Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Estrogen plus progestin reduced the incidence of diabetes in postmenopausal women with coronary heart disease

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ACP J Club. 2003 Sep-Oct;139:39. doi:10.7326/ACPJC-2003-139-2-039


Clinical Impact Ratings

GIM/FP/GP: 6 stars

Cardiology: 3 stars

Endocrinology: 6 stars


Source Citation

Kanaya AM, Herrington D, Vittinghoff E, et al. Glycemic effects of postmenopausal hormone therapy: the Heart and Estrogen/progestin Replacement Study. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2003;138:1-9. [PubMed ID: 12513038]


Abstract

Question

In postmenopausal women with coronary heart disease (CHD), does hormone replacement therapy (HRT) prevent an increase in fasting glucose level and reduce the incidence of diabetes in those at risk?

Design

Randomized (allocation concealed*), blinded (participants, investigators, and outcome assessors),* placebo-controlled trial with a mean follow-up of 4.1 years.

Setting

20 clinical centers in the United States.

Participants

2763 postmenopausal women < 80 years of age (mean age 67 y, 89% white) who had objectively documented CHD. Exclusion criteria included CHD event ≤ 6 months or sex hormone use ≤ 3 months before entry, serum triglyceride levels ≥ 3.39 mmol/L, fasting glucose levels ≥ 16.5 mmol/L, and uncontrolled hypertension. 2029 women (mean age 67 y, 91% white) without diabetes were followed for incident diabetes with a follow-up of 98%.

Intervention

Women were allocated to HRT consisting of conjugated estrogen, 0.625 mg plus medroxyprogesterone acetat 2.5 mg once daily (n = 1380, including 999 without diabetes), or placebo (n = 1383, including 1030 without diabetes).

Main outcome measures

Fasting glucose levels and incidence of diabetes (self-report of diabetes or fasting serum glucose level ≥ 6.9 mmol/L).

Main results

Analysis was by intention to treat. Increase in fasting glucose levels from baseline was lower in the HRT group than in the placebo group (P = 0.001) (Table). Cumulative incidence of diabetes was lower in the HRT group than in the placebo group (Table).

Conclusion

In postmenopausal women with coronary heart disease, hormone replacement therapy slowed increase in fasting glucose level and reduced the incidence of diabetes in those at risk.

*See Glossary.

Sources of funding: Faculty Development in General Internal Medicine and Wyeth-Ayerst Research.

For correspondence: Dr. A.M. Kanaya, University of California at San Francisco, San Francisco, CA, USA. E-mail alkak@itsa.ucsf.edu.


Table. Hormone replacement therapy (HRT) vs placebo in postmenopausal women with coronary heart disease at 4.1 years†

Outcomes HRT Placebo Difference between groups (95% CI)
Mean change (increase) From baseline in FSGL (mmo1/L) 0.028 0.266 −0.233 (−0.372 to −0.100)§
RRR (CI) NNT (CI)
Incidence of diabetes 6% 10% 35% (12 to 52) 31 (18 to 103)

†FSGL = fasting serum glucose level based on 2763 participants; incidence of diabetes is based on 2029 participants at risk. Other abbreviations defined in Glossary; RRR, NNT, and CI.
§Information provided by author.


Commentary

The study by Kanaya and colleagues showed that HRT reduced the risk for onset of diabetes by 35% in women with both normal and impaired fasting glucose at baseline. Other interventions that reduce the incidence of type 2 diabetes in patients with insulin resistance (without risking the small but measurable increase in cardiovascular events associated with HRT) do exist.

In the trial by the Diabetes Prevention Program Research Group (1), a 7% reduction in body weight in obese persons plus walking (30 min, 5 d per wk) reduced the risk for onset of diabetes by 58%. Trials using such weight loss drugs as sibutramine and orlistat have shown similar reductions in the onset of diabetes (2).

Drugs that directly reduce insulin resistance can also prevent the onset of type 2 diabetes. Such drugs include metformin, which reduced the incidence of diabetes by 31% in the trial by the Diabetes Prevention Program Research Group (1); troglitazone, a thiazolidinedione, which decreased the incidence of type 2 diabetes by 50% in high-risk Hispanic women (3); and acarbose, which reduced the risk for diabetes in participants with impaired glucose tolerance by 25% (4). Other drugs, including pravastatin (5), ramipril (6), and losartan (7), have been found to decrease the risk for type 2 diabetes.

Clearly HRT is not the method of choice to reduce the onset of type 2 diabetes. If pharmaceuticals are chosen rather than the more powerful lifestyle changes, one should choose drugs proven to decrease cardiovascular risk as well as type 2 diabetes. Such drugs include metformin, ramipril, losartan, and pravastatin.

Donald A. Smith, MD, MPH
Mount Sinai Medical Center
New York, New York, USA


References

1. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393−403. [PubMed ID: 11832527]

2. Gokcel A, Gumurdulu Y, Karakose H, et al. Evaluation of the safety and efficacy of sibutramine, orlistat and metformin in the treatment of obesity. Diabetes Obes Metab. 2002;4:49−55. [PubMed ID: 11874442]

3. Buchanan TA, Xiang AH, Peters RK, et al. 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;51:2796-803. [PubMed ID: 12196473]

4. Chiasson JL, Josse RG, Gomis R, et al. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet. 2002;359:2072−7. [PubMed ID: 12086760]

5. Freeman DJ, Norrie J, Sattar N, et al. Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study. Circulation. 2001;103:357−62. [PubMed ID: 11157685]

6. Dagenais GR, Yusuf S, Bourassa MG, et al. Effects of ramipril on coronary events in high-risk persons: results of the Heart Outcomes Prevention Evaluation Study. Circulation. 2001;104:522−6. [PubMed ID: 11479247]

7. Kjeldsen SE, Dahlof B, Devereux RB, et al. Effects of losartan on cardiovascular morbidity and mortality in patients with isolated systolic hypertension and left ventricular hypertrophy: a Losartan Intervention for Endpoint Reduction (LIFE) substudy. JAMA. 2002;288:1491−8. [PubMed ID: 12243636]