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Salim Yusuf, DPhil,FRCPC; Hertzel Gerstein, FRCP; Byron Hoogwerf, MD; Janice Pogue, MSc; Jackie Bosch, MSc; Bruce H. R. Wolffenbuttel, MD; Bernard Zinman, FRCP; for the HOPE Study Investigators

JAMA. 2001;286:1882-1885.

ABSTRACT
Context  Type 2 diabetes is a growing clinical and public health problem. Preventive efforts related to lifestyle modification are not always successful; therefore, alternative prevention strategies need to be studied.

Objective  To investigate the effectiveness of ramipril, an angiotensin-converting enzyme inhibitor, in preventing diabetes among high-risk persons.

Design, Setting, and Participants  The randomized, controlled Heart Outcomes Prevention Evaluation trial of 5720 patients older than 55 years without known diabetes but with vascular disease who were followed up for a mean of 4.5 years. The study included 267 hospitals in 19 countries and was conducted between 1994 and 1999.

Intervention  Patients were randomly assigned to receive ramipril, up to 10 mg/d (n = 2837), or placebo (n = 2883).

Main Outcome Measure  Diagnosis of diabetes determined from self-report at follow-up visits every 6 months, compared between the 2 groups.

Results  One hundred and two individuals (3.6%) in the ramipril group developed diabetes compared with 155 (5.4%) in the placebo group (relative risk [RR], 0.66; 95% confidence interval [CI], 0.51-0.85, P<.001). Similar results were noted when different diagnostic criteria were used; in the ramipril group, the RR for diagnosis of diabetes and hemoglobin A_1c greater than 110% was 0.60 (95% CI, 0.43-0.85), for initiation of glucose-lowering therapy, 0.56 (95% CI, 0.41-0.77), and for both, 0.51 (95% CI, 0.34-0.76). These effects were also consistently seen in several subgroups examined.

Conclusions  Ramipril is associated with lower rates of new diagnosis of diabetes in high-risk individuals. Because these results have important clinical and public health implications, this hypothesis requires prospective confirmation.

INTRODUCTION

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Type 2 diabetes is an important and common risk factor for the development of coronary artery disease, strokes, peripheral arterial disease, and renal and eye disease. Currently, in North America, the direct and indirect costs of diabetes and its complications exceeds $100 billion per year.¹ This health and economic impact of diabetes is bound to increase, as the global prevalence of diabetes rises from 4.2% to 5.4% by the year 2025.²

A growing amount of literature shows that the complications of diabetes can be reduced or prevented by improving glucose control,^3-4 lowering blood pressure⁵ and lipids,⁶ smoking cessation, and taking angiotensin converting enzyme (ACE) inhibitors.⁷ An even more effective approach to preventing these problems would be to prevent diabetes from developing. Whereas recent evidence from trials suggests that lifestyle modifications may reduce the risk of diabetes,⁸ the long-term adherence to such interventions has not been high. Therefore alternative strategies that are more easily implemented, safe and likely to prevent not only diabetes⁸ but also its chronic consequences, deserve to be investigated.

Recently, we demonstrated that the ACE inhibitor, ramipril, reduces myocardial infarction, strokes, deaths, and the development of diabetic nephropathy among high risk people both with and without a diagnosis of diabetes.^{7, 9} We also observed that ramipril reduced the development of diabetes in study participants without known diabetes at randomization.⁹ This article describes this finding in detail and explores possible explanations.

METHODS

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The design of the Heart Outcomes Prevention Evaluation (HOPE) trial has been described in detail in previous publications. Briefly, individuals who were 55 years or older with no evidence of left ventricular dysfunction or heart failure and who had evidence of vascular disease or who had diabetes and 1 other risk factor were eligible as long as they had no indication or contraindication to receiving an ACE-inhibitor. The study was conducted in 267 hospitals in 19 countries from 1994 to 1999. All patients provided written informed consent.

Of 10 576 eligible patients who participated in a run-in period during which they received 2.5 mg ramipril once daily for 1 week followed by matching placebo for 10 to 14 days, 1035 (9.8%) were excluded from randomization (3.2% for side effects, 3.7% for lack of consent). Of the remaining 9541 patients, 3654 (38.3%) had a clinical diagnosis of diabetes and 5887 (61.7%) did not at randomization. This article focuses primarily on the latter group of patients. Of these patients, 5720 were randomized to receive up to 10 mg of ramipril once per day or equivalent placebo. One hundred sixty-seven patients who were randomized to receive a low dose (2.5 mg/day) of ramipril as part of the Study to Evaluate Carotid Ultrasound changes with Ramipril and Vitamin E (SECURE). Substudy results are not included. All patients were also randomized to receive 400 IU of vitamin E or placebo.

Follow-up visits occurred at 1 month and 6 months after randomization and then every 6 months (mean follow-up of 4.5 years). At each visit, we documented whether the diagnosis of diabetes had been made since the previous visit.

The primary outcome of this analysis is a new diagnosis of diabetes recorded on the basis of self-report. This diagnosis was made blinded to treatment allocation and, hence, is likely to be unbiased. Hemoglobin A_1c (HbA_1c)levels and medications used among those diagnosed as having diabetes were also recorded. The HbA_1c levels were determined locally. Values higher than 110% of the upper limit of normal for each laboratory were considered to be biochemical confirmation of diabetes.

Survival curves utilizing the Kaplan Meier and log-rank procedures were used to describe and compare the results in the 2 treatment groups. Because of the factorial design, all analyses were stratified for randomization to vitamin E or placebo. Subgroup analyses were conducted using tests of interaction in the Cox regression model.

RESULTS

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The baseline characteristics of the patients who did not have diabetes are provided in Table 1. The proportion of patients taking study ramipril or open label ACE-inhibitors in the active group was 98.3% at 2 years and 89.7% at 4 years. The proportion taking open label ACE-inhibitors in the control group was 11.6% and 27.4% respectively.

View this table: [in this window] [in a new window] Table 1. Baseline Demographics in Patients Without Diabetes Who Entered into HOPE

There were 102 individuals (3.6%) in the ramipril group compared with 155 (5.4%) in the placebo group (relative risk [RR], 0.66; 95% confidence interval [CI], 0.51-0.85; P<.001) who reported a new diagnosis of diabetes (Figure 1). The proportion of patients diagnosed to have diabetes and a documented glycated hemoglobin of 110% or more above the upper limit of normal (1.8% vs 3.0%; RR, 0.60; 95% CI, 0.43-0.85; P = .003), those receiving an oral glucose lowering agent or insulin (2.1% vs 3.6%; RR, 0.56; 95% CI, 0.41-0.77; P<.001). Those with all criteria (1.3% vs 2.5%; RR, 0.51; 95% CI, 0.34-0.76; P<.001) were significantly lower in the ramipril group compared with the placebo group. Vitamin E and placebo did not differ in their effect on diabetes.

View larger version (19K): [in this window] [in a new window] Figure 1. Development of Diabetes: Ramipril vs Placebo The relative risk for developing diabetes among patients taking ramipril vs placebo is 0.66 (95% confidence interval, 0.51-0.85; P<.001).

Because ramipril reduced the risk of cardiovascular events and diabetic nephropathy, we assessed whether the higher occurrence of these clinical events in placebo-treated patients increased the likelihood of ascertainment of diabetes in this group. Similar stratified analyses by the occurrence of other outcomes was also examined. As noted in Table 2 the impact of ramipril on the development of diabetes could not be explained by any confounding factor such as preferential ascertainment in one group vs the other or use of concomitant medications.

View this table: [in this window] [in a new window] Table 2. Effect of Ramipril on the Development of Diabetes Using a Range of Criteria and Stratified by the Occurrence of Specific Events*

Figure 2 demonstrates the results among subgroups of patients with different risk factors for developing diabetes. The results are consistent among those with a waist-to-hip ratio below or above the median of 0.93 and consistent among those with a body mass index (BMI) of 27.7 kg/m²or less or higher than 27.7 kg/m², those with or without a history or hypertension, those receiving or not receiving -blockers or diuretics at randomization. A higher proportion of individuals without diabetes who were randomized to the placebo group than those randomized to the ramipril group received diuretics or -blockers (drugs that are associated with glucose intolerance or diabetes) during the study. However, the RR for diabetes in the subgroup of individuals who never took these drugs during the study was consistent with the overall results (RR, 0.62; 95% CI, 0.43-0.90).

View larger version (39K): [in this window] [in a new window] Figure 2. Effect of Ramipril in Preventing Diabetes in Subgroups Defined at Randomization Waist-hip ratio and body mass index are subdivided above and below the median. The size of the boxes are proportionate to the number of patients. Dashed line indicates the average treatment effect; dotted line, relative risk equal to 1.

In 4074 patients weight was recorded at baseline and at study end. Weight increased by a mean (SD) of 0.98 (6.93) kg in the active group and 0.76 (8.10) kg in the control group.

COMMENT

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These analyses indicate that ramipril reduces the risk of new diagnosis of diabetes among individuals with no previous history of diabetes. The magnitude of the benefit appears to be large and moreover, ACE-inhibitors also reduce macrovascular and microvascular complications of diabetes.⁷ Although the data on new diagnoses of diabetes were collected prospectively in the HOPE study, it was not a primary or secondary outcome of the trial. Therefore the results should be interpreted with caution. Nevertheless, the results are plausible given the clear statistical significance and consistency of results across subgroups, as well as using a range of approaches to diagnosing diabetes.

The Study to Evaluate Carotid Ultrasound changes in patients treated with Ramipril and vitamin E (SECURE) supports our findings that fasting glucose increased more with placebo (15.8 mg/dL [0.41 mmols]) than with ramipril (9.6 mg/dL [0.25 mmols]; P = .03).¹⁰ Among the patients with diabetes in the HOPE study, a significant reduction in HbA_1c levels during serial annual recordings occured during the first 2 years (absolute difference, 0.2%)⁷ In the UK Prospective Diabetes Study (UKPDS)⁵ and in the Captopril Prevention Project,¹¹ patients randomized to receive ACE inhibitors had lower levels of HbA_1c or less development of diabetes compared with those taking -blockers or diuretics. It is not clear whether the differences in development of diabetes observed in these studies are due to a protective effect of ACE inhibitors or an adverse effect of -blockers or diuretics.

Hypokalemia substantially impairs the insulin secretory response to glucose,¹² which may be favorably affected by ACE inhibitors. ACE inhibitors also lower aldosterone secretion and renal potassium wasting, which could preserve -cell responsiveness. ACE inhibitors may increase islet blood flow and pancreatic -cell perfusion by reducing angiotensin-2 mediated vasoconstriction in the pancreas.¹³ These effects may potentially slow or reverse the decline in -cell function.

ACE inhibitors may reduce insulin resistance in skeletal muscles,^14-15 increase insulin-mediated glucose disposal thereby decreasing the need for pancreatic insulin secretion. The increased insulin mediated glucose uptake by skeletal muscle in response to an ACE inhibitor is due to increased bradykinin-mediated nitric oxide production and not to reductions in angiotensin 2 production or action.^16-17 Several observations suggest that agents that increase nitric oxide (such as ACE-inhibitors) may also increase insulin-mediated glucose uptake. These observations include (1) both insulin-mediated vasodilation and skeletal muscle glucose metabolism are reduced in obese persons who do not have diabetes (ie, individuals at risk for diabetes) and in individuals with type 2 diabetes, (2) inhibition of nitric oxide production reproduces this effect in lean individuals, and (3) the effect on insulin sensitivity is greater than can be accounted for by just increased skeletal muscle blood flow.¹⁸ ACE inhibitors may also reduce insulin resistance at the liver and fat cell, which would reduced hepatic glucose production and lower free fatty acid levels.¹⁹

Our data suggesting that ramipril, an ACE inhibitor, reduces the risk of developing diabetes mellitus require confirmation because of the enormous clinical and public health potential of these findings. We are therefore embarking on a large prospective trial (Diabetes Reduction Assessment with Ramipril and rosiglitizone Medication [DREAM]) among individuals with impaired glucose tolerance to evaluate prospectively whether ramipril prevents diabetes.

AUTHOR INFORMATION

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Author Contributions: Study concept and design: Yusuf, Gerstein, Zinman.

Acquisition of data: Yusuf, Gerstein, Hoogwerf, Pogue, Bosch, Wolffenbuttel, Zinman.

Analysis and interpretation of data: Yusuf, Gerstein, Pogue, Zinman.

Drafting of the manuscript: Yusuf, Gerstein, Pogue.

Critical revision of the manuscript for important intellectual content: Yusuf, Gerstein, Hoogwerf, Bosch, Wolffenbuttel, Zinman.

Statistical expertise: Pogue.

Obtained funding: Yusuf, Gerstein.

Administrative, technical, or material support: Yusuf, Bosch.

Study supervision: Yusuf, Wolffenbuttel, Zinman.

Expertise in diabetes: Hoogwerf.

Funding/Support: The HOPE study was supported by grants from the Medical Research Council of Canada, Heart and Stroke Foundation of Ontario, and by several pharmaceutical companies: Aventis, Astra, Monarch Pharmaceuticals, Vitamin E Manufacturers Association of North America, and NEGMA France. However, the study was independently conducted by the HOPE investigators. Dr Yusuf is supported by a Senior Scientist Award of the Medical Research Council of Canada and holds an Endowed Chair of the Heart and Stroke Foundation of Ontario.

Financial Disclosure: Dr Yusuf has received honoraria and research grants from Aventis Pharmaceuticals and King Pharmaceuticals, both of which comarket ramipril. Dr Gerstein has received grant support or consulting and speaking honoraria from Monarch/King, Aventis, and Wyeth Ayerst.

Corresponding Author and Reprints: Salim Yusuf, DPhil, FRCPC, Canadian Cardiovascular Collaboration Project Office, Hamilton General Hospital, 237 Barton St East, Hamilton, Ontario, Canada L8L 2X2, (e-mail: yusufs{at}mcmaster.ca).

Author Affiliations: McMaster University, Hamilton, Canada (Drs Yusuf and Gerstein and Mss Pogue and Bosch); Cleveland Clinic Foundation, Cleveland, Ohio (Dr Hoogwerf); Clinic of Maastricht, Maastricht, the Netherlands (Dr Wolffenbuttel); Mt Sinai and Toronto Hospitals, Toronto, Canada (Dr Zinman). A complete list of the HOPE investigators has been previously published.¹¹

REFERENCES

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1. American Diabetes Association. Economic consequences of diabetes mellitus in the US in 1997. Diabetes Care. 1998;21:296-309. ABSTRACT 2. King H, Aubert RE, Herman WH. Global burden of diabetes, 1995-2025. Diabetes Care. 1998;21:1414-1431. ABSTRACT 3. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977-986. FREE FULL TEXT 4. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837-853. FULL TEXT | ISI | PUBMED 5. UK Prospective Diabetes Study (UKPDS) Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ. 1998;317:713-720. FREE FULL TEXT 6. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease. Lancet. 1994;344:1383-1389. FULL TEXT | ISI | PUBMED 7. Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus. Lancet. 2000;355:253-259. FULL TEXT | ISI | PUBMED 8. Pan SR, Li GW, Hu YW, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. Diabetes Care. 1997;20:537-544. ABSTRACT 9. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:145-153. FREE FULL TEXT 10. Lonn E, Weitz J, Dzavik V, et al for the SECURE and HOPE Investigators. Effects of ramipril and vitamin E on hematological markers of fibrinolysis, coagulation and endothelial function: results of the MORE-HOPE study. Can J Cardiol. 2000;16(suppl F):233F. 11. Hansson L, Lindholmn LH, Niskanen L, et al. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension. Lancet. 1999;353:611-616. FULL TEXT | ISI | PUBMED 12. Ferrannini E, Seghieri G, Muscelli E. Insulin and the renin-angiotensin-aldosterone system. J Cardiovasc Pharmacol. 1994;24(suppl 3):S61-S69. 13. Carlsson PO, Berne C, Jansson L. Angiotensin II and the endocrine pancreas. Diabetologia. 1998;41:127-133. FULL TEXT | ISI | PUBMED 14. Henriksen EJ, Jacob S. Effects of captopril on glucose transport activity in skeletal muscle of obese Zucker rats. Metabolism. 1995;44:267-272. FULL TEXT | ISI | PUBMED 15. Vuorinen-Markkola H, Yki-Jarvinen H. Antihypertensive therapy with enalapril improves glucose storage and insulin sensitivity in hypertensive patients with non-insulin-dependent diabetes mellitus. Metabolism. 1995;44:85-89. FULL TEXT | ISI | PUBMED 16. Henriksen EJ, Jacob S, Kinnick TR, Youngblood EB, Schmit MB, Dietze GJ. ACE inhibition and glucose transport in insulin resistant muscle: roles of bradykinin and nitric oxide. Am J Physiol. 1999;277:R332-R336. 17. Fogari R, Zoppi A, Corradi L, Lazzari P, Mugellini A, Lusardi P. Comparative effects of lisinopril and losartan on insulin sensitivity in the treatment of nondiabetic hypertensive patients. Br J Clin Pharmacol. 1998;46:467-471. FULL TEXT | ISI | PUBMED 18. Baron AD. Vascular reactivity. Am J Cardiol. 1999;84:25J-27J. 19. Torlone E, Rambotti AM, Perriello G, et al. ACE-inhibition increases hepatic and extrahepatic sensitivity to insulin in patients with type 2 (non-insulin-dependent) diabetes mellitus and arterial hypertension. Diabetologia. 1991;34:119-125. FULL TEXT | ISI | PUBMED

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Prevalence and Characteristics of the Metabolic Syndrome in the San Antonio Heart and Framingham Offspring Studies
Meigs et al.
Diabetes 2003;52:2160-2167.
ABSTRACT | FULL TEXT  

Blockade of the Renin-Angiotensin System Increases Adiponectin Concentrations in Patients With Essential Hypertension
Furuhashi et al.
Hypertension 2003;42:76-81.
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Minireview: Adiposity, Inflammation, and Atherogenesis
Lyon et al.
Endocrinology 2003;144:2195-2200.
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HOPE Study Impact on ACE Inhibitors Use
Hemels et al.
The Annals of Pharmacotherapy 2003;37:640-645.
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Long-term Cardiovascular Consequences of Diuretics vs Calcium Channel Blockers vs Angiotensin-Converting Enzyme Inhibitors
Messerli and Weber
JAMA 2003;289:2067-2068.
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Vasopeptidase Inhibitor Omapatrilat Induces Profound Insulin Sensitization and Increases Myocardial Glucose Uptake in Zucker Fatty Rats: Studies Comparing a Vasopeptidase Inhibitor, Angiotensin-Converting Enzyme Inhibitor, and Angiotensin II Type I Receptor Blocker
Wang et al.
Circulation 2003;107:1923-1929.
ABSTRACT | FULL TEXT  

The Daily Walk or the Daily Pill?
Marks
Clin. Diabetes 2003;21:51-52.
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Applying the Lessons of the DPP to Clinical Practice
Inzucchi and Sherwin
Clin. Diabetes 2003;21:91-92.
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American Association of Clinical Endocrinologists (AACE) Consensus Conference on the Insulin Resistance Syndrome: 25-26 August 2002, Washington, DC
Bloomgarden
Diabetes Care 2003;26:1297-1303.
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Insulin resistance: a global epidemic in need of effective therapies
Califf
Eur Heart J Suppl 2003;5:C13-C18.
ABSTRACT  

Enalapril Reduces the Incidence of Diabetes in Patients With Chronic Heart Failure: Insight From the Studies Of Left Ventricular Dysfunction (SOLVD)
Vermes et al.
Circulation 2003;107:1291-1296.
ABSTRACT | FULL TEXT  

Pharmacological Agents That Directly Modulate Insulin Secretion
Doyle and Egan
Pharmacol. Rev. 2003;55:105-131.
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Pharmacologic Treatment of Type 2 Diabetes
Bloomgarden
Diabetes Care 2003;26:526-533.
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Cardiovascular Disease in Type 2 Diabetes Mellitus: Current Management Guidelines
Mooradian
Arch Intern Med 2003;163:33-40.
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Pharmacologic Approaches to the Prevention of Type 2 Diabetes in High Risk Pediatric Patients
Freemark
J. Clin. Endocrinol. Metab. 2003;88:3-13.
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Functional Interplay Between Angiotensin II and Nitric Oxide: Cyclic GMP as a Key Mediator
Yan et al.
Arterioscler. Thromb. Vasc. Bio. 2003;23:26-36.
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Impaired glucose tolerance: do pharmacological therapies correct the underlying metabolic disturbance?
Defronzo
British Journal of Diabetes & Vascular Disease 2003;3:S24-S40.
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Mechanisms of cardiovascular risk reduction with ramipril: insights from HOPE and HOPE substudies
Lonn et al.
Eur Heart J Suppl 2003;5:A43-A48.
ABSTRACT  

Angiotensin Blockade Prevents Type 2 Diabetes by Formation of Fat Cells
Sharma et al.
Hypertension 2002;40:609-611.
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Type 2 diabetes and atherosclerotic cardiovascular disease: do they share common antecedents?
Krentz
British Journal of Diabetes & Vascular Disease 2002;2:370-378.
ABSTRACT  

Prevention of diabetes in cardiovascular studies: implications for the aetiology of type 2 diabetes
Mcdougall and Fisher
British Journal of Diabetes & Vascular Disease 2002;2:384-389.
ABSTRACT  

Dysmetabolic Syndrome: Multiple Risk Factors for Premature Adult Disease in an Adolescent Girl
Falkner et al.
Pediatrics 2002;110:e14-14.
ABSTRACT | FULL TEXT  

Ramipril and Risk of Diabetes
Potyk et al.
JAMA 2002;287:186-187.
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Can ACE Inhibitors Prevent Diabetes?
Journal Watch Cardiology 2001;2001:1-1.
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