Curr Hypertens Rep (2014) 16:410 DOI 10.1007/s11906-013-0410-z
ANTIHYPERTENSIVE AGENTS: MECHANISMS OF DRUG ACTION (M ERNST, SECTION EDITOR)
The Glycemic Effects of Antihypertensive Medications Joshua I. Barzilay & Barry R. Davis & Paul K. Whelton
Published online: 13 December 2013 # Springer Science+Business Media New York 2013
Abstract Older antihypertensive medications are believed to be associated with metabolic disturbances, especially raised glucose levels. Owing to this, many physicians shun their use. Newer antihypertensive medications are metabolically neutral or metabolically favorable; therefore, they are looked upon favorably and are chosen as primary medications for the treatment of hypertension. Here we review the literature on the glucose effects of older and newer antihypertensive medications. We also consider what, if any, impact these metabolic effects have on cardiovascular disease outcomes. We show that the diabetogenic effects of thiazide diuretics and beta blockers are small relative to the glucose effects of angiotensin-converting enzyme inhibitors (ACEIs) and calcium channel blockers, and that over time, the glucose differences between older and newer medications diminish. Importantly, we show that the diabetogenic effects of older antihypertensive medications do not translate into increased cardiovascular disease risk.
This article is part of the Topical Collection on Antihypertensive Agents: Mechanisms of Drug Action J. I. Barzilay (*) Kaiser Permanente of Georgia, 3650 Steve Reynolds Blvd, Atlanta, GA 30096, USA e-mail: [email protected] J. I. Barzilay Division of Endocrinology, Emory University School of Medicine, Atlanta, GA, USA B. R. Davis Division of Biostatistics, School of Public Health, University of Texas Medical Center, Houston, TX, USA P. K. Whelton School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, USA
Keywords Diabetes . Hypertension . Risk . Chlorthalidone . Lisinopril . Amlodipine . Beta blocker . ALLHAT . Cardiovascular disease . Side effect
Introduction Were medications that are used for the treatment of hypertension (HTN) able to lower blood glucose levels or prevent diabetes mellitus (diabetes) from occurring, drugs from that class of agents would be considered “ideal” for controlling HTN in individuals with diabetes or at high risk for diabetes. Conversely, use of anti-hypertensive medications from a drug class that increased blood glucose levels or the risk of incident diabetes might be expected to be considered “less desirable” for the management of HTN in the context of diabetes. These considerations have played a major role in selecting anti-hypertensive drug therapy for individuals with diabetes or at high risk for diabetes. Thiazide diuretics and beta blockers have been considered to be diabetogenic and are frequently shunned by the medical community. In contrast, renin angiotensin system (RAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blocker (ARB), have been thought to be metabolically favorable, and have been recommended by many medical societies as the preferred drug classes for controlling HTN in individuals with hyperglycemia or overt diabetes. In this article, we will review the scientific evidence for these recommendations. In addition to reviewing the effects of thiazide diuretics, RAS inhibitors, and first generation beta blockers on blood sugar and incidence of diabetes, we will present corresponding information for calcium channel blockers (CCB). This topic has broader implications. Statin medications, which are used with great effectiveness for the treatment of lipid disorders in people with glucose disorders, have recently been reported to increase blood glucose levels [1]. The lessons
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learned from study of the glycemic effects of anti-hypertensive medications may be pertinent to statin therapy. Mechanisms by which Antihypertensive Medications Impact Glucose Levels Upregulation of bradykinin and nitric oxide, both of which promote increased skeletal muscle and pancreatic blood flow, are thought to be the mediators of the improved glycemia noted during ACEI and ARB therapy. Use of agents from these drug classes is also reported to improve angiotensin-II– mediated oxidative stress in the beta cell [2, 3]. Thiazide diuretics deplete body potassium stores, which are important for insulin release from pancreatic beta cells. Furthermore, diuresis may lead to decreased blood volume and cardiac output, which can activate the sympathetic nervous system, leading to reduced blood flow to the skeletal muscle, ultimately causing peripheral insulin resistance [4, 5]. The higher glucose levels and increased risk of diabetes noted during thiazide therapy is most likely a consequence of these changes. CCBs inhibit insulin release, but this is counterbalanced by vasodilation, leading to increased peripheral glucose uptake and improved insulin sensitivity [6]. As a consequence, they appear to have no major effect on glucose metabolism and are considered metabolically neutral. First generation beta blockers, such as propranolol and metoprolol, have been associated with worsening of glycemic control and an increased risk of diabetes, possibly because of inhibition of pancreatic insulin secretion through blockade of β2-adrenergic receptors, inhibition of peripheral glucose uptake, and resultant unopposed α2-adrenergic receptor– mediated stimulation of hepatic glycogenolysis [7]. Table 1 summarizes how antihypertensive medications affect glycemia. Impact of RAS Inhibitor Add-On Therapy on Blood Glucose and Diabetes in Persons at High Risk for Cardiovascular Disease (CVD) It is uncertain whether RAS blockade, as compared to placebo, reduces the risk of incident diabetes when added
Table 1 How anti-hypertensive medications affect glycemia: proposed mechanisms Renin Angiotensin Blockade – increased bradykinin & nitric oxide → skeletal muscle flow → greater muscle glucose extraction Diuretics – reduced body potassium → reduced insulin release by pancreatic β cells – reduced vascular volume → increased sympathetic tone → insulin resistance Calcium Channel Blockers – no net effect on glycemia Older Beta Blockers – inhibit insulin release from pancreatic beta cells – increased hepatic glycogenolysis
Curr Hypertens Rep (2014) 16:410
to usual care antihypertensive therapy in persons at high risk for cardiovascular disease or diabetes. In the Heart Outcomes Prevention Evaluation (HOPE) trial [8], the risk of self-reported incident diabetes was less in those assigned to the ACEI ramipril compared to placebo (3.6 vs. 5.4 %; relative ratio [RR] 0.66 [95 % CI 0.51–0.85]; P 125 mg/dl) at 2 years in those taking chlorthalidone compared with those taking amlodipine or lisinopril. During the first 2 years, the odds for developing diabetes were lower for those assigned to lisinopril (odds ratio [OR], 0.55 [95 % confidence interval [CI], 0.430.70]) or amlodipine (OR, 0.73 [95 % CI, 0.58-0.91]) compared to their counterparts assigned to chlorthalidone. At years 4 and 6, assignment to amlodipine or lisinopril was still associated with a lower OR of developing diabetes, but the ORs were no longer statistically significant. The 4-year and 6-year cumulative incidence of new onset diabetes (defined as a fasting glucose level>125 mg/dl) among participants without diabetes at baseline was 11.0 and 13.8 % in those assigned to chlorthalidone, 9.3 and 12.0 % in those assigned to amlodipine, and 7.8 and 11.0 % in those assigned to lisinopril. These rates allowed for a calculation that provides an important perspective on thiazide-associated diabetes. If amlodipine is assumed to be metabolically neutral, then (based on the 4-year rates) 85 % (9.3/11.0) of diabetes associated with a diuretic is not induced by the diuretic, at least in an older, mostly overweight, ethnically diverse population. Findings similar to the above were noted in two other studies that reported on change in FG levels with different HTN medications [18, 19]. As was the case in ALLHAT, the changes in FG levels were small in both studies (mean, 2.0– 3.5 mg/dL), but the relative risk of developing new-onset diabetes was significantly increased. In other words, a small change in FG levels translates into a much larger increase in biochemical “diabetes”. We next examined whether these small differences in FG had an impact on CVD and renal disease outcomes. We failed to recognize an effect of the change in FG level on any study end point, both for an exploration of all the treatment groups combined and the chlorthalidone group separately. Further, the hazard ratio for a 10-mg/dL change in FG level was no larger for chlorthalidone than for amlodipine or lisinopril. For incident diabetes, CHD was the only outcome with a statistically significant increased hazard ratio, and this did not differ significantly across the three treatment groups. These findings are consistent with other studies in that hazard ratios for the CVD end points have tended to be lower in those treated with chlorthalidone compared with the other treatment groups. In a 14-year follow-up of the Systolic Hypertension in the Elderly Program [18], diabetes diagnosed during chlorthalidone therapy was not associated with a significant increase in CVD mortality (HR, 1.04 [95 % CI, 0.75– 1.46]) compared with diabetes that occurred in the absence of diuretic administration (HR, 1.56 [95 % CI, 1.12–2.18]). In a second study, a 15-year follow-up of 686 middle-aged adults
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with hypertension treated with diuretics [19], incident diabetes did not have a significant effect on CVD mortality, whereas prevalent diabetes at baseline did. This apparent conundrum—of noting increased blood glucose and biochemical diabetes in association with thiazide diuretic treatment but no corresponding increase in coronary heart disease risk—deserves an explanation. First, it is possible that the elevated glucose levels are a surrogate marker for other processes associated with a medication’s effect. For example, in the Cardiac Arrhythmia Suppression Trial (CAST) [20], antiarrhythmia medications successfully suppressed premature ventricular beats. Despite this, mortality was increased in patients treated with the antiarrhythmia medications compared with those receiving placebo. Second, older studies have shown that glucose levels decrease when diuretic therapy is discontinued for any reason [21]. In contrast, ‘classic’ diabetes is characterized by persistent elevation of blood glucose levels. This suggests the elevation in glucose levels that can occur during diuretic therapy is likely to be caused by mechanisms other than insulin resistance—the underlying pathway for ‘classic’ diabetes. As previously mentioned, only a small proportion of the diabetes that arises during diuretic therapy is actually “caused” by the diuretic. Incident diabetes in participants treated with lisinopril was associated with a significantly elevated risk of coronary heart disease. Also those treated with amlodipine who developed diabetes had a higher total mortality and stroke. Given that these medications are ‘glucose protective’ or ‘glucose neutral’, the development of diabetes in association with their use suggests the presence of a high degree of insulin resistance. Finally, analysis of ALLHAT showed that even though the incidence of diabetes at year 4 of follow-up was higher in the participants taking chlorthalidone, the absolute difference in FG levels between them and those treated with amlodipine and lisinopril was small, at 1.5 and 4.0 mg/dl, respectively. Such small differences in FG are unlikely to have much impact on CVD risk. In a subsequent analysis, we employed administrative data sets to explore the impact of antihypertensive medications on glucose metabolism in the ALLHAT participants during 4– 5 years of observation after completion of the trial [22]. During the period of post-trial observation, the ALLHAT participants were no longer assigned to treatment with their study medication. We conducted this analysis because it could be argued that the mean follow-up period of 4.9 years during the trial might be insufficient to detect the effects of elevated glucose levels on CVD outcomes. An increase in blood glucose might only lead to an increase in CVD risk over a longer period of time. Post-trial monitoring of participants in the UK Prospective Diabetes Study (UKPDS) [23] suggested that a sustained period of glycemic control in patients with newly diagnosed diabetes reduced cardiovascular morbidity and mortality, but two decades or more of follow-up were required before the effects achieved statistical significance.
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In our extended analysis of the ALLHAT participants, those with diabetes at baseline experienced higher rates of CVD compared to their counterparts without diabetes, and those with incident diabetes generally had outcome rates that were intermediate between those with and without baseline diabetes. A more provocative finding involved the comparison between those who did and those who did not develop diabetes during the trial, based on treatment assignment. The hazard ratios (HRs) in the chlorthalidone cohort with versus without incident diabetes for CVD mortality (HR, 1.04 [95 % CI, 0.74–1.47]), all-cause mortality (HR, 1.04 [95 % CI, 0.82– 1.30]), and non–CVD mortality (HR, 1.05 [95 % CI, 0.77– 1.42]) were consistently lower than the comparable HRs in the corresponding amlodipine and lisinopril cohorts (HRs, 1.22– 1.53). For example, those who developed diabetes in the chlorthalidone cohort had a statistically insignificant increase in the risk for total CHD events when compared with those who remained nondiabetic (HR, 1.18 [95 % CI, 0.77–1.81]), whereas the opposite was true for participants with versus without incident diabetes who had originally been assigned to lisinopril (HR, 2.57 [95 % CI, 1.45–4.54]). Similarly, the HRs (CIs) for all-cause mortality and stroke were not significantly different in the chlorthalidone cohort based on incident diabetes status: 1.04 (0.82–1.30) and 0.91 (0.49–1.67), respectively. In summary, the results were similar to and confirmed the results of the first phase (in-trial) period of ALLHAT. Table 2 summarizes the takeaway message from the ALLHAT study. First Generation Beta Blockers Newer generation beta blockers, such as carvedilol and nebivolol, have fewer metabolic effects than first generation beta blockers and are considered metabolically favorable [24]. First generation beta blockers (such as propranolol, metoprolol, and atenolol) are still widely used. They are effective for HTN management and for preventing ischemic cardiovascular disease and sudden death. In the United Kingdom Prospective Diabetes Study [25], atenolol-based therapy was as effective for cardiovascular protection as was ACE-based therapy. In the Beta Blocker Heart Attack Trial [26], a first generation beta blocker was effective for preventing recurrence of ischemia compared to a placebo in people with diabetes. In other studies, diabetic people prescribed first generation β-blockers had significantly lower 1-year mortality Table 2 Take away message from the ALLHAT study As compared to ACE inhibitors and CCB, diuretic use is associated with a small increase in fasting glucose levels (1.5–4.0 mg/dl) after 2 years of use. Over time, these differences recede. The small increases in fasting glucose levels with the use of a diuretic early on do not translate into increased cardiovascular disease risk later on.
Curr Hypertens Rep (2014) 16:410
than those not receiving these agents, regardless of type and severity of diabetes [27, 28]. In the Atheroscerosis Risk in Communities (ARIC) study [29], an observational cohort, there was a 28 percent increase in the risk of diabetes associated with the use of beta blockers (relative hazard, 1.28; 95 % CI, 1.04 to 1.57). Similar findings have been noted in other observational studies [14, 30]. In contrast, a retrospective, observational cohort study [31] of previously untreated patients, aged≥66 years, identified as new users of an antihypertensive drug class between April 1995 and March 2000, found that neither ACEI use (hazard ratio 0.96 [95 % CI 0.84–1.1]) nor beta blocker use (0.86 [0.74– 1.0]) was associated with a statistically significant difference in type 2 diabetes incidence compared with the CCB control group (n =76,176). In the secondary analysis (n =100,653), compared with CCB users, type 2 diabetes incidence was not significantly different between users of ACEIs (0.97 [0.83– 1.1]), beta blockers (0.84 [0.7–1.0]), or thiazide diuretics (1.0 [0.89–1.2]). Clinical trials of beta blockers have yielded mixed results. The Veterans Administration Cooperative Study Group on Antihypertensive Agents [32] identified a hyperglycemic effect following 12 months of propranolol that persisted for one month after the discontinuation of drug therapy. The Medical Research Council Working Party on Mild to Moderate Hypertension [33] found that the rate of withdrawal from the trial because of hyperglycemia was higher in the propranolol group than in the placebo group, but this difference was not statistically significant. In the Oslo study [34], fasting serum glucose was significantly higher in the group treated with propranolol in combination with a thiazide diuretic compared to the placebo group, whereas there was no difference in serum glucose concentrations between the thiazide diuretic and placebo groups. On the other hand, in the Systolic Hypertension in the Elderly Program [35] there was not an increased risk of hyperglycemia or diabetes in subjects taking beta blockers with thiazide diuretics. Differences in these results may stem from differences in the dosage of medication, the type of beta blocker used (e.g., cardioselective as compared with nonselective), and the duration of treatment. In summary, there is evidence of a small diabetogenic effect associated with first generation beta blocker therapy. This effect should be balanced against the proven effectiveness of these agents for prevention of CAD and ASHD. As one example, in the Women’s Health Initiative Observational Study (93,676 women, aged 50–79 years at baseline) [36], among women with hypertension but no history of CVD, a 2drug-class regimen of calcium channel blockers plus diuretics was associated with a higher risk of CVD mortality vs. beta blockers plus diuretics. Risks were similar for ACEIs plus diuretics and beta blockers plus diuretics with or without diabetes.
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Conclusions No medication is without side effects. To judge a treatment’s efficacy, the positive and negative effects need to be weighed against one another. It is our opinion that the CVD protective effects derived from thiazide diuretics and beta blockers outweigh their negative metabolic effects. Much the same conclusions have been arrived at regarding the diabetogenic effects of statin medications [37]. The salutary effects of ACEIs and ARBs on glucose metabolism are small, and, in our opinion, not sufficiently important to be used as a principal criterion for choice of antihypertensive drug therapy in individuals with hyperglycemia or diabetes. Efficacy in lowering blood pressure, preventing CVD, and the agent’s mechanism of action should play a more important role in determining choice of medication. The widespread use of combination therapy for the management of HTN makes concern regarding the diabetogenic effects of thiazides and beta blockers moot. ACEIs are now frequently combined with thiazide diuretics. Beta blockers are often added to multidrug regimens when blood pressure control has not been achieved. As such, many of the issues that were discussed here appear to be moot. Compliance with Ethics Guidelines Conflict of Interest Joshua I. Barzilay and Paul K. Whelton declare that they have no conflict of interest. Barry R. Davis has received a grant from the National Institutes of Health and has been a consultant for Merck & Co., Inc., as a DSMB member. None of the authors has a conflict of interest regarding the contents of this study. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
References Papers of particular interest, published recently, have been highlighted as: • Of importance
1.
2.
3.
Gomes T, Camacho X, Juurlink DN, Shah BR, Mamdani MM. Risk of incident diabetes among patients treated with statins: population based study. BMJ. 2013;346:f2610. Muscogiuri G, Chavez AO, Gastaldelli A, Perego L, Tripathy D, Saad MJ, et al. The crosstalk between insulin and reninangiotensin-aldosterone signaling systems and its effect on glucose metabolism and diabetes prevention. Curr Vasc Pharmacol. 2008;6: 301–12. Scheen AJ. Renin-angiotensin system inhibition prevents type 2 diabetes mellitus. Part 2. Overview of physiological and biochemical mechanisms. Diabetes Metab. 2004;30:498–505.
410, Page 6 of 6 4.
5.
6.
7.•
8. 9.
10.
11.
12.
13.
14.•
15.•
16.
17.
18.
19.
20.
21.
Shafi T, Appel LJ, Miller 3rd ER, Klag MJ, Parekh RS. Changes in serum potassium mediate thiazide-induced diabetes. Hypertension. 2008;52:1022–9. Aksnes TA, Kjeldsen SE, Mancia G. The effect of antihypertensive agents on new-onset diabetes mellitus: time to amend the guidelines? Am J Cardiovasc Drugs. 2006;6:139–47. Noto H, Goto A, Tsujimoto T, Noda M. Effect of calcium channel blockers on incidence of diabetes: a meta-analysis. Diabetes Metab Syndr Obes. 2013;6:257–61. Lleva RR, Inzucchi SE. Glucose, blood pressure, and cardiovascular risk. Circ Cardiovasc Qual Outcomes. 2012;5:145–7. An informative review of the effects of anti-hypertensive medications on glucose metabolism. Yusuf S, Gerstein H, Hoogwerf B, et al. HOPE Study Investigators. Ramipril and the development of diabetes. JAMA. 2001;286:1882–5. Holman RR, Haffner SM, McMurray JJ, et al. NAVIGATOR Study Group. Effect of nateglinide on the incidence of diabetes and cardiovascular events. N Engl J Med. 2010;362:1463–76. Bosch J, Yusuf S, Gerstein HC, et al. DREAM Trial Investigators. Effect of ramipril on the incidence of diabetes. N Engl J Med. 2006;355:1551–62. Barzilay JI, Gao P, Rydén L, Schumacher H, Probstfield J, Commerford P, et al. Effects of telmisartan on glucose levels in people at high risk for cardiovascular disease but free from diabetes: The TRANSCEND Study. Diabetes Care. 2011;34:1902–7. European Society of Hypertension-European Society of Cardiology. 2013 Guidelines for the management of arterial hypertension. Available at: http://www.escardio.org/guidelines-surveys/ esc-guidelines/Pages/arterial-hypertension.aspx Hypertension NICE. Management of Hypertension in Adults with Primary Care – Partial Update. London: National Institute of Health and Clinical Excellence; 2006. Padwal R, Laupacis A. Antihypertensive therapy and incidence of type 2 diabetes. A systemic review. Diabetes Care. 2004;27:247– 55. A review of anti-hypertension studies and the effects of medications on glycemia. Elliott WJ, Meyer PM. Incident diabetes in clinical trials of antihype rte nsi ve drugs: a ne tw ork met a-ana lysi s. La nc et . 2007;369(9557):201–7. A review of anti-hypertension studies and the effects of medications on glycemia. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin converting enzyme inhibitor or calcium channel blocker vs. diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288:2981–97. Barzilay JI, Davis BR, Cutler J, et al. Fasting glucose levels and incident diabetes mellitus in older non-diabetic adults randomized to three different classes of antihypertensive treatment: a report from the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med. 2006;166:2191–201. Kostis JB, Wilson AC, Freudenberger RS, Cosgrove NM, Pressel SL, Davis BR. Long-term effect of diuretic-based therapy on fatal outcomes in subjects with isolated systolic hypertension with and without diabetes. Am J Cardiol. 2005;95:29–35. Samuelsson O, Pennert K, Andersson O, et al. Diabetes mellitus and raised serum triglyceride concentration in treated hypertension: are they of prognostic importance? observational study. BMJ. 1996;313:660–3. The Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med. 1989;321:406–12. Rowe JW, Tobin JD, Rosa RM, Andres R. Effect of experimental potassium deficiency on glucose and insulin metabolism. Metabolism. 1980;29:498–502.
Curr Hypertens Rep (2014) 16:410 22.• Barzilay JI, Davis BR, Pressel SL, Cutler JA, Einhorn PT, Black HR, et al. ALLHAT Collaborative Research Group. Long-term effects of incident diabetes mellitus on cardiovascular outcomes in people treated for hypertension: the ALLHAT Diabetes Extension Study. Circ Cardiovasc Qual Outcome. 2012;5:153–62. A 10-year follow-up of ALLHAT and the effects of incident diabetes associated with the three antihypertensive medications used during the trial on CVD outcomes. 23. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577–89. 24. Kveiborg B, Hermann TS, Major-Pedersen A, Christiansen B, Rask-Madsen C, Raunsø J, et al. Metoprolol compared to carvedilol deteriorates insulin-stimulated endothelial function in patients with type 2 diabetes—a randomized study. Cardiovasc Diabetol. 2010;9:21. 25. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. UK Prospective Diabetes Study Group. BMJ 1998; 317: 713–720. 26. A randomized trial of propranolol in patients with acute myocardial infarction. II. Morbidity results. JAMA 1983; 250: 2814–2819. 27. Gottlieb SS, McCarter RJ, Vogel RA. Effect of beta-blockade on mortality among high-risk and low-risk patients after myocardial infarction. N Engl J Med. 1998;339:489–97. 28. Chen J, Marciniak TA, Radford MJ, Wang Y, Krumholz HM. Betablocker therapy for secondary prevention of myocardial infarction in elderly diabetic patients. Results from the National Cooperative Cardiovascular Project. J Am Coll Cardiol. 1999;34:1388–94. 29. Gress TW, Nieto FJ, Shahar E, Wofford MR, Brancati FL. Hypertension and antihypertensive therapy as risk factors for type 2 diabetes mellitus. Atherosclerosis Risk in Communities Study. N Engl J Med. 2000;342:905–12. 30. Samuelsson O, Hedner T, Berglund G, Persson B, Andersson OK, Wilhelmsen L. Diabetes mellitus in treated hypertension: incidence, predictive factors and the impact of non-selective beta-blockers and thiazide diuretics during 15 years treatment of middle-aged hypertensive men in the Primary Prevention Trial Goteborg, Sweden. J Hum Hypertens. 1994;8:257–63. 31. Padwal R, Mamdani M, Alter DA, Hux JE, Rothwell DM, Tu K, et al. Antihypertensive therapy and incidence of type 2 diabetes in an elderly cohort. Diabetes Care. 2004;27:2458–63. 32. Propranolol or hydrochlorothiazide alone for the initial treatment of hypertension. IV. Effect on plasma glucose and glucose tolerance. Veterans Administration Cooperative Study Group on Antihypertensive Agents. Hypertension 1985; 7(6 Pt 1):1008–1016. 33. Adverse reactions to bendrofluazide and propranolol for the treatment of mild hypertension. Report of Medical Research Council Working Party on Mild to Moderate Hypertension. Lancet 1981; 2(8246): 539–543. 34. Helgeland A, Leren P, Foss OP, Hjermann I, Holme I, Lund-Larsen PG. Serum glucose levels during long-term observation of treated and untreated men with mild hypertension. The Oslo study. Am J Med. 1984;76:802–5. 35. Savage PJ, Pressel SL, Curb JD, Schron EB, Applegate WB, Black HR, et al. Influence of long-term, low-dose, diuretic-based, antihypertensive therapy on glucose, lipid, uric acid, and potassium levels in older men and women with isolated systolic hypertension: The Systolic Hypertension in the Elderly Program. SHEP Cooperative Research Group. Arch Intern Med. 1998;158:741–51. 36. Wassertheil-Smoller S, Psaty B, Greenland P, Oberman A, Kotchen T, Mouton C, et al. Association between cardiovascular outcomes and antihypertensive drug treatment in older women. JAMA. 2004;292:2849–59. 37. Minder CM, Blumenthal RS, Blaha MJ. Statins for primary prevention of cardiovascular disease: the benefits outweigh the risks. Curr Opin Cardiol. 2013;28:554–60.
ANTIHYPERTENSIVE AGENTS: MECHANISMS OF DRUG ACTION (M ERNST, SECTION EDITOR)
The Glycemic Effects of Antihypertensive Medications Joshua I. Barzilay & Barry R. Davis & Paul K. Whelton
Published online: 13 December 2013 # Springer Science+Business Media New York 2013
Abstract Older antihypertensive medications are believed to be associated with metabolic disturbances, especially raised glucose levels. Owing to this, many physicians shun their use. Newer antihypertensive medications are metabolically neutral or metabolically favorable; therefore, they are looked upon favorably and are chosen as primary medications for the treatment of hypertension. Here we review the literature on the glucose effects of older and newer antihypertensive medications. We also consider what, if any, impact these metabolic effects have on cardiovascular disease outcomes. We show that the diabetogenic effects of thiazide diuretics and beta blockers are small relative to the glucose effects of angiotensin-converting enzyme inhibitors (ACEIs) and calcium channel blockers, and that over time, the glucose differences between older and newer medications diminish. Importantly, we show that the diabetogenic effects of older antihypertensive medications do not translate into increased cardiovascular disease risk.
This article is part of the Topical Collection on Antihypertensive Agents: Mechanisms of Drug Action J. I. Barzilay (*) Kaiser Permanente of Georgia, 3650 Steve Reynolds Blvd, Atlanta, GA 30096, USA e-mail: [email protected] J. I. Barzilay Division of Endocrinology, Emory University School of Medicine, Atlanta, GA, USA B. R. Davis Division of Biostatistics, School of Public Health, University of Texas Medical Center, Houston, TX, USA P. K. Whelton School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, USA
Keywords Diabetes . Hypertension . Risk . Chlorthalidone . Lisinopril . Amlodipine . Beta blocker . ALLHAT . Cardiovascular disease . Side effect
Introduction Were medications that are used for the treatment of hypertension (HTN) able to lower blood glucose levels or prevent diabetes mellitus (diabetes) from occurring, drugs from that class of agents would be considered “ideal” for controlling HTN in individuals with diabetes or at high risk for diabetes. Conversely, use of anti-hypertensive medications from a drug class that increased blood glucose levels or the risk of incident diabetes might be expected to be considered “less desirable” for the management of HTN in the context of diabetes. These considerations have played a major role in selecting anti-hypertensive drug therapy for individuals with diabetes or at high risk for diabetes. Thiazide diuretics and beta blockers have been considered to be diabetogenic and are frequently shunned by the medical community. In contrast, renin angiotensin system (RAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blocker (ARB), have been thought to be metabolically favorable, and have been recommended by many medical societies as the preferred drug classes for controlling HTN in individuals with hyperglycemia or overt diabetes. In this article, we will review the scientific evidence for these recommendations. In addition to reviewing the effects of thiazide diuretics, RAS inhibitors, and first generation beta blockers on blood sugar and incidence of diabetes, we will present corresponding information for calcium channel blockers (CCB). This topic has broader implications. Statin medications, which are used with great effectiveness for the treatment of lipid disorders in people with glucose disorders, have recently been reported to increase blood glucose levels [1]. The lessons
410, Page 2 of 6
learned from study of the glycemic effects of anti-hypertensive medications may be pertinent to statin therapy. Mechanisms by which Antihypertensive Medications Impact Glucose Levels Upregulation of bradykinin and nitric oxide, both of which promote increased skeletal muscle and pancreatic blood flow, are thought to be the mediators of the improved glycemia noted during ACEI and ARB therapy. Use of agents from these drug classes is also reported to improve angiotensin-II– mediated oxidative stress in the beta cell [2, 3]. Thiazide diuretics deplete body potassium stores, which are important for insulin release from pancreatic beta cells. Furthermore, diuresis may lead to decreased blood volume and cardiac output, which can activate the sympathetic nervous system, leading to reduced blood flow to the skeletal muscle, ultimately causing peripheral insulin resistance [4, 5]. The higher glucose levels and increased risk of diabetes noted during thiazide therapy is most likely a consequence of these changes. CCBs inhibit insulin release, but this is counterbalanced by vasodilation, leading to increased peripheral glucose uptake and improved insulin sensitivity [6]. As a consequence, they appear to have no major effect on glucose metabolism and are considered metabolically neutral. First generation beta blockers, such as propranolol and metoprolol, have been associated with worsening of glycemic control and an increased risk of diabetes, possibly because of inhibition of pancreatic insulin secretion through blockade of β2-adrenergic receptors, inhibition of peripheral glucose uptake, and resultant unopposed α2-adrenergic receptor– mediated stimulation of hepatic glycogenolysis [7]. Table 1 summarizes how antihypertensive medications affect glycemia. Impact of RAS Inhibitor Add-On Therapy on Blood Glucose and Diabetes in Persons at High Risk for Cardiovascular Disease (CVD) It is uncertain whether RAS blockade, as compared to placebo, reduces the risk of incident diabetes when added
Table 1 How anti-hypertensive medications affect glycemia: proposed mechanisms Renin Angiotensin Blockade – increased bradykinin & nitric oxide → skeletal muscle flow → greater muscle glucose extraction Diuretics – reduced body potassium → reduced insulin release by pancreatic β cells – reduced vascular volume → increased sympathetic tone → insulin resistance Calcium Channel Blockers – no net effect on glycemia Older Beta Blockers – inhibit insulin release from pancreatic beta cells – increased hepatic glycogenolysis
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to usual care antihypertensive therapy in persons at high risk for cardiovascular disease or diabetes. In the Heart Outcomes Prevention Evaluation (HOPE) trial [8], the risk of self-reported incident diabetes was less in those assigned to the ACEI ramipril compared to placebo (3.6 vs. 5.4 %; relative ratio [RR] 0.66 [95 % CI 0.51–0.85]; P 125 mg/dl) at 2 years in those taking chlorthalidone compared with those taking amlodipine or lisinopril. During the first 2 years, the odds for developing diabetes were lower for those assigned to lisinopril (odds ratio [OR], 0.55 [95 % confidence interval [CI], 0.430.70]) or amlodipine (OR, 0.73 [95 % CI, 0.58-0.91]) compared to their counterparts assigned to chlorthalidone. At years 4 and 6, assignment to amlodipine or lisinopril was still associated with a lower OR of developing diabetes, but the ORs were no longer statistically significant. The 4-year and 6-year cumulative incidence of new onset diabetes (defined as a fasting glucose level>125 mg/dl) among participants without diabetes at baseline was 11.0 and 13.8 % in those assigned to chlorthalidone, 9.3 and 12.0 % in those assigned to amlodipine, and 7.8 and 11.0 % in those assigned to lisinopril. These rates allowed for a calculation that provides an important perspective on thiazide-associated diabetes. If amlodipine is assumed to be metabolically neutral, then (based on the 4-year rates) 85 % (9.3/11.0) of diabetes associated with a diuretic is not induced by the diuretic, at least in an older, mostly overweight, ethnically diverse population. Findings similar to the above were noted in two other studies that reported on change in FG levels with different HTN medications [18, 19]. As was the case in ALLHAT, the changes in FG levels were small in both studies (mean, 2.0– 3.5 mg/dL), but the relative risk of developing new-onset diabetes was significantly increased. In other words, a small change in FG levels translates into a much larger increase in biochemical “diabetes”. We next examined whether these small differences in FG had an impact on CVD and renal disease outcomes. We failed to recognize an effect of the change in FG level on any study end point, both for an exploration of all the treatment groups combined and the chlorthalidone group separately. Further, the hazard ratio for a 10-mg/dL change in FG level was no larger for chlorthalidone than for amlodipine or lisinopril. For incident diabetes, CHD was the only outcome with a statistically significant increased hazard ratio, and this did not differ significantly across the three treatment groups. These findings are consistent with other studies in that hazard ratios for the CVD end points have tended to be lower in those treated with chlorthalidone compared with the other treatment groups. In a 14-year follow-up of the Systolic Hypertension in the Elderly Program [18], diabetes diagnosed during chlorthalidone therapy was not associated with a significant increase in CVD mortality (HR, 1.04 [95 % CI, 0.75– 1.46]) compared with diabetes that occurred in the absence of diuretic administration (HR, 1.56 [95 % CI, 1.12–2.18]). In a second study, a 15-year follow-up of 686 middle-aged adults
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with hypertension treated with diuretics [19], incident diabetes did not have a significant effect on CVD mortality, whereas prevalent diabetes at baseline did. This apparent conundrum—of noting increased blood glucose and biochemical diabetes in association with thiazide diuretic treatment but no corresponding increase in coronary heart disease risk—deserves an explanation. First, it is possible that the elevated glucose levels are a surrogate marker for other processes associated with a medication’s effect. For example, in the Cardiac Arrhythmia Suppression Trial (CAST) [20], antiarrhythmia medications successfully suppressed premature ventricular beats. Despite this, mortality was increased in patients treated with the antiarrhythmia medications compared with those receiving placebo. Second, older studies have shown that glucose levels decrease when diuretic therapy is discontinued for any reason [21]. In contrast, ‘classic’ diabetes is characterized by persistent elevation of blood glucose levels. This suggests the elevation in glucose levels that can occur during diuretic therapy is likely to be caused by mechanisms other than insulin resistance—the underlying pathway for ‘classic’ diabetes. As previously mentioned, only a small proportion of the diabetes that arises during diuretic therapy is actually “caused” by the diuretic. Incident diabetes in participants treated with lisinopril was associated with a significantly elevated risk of coronary heart disease. Also those treated with amlodipine who developed diabetes had a higher total mortality and stroke. Given that these medications are ‘glucose protective’ or ‘glucose neutral’, the development of diabetes in association with their use suggests the presence of a high degree of insulin resistance. Finally, analysis of ALLHAT showed that even though the incidence of diabetes at year 4 of follow-up was higher in the participants taking chlorthalidone, the absolute difference in FG levels between them and those treated with amlodipine and lisinopril was small, at 1.5 and 4.0 mg/dl, respectively. Such small differences in FG are unlikely to have much impact on CVD risk. In a subsequent analysis, we employed administrative data sets to explore the impact of antihypertensive medications on glucose metabolism in the ALLHAT participants during 4– 5 years of observation after completion of the trial [22]. During the period of post-trial observation, the ALLHAT participants were no longer assigned to treatment with their study medication. We conducted this analysis because it could be argued that the mean follow-up period of 4.9 years during the trial might be insufficient to detect the effects of elevated glucose levels on CVD outcomes. An increase in blood glucose might only lead to an increase in CVD risk over a longer period of time. Post-trial monitoring of participants in the UK Prospective Diabetes Study (UKPDS) [23] suggested that a sustained period of glycemic control in patients with newly diagnosed diabetes reduced cardiovascular morbidity and mortality, but two decades or more of follow-up were required before the effects achieved statistical significance.
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In our extended analysis of the ALLHAT participants, those with diabetes at baseline experienced higher rates of CVD compared to their counterparts without diabetes, and those with incident diabetes generally had outcome rates that were intermediate between those with and without baseline diabetes. A more provocative finding involved the comparison between those who did and those who did not develop diabetes during the trial, based on treatment assignment. The hazard ratios (HRs) in the chlorthalidone cohort with versus without incident diabetes for CVD mortality (HR, 1.04 [95 % CI, 0.74–1.47]), all-cause mortality (HR, 1.04 [95 % CI, 0.82– 1.30]), and non–CVD mortality (HR, 1.05 [95 % CI, 0.77– 1.42]) were consistently lower than the comparable HRs in the corresponding amlodipine and lisinopril cohorts (HRs, 1.22– 1.53). For example, those who developed diabetes in the chlorthalidone cohort had a statistically insignificant increase in the risk for total CHD events when compared with those who remained nondiabetic (HR, 1.18 [95 % CI, 0.77–1.81]), whereas the opposite was true for participants with versus without incident diabetes who had originally been assigned to lisinopril (HR, 2.57 [95 % CI, 1.45–4.54]). Similarly, the HRs (CIs) for all-cause mortality and stroke were not significantly different in the chlorthalidone cohort based on incident diabetes status: 1.04 (0.82–1.30) and 0.91 (0.49–1.67), respectively. In summary, the results were similar to and confirmed the results of the first phase (in-trial) period of ALLHAT. Table 2 summarizes the takeaway message from the ALLHAT study. First Generation Beta Blockers Newer generation beta blockers, such as carvedilol and nebivolol, have fewer metabolic effects than first generation beta blockers and are considered metabolically favorable [24]. First generation beta blockers (such as propranolol, metoprolol, and atenolol) are still widely used. They are effective for HTN management and for preventing ischemic cardiovascular disease and sudden death. In the United Kingdom Prospective Diabetes Study [25], atenolol-based therapy was as effective for cardiovascular protection as was ACE-based therapy. In the Beta Blocker Heart Attack Trial [26], a first generation beta blocker was effective for preventing recurrence of ischemia compared to a placebo in people with diabetes. In other studies, diabetic people prescribed first generation β-blockers had significantly lower 1-year mortality Table 2 Take away message from the ALLHAT study As compared to ACE inhibitors and CCB, diuretic use is associated with a small increase in fasting glucose levels (1.5–4.0 mg/dl) after 2 years of use. Over time, these differences recede. The small increases in fasting glucose levels with the use of a diuretic early on do not translate into increased cardiovascular disease risk later on.
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than those not receiving these agents, regardless of type and severity of diabetes [27, 28]. In the Atheroscerosis Risk in Communities (ARIC) study [29], an observational cohort, there was a 28 percent increase in the risk of diabetes associated with the use of beta blockers (relative hazard, 1.28; 95 % CI, 1.04 to 1.57). Similar findings have been noted in other observational studies [14, 30]. In contrast, a retrospective, observational cohort study [31] of previously untreated patients, aged≥66 years, identified as new users of an antihypertensive drug class between April 1995 and March 2000, found that neither ACEI use (hazard ratio 0.96 [95 % CI 0.84–1.1]) nor beta blocker use (0.86 [0.74– 1.0]) was associated with a statistically significant difference in type 2 diabetes incidence compared with the CCB control group (n =76,176). In the secondary analysis (n =100,653), compared with CCB users, type 2 diabetes incidence was not significantly different between users of ACEIs (0.97 [0.83– 1.1]), beta blockers (0.84 [0.7–1.0]), or thiazide diuretics (1.0 [0.89–1.2]). Clinical trials of beta blockers have yielded mixed results. The Veterans Administration Cooperative Study Group on Antihypertensive Agents [32] identified a hyperglycemic effect following 12 months of propranolol that persisted for one month after the discontinuation of drug therapy. The Medical Research Council Working Party on Mild to Moderate Hypertension [33] found that the rate of withdrawal from the trial because of hyperglycemia was higher in the propranolol group than in the placebo group, but this difference was not statistically significant. In the Oslo study [34], fasting serum glucose was significantly higher in the group treated with propranolol in combination with a thiazide diuretic compared to the placebo group, whereas there was no difference in serum glucose concentrations between the thiazide diuretic and placebo groups. On the other hand, in the Systolic Hypertension in the Elderly Program [35] there was not an increased risk of hyperglycemia or diabetes in subjects taking beta blockers with thiazide diuretics. Differences in these results may stem from differences in the dosage of medication, the type of beta blocker used (e.g., cardioselective as compared with nonselective), and the duration of treatment. In summary, there is evidence of a small diabetogenic effect associated with first generation beta blocker therapy. This effect should be balanced against the proven effectiveness of these agents for prevention of CAD and ASHD. As one example, in the Women’s Health Initiative Observational Study (93,676 women, aged 50–79 years at baseline) [36], among women with hypertension but no history of CVD, a 2drug-class regimen of calcium channel blockers plus diuretics was associated with a higher risk of CVD mortality vs. beta blockers plus diuretics. Risks were similar for ACEIs plus diuretics and beta blockers plus diuretics with or without diabetes.
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Conclusions No medication is without side effects. To judge a treatment’s efficacy, the positive and negative effects need to be weighed against one another. It is our opinion that the CVD protective effects derived from thiazide diuretics and beta blockers outweigh their negative metabolic effects. Much the same conclusions have been arrived at regarding the diabetogenic effects of statin medications [37]. The salutary effects of ACEIs and ARBs on glucose metabolism are small, and, in our opinion, not sufficiently important to be used as a principal criterion for choice of antihypertensive drug therapy in individuals with hyperglycemia or diabetes. Efficacy in lowering blood pressure, preventing CVD, and the agent’s mechanism of action should play a more important role in determining choice of medication. The widespread use of combination therapy for the management of HTN makes concern regarding the diabetogenic effects of thiazides and beta blockers moot. ACEIs are now frequently combined with thiazide diuretics. Beta blockers are often added to multidrug regimens when blood pressure control has not been achieved. As such, many of the issues that were discussed here appear to be moot. Compliance with Ethics Guidelines Conflict of Interest Joshua I. Barzilay and Paul K. Whelton declare that they have no conflict of interest. Barry R. Davis has received a grant from the National Institutes of Health and has been a consultant for Merck & Co., Inc., as a DSMB member. None of the authors has a conflict of interest regarding the contents of this study. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
References Papers of particular interest, published recently, have been highlighted as: • Of importance
1.
2.
3.
Gomes T, Camacho X, Juurlink DN, Shah BR, Mamdani MM. Risk of incident diabetes among patients treated with statins: population based study. BMJ. 2013;346:f2610. Muscogiuri G, Chavez AO, Gastaldelli A, Perego L, Tripathy D, Saad MJ, et al. The crosstalk between insulin and reninangiotensin-aldosterone signaling systems and its effect on glucose metabolism and diabetes prevention. Curr Vasc Pharmacol. 2008;6: 301–12. Scheen AJ. Renin-angiotensin system inhibition prevents type 2 diabetes mellitus. Part 2. Overview of physiological and biochemical mechanisms. Diabetes Metab. 2004;30:498–505.
410, Page 6 of 6 4.
5.
6.
7.•
8. 9.
10.
11.
12.
13.
14.•
15.•
16.
17.
18.
19.
20.
21.
Shafi T, Appel LJ, Miller 3rd ER, Klag MJ, Parekh RS. Changes in serum potassium mediate thiazide-induced diabetes. Hypertension. 2008;52:1022–9. Aksnes TA, Kjeldsen SE, Mancia G. The effect of antihypertensive agents on new-onset diabetes mellitus: time to amend the guidelines? Am J Cardiovasc Drugs. 2006;6:139–47. Noto H, Goto A, Tsujimoto T, Noda M. Effect of calcium channel blockers on incidence of diabetes: a meta-analysis. Diabetes Metab Syndr Obes. 2013;6:257–61. Lleva RR, Inzucchi SE. Glucose, blood pressure, and cardiovascular risk. Circ Cardiovasc Qual Outcomes. 2012;5:145–7. An informative review of the effects of anti-hypertensive medications on glucose metabolism. Yusuf S, Gerstein H, Hoogwerf B, et al. HOPE Study Investigators. Ramipril and the development of diabetes. JAMA. 2001;286:1882–5. Holman RR, Haffner SM, McMurray JJ, et al. NAVIGATOR Study Group. Effect of nateglinide on the incidence of diabetes and cardiovascular events. N Engl J Med. 2010;362:1463–76. Bosch J, Yusuf S, Gerstein HC, et al. DREAM Trial Investigators. Effect of ramipril on the incidence of diabetes. N Engl J Med. 2006;355:1551–62. Barzilay JI, Gao P, Rydén L, Schumacher H, Probstfield J, Commerford P, et al. Effects of telmisartan on glucose levels in people at high risk for cardiovascular disease but free from diabetes: The TRANSCEND Study. Diabetes Care. 2011;34:1902–7. European Society of Hypertension-European Society of Cardiology. 2013 Guidelines for the management of arterial hypertension. Available at: http://www.escardio.org/guidelines-surveys/ esc-guidelines/Pages/arterial-hypertension.aspx Hypertension NICE. Management of Hypertension in Adults with Primary Care – Partial Update. London: National Institute of Health and Clinical Excellence; 2006. Padwal R, Laupacis A. Antihypertensive therapy and incidence of type 2 diabetes. A systemic review. Diabetes Care. 2004;27:247– 55. A review of anti-hypertension studies and the effects of medications on glycemia. Elliott WJ, Meyer PM. Incident diabetes in clinical trials of antihype rte nsi ve drugs: a ne tw ork met a-ana lysi s. La nc et . 2007;369(9557):201–7. A review of anti-hypertension studies and the effects of medications on glycemia. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin converting enzyme inhibitor or calcium channel blocker vs. diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288:2981–97. Barzilay JI, Davis BR, Cutler J, et al. Fasting glucose levels and incident diabetes mellitus in older non-diabetic adults randomized to three different classes of antihypertensive treatment: a report from the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med. 2006;166:2191–201. Kostis JB, Wilson AC, Freudenberger RS, Cosgrove NM, Pressel SL, Davis BR. Long-term effect of diuretic-based therapy on fatal outcomes in subjects with isolated systolic hypertension with and without diabetes. Am J Cardiol. 2005;95:29–35. Samuelsson O, Pennert K, Andersson O, et al. Diabetes mellitus and raised serum triglyceride concentration in treated hypertension: are they of prognostic importance? observational study. BMJ. 1996;313:660–3. The Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med. 1989;321:406–12. Rowe JW, Tobin JD, Rosa RM, Andres R. Effect of experimental potassium deficiency on glucose and insulin metabolism. Metabolism. 1980;29:498–502.
Curr Hypertens Rep (2014) 16:410 22.• Barzilay JI, Davis BR, Pressel SL, Cutler JA, Einhorn PT, Black HR, et al. ALLHAT Collaborative Research Group. Long-term effects of incident diabetes mellitus on cardiovascular outcomes in people treated for hypertension: the ALLHAT Diabetes Extension Study. Circ Cardiovasc Qual Outcome. 2012;5:153–62. A 10-year follow-up of ALLHAT and the effects of incident diabetes associated with the three antihypertensive medications used during the trial on CVD outcomes. 23. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577–89. 24. Kveiborg B, Hermann TS, Major-Pedersen A, Christiansen B, Rask-Madsen C, Raunsø J, et al. Metoprolol compared to carvedilol deteriorates insulin-stimulated endothelial function in patients with type 2 diabetes—a randomized study. Cardiovasc Diabetol. 2010;9:21. 25. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. UK Prospective Diabetes Study Group. BMJ 1998; 317: 713–720. 26. A randomized trial of propranolol in patients with acute myocardial infarction. II. Morbidity results. JAMA 1983; 250: 2814–2819. 27. Gottlieb SS, McCarter RJ, Vogel RA. Effect of beta-blockade on mortality among high-risk and low-risk patients after myocardial infarction. N Engl J Med. 1998;339:489–97. 28. Chen J, Marciniak TA, Radford MJ, Wang Y, Krumholz HM. Betablocker therapy for secondary prevention of myocardial infarction in elderly diabetic patients. Results from the National Cooperative Cardiovascular Project. J Am Coll Cardiol. 1999;34:1388–94. 29. Gress TW, Nieto FJ, Shahar E, Wofford MR, Brancati FL. Hypertension and antihypertensive therapy as risk factors for type 2 diabetes mellitus. Atherosclerosis Risk in Communities Study. N Engl J Med. 2000;342:905–12. 30. Samuelsson O, Hedner T, Berglund G, Persson B, Andersson OK, Wilhelmsen L. Diabetes mellitus in treated hypertension: incidence, predictive factors and the impact of non-selective beta-blockers and thiazide diuretics during 15 years treatment of middle-aged hypertensive men in the Primary Prevention Trial Goteborg, Sweden. J Hum Hypertens. 1994;8:257–63. 31. Padwal R, Mamdani M, Alter DA, Hux JE, Rothwell DM, Tu K, et al. Antihypertensive therapy and incidence of type 2 diabetes in an elderly cohort. Diabetes Care. 2004;27:2458–63. 32. Propranolol or hydrochlorothiazide alone for the initial treatment of hypertension. IV. Effect on plasma glucose and glucose tolerance. Veterans Administration Cooperative Study Group on Antihypertensive Agents. Hypertension 1985; 7(6 Pt 1):1008–1016. 33. Adverse reactions to bendrofluazide and propranolol for the treatment of mild hypertension. Report of Medical Research Council Working Party on Mild to Moderate Hypertension. Lancet 1981; 2(8246): 539–543. 34. Helgeland A, Leren P, Foss OP, Hjermann I, Holme I, Lund-Larsen PG. Serum glucose levels during long-term observation of treated and untreated men with mild hypertension. The Oslo study. Am J Med. 1984;76:802–5. 35. Savage PJ, Pressel SL, Curb JD, Schron EB, Applegate WB, Black HR, et al. Influence of long-term, low-dose, diuretic-based, antihypertensive therapy on glucose, lipid, uric acid, and potassium levels in older men and women with isolated systolic hypertension: The Systolic Hypertension in the Elderly Program. SHEP Cooperative Research Group. Arch Intern Med. 1998;158:741–51. 36. Wassertheil-Smoller S, Psaty B, Greenland P, Oberman A, Kotchen T, Mouton C, et al. Association between cardiovascular outcomes and antihypertensive drug treatment in older women. JAMA. 2004;292:2849–59. 37. Minder CM, Blumenthal RS, Blaha MJ. Statins for primary prevention of cardiovascular disease: the benefits outweigh the risks. Curr Opin Cardiol. 2013;28:554–60.
