DIABETES/METABOLISM RESEARCH AND REVIEWS REVIEW Diabetes Metab Res Rev 2012; 28(Suppl 2): 6066.

Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/dmrr.2355

ARTICLE

What should be the antihypertensive drug of choice in diabetic patients and should we avoid drugs that increase glucose levels? Pro and Cons

Eberhard Standl Michael Erbach Oliver Schnell

Munich Diabetes Research Group e.V. at the Munich Helmholtz Centre, Munich-Neuherberg DE-85764, Germany *Correspondence to: E. Standl, Munich Diabetes Research Group e.V., at the Munich Helmholtz Centre, Ingolstaedter Landstrasse 1, Munich-Neuherberg DE-85764, Germany. E-mail: eberhard.standl@lrz.unimuenchen.de

Summary
It has long been known that antihypertensive drugs may affect blood glucose in a differential manner. In particular new onset diabetes is signicantly increased in association with the use of thiazides or beta-blockers, respectively, compared to placebo, whereas treatment with angiotensin-conversionenzyme-inhibitors or angiotensin-receptor-blockers is associated with a lower than expected frequency, as also assessed in several meta-analyses. In line with these notions, the NAVIGATOR Trial was the rst to report a signicant preventive effect of an angiotensin-receptor-blocker on new onset diabetes evaluated as a primary outcome in a prospective randomized study. Hence, and in view of the fact that comparable blood pressure lowering with any of the ve major classes of antihypertensive drugs, including calcium-channelblockers, give comparable benets in reducing cardiovascular complications, unless there are specic indications or contraindications for an individual drug, caution should be exercised, therefore, to use beta-blockers or thiazides as rst-line drugs for blood pressure lowering indications in subjects at high risk to develop diabetes, especially in patients with so called metabolic syndrome. The potential of glycemic worsening in overt diabetic patients with thiazides or beta-blockers has less well been studied systematically, yet paradigmatically in UKPDS evaluating a randomized comparison of a betablocker with an angiotensin-conversion-enzyme(ACE)-inhibitor. Not only was there HbA1c worsening with beta-blocker use which required additional blood glucose lowering therapy, but also signicantly more weight gain which still was detectable at the 20 year follow-up. On the other hand, the overall cardiovascular outcomes were comparable in the two treatment groups irrespective whether therapy was based on the beta blocker atenolol or the ACE-inhibitor captopril. Awareness of these facts and highly individualized therapy seem to be the way forward.

Keywords blood glucose increasing antihypertensive drugs; beta-blockers; thiazides; calcium-channel-blockers; angiotensin-conversion-enzyme-inhibitors; angiotensin-receptor-blockers

Introduction
Received: 25 January 2012 Revised: 19 March 2012 Accepted: 21 May 2012

Diabetes mellitus and hypertension have been called the bad companions, as rst of all this combination is very common and secondly not only carries an excessively high risk for microvascular disease of the kidney and the retina, but also for excessive cardiovascular morbidity and mortality [1,2]. In most diabetic populations, some 80% have coexisting hypertension

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and, vice versa, some 70% of patients with hypertension do have or will develop type 2 diabetes or its pre-states, e.g. impaired glucose tolerance (IGT) [15]. Furthermore, drugs for the treatment of hypertension exhibit a long record of potentially affecting also gluco-metabolic parameters, such as blood glucose, insulin sensitivity, and HbA1c [69]. In particular, beta-blockers (also the so-called cardio-selective ones) and thiazide thiazide-like diuretics have been known to increase blood glucose for many years, including the precipitation of hyperosmolar hyperglycaemic coma at high dose by the latter [611]. So, it seems to be an important issue whether antihypertensive drugs which increase blood glucose should be avoided, i.e. drugs which may worsen glycemic control in patients with diabetes or induce new onset diabetes in patients with hypertension, and by doing so may increase microvascular and macrovascular risk [6,811]. This paper aims to evaluate both sides, the pros and cons, and at the end weighing the evidence comes to some practical conclusions.

Risk of new onset diabetes

In a recent meta-analysis based on 22 available randomized trials, the risk of new onset diabetes in relation to all ve major classes of antihypertensive drugs has been assessed and compared to placebo [6], (see also Table 1). Clearly, the risk of thiazide diuretics was significantly increased versus placebo, whereas beta-blockers (BBs) showed only a non-signicant trend towards an increased risk. Compared to angiotensin-receptorblockers (ARBs), however, also beta-blockers exhibited an increased risk of new onset diabetes, as did diuretics in comparison with calcium-channel-blockers (CCBs), angiotensin-conversion-enzyme-inhibitors (ACE-Is), and ARBs. The strength of these results, however, is somewhat limited, since new onset diabetes was not a predened primary outcome in most of the trials used in this meta-analysis. Studies like the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ALLHAT [12], the Systolic Hypertension in the Elderly Program (SHEP) [13], or published by Verdecchia et al. [14] or Bakris et al. [15] leave little doubt that therapy with thiazide diuretics such as chlorthalidone or hydrochlorothiazide is associated with a signicantly increased risk of new onset diabetes somewhere in the range of 50250% relative increase. Controversy exists, however, whether this also matters in terms of clinical outcomes. Although the primary combined outcome of fatal coronary heart disease and non-fatal myocardial infarction analyzed by intent-to-treat in ALLHAT was similar in the three treatment arms randomized either to treatment with the thiazide chlorthalidone or the CCB amlodipine or the ACE-inhibitor lisinopril, respectively[12], there were in fact clear benets in secondary outcomes in favour of chlorthalidone over lisinopril and to some degree also over amlodipine despite of the glycemic worsening and
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the signicantly increased risk of new onset diabetes [12]. Chlorthalidone was especially superior in preventing heart failure, stroke and a combined cardiovascular (CV) outcome. As has been commented, however, there may be specic reasons for these ndings in ALLHAT, since the attained blood pressure was signicantly lower on treatment with chlorthalidone and about 35% of the study population consisted of black patients, i.e. low renin and volume dependent hypertensives, who respond better to monotherapy with a diuretic or CCB than to ACE-inhibitors [16]. The SHEP study seems to conrm the ndings in ALLHAT [13]. E.g. at a mean follow-up of 14.3 years, CV mortality rate in SHEP was signicantly lower in the chlorthalidone group (19%) than in the placebo group (22%; adjusted hazard ratio [HR] 0.854, 95% condence interval [CI] 0.7510.972) not withstanding the higher risk of new onset diabetes in the chlorthalidone group. Although diabetes that developed during the trial among subjects on placebo (n = 169) was associated with increased CV adverse outcome (adjusted HR 1.562, 95% CI: 1.1172.184) and total mortality rate (adjusted HR 1.348, 95% CI: 1.0511.727), diabetes that developed among subjects during diuretic therapy (n = 258) did not have signicant associations with CV mortality rate (adjusted HR 1.043, 95% CI: 0.7451.459) or total mortality rate (adjusted HR 1.151, 95% CI: 0.9251.433). The benet of chlorthalidone based therapy was also apparent at the 22-year follow-up of SHEP in terms of a superior gain in life expectancy [17]. However, on the con-side, the long term cohort study of Verdecchia et al. in some 800 hypertensive subjects has to be considered [14]. They showed a 50% increase of new onset diabetes at a median follow-up of 6 years in close association with thiazide diuretic therapy. New onset diabetes in turn was associated with a relative risk increase of CV events of 2.92 (95% CI: 1.336.41; p = 0.007) after adjustment for confounders. This risk was comparable to the group with pre-existing diabetes at entry of the study (RR 3.57; 95% CI: 1.657.73; p = 0.001) pointing to the importance of thiazide associated new diabetes. Focusing exclusively on BBs, another recent meta-analysis indicated, they seem to differ in terms of their mechanism of action and their effects on glucose and lipid metabolism [18]. Non-vasodilating BBs (atenolol, metoprolol, and propranolol) reduce blood pressure in association with a cardiac output reduction and may increase or have no appreciable effect on peripheral vascular resistance. As a result, non-vasodilating BBs are associated with a worsening of glycemic and lipid control. In contrast, vasodilating BBs (carvedilol, labetalol, and nebivolol) reduce peripheral vascular resistance, but have little or no effect on cardiac output. So, the risk of new onset diabetes and glucose worsening seems to be conned to nonvasodilating BBs, whereas vasodilating BBs are associated with more favorable effects on glucose and lipid proles.
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Table 1. Trials on antihypertensive treatment with diabetes-related outcomes Treatment Newly diagnosed diabetes 0.73 (0.580.91) [OR] 0.55 (0.430.70) [OR] 13% versus 8.7% Diabetes-related endpoint Result* p-value <.01

Trial

ALLHAT [12]: 18411 non-diabetic patients 55 years New onset of diabetes

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Amlodipine (n = 4958) or Lisinopril (n = 5034) versus Chlorthalidone (n = 8419) Chlorthalidone (n = 2363) versus Placebo (n = 369) New onset of diabetes (found in 5.8% of patients) Changes in 2-h OGTT (52 weeks versus baseline)

<0.001

0.004

SHEP [13]: 4732 patients with isolated systolic hypertension with and without diabetes PIUMA [14]: 743 initially nondiabetic subjects with hypertension STAR [15]: 240 patients with impaored glucose tolerance and hypertension

Exposure to diuretics identied as an independent predictor of new-onset diabetes )0.2 0.2 mmol l +1.4 0.4 mmol l

0.329 <0.001

Lifestyle intervention, Diuretics, Betablockers, ACE inhibitors, Calcium-channel blockers Trandolapril Verapamil (n = 119) versus Losartan Hhydrochlorothiazide (n = 121) [each xed-dose combination] Valsartan (n = 4631) versus Placebo (n = 4675) Progresssion to diabetes

0.86 (0.800.92) [HR]

<0.001

Ramipril (n = 2623) versus Placebo (n = 2646)

Diabetes

0.91 (0.801.03) [HR]

0.15

NAVIGATOR [19]: 9306 patients with impaired glucose tolerance and established CV disease or CV risk factors DREAM [20]: 5 269 participants without CV disease but with impaired fasting glucose or impaired glucose tolerance UKPDS 38 [35]: 1148 hypertensive patients with type 2 diabetes Any diabetes-related endpoint Tight versus less tight control of blood pressure with main use of Captopril or Atenolol (n = 758 versus n = 390) Captopril (n = 400) versus Atenolol (n = 358) Any diabetes-related endpoint

0.76 (0.620.92) [RR]

0.0046

UKPDS 39 [36]: 758 hypertensive patients with type 2 diabetes on tight control of BP

1.10 (0.861.41) [RR]

0.43

Diabetes Metab Res Rev 2012; 28(Suppl 2): 6066. DOI: 10.1002/dmrr.2355

*OR = Odds ratio HR = Hazard ratio RR = Relative risk

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The ARB valsartan was the rst antihypertensive drug to show a signicant primary protective effect against new onset diabetes in a large cohort of some 10 000 subjects with IGT [19]. In this NAVIGATOR trial, gluco-metabolic state was assessed by repeat oral glucose tolerance tests. The cumulative incidence of diabetes during a 6 year follow-up was 33.1% in the valsartan group, as compared with 36.8% in the placebo group (HR 0.86; 95% CI: 0.800.92; p < 0.001). This was in contrast to a non-signicant result seen with the ACE-inhibitor ramipril in the DREAM study [20]. The numbers-needed-to-treat or to-harm, respectively, when looking at new onset diabetes as an outcome in the aforementioned studies [6,19,20], usually run somewhere between 30 and 50. So, the effects appear to be less strong as compared to the protective effects on diabetes prevention by life style changes or antidiabetic drugs, e.g. by metformin [21], alpha-glucosidase-inhibitors [22] or thiazolidinedions [23,24]. On the other hand, so far nothing seems to be able to stop the worldwide epidemic of diabetes mellitus which is anticipated to surpass the mark of 500 million cases by the year 2030 [5]. Meanwhile, diabetes has become a major if not the major cause of premature death, kidney failure, blindness and lower limb amputations on a global scale, also in middle-aged populations. So, it appears to be important to use every opportunity to reduce the numbers of new onset diabetes.

Worsening of glycemic control

Good glycemic control is protective against the retinorenal complications of diabetes, both in type 1 and type 2 diabetes [2,5,25,26]. In recent years, increasing evidence has also been accumulated for an overall benecial effect of good glycemic control on the prevention of CV complications longer term, especially myocardial infarction as assessed in several meta-analyses [27,28]. A legacy effect of better glycemic control has been described for type 1 diabetes in the DCCT EPIC trial [29] and for type 2 diabetes in the ten year follow-up study of the randomized UKPD Study [30], though there may be limiting factors of aiming at near-normal glycemic control, such as hypoglycaemia and weight gain. Conversely, good glycemic control is just one component of multifactorial therapy which is todays gold standard in preventing cardiovascular sequelae of patients with diabetes [31,32]. In that context, antihypertensive drugs which increase blood sugar, however, can add to the challenge of striving for good glycemic control. The in-built randomized blood pressure study in UKPDS seems to be paradigmatic for this notion [33,34]. More intensive blood pressure lowering based on therapy with the potentially blood glucose increasing BB atenolol was compared to therapy based on the ACE-inhibitor captopril. The latter has been thought to improve metabolic control [6]. There was no difference in the incidence of side effects
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or hypoglycaemic episodes between those allocated to atenolol or captopril, but those allocated to atenolol increased their body weight by a mean of 2.3 kg compared to 0.5 kg in those allocated to captopril (p < 0.01), perhaps due to an aggravation of insulin resistance [18]. Allocation to atenolol was also associated with a slight increase of triglycerides and decreases of HDL and LDL cholesterol [33,34]. More importantly, allocation to atenolol was associated with a mean increase of HbA1c of 0.6% for some 6 month which required compensation by more blood glucose lowering drugs [3336]. It is of particular note that the initially induced weight gain in the atenolol group compared to the captopril group was still apparent at the 20 year follow-up of the study [37]. So, therapeutic decisions in blood pressure therapy early on seem to have very longlasting metabolic effects. Despite these differential metabolic effects, however, the overall microvascular and macrovascular outcomes obtained in the UKPDS Blood Pressure Study seemed to be quite comparable in the two treatment groups irrespective whether therapy was based on atenolol or captopril. There was even a slight tendency towards somewhat more favourable cardiac results longer-term associated with the BB [36,37]. Furthermore, as observed in SHEP, diuretic treatment with chlorthalidone in subjects who had diabetes at baseline (n = 799) was even strongly associated with lower long-term CV mortality rate (adjusted HR 0.688, 95% CI: 0.5260.848) and total mortality rate (adjusted HR 0.805, 95% CI: 0.6800.952) as compared to placebo treatment [13]. Similarly, the benet of chlorothalidone versus lisinopril treatment on secondary outcomes in ALLHAT was also seen in the large subgroup of patients with pre-existing diabetes (36% of the total population) despite a signicant overall increase of fasting plasma glucose [12]. Unfortunately, however, no further details of glycemic control, e.g. HbA1c and postprandial blood glucose values are available in ALLHAT. Conversely, Bakris et al. have published a study in IGT patients indicating a glucose worsening effect of 0.46 mmol l for FPG, of 1.7 mmol l for the 2 h post challenge glucose, and of 0.3% for HbA1c along with a 1 year treatment of hydrochlorothiazide (12.525 mg day) in combination with the ARB losartan compared to a combination of an ACE-inhibitor and a CCB [15]. No CV outcome data are yet available from this cohort. In contrast to the ndings in ALLHAT and SHEP, the long term cohort study of Verdecchia et al. has shown a threefold increased risk of CV events associated with glucose worsening and new onset diabetes in hypertensive patients treated with diuretics [14]. In the randomized, placebo-controlled ADVANCE Trial a combination of a potentially blood glucose improving ACE-I (perindopril) with a potentially blood glucose worsening thiazide-like drug (indapamid) was used in a study population of some 10 000 subjects with type 2 diabetes. Importantly, no negative effects of this blood pressure lowering therapy have been reported in the
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ADVANCE Trial, neither on glycemic control nor on microvascular or macrovascular outcomes [38]. So, at present time, the situation remains inconclusive and it is unfortunate that no further systemic evaluations seem to be available in diabetic patients on the metabolic impact of the various antihypertensive drugs that increase blood glucose. In all likelihood, provided it is looked for, signicant glycemic worsening of some 0.30.5% HbA1c can be detected in diabetic patients in association with thiazide diuretic or (nonvasodilating) BB treatment. Whether this impacts negatively, if not compensated for, on micro- or macrovascular complications has yielded conicting results in patients with diabetes. Taking a purists view, it is largely unknown. However, in combination with other blood glucose worsening drugs, e.g. statins or spironolactone, which often need to be used in diabetic patients and which all have a glycemic worsening potential of around 0.3% HbA1c [39,40], this might become a real serious issue.

Differential efcacy of antihypertensive classes of drugs, especially in patients with diabetes?

The CV outcome studies are available in more than 40 000 patients with type 2 diabetes, often as subgroup analysis of many of the randomized intervention trials on blood pressure lowering with all ve major classes of drugs, i.e. thiazides, BBs, CCBs, ACE-Is, and ARBs [2,9,3638,41,42]. A recent systematic review which pooled data from 27 randomized trials reported similar reductions in major cardiovascular events for patients with and without diabetes [43]. In addition, a number of studies examining the effects of specic blood pressure lowering drugs have found the relative benets of blood pressure lowering therapy to be similar in those with or without hypertension at study entry [9,38,44,45]. So, the overarching notion seems to be that all (adult) diabetic patients with prior cardiovascular disease or at high risk for microvascular or macrovascular complications should receive blood pressure lowering therapy irrespective of their blood pressure levels unless contraindicated by hypotension or other serious side effects. In terms of drug specic recommendations for antihypertensive therapy in diabetic subjects with few exceptions no signicant general advantage of one drug over the other has been substantiated for cardiovascular outcomes [2,9,43]. Some exceptions though not very consistently emerge, when combination therapies (which often are warranted in diabetics) based on ACE-Is or ARBs are compared to BB thiazide combinations which should generate the most blood glucose increasing effect [6]. Lower efcacy has been described in reducing (CV) mortality or CV disease by the latter combination in some studies [2,911,44,45]. Primary combinations of ACE-Is
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with CCBs (which are at least blood glucose neutral) may be particularly useful in patients with diabetes and higher baseline blood pressure levels [41,42]. CCBs, however should not be used in heart failure patients [45]. A systematic review looking differentially into preventing stroke events versus coronary heart disease events (independent from coexisting diabetes) has reported BBs less and CCBs more effective in preventing stroke events, whereas all drug classes, i.e. thiazides, BBs, CCBs, ACEIs, and ARBs equally reduced coronary heart disease events [9]. In this context it should be emphasized that BBs apart from the issues discussed here specically around blood pressure lowering therapy are clearly indicated in patients with established coronary heart disease, heart failure and some cardiac arrhythmias, irrespective of their potential effect of increasing blood glucose [2]. In terms of preventing microalbuminuria or deterioration of kidney function in diabetic subjects ACE-I or ARB based therapies may be superior to other strategies [2]. Finally, it should be mentioned that BBs and thiazides seem to be less effective in inducing regression of leftventricular hypertrophy by antihypertensive therapy compared to ACE-Is, ARBs, and CCBs [46], and that thiazides and BBs yield the lowest drug specic long term persistence in antihypertensive therapy, probably due to the spectrum of side effects [47].

Conclusions for blood pressure therapy

In light of the evidence discussed in this paper, the following conclusions for blood pressure therapy can be drawn: (1) Thiazides and BBs have a potential to induce new onset diabetes mellitus. (2) Caution should be exercised, therefore, to use these drugs for blood pressure lowering indications in subjects at high risk to develop diabetes, especially in patients with so called metabolic syndrome. (3) These drugs also seem to have a potential to worsen metabolic control in patients with diabetes. (4) This warrants anticipatory monitoring of blood glucose and body weight if therapy with these drugs is newly started in patients with diabetes, and may require additional blood glucose lowering measures. (5) With this provision, cardiac outcome does not appear to be negatively affected in patients with diabetes by these drugs. In general, all ve classes of antihypertensive drugs, i.e. ACE-Is, ARBs, CCBs, BBs and thiazide thiazide like drugs are similarly effective in reducing coronary artery disease events. (6) Irrespective of diabetes, BBs are clearly indicated in patients with signicant coronary artery disease, heart failure, and some arrhythmias, yet less efcient in the prevention of stroke events.

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(7) In diabetic patients, ACE-Is and ARBs which seem to have a potential to decrease blood glucose, may have specic benets, especially in preventing microalbuminurea, worsening of kidney function or other microvascular complications. (8) Adequate blood pressure lowering therapy should be implemented in all diabetic patients with prior cardiovascular disease or at high risk for microvascular and macrovascular complications irrespective of the initial blood pressure. Usually a combination of antihypertensive drugs is needed to achieve blood pressure targets which should be tailored to the individual along the aforementioned recommendations.

Acknowledgement
This activity has been supported by an educational grant of the Association for the Support of International Scientic Communication in Diabetology.

Conicts of interest
ES: Data safety monitoring board, NAVIGATOR Trial (sponsor Novartis).

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Diabetes Metab Res Rev 2012; 28(Suppl 2): 6066. DOI: 10.1002/dmrr.2355