PROBLEM

3 Diabetes Risk after the Menopause

Case History

Ir-n A 54-year-old Afro-Caribbean woman is referred to you. She is two years post-

menopausal and type 2 diabetes was diagnosed eight months ago. Despite having visited the dietician three times since then, her body mass index remains high at 30 kg/m2. She takes atenolol 50 mg/day for hypertension, which is well controlled. Diabetes is treated by diet alone, and her glycosylated haemoglobin (HbA1c) is reasonable at 7.1%. Fasting cholesterol is 5.8 mmol/l and triglycerides 2.5 mmol/l. She has a strong family history of type 2 diabetes.

How would you manage her diabetes and hypertension?

Is her age and menopausal status relevant to her management?

Is her racial background important?

She wants to know whether she should consider hormone replacement therapy

Background

Compared with men, women are relatively protected from cardiovascular disease except when they are post-menopausal or they have diabetes. Sex steroids have important roles in regulating lipid metabolism, endothelial function, blood vessel tone and other aspects of vascular function. Menopause is associated with a relatively abrupt decrease in circulating oestrogen. There is no comparable process in men. Since the general population is aging, and women spend an increasing proportion of their life in an oestrogen-deficient state in which they are at risk of atherosclerotic disorders, management of cardiovascular risk in the peri- and post-menopausal periods is of particular importance.

The period of declining ovarian function leading up to the menopause, the peri-menopause, is associated with declining sex steroid levels and important alterations in body composition. Thus total and visceral adiposity increase, and bone mineral density decreases. The change in fat mass and distribution may relate to decreased lipolysis and increased activity of lipoprotein lipase. Weight gain around the menopause is greater in women from more deprived socio-economic backgrounds and in those who do not smoke, do not exercise regularly and have never used HRT. In a prospective 9-year study of women during the menopausal transition, Guthrie et aV demonstrated that mood changes and decreased quality of life appeared to contribute to the changes in body composition and cardiovascular risk profile around the menopause.

HRT is not currently recommended for prevention of cardiovascular disease. Although benefits in risk-markers have been documented, there is debate about which oestrogen, which progestogen, or which combination, and which route of administration. Set against the possibility of a marginal benefit in cardiovascular disease prevention, there is undoubtedly increased risk of thromboembolic events and breast cancer. Moreover, two important trials—the Women's Health Initiative (WHI) and the Hormone Estrogen-Progestin Replacement Study (HERS)—actually reported increased cardiac events in the short term. A recent large, Swedish study2 appears to confirm that oestrogen use can improve cardiovascular risk profile and there are now several lines of evidence that either oral or transdermal oestrogen may improve insulin sensitivity and slow the progress of the metabolic syndrome, thus retarding development of diabetes in those at risk.3

The impact of diabetes on cardiovascular risk is higher for women than it is for men. In a recent Finnish study,4 the event rate per 1000 patient-years was 11.6 for non-diabetic men and 1.8 for non-diabetic women, while comparable event rates for males and females with diabetes were 36.3 and 31.6, respectively. In the recent Study of Women's health Across the Nation (SWAN),5 differences between insulin sensitivity and beta cell function were compared in groups of pre- or peri-menopausal women from differing racial backgrounds. Insulin sensitivity was lower in African-Americans compared with other racial groups, while beta cell function was relatively preserved in this group. Thus measures to improve insulin sensitivity, including weight loss, should be the approach of choice in this group.

Recent Developments

1 Increased abdominal obesity in women is linked with insulin resistance and with markers of inflammation that predispose to ischaemic heart disease and other complications of obesity (Figure 3.1).6 Although visceral obesity does not account for all of the increased risk associated with the post-menopausal state, it is an important therapeutic target, and regular exercise goes a long way to ameliorate the fat accumulation and accompanying risk factors.7

2 Attempts to improve health and deal with cardiovascular risk factors should not wait until the menopause. Recent data from the Nurses Health Study8 demonstrate that

Fig. 3.1 Contributions of visceral adipose tissue (VAT) and insulin resistance (IR) to risk of diabetes. Postmenopausal women were screened for diabetes using an oral glucose tolerance test. Diabetes was particularly prevalent in women who had both increased visceral adipose tissue and insulin resistance. *P<0.0001. Source: Piché etal. 2005.6

Fig. 3.1 Contributions of visceral adipose tissue (VAT) and insulin resistance (IR) to risk of diabetes. Postmenopausal women were screened for diabetes using an oral glucose tolerance test. Diabetes was particularly prevalent in women who had both increased visceral adipose tissue and insulin resistance. *P<0.0001. Source: Piché etal. 2005.6

increasing obesity in the pre-menopause is associated with increased levels of inflammatory markers (tumour necrosis factor-receptor, interleukin-6 and C-reactive protein), and these markers are predictive of the development of diabetes.

3 Micronutrient status also changes around the time of the menopause and there is considerable evidence now that some of these changes may relate to risk of diabetes and cardiovascular disease. Thus, decreased magnesium levels are more common after the menopause, and predispose to insulin resistance and the metabolic syndrome.9 Increased iron stores are associated with increased cardiovascular risk factors,10 and this may be a factor in the peri-menopausal period for many women.11

Conclusion

|.—~J This woman is at increased risk on the grounds of age, ethnicity, menopausal status and r^J the fact that she has diabetes. She should try hard with diet and exercise to manage her weight and glycaemic control (Figure 3.2). Given her imperfect glycaemic control at present, she might consider metformin to help preserve her beta cell function long term. Her hypertension is well controlled but atenolol might not be the ideal agent given her weight and imperfect glycaemic control. An angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker might be preferable. HRT is not routinely recommended for cardiovascular disease prevention but patient choice is important, and she may consider this if she is experiencing menopausal symptoms. She may benefit from aspirin treatment (see Chapter 33).

Fig. 3.2 Figure suggests a scheme for managing cardiovascular risk in a patient approaching, or soon after, the menopause. HRT = hormone replacement therapy.

Further Reading

Climacteric 2004; 7:375-89.

2 Shakir YA, Samsioe G, Nyberg P, Lidfeldt J, Nerbrand C. Cardiovascular risk factors in middle-aged women and the association with use of hormone therapy: results from a population-based study of Swedish women. The Women's Health in the Lund Area (WHILA) Study. Climacteric 2004; 7:274-83.

3 Rossi R, Origliani G, Modena MG. Transdermal 17-beta-estradiol and risk of developing type 2 diabetes in a population of healthy, nonobese postmenopausal women. Diabetes Care 2004; 27: 645-9.

4 Juutilainen A, Kortelainen S, Lehto S, Rónnemaa T, Pyórala K, Laakso M. Gender difference in the impact of type 2 diabetes on coronary heart disease risk. Diabetes Care 2004; 27:2898-904.

5 Torrens JI, Skurnick J, Davidow AL, Korenman SG, Santoro N, Soto-Greene M, Lasser N, Weiss G. Ethnic differences in insulin sensitivity and beta-cell function in premenopausal or early perimenopausal women without diabetes: the Study of Women's health Across the Nation (SWAN). Diabetes Care2004; 27:354-61.

6 Piché ME,Weisnagel SJ, Corneau L,Nadeau A, Bergeron J, Lemieux S. Contribution of abdominal visceral obesity and insulin resistance to the cardiovascular risk profile of postmenopausal women. Diabetes 2005; 54:770-7.

7 Holcomb CA, Heim DL, Loughin TM. Physical activity minimizes the association of body fatness with abdominal obesity in white, premenopausal women: results from the Third National Health and Nutrition Examination Survey. J Am Diet Assoc 2004; 104:1859-62.

S3 1

Guthrie JR, Dennerstein L, Taffe JR, Lehert P, Burger HG. The menopausal transition: a 9-year prospective population-based study. The Melbourne Women's Midlife Health Project.

8 Hu FB, Meigs JB, Li TY, Rifai N, Manson JE. Inflammatory markers and risk of developing type 2 diabetes in women. Diabetes 2004; 53:693-700.

9 Laires MJ, Moreira H,Monteiro CP, Sandinha L, Limao F,Veiga L, Goncalves A, Ferreira A, Bicho M. Magnesium, insulin resistance and body composition in healthy postmenopausal women. J Am Coll Nutr2004; 23:510S-513S.

10 Jehn M, Clark JM, Guallar E. Serum ferritin and risk of the metabolic syndrome in U.S. adults. Diabetes Care2004; 27:2422-8.

11 Masse PG, Dosy J, Cole DEC, Evroski J, Allard J, D'Astous M. Is serum ferritin an additional cardiovascular risk factor for all postmenopausal women? Ann Nutr Metab 2004; 48:381-9.

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