Published online before print March 22, 2004, doi: 10.1161/01.HYP.0000125727.92964.e2
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(Hypertension. 2004;43:941.)
© 2004 American Heart Association, Inc.
Editorial Commentaries |
When Does New Onset Diabetes Resulting From Antihypertensive Therapy Increase Cardiovascular Risk
From the Hypertension/Clinical Research Center, Rush University Medical Center (G.L.B.), Chicago, Ill, and University of Missouri-Columbia Health Sciences Center (J.R.S.), Columbia, Mo.
Correspondence to George Bakris, MD, 1700 W. VanBuren St., Suite 470 Chicago, IL 60612. E-mail gbakris{at}earthlink.net.
The report in this issue of Hypertension by Verdecchia et al,1 a prospective study in a relatively large group of patients with uncomplicated essential hypertension, demonstrated two important findings. First, baseline level of plasma glucose and use of diuretics after a median follow-up of 6 years were independent predictors for development of new onset diabetes. Second, they observed that the occurrence of a new onset of diabetes in treated hypertensive patients carried a risk for subsequent cardiovascular disease (CVD) events that was not statistically different from those who already had diabetes and hypertension at the onset of the study. Indeed, the risk of CVD events in those with new onset diabetes was not substantially different compared with those who already had diabetes at the onset of the investigation, with both groups having much higher risk than those who remained free of diabetes. These are important and clinically relevant observations.
It is increasingly recognized that persons with hypertension have a high prevalence of insulin resistance and are at substantially higher risk of developing type 2 diabetes mellitus.2–4 Verdecchia et al’s data support prior observations that certain antihypertensive drug classes (diuretics and ß-blockers) may increase this propensity of patients with hypertension to develop type 2 diabetes.3 Use of diuretics or ß-blockers compared with angiotensin-converting enzyme inhibitors or calcium antagonists was associated with an increased incidence of new diabetes in the Captopril Prevention Project (CAPP)5 and the Intervention as a Goal in Hypertension Treatment Study (INSIGHT).6 In a prospective study of the Atherosclerosis Risk in Communities study and the Losartan Intervention for End-Point Reduction (LIFE), use of a ß-blocker was associated with an 18% to 27% higher incidence of new diabetes.3,7 In the recent Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), the incidence of new diabetes was highest in the chlorthalidone group compared with either the amlodipine or lisinopril groups.8 In the recently reported Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial, there was a tendency for lesser new onset diabetes for patients randomized to verapamil versus conventional therapy (ie, ß-blockers).9 The very recently reported International Verapamil SR-trandolapril Study (INVEST), demonstrated a significantly lower incidence of new onset diabetes in the verapamil group compared with the ß-blocker group.10 In both CONVINCE and INVEST, verapamil provided similar CVD risk reduction to a ß-blocker with better tolerability. Thus, the totality of data from clinical trials indicates that thiazide diuretics and ß-blockers increase risk for new onset diabetes. The current report in this journal indicates that the associated development of diabetes significantly increases the risk for CVD. It is now generally recognized that macrovascular disease starts long before the presentation of patients with clinical diabetes, as several studies have shown the increased risk of CVD in patients with impaired glucose tolerance even after adjusting for conventional risk factors.11–13 The current study suggests that the accelerated development of clinical diabetes associated with antihypertensive therapy further enhances the risk for CVD in patients with essential hypertension.1 This increased risk, however, is not appreciated for at least 6 or more years after its development, a duration much longer than any of the follow-up trials. The current study also suggests that patients with elevated fasting glucose are at a particularly high risk for new onset diabetes and associated enhanced CVD risk. Collectively, these observations suggest that thiazide diuretics and ß-blockers should be initiated cautiously in hypertensive patients with elevated fasting glucoses ie, above 100 mg/dL or those who have a body mass index of 
30.14 Further, the risks of new onset diabetes and associated CVD risk should be factored into further recommendations of antihypertensive therapy. This will be increasingly important as the numbers of hypertensive patients with insulin resistance increase in parallel with increases in obesity and aging of the essential hypertension population throughout the world.2
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
References
- Verdecchia P, Borgioni C, Angeli F, Reboldi G, Gattobigio R, Filippucci L, Norgiolini S, Bracco C, Porcellati C. Adverse Prognostic Significance of New Diabetes in Treated Hypertensive Subjects. Hypertension. 2004; 43: 963–969.
[Abstract/Free Full Text] - McFarlane SI, Banerji M, Sowers JR. Insulin resistance and cardiovascular disease. J Clin Endocrinol Metab. 2001; 86: 713–718.
[Free Full Text] - 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: 905–912.
[Abstract/Free Full Text] - Sowers JR, Bakris GL. Antihypertensive therapy and the risk of type 2 diabetes mellitus. N Engl J Med. 2000; 342: 969–970.
[Free Full Text] - Hansson L, Lindholm LH, Niskanen L, Lanke J, Hedner T, Niklason A, Luomanmaki K, Dahlof B, De Faire U, Morlin C, Karlberg BE, Wester PO, Bjorck JE. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet. 1999; 353: 611–616.[CrossRef][Medline] [Order article via Infotrieve]
- Brown MJ, Palmer CR, Castaigne A, de Leeuw PW, Mancia G, Rosenthal T, Ruilope LM. Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet. 2000; 356: 366–372.[CrossRef][Medline] [Order article via Infotrieve]
- Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, Faire U, Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Wedel H. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002; 359: 995–1003.[CrossRef][Medline] [Order article via Infotrieve]
- 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: 2981–2997.
[Abstract/Free Full Text] - Black HR, Elliott WJ, Grandits G, Grambsch P, Lucente T, White WB, Neaton JD, Grimm RH, Jr, Hansson L, Lacourciere Y, Muller J, Sleight P, Weber MA, Williams G, Wittes J, Zanchetti A, Anders RJ. Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial. JAMA. 2003; 289: 2073–2082.
[Abstract/Free Full Text] - Pepine CJ, Handberg EM, Cooper-DeHoff RM, Marks RG, Kowey P, Messerli FH, Mancia G, Cangiano JL, Garcia-Barreto D, Keltai M, Erdine S, Bristol HA, Kolb HR, Bakris GL, Cohen JD, Parmley WW. A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial. JAMA. 2003; 290: 2805–2816.
[Abstract/Free Full Text] - Haffner SM, Stern MP, Hazuda HP, Mitchell BD, Patterson JK. Cardiovascular risk factors in confirmed prediabetic individuals. Does the clock for coronary heart disease start ticking before the onset of clinical diabetes? JAMA. 1990; 263: 2893–2898.[Abstract]
- Barzilay JI, Spiekerman CF, Wahl PW, Kuller LH, Cushman M, Furberg CD, Dobs A, Polak JF, Savage PJ. Cardiovascular disease in older adults with glucose disorders: comparison of Am Diabetes Association criteria for diabetes mellitus with WHO criteria. Lancet. 1999; 354: 622–625.[CrossRef][Medline] [Order article via Infotrieve]
- Tominaga M, Eguchi H, Manaka H, Igarashi K, Kato T, Sekikawa A. Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose. The Funagata Diabetes Study. Diabetes Care. 1999; 22: 920–924.[Abstract]
- Mykkanen L, Kuusisto J, Pyorala K, Laakso M, Haffner SM. Increased risk of non-insulin-dependent diabetes mellitus in elderly hypertensive subjects. J Hypertens. 1994; 12: 1425–1432.[Medline] [Order article via Infotrieve]
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