Why I would encourage my wife totake HRT if she had type 2 diabetes

Geoff Gill*

ABSTRACTPost-menopausal type 2 diabetic patients are at enormous risk of increased mortality and morbidity from coronaryartery disease (CAD). Attempts to modify contributory risk factors are likely to be only partially successful, and anyother bene®cial strategy should be vigorously adopted. Such a potential strategy is hormone (oestrogen) replacementtherapy (HRT). Though a prospective randomised controlled trial of HRT for CAD primary prevention in type 2diabetic females is lacking, there is considerable supportive evidence for its use, particularly of modern preparations.HRT should be seriously considered as a preventive strategy in this very high risk group of patients. Copyright # 2000John Wiley & Sons, Ltd.

Practical Diabetes Int 2000: 17(5); 161±162

KEY WORDSdiabetes mellitus; type 2 diabetes; menopause; HRT; coronary artery disease

The major threat to the patient withtype 2 diabetes is coronary heartdisease (CHD). It overwhelms allother complications as the majorthreat to health and life in this typeof diabetes1. In both diabetic andnon-diabetic populations, womenhave considerable protection againstCHD until the menopause ± there-after the protection is lost and risksrapidly equate to those of men. Thereis evidence from diabetic cohort stu-dies that coronary risk factors andCHD rates in post-menopausal type 2diabetic females may actually be in

excess of rates in age-matched type 2diabetic males2. For example, in onestudy of 130 post-menopausal type 2diabetic women (mean age 67 years)compared with 127 type 2 diabeticmen (mean age 65 years), 38% of thewomen were on anti-anginal medica-tion compared with 26% of the men( p<0.05).

Adverse CHD events in suchwomen are not surprising when theirrisk factor pro®le is examined indetail. In the same study as mentionedabove, the women were signi®cantlymore obese (body mass index 31.0versus 28.7, p<0.005) and hadpoorer glycaemic control (HbA1c

8.1% versus 7.5%, p<0.01). Lipidpro®les were particularly adverse ±total cholesterol was higher inwomen (6.1 versus 5.3 mmol/l,p<0.0001), as were triglycerides (2.5versus 2.0 mmol/l, p<0.05) and LDLcholesterol (3.8 versus 3.4 mmol/l,p<0.005). Hypertension was morecommon (43% versus 33%) thoughnot signi®cantly so, and smoking wasthe only risk factor less frequent in thewomen (21% versus 26%). Current

smoking trends suggest that even thisbene®t may soon be lost.

The vast majority of female type 2diabetic patients are post-menopausal(most have indeed ended menstrua-tion at diagnosis). The adverse riskfactors in these women have now beenwidely observed elsewhere3,4. Theyexplain why women with type 2diabetes have been found to havethree times the risk of myocardialinfarction (MI) compared with menin the Framingham Study5. The samestudy showed a sixfold increase in therisk of sudden cardiac death in femalecompared with male diabetic patients.

What can be done about thishugely increased CHD risk? As diabe-tologists, we have singularly failed topersuade our type 2 patients to loseweight and stop smoking. We do havea limited ability to improve glycaemiccontrol, but even with our currenttreatment strategies there is an inexor-able tendency for patients' glycaemiccontrol to steadily deteriorate as theyears go by. Also, the UKPDS did notgive a clear indication that `tight'HbA1c control improved macrovascu-

Geoff Gill, MA, MSc, MD, FRCP, Reader in

Medicine, Diabetes/Endocrine Unit,

University Hospital Aintree, Liverpool

L9 1AE, UK

*Correspondence to:

Dr Geoff Gill

MA, MSc, MD, FRCP, Reader in Medicine,

Diabetes/Endocrine Unit, University Hospital

Aintree, Liverpool L9 1AE, UK.

Submitted: 15 February 2000

Accepted: 17 April 2000

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Pract Diab Int July/August 2000 Vol. 17 No. 5 Copyright # 2000 John Wiley & Sons, Ltd. 161

lar disease occurrence and outcome6.Hypertension is certainly treatable,but it is a stronger risk factor forstroke than CHD. Lipid controlwould seem to be our best option.We can lower total and LDL choles-terol effectively with statin drugs now,but normalising hypertriglyceridaemiaand raising HDL cholesterol levels ismore dif®cult. The relative impor-tance of LDL cholesterol and trigly-ceride in the genesis of diabeticmacroangiopathy remains in doubthowever, and it is uncertain whether®brates, statins or combinations ofboth should be our ®rst-line ther-apy for primary CHD preventionin dyslipidaemic type 2 diabeticpatients7. Aspirin may be useful, butso far there is only an evidence-basefor primary CHD prevention indiabetic patients with multiple riskfactors8 ± though perhaps we shouldconsider the post-menopausal type 2diabetic patients exactly in thiscategory?

We come to hormone-replacementtherapy (HRT) with oestrogen as apossible modality for CHD reductionin these very high-risk patients. Pre-vious studies have demonstrated sig-ni®cant CHD reduction associatedwith HRT use in general cohorts9,10.The mechanism is uncertain but itmay be lipid mediated. In particular,the use of natural oestrogens withnon-androgenic progestogens leads toreductions in LDL and increases inHDL cholesterol levels. Additionally,it is now accepted that HRT has nodeleterous effect on glycaemic controlor blood pressure, as was previouslybelieved11,12. Newer preparations,such as transdermal 17b-oestradial,may have even more bene®cial effects,including reduction of triglyceridelevels.

So far, the argument for HRT inpost-menopausal type 2 diabetic

women would seem to be persuasive.To be fair however, the epidemiologi-cal studies concerning HRT andCHD have been observational ratherthan properly designed randomisedprospective blinded trials. The onetrial available that was prospective andrandomised is the `HERS' trial13, andit is much quoted by the `anti-HRT'lobby, since it was essentially negative.The HERS trial however was asecondary prevention study ± all thepatients had coronary artery disease.Though CHD is common in post-menopausal type 2 diabetic females, itis not prevalent in the majority, so thestudy does not address the major issueof primary prevention. Also, it wasnot an exclusively diabetic study,which is what is really needed. Itshould also be noted that though thestudy was negative overall, it did showa trend towards CHD reduction at theend of the period of observation (5years). A longer time period may beneeded to demonstrate signi®cantCHD reduction. Finally, the HRTpreparation used in this study wasrelatively `old fashioned', and as dis-cussed above this may be of relevanceto the lipid status of HRT recipients.

What is needed, of course, is along-term prospective randomisedtrial of HRT in a diabetic cohortonly. That is going to take a longtime, and until we have such informa-tion, diabetologists must use whatindirect evidence is available to them.The absolute risks of HRT are verysmall, but the potential bene®ts high.Knowledge of HRT bene®ts is lowamongst diabetic women12, andgeneral practitioners under-prescribeHRT to diabetic compared with non-diabetic women14. The potential ben-e®ts of HRT need to be made morewidely available to diabetic femalepatients and their doctors. This treat-ment should become one of our

weapons against the scourge of CHDin post-menopausal diabetic women.As was stated in a 1998 leading article,`. . .we should be actively encouragingpostmenopausal women with diabetesto take HRT'11.

References1. Zimmet P, Alberti KGMM. The changing face

of macrovascular disease in non-insulin depen-dent diabetes. Lancet 1997; 350 (Suppl. 1) 1±4.

2. Ismail AA, Gill GV. Coronary risk factors inpost-menopausal type 2 diabetic patients: a casefor oestrogen replacement therapy. PracticalDiabetes Int 1999; 16: 131±133.

3. Laakso M, Letho S, Pentilal P, Pyrola K. Lipidsand lipoproteins predicting coronary heart dis-ease mortality and morbidity in patients withnon-insulin dependent diabetes. Circulation1993; 88: 1421±1430.

4. Brand F, Abbott R, Kannel W. Diabetes,intermittent claudication, and risk of cardio-vascular events. The Framingham Study. Diabetes1989; 38: 504±509.

5. Annal WB, McGee DL. Diabetes and glucosetolerance as risk factors for cardiovascular disease:the Framingham Study. Diabetes Care 1979; 2:120±126.

6. UK Prospective Diabetes Study (UKPDS)Group. Intensive blood-glucose control withsulphonylureas or insulin compared with con-ventional treatment and risk of complications inpatients with type 2 diabetes (UKPDS 33).Lancet 1998; 352: 837±853.

7. Durrington PN. Diabetic dyslipidaemia. InClinical Endocrinology and Metabolism ± Frontiersin Clinical Diabetology, Gill GV, MacFarlane IA(eds). London: Bailliere-Tindall, 1999; 265±278.

8. Pozzilli P, Leslie RDG. Aspirin and diabetes.Practical Diabetes Int 1999; 16: 259±261.

9. Dallongeville J, Merecaux N, Isores D, et al.Multiple coronary heart disease factors areassociated with the menopause and in¯uencedby substitutive hormonal therapy in a cohort ofFrench women. Atherosclerosis 1995; 118:123±133.

10. Stevenson JC. Mechanisms whereby oestrogensin¯uence arterial health. Eur J Obstet GynaecolReprod Biol 1996; 65: 39±42.

11. Leatherdale B. HRT in diabetes: time for action.Practical Diabetes Int 1998; 15: 70.

12. Davies PH, Barnett AH. Hormone replacementtherapy in women with diabetes mellitus: asurvey of knowledge of risks and bene®ts.Practical Diabetes Int 1998; 15: 78±81.

13. Hulley S, Grady D, Bush T, et al. Randomisedtrial of estrogen for secondary prevention ofcoronary heart disease in postmenopausalwomen. JAMA 1998; 280: 605±613.

14. Laurenson RA, Newson RB, Feher MD. Dowomen with diabetes receive hormone replace-ment therapy? Practical Diabetes Int 1998; 15:71±72.

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Why I would encourage my wife to take HRT

162 Pract Diab Int July/August 2000 Vol. 17 No. 5 Copyright # 2000 John Wiley & Sons, Ltd.