Review
Exploring the optimal combination therapy in hypertensive patients with diabetes mellitus Expert Rev. Cardiovasc. Ther. 7(11), 1349–1361 (2009)
Gianpaolo Reboldi†, Giorgio Gentile, Fabio Angeli and Paolo Verdecchia † Author for correspondence Department of Internal Medicine, University of Perugia, Perugia, Italy Tel.: +39 075 578 3637 Fax: +39 075 573 0855
[email protected]
Diabetes causes approximately 2.9 million deaths yearly, mainly through an increased risk of cardiovascular disease. In hypertensive diabetics, blood pressure reduction determines a significantly lower rate of cardiovascular and renal events. Conversely, reaching the generally recommended target of lower than 130/80 mmHg is a difficult challenge and, in most cases, two or more antihypertensive drugs are required. Until recently, there was a general consensus that combination treatment should include a diuretic as one of the two fundamental agents. However, recently published trials using calcium channel blockers plus renin–angiotensin systemblocking agents showed that such a combination reduces the risk of major cardiovascular events, provides greater renoprotection, and improves metabolic outcomes as compared with diureticbased combinations. The present review explores the potential for an ‘optimal’ combination therapy in patients with diabetes mellitus and hypertension, in view of recent experimental and clinical evidence. Keywords : angiotensin II type 1 receptor blocker • angiotensin-converting enzyme inhibitor • antihypertensive agent • calcium channel blocker • combination • diabetes mellitus • diuretic • drug combination • drug therapy • hypertension
The diabetes epidemic has increasingly alarmed public health advocates [1] , since it accounts for at least 10% of total healthcare expenditure in many countries [2] . In 1985, an estimated 30 million people worldwide had diabetes; in the year 2000, the global burden of diabetes was estimated to be 171 million, and this number is projected to rise to 366 million in 2030 [3] . Two major concerns are that much of this increase in diabetes will occur in developing countries, and that there is a growing incidence of Type 2 diabetes (which accounts for ~90% of cases) at a younger age. Global excess mortality attributable to diabetes is estimated at 2.9 million deaths yearly, which is equivalent to 5.2% of world all-cause mortality in the year 2000 [4] , mainly through the increased risk of cardiovascular (CV) disease [5,6] . At the time of diagnosis, hypertension is present in approximately 50, 70 and 80% of normo-, micro- and macro-albuminuric Type 2 diabetics, respectively [7] . In such patients, blood pressure (BP) reduction is of paramount importance www.expert-reviews.com
10.1586/ERC.09.133
for primary and secondary prevention of cardiovascular and renal outcomes, including stroke [8] , coronary heart disease, left ventricular hypertrophy [9] , and end-stage renal disease [10] . Consequently, hypertension guidelines unanimously recommend achieving a target of lower than 130/80 mmHg in patients with diabetes and hypertension [11–13] . However, successful treatment of these patients will often require combination therapy [14] . Combining BP-lowering drugs from different classes is nearly five-times more effective than doubling the dose of one drug, and while BP reductions are additive, adverse effects are less than additive [15,16] . Combination therapy, even using low doses to minimize side effects, effectively reduces BP and related clinical end points to a greater extent than monotherapy and, although not widely accepted, it might be considered as initial therapy for many patients [15–17] . In hypertensive diabetics, commonly used combinations include a renin–angiotensin system (RAS)-blocking agent (angiotensin-converting
© 2009 Expert Reviews Ltd
ISSN 1477-9072
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enzyme [ACE]-inhibitor or angiotensin receptor blocker [ARB]) plus a diuretic or a calcium channel blocker (CCB). ACE-inhibitors [201] and ARBs [202] , the cornerstone of most combinations, have similar long-term effects on BP, as well as on a number of other outcomes, including death, cardiovascular events, progression to diabetes, left ventricular mass or function, and kidney disease [18] . At least theoretically, different antihypertensive combinations might offer specific cardiac, vascular and renal advantages beyond BP reduction per se. The present review explores the potential for an ‘optimal’ combination therapy in patients with diabetes mellitus and hypertension, in light of recent experimental and clinical evidence. Metabolic control
Although the preventive effect of near-normal glycemic control on cardiovascular outcomes is still a matter of lively debate [19,20] , compelling evidence from randomized trials in Type 1 [21,22] and Type 2 [23–25] diabetes clearly established that tight glycemic control decreases the rate of microvascular complications, including diabetic nephropathy, which is the leading cause of end-stage renal disease (ESRD) both in the UK [10] and the USA [26] , where over 40% of dialysis patients are diabetics. Thus, focusing solely on BP-lowering might not be the most appropriate approach; consequently, it appears reasonable to choose a combination therapy that does not worsen glycemic control and possibly improves it. Diuretics (usually thiazides or thiazide-like indoline diuretics such as indapamide) are among the most effective treatments for elevated BP [11] . On the other hand, they may be associated with undesirable metabolic effects (e.g., hyperglycemia, hyperuricemia, dyslipidemia and hypokalemia), increasing a patient’s likelihood of developing diabetes or worsening glycemic control in those who already have diabetes [27,28] . Although the diabetogenic effects of thiazides are most likely multifactorial, approximately 50% of the hyperglycemic effect of thiazides is thought to be the result of decreased insulin release from pancreatic b-cells either mediated or not by the reduction in serum potassium below 3.5 mmol/l [29,30] . Renin–angiotensin-blocking agents could at least theoretically mitigate the alterations of glucose metabolism induced by diuretics [31] . ACE-inhibitors and ARBs can increase pancreatic insulin secretion and improve insulin action on whole-body and skeletal muscle glucose disposal [32–37] . In addition, RAS inhibition may decrease sympathetic activity and promote favorable effects on the adipose tissue, such as adipocyte differentiation and increased adiponectin levels [35,36] . Finally, certain ARBs (i.e,. telmisartan and irbesartan) may simultaneously block angiotensin II function and activate PPAR- g, providing a potential mechanism for their favorable effect on blood glucose [38] . A meta-analysis including 11 trials [39] showed that ACE-inhibitors or ARBs prevented newonset diabetes mellitus (odds ratio: 0.78; 95% CI: 0.73–0.83), regardless of the indication of use (i.e., hypertension, coronary artery disease, congestive heart failure), and a later network meta-analysis [40] showed that hyperglycemia and subsequent diabetes occur more often in patients receiving diuretics (or b-blockers) instead of RAS-blocking agents (ACE-inhibitors or ARBs). However, while most of the available evidence derives 1350
from studies of hypertensive or prediabetic patients [41–44] , only a few studies have explored the metabolic effects of RAS-blocking agent/diuretic combinations in diabetic patients. In a small trial, ten patients with Type 2 diabetes and hypertension were initially treated for 8 weeks with enalapril alone and then with enalapril alone or in combination with hydrochlorothiazide (HCTZ) [45] . No significant difference was observed in any of the explored metabolic characteristics, including insulin sensitivity, between the enalapril alone- and the enalapril/HCTZ-treated groups. Despite later trials raising concerns about the metabolic effects of ACE-inhibitor/diuretic combination [46,47] , a recent large, randomized trial, Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation (ADVANCE), showed a neutral effect on glycemic control of the perindopril plus indapamide combination [48] . On the other hand, available evidence strongly supports the metabolic benefits of a RAS-blocking agent/CCB combination, particularly in patients with prediabetes (glucose intolerance, metabolic syndrome or history of gestational diabetes) or clinical diabetes mellitus [49–51] . In the Trandolapril–Verapamil in Non-insulin Dependent Diabetics (TRAVEND) trial, 103 patients with Type 2 diabetes, microalbuminuria and BP uncontrolled on monotherapy were randomized to either verapamil SR/trandolapril or enalapril/HCTZ [52] . The ACE/CCB combination allowed better metabolic control than the ACE/diuretic combination, as also observed when verapamil/trandolapril was compared with atenolol/chlorthalidone (HBA1c: 7.9 vs 8.6%; p = 0.001) in 463 hypertensive diabetics [53] . Similarly, in elderly hypertensives with Type 2 diabetes, treatment with delapril/manidipine caused no changes in metabolic parameters, whereas an increase in HBA1c was found in the olmesartan/ HCTZ arm [54] . The metabolic results are even better with newer long-acting dihydropyridines, as shown in obese, insulin-resistant hypertensives [51] . Two mechanisms have been advocated to explain the favorable effect of CCBs on insulin resistance: first, these compounds determine vasodilation and enhance blood flow to skeletal muscle with an increased delivery of insulin and glucose, thus favoring its nonoxidative utilization; second, CCBs may also improve insulin sensitivity at the intracellular level by decreasing the cytosolic free calcium concentrations [55,56] . Traditional b-blockers, both nonselective b1 and b2 antagonists (i.e., propranolol) and b1-selective antagonists (i.e., metoprolol), have vasoconstrictive properties, due to the consequent unopposed a1-adrenergic activity, and may have negative metabolic effects on insulin resistance [57] . Conversely, newer vasodilating b-blockers (i.e., nebivolol and carvedilol) appear to be associated with significantly better metabolic profiles [58] . In the large Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) trial [59] , 1235 patients with Type 2 diabetes and hypertension, already receiving a RASblocking agent (ACE-inhibitor or ARB), were randomized to either a traditional b-blocker, metoprolol, or a newer b-blocker, carvedilol. After 5 months of treatment, whereas metoprolol increased HBA1c by 0.15%, carvedilol had no adverse effect on Expert Rev. Cardiovasc. Ther. 7(11), (2009)
Combination therapy in diabetes
metabolic control. Although a favorable metabolic profile might be considered in selecting a specific b-blocker, we should make it very clear that these agents, both traditional and newer, have well-established indications in diabetics with a myocardial infarction, rhythm disorders, or heart failure, because of their proven effectiveness in reducing mortality [60] . Hypertension RAS-blocking agents plus diuretics
The Study of Micardis in Overweight/Obese patients with Type 2 diabetes and Hypertension (SMOOTH) [61] enrolled 840 diabetic hypertensives (mean BMI: 33.5 kg/m 2), randomized to either telmisartan/HCTZ or valsartan/HCTZ, after 4 weeks of telmisartan or valsartan monotherapy, respectively. The primary end point was the change from baseline in mean ambulatory systolic blood pressure (SBP) and diastolic blood pressure (DBP) during the last 6 h of the 24-h dosing interval. The percentage of patients achieving target BP (
