Ramipril and the Development of Diabetes
Salim Yusuf, DPhil, FRCPC
Context Type 2 diabetes is a growing clinical and public health problem. Preventive
efforts related to lifestyle modification are not always successful; therefore, alterna-tive prevention strategies need to be studied.
Objective To investigate the effectiveness of ramipril, an angiotensin-converting en-
zyme inhibitor, in preventing diabetes among high-risk persons.
Design, Setting, and Participants The randomized, controlled Heart Outcomes Pre-
vention Evaluation trial of 5720 patients older than 55 years without known diabetes butwith 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).
TYPE2DIABETESISANIMPOR- MainOutcomeMeasureDiagnosisofdiabetesdeterminedfromself-reportatfol-
low-up visits every 6 months, compared between the 2 groups.
Results One hundred and two individuals (3.6%) in the ramipril group developed dia-
betes compared with 155 (5.4%) in the placebo group (relative risk [RR], 0.66; 95% con- eral arterial disease, and renal and eye dis- fidence interval [CI], 0.51-0.85, PϽ.001). Similar results were noted when different di- agnostic criteria were used; in the ramipril group, the RR for diagnosis of diabetes and direct and indirect costs of diabetes and hemoglobin A1c 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.
pact of diabetes is bound to increase, as 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.
that the complications of diabetes can bereduced or prevented by improving glu- tries from 1994 to 1999. All patients pro- sure5 and lipids,6 smoking cessation, and ticipated in a run-in period during which betes at randomization.9 This article de- Author Affiliations: McMaster University, Hamil-
from trials suggests that lifestyle modi- ton, Canada (Drs Yusuf and Gerstein and Mss Pogue and Bosch); Cleveland Clinic Foundation, Cleveland, tes,8 the long-term adherence to such in- Ohio (Dr Hoogwerf ); Clinic of Maastricht, Maas-tricht, the Netherlands (Dr Wolffenbuttel); Mt Sinai and Toronto Hospitals, Toronto, Canada (Dr Zinman).
alternative strategies that are more eas- been described in detail in previous pub- A complete list of the HOPE investigators has beenpreviously published.11 Financial Disclosure: Dr Yusuf has received hono-
55 years or older with no evidence of left raria and research grants from Aventis Pharmaceuti-cals and King Pharmaceuticals, both of which comar- ket ramipril. Dr Gerstein has received grant support or consulting and speaking honoraria from Monarch/King, Aventis, and Wyeth Ayerst.
ease or who had diabetes and 1 other risk Corresponding Author and Reprints: Salim Yusuf,
DPhil, FRCPC, Canadian Cardiovascular Collabora- tion Project Office, Hamilton General Hospital, 237Barton St East, Hamilton, Ontario, Canada L8L 2X2, 1882 JAMA, October 17, 2001—Vol 286, No. 15 (Reprinted)
2001 American Medical Association. All rights reserved.
Table 1. Baseline Demographics in Patients Without Diabetes Who Entered into HOPE
Ramipril Group
Placebo Group
side effects, 3.7% for lack of consent).
Of the remaining 9541 patients, 3654(38.3%) had a clinical diagnosis of dia- Mean (SD)
Mean (SD)
with Ramipril and Vitamin E (SECURE).
Substudy results are not included. All pa- *History or blood pressure greater than 140/90 mm Hg.
†To convert total and high-density lipoprotein cholesterol from mg/dL to mmol/L, multiply by 0.0259.
those diagnosed as having diabetes werealso recorded. The HbA1c levels were de- Figure 1. Development of Diabetes:
biochemical confirmation of diabetes.
(5.4%) in the placebo group (relative risk [RR], 0.66; 95% confidence interval [CI], 0.51-0.85; PϽ.001) who reported a new cause of the factorial design, all analy- diagnosis of diabetes (FIGURE 1). The
Placebo 2883 2867 2800 2765 2682 2645 2571 2497 1279 teraction in the Cox regression model.
Ramipril 2837 2807 2772 2725 2672 2635 2571 2528 1317 0.60; 95% CI, 0.43-0.85; P=.003), those The relative risk for developing diabetes among pa- tients taking ramipril vs placebo is 0.66 (95% confi- dence interval, 0.51-0.85; PϽ.001).
CI, 0.41-0.77; PϽ.001). Those with all provided in TABLE 1. The proportion
criteria (1.3% vs 2.5%; RR, 0.51; 95% CI, of patients taking study ramipril or open 0.34-0.76; PϽ.001) were significantly placebo did not differ in their effect on 2001 American Medical Association. All rights reserved.
(Reprinted) JAMA, October 17, 2001—Vol 286, No. 15 1883
Table 2. Effect of Ramipril on the Development of Diabetes Using a Range of Criteria and
Stratified by the Occurrence of Specific Events* higher occurrence of these clinical events Variables
RR (95% CI)
P Value
in placebo-treated patients increased the New Diabetes†
in this group. Similar stratified analyses also examined. As noted in TABLE 2 the
New Diabetes With Glycated Hemoglobin Ն110%, ULN‡
of diabetes could not be explained by any FIGURE 2 demonstrates the results
New Diabetes With Oral Agents or Insulin§
ferent risk factors for developing diabe- New Diabetes With Oral Agents or Insulin and Glycated Hemoglobin Ն110%, ULN
*RR indicates relative risk; CI, confidence interval; MA, microalbuminuria; ON, overt nephropathy; ULN, upper limits of normal; and primary event, death, myocardial infarction, or stroke.
†Controlling for primary events and development of MA or ON, new diabetes with glycated hemoglobin Ն110% had a ‡Controlling for primary events and development of MA or ON, new diabetes with glycated hemoglobin Ն110% had a §Controlling for primary events and development of MA or ON, new diabetes with patient taking glucose-lowering therapy ࿣Controlling for primary events and development of MA or ON, new diabetes with elevated glycated hemoglobin or receiving treatment had a 0.52 RR (95% CI, 0.35-0.78).
␤-blockers (drugs that are associatedwith glucose intolerance or diabetes) Figure 2. Effect of Ramipril in Preventing Diabetes in Subgroups Defined at Randomization
during the study. However, the RR fordiabetes in the subgroup of individuals study was consistent with the overall re- sults (RR, 0.62; 95% CI, 0.43-0.90).
corded at baseline and at study end.
0.76 (8.10) kg in the control group.
These analyses indicate that ramipril re-duces the risk of new diagnosis of dia- plications of diabetes.7 Although the data 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, rela- 1884 JAMA, October 17, 2001—Vol 286, No. 15 (Reprinted)
2001 American Medical Association. All rights reserved.
Senior Scientist Award of the Medical Research Coun-cil of Canada and holds an Endowed Chair of the Heart ertheless, the results are plausible given tion or action.16,17 Several observations the clear statistical significance and con- REFERENCES
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cose transport activity in skeletal muscle of obese Zuckerrats. Metabolism. 1995;44:267-272.
Analysis and interpretation of data: Yusuf, Gerstein, 15. Vuorinen-Markkola H, Yki-Jarvinen H. Antihy-
flow and pancreatic ␤-cell perfusion by pertensive therapy with enalapril improves glucose stor- Drafting of the manuscript: Yusuf, Gerstein, Pogue.
age and insulin sensitivity in hypertensive patients with Critical revision of the manuscript for important in- non-insulin-dependent diabetes mellitus. Metabo- tellectual content: Yusuf, Gerstein, Hoogwerf, Bosch, 16. Henriksen EJ, Jacob S, Kinnick TR, Youngblood EB,
Statistical expertise: Pogue.
Schmit MB, Dietze GJ. ACE inhibition and glucose trans- Obtained funding: Yusuf, Gerstein.
port in insulin resistant muscle: roles of bradykinin and Administrative, technical, or material support: nitric oxide. Am J Physiol. 1999;277:R332-R336.
17. Fogari R, Zoppi A, Corradi L, Lazzari P, Mugellini
resistance in skeletal muscles,14,15 increase Study supervision: Yusuf, Wolffenbuttel, Zinman.
A, Lusardi P. Comparative effects of lisinopril and lo- Expertise in diabetes: Hoogwerf.
sartan on insulin sensitivity in the treatment of non- Funding/Support: The HOPE study was supported by
diabetic hypertensive patients. Br J Clin Pharmacol.
grants from the Medical Research Council of Canada, 18. Baron AD. Vascular reactivity. Am J Cardiol. 1999;
Heart and Stroke Foundation of Ontario, and by sev- atic insulin secretion. The increased insu- eral pharmaceutical companies: Aventis, Astra, Mon- 19. Torlone E, Rambotti AM, Perriello G, et al. ACE-
arch Pharmaceuticals, Vitamin E Manufacturers As- inhibition increases hepatic and extrahepatic sensitiv- sociation of North America, and NEGMA France.
ity to insulin in patients with type 2 (non-insulin- However, the study was independently conducted by dependent) diabetes mellitus and arterial hypertension.
the HOPE investigators. Dr Yusuf is supported by a Diabetologia. 1991;34:119-125.
2001 American Medical Association. All rights reserved.
(Reprinted) JAMA, October 17, 2001—Vol 286, No. 15 1885


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