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ACE-Inhibitors and new-onset diabetes

An article from the e-journal of the ESC Council for Cardiology Practice

Results from the DREAM trial indicate that ACE-I ramipril at a maximal dose of 15mg/day cannot significantly reduce the incidence of diabetes and death in non-diabetic patients. Patients on ACE-I due to hypertension, congestive heart failure, or high-risk for cardiovascular events may however potentially benefit from a positive effect on their glucose metabolism.

Prevention


1 - Epidemiology

Type 2 diabetes is a major risk factor for cardiovascular mortality and morbidity. The prevalence of diabetes is increasing worldwide causing tremendous social economic burden to patients and health care providers.

Effective strategies for the prevention of diabetes include diet and exercise in order to reduce insulin-resistant fatty tissue and improve insulin sensitivity 1.

Randomised trials have convincingly demonstrated that lifestyle changes are associated with a convincing reduction in the progression to diabetes 1. However, the implementation of lifestyle modifications is challenging and therefore, new strategies for the prevention of diabetes are warranted.

2 - Preventive Treatment

Peroxisome-proliferator-activated receptor (PPAR) agonists which are known to improve insulin sensitivity and metformin have been shown to reduce the incidence of diabetes 2.

In addition, various clinical trials in more than 66,608 patients with coronary artery disease, hypertension, or heart failure have demonstrated a delay and/or prevention of new-onset diabetes with substances directed to inhibit the renin-angiotensin system (RAS) 3-6. However, in all these studies, the incidence of diabetes was not the primary endpoint and in most of the studies results were obtained from post-hoc analyses. In addition, glucose levels were not systematically reviewed. Since inhibition of the RAS is an effective and widely used method for reducing mortality and morbidity in patients with cardiovascular disease, additional positive effects on plasma glucose levels would be intriguing.

3 - The Dream Trial

In order to further elucidate the effect of inhibitors of the RAS and the incidence of diabetes the Diabetes Reduction Assessment of Ramipril and Rosiglitazone Medications (DREAM) trial was performed 7.

5269 patients without cardiovascular disease were recruited to this double blind, randomized clinical trial with a two-by-two factorial design.

Table 1  DREAM trial : Main inclusion criteria

  • Impaired fasting glucose levels of at least 110mg/dl (6.1mmol/l) but less than 126mg/dl (7.0mmol/l)
  • or
  • Impaired glucose tolerance 2 hours after an oral glucose load of  at least 140mg/dl (7.8mmol/l) but less than 200mg/dl (11.1mmol/l)

Eligible patients were randomized to receive the angiotensin converting enzyme inhibitor (ACE-I) ramipril or placebo (and rosiglitazone or placebo).

Ramipril was started at a dose of 5mg/day for 2 months, increased to 10mg/d and finally 15 mg/d after 2 and 12 months, respectively.

Patients were followed for a median of 3 years.  At the 2-year and the final study visits, a glucose tolerance test was performed. The primary endpoint of the study was a new onset of diabetes or death. Secondary outcomes included a composite endpoint of cardiac and renal events, glucose levels and regression to normal glucose levels. Patient groups did not differ in their baseline characteristics.

At the end of the study, about 70% of the patients were still taking their medication and this was similar in both groups. Ramipril effectively reduced blood pressure (8.2mmHg vs 3.9mmHg in mean systolic blood pressure) but had no effect on creatinine levels. With ramipril, slightly fewer patients met the primary endpoint criteria of diabetes or death but the difference with placebo was non significant. (table 2). 

Table 2 :  DREAM trial : Study results

 
 
 
Ramipril
N=2623
Placebo
N=2623
Hazard ratio
95% CI
P-value
Primary Enpoint Diabetes and Death    475 (18.1%) 517 (19.5%) 0.91 (0.81 – 1.03) 0.015
Diabetes                                       449 (17.1)  489 (18.5%) 0.91 (0.80 – 1.03)  
Death                                           31 (1.2%)  32 (1.2%) 0.98 (0.60 – 1.60)  
Regression to Normoglycemia 1116 (42.5%) 1012 (38.2%) 1.16 (1.07 – 1.27)  0.001

475 patients (18.1%) met the criteria of the primary endpoint diabetes or death in the ramipril group vs. 517 patients (19.5%) in the placebo treated group (with 31 and 32 deaths, respectively). 17.1% of patients on ACE-I treatment developed diabetes vs. 18.5% in the placebo group. This difference was not statistically significant (p=0.15).

Regression analysis correcting for the use of drugs known to increase the incidence of diabetes (e.g. diuretics, betablockers) or angiotensin-receptor blockers (ARB) did not change the results for the primary endpoint.

Median fasting plasma glucose levels were not different between the ramipril and placebo. However, the median glucose level, two hours after load, was significantly reduced in the ramipril group compared to control; also the regression to normal glucose levels was enhanced with ramipril.

The two-by-two factorial design additionally evaluated the effect of rosiglitazone on the incidence of diabetes and death. These results published previously demonstrated a significant reduction in the incidence of death or diabetes (Hazard ratio 0.40; 95% confidence interval 0.35-0.46; p<0.001) in rosiglitazone treated patients 8. There was no significant interaction detectable between rosiglitazone and ramipril with respect to the primary endpoint.

4 - Conclusion

The DREAM trial 7 demonstrates that the ACE-I ramipril at a maximal dose of 15mg/day cannot significantly reduce the incidence of diabetes and death in non-diabetic patients without cardiovascular disease and impaired fasting glucose or glucose tolerance. The observation that patients receiving ramipril showed a higher regression to normoglycemia and significantly lower 2 hour glucose plasma levels after an oral glucose load suggests a beneficial role of ACE-inhibition in pre-diabetic patients.

Why are the results of the DREAM trial so discrepant to the previously published studies? Potentially various factors have to be taken into account. None of the published studies had a primary endpoint which was defined as the incidence of new-onset diabetes. None of the studies consistently measured glucose levels or performed oral glucose tolerance tests. Different patient groups were evaluated including patients with coronary artery disease, hypertension, and heart failure. In contrast the DREAM trial investigated patients without any evidence of cardiovascular disease. Meta-analysis suggest the incidence of diabetes may be more important in higher risk patients for type 2 diabetes. Unfortunately, subgroup analyses stratifying this population for impaired fasting glucose versus normal glucose levels do not exist 3.

Taken together ramipril is currently not the drug of choice for the prevention of type 2 diabetes 7;9. Patients already on ACE-I due to hypertension, congestive heart failure, or high-risk for cardiovascular events may potentially benefit from a positive effect on glucose metabolism. Further studies such as the ONTARGET trial may provide deeper insights into the role of RAS inhibition and new-onset diabetes.

 The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

References


1.  Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.

2.  Buchanan TA, Xiang AH, Peters RK, Kjos SL, Marroquin A, Goico J, Ochoa C, Tan S, Berkowitz K, Hodis HN, Azen SP. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women. Diabetes. 2002;51:2796-2803.

3.  Gillespie EL, White CM, Kardas M, Lindberg M, Coleman CI. The impact of ACE inhibitors or angiotensin II type 1 receptor blockers on the development of new-onset type 2 diabetes. Diabetes Care. 2005;28:2261-2266.


4.  Jandeleit-Dahm KA, Tikellis C, Reid CM, Johnston CI, Cooper ME. Why blockade of the renin-angiotensin system reduces the incidence of new-onset diabetes. J Hypertens. 2005;23:463-473.

5.  Mancia G, Grassi G, Zanchetti A. New-onset diabetes and antihypertensive drugs. J Hypertens. 2006;24:3-10.

6.  Pahor M, Psaty BM, Alderman MH, Applegate WB, Williamson JD, Furberg CD. Therapeutic benefits of ACE inhibitors and other antihypertensive drugs in patients with type 2 diabetes. Diabetes Care. 2000;23:888-892.

7.   Effect of Ramipril on the Incidence of Diabetes. N Engl J Med. 2006;355, published online.

8.  DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators; Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, Dinccag N, Hanefeld M, Hoogwerf B, Laakso M, Mohan V, Shaw J, Zinman B, Holman RR.
Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomized controlled trial. Lancet. 2006;368:1096-1105. 

9.  Ingelfinger JR, Solomon CG. Angiotensin-Converting-Enzyme Inhibitors for Impaired Glucose Tolerance -- Is There Still Hope? N Engl J Med. 2006;355, published online.
.

 

VolumeNumber:

Vol5 N°05

Notes to editor


Dr N. Werner* and Prof. M. Böhm**
* Bonn, Germany, and ** Homburg-Saar, Germany
**Board member of the Heart Failure Association of the ESC

Nikos Werner, MD
Medizinische Klinik und Poliklinik II
Universitätsklinikum Bonn
Sigmund-Freud-Str. 25
53105 Bonn
phone +49-228-287-15217/15218
fax +49-228-287-16423
Email: nwerner@uni-bonn.de

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.