is inadequately controlled by monotherapy in most type 2 diabetic patients. Long-acting calcium channel blockers (CCBs) appear to be an appropriate candidate to lower systolic BP levels below 130 mm Hg (12).

Cilnidipine - L/N-type calcium channel blocker (CCB), has been reported to have more beneficial effects on proteinuria progression in hypertensive patients than amlodipine, an L-type CCB. The N-type calcium channel blockade that inhibits renal sympathetic nerve activity might reduce glomerular hypertension by facilitating vasodilation of the efferent arterioles (13). Cilnidipine is known to dilate both afferent and efferent arterioles by its effect on N-type calcium channels and thus reduces urinary albumin and protein excretion (14). In a study conducted on Indian Diabetic patients, cilnidipine use resulted in an additive effect in microalbuminuria reduction over and above the well- proven effect of ACE inhibitors (15). Telmisartan is reported to be effective in lowering blood pressure and improving metabolic parameters in Indian T2DM patients with or without complications (16)

Angiotensin Receptor Blockers in combination with newer generation calcium channel blockers like cilnidipine may offer specific clinical benefits, which in turn, could improve long term cardiovascular outcomes. Thus, cilnidipine – dual type (L- and N-type) calcium channel blocker and telmisartan – a well-established long-acting, often referred to as a 'metabolic sartan' seem to be a valuable single-pill combination for management of hypertension with diabetes as initial therapy for optimising long term renal, metabolic and cardiovascular outcomes in these patients.

Adapted from

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