INTRODUCTION
The pandemic of type 2 diabetes mellitus (T2DM) is probably the greatest threat to the well-being of humans and continues unabated affecting men and women alike. United States (US) data from the 2011 National Diabetes Fact Sheet puts the number of American women with diabetes at 12.6 million, affecting 10.8% of all women aged 20 years or older. Management of hyperglycemia has traditionally occupied center stage in the management of diabetes and rightly so as several trials have evidenced its role in significantly reducing morbidity and mortality. Although it seems that there is not any apparent difference in managing hyperglycemia between the sexes, there are in fact a number of practical issues which separate them. Medical management of hyperglycemia in women with T2DM throws up interesting challenges on account of occurrence of unique events in a woman's lifecycle which are exclusive to this gender. Management may differ on account of coexistence of polycystic ovarian syndrome (PCOS), a woman getting pregnant, and the postmenopausal state.
American Diabetes Association-European Association for the study of Diabetes POSITION STATEMENT1
Lowering glycosylated hemoglobin (HbA1c) to less than 7.0% is recommended in most patients to reduce the incidence of microvascular disease. More stringent HbA1c targets (6.0–6.5%) might be considered in selected patients [with short disease duration, long life expectancy, no significant cardiovascular disease (CVD)] if this can be achieved without significant hypoglycemia or other adverse effects of treatment. On the other hand, less stringent HbA1c goals of 7.5–8.0% or even slightly higher are appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced complications, extensive comorbid conditions, and those in whom the target is difficult to attain despite intensive self-management education, repeated counseling, and effective doses of multiple glucose-lowering agents, including insulin.4
Choice of specific antihyperglycemic agents is predicated on their effectiveness in lowering glucose, extra glycemic effects that may reduce long-term complications (including effects on cardiovascular risk factors and events), safety profiles, tolerability, ease of use, and expense. With rare exceptions, lifestyle interventions are a part and parcel of treatment for every patient. In addition to the beneficial effects of weight loss on glycemia, dietary modification and exercise improves coincident cardiovascular risk factors, such as elevated blood pressure and atherogenic lipid profiles, and ameliorates other consequences of obesity.
Metformin therapy should be initiated concurrently with lifestyle intervention at diagnosis in almost all patients in the absence of specific contraindications. However, highly motivated patients with HbA1c already near target (<7.5%) could be given the opportunity to engage in lifestyle change alone for a period of 3–6 months before embarking on metformin. Metformin therapy is well validated and there is substantial evidence regarding its beneficial effect on glycemia, absence of weight gain or hypoglycemia, generally low level of side effects, high level of acceptance, and relatively low cost. Metformin is started at a low dose (500 mg taken once or twice per day with meals or 850 mg once per day) and after 5–7 days, if gastrointestinal side effects have not occurred, dose is increased to 850 mg, or two 500 mg tablets, twice per day (medication to be taken before breakfast and/or dinner). If gastrointestinal side effects appear with advanced doses, it should be decreased to previous lower dose with an attempt at advancement made on a later occasion. The maximum effective dose can be up to 1,000 mg twice per day although modestly greater effectiveness has been observed with doses up to about 2,500 mg/day.
If monotherapy alone does not achieve/maintain an HbA1c target over 3 months, a second oral agent, a glucagon-like peptide-1 (GLP-1) receptor agonist, or basal insulin should be added. The present position statement emphasizes individualized treatment using a patient-centered approach which will also dictate the choice of antihyperglycemic agent. If necessary, a third noninsulin drug can be added to control hyperglycemia although insulin is the preferred agent with higher degrees of hyperglycemia (≥8.5%). Patients with a high baseline HbA1c (≥9.0%) may be put directly on a combination of two noninsulin agents or with insulin itself. If a patient presents with significant hyperglycemic symptoms and/or has dramatically elevated plasma glucose concentrations (300–350 mg/dL) or HbA1c more than or equal to 10.0–12.0%, insulin therapy should be started from the outset.
Regarding the choice of agents, risk of bone fractures is a specific concern in postmenopausal women which makes pioglitazone a less preferred agent in this group, particularly in those with established osteoporosis.
POLYCYSTIC OVARIAN SYNDROME
Adolescents and adult women with PCOS are at 5- to 10-fold increased risk for developing impaired glucose tolerance (IGT) and T2DM.2 The overall prevalence 5of IGT among US women and adolescents with PCOS is 30–35%, and 3–10% have T2DM.3 Nonobese women with PCOS have a 10–15% prevalence of IGT and a 1–2% prevalence of T2DM.3 A fasting and a 2-hour glucose level using a 75 g oral glucose load should be done in women with PCOS and Hb1Ac testing considered only when a patient is unable or unwilling to complete an oral glucose tolerance test (OGTT). Use of metformin is recommended in women with PCOS who have T2DM or IGT who fail lifestyle modification and as second line therapy for women with PCOS with menstrual irregularity who cannot take or do not tolerate hormonal contraceptives.4 Metformin leads to improvement in menstrual cyclicity and ovulation rates in women with PCOS. The routine use of metformin during pregnancy in women with PCOS is unwarranted, although it may be useful to treat gestational diabetes. There is no effect of metformin on abortion rate, prevalence of preeclampsia, preterm delivery, or gestational DM in women with PCOS treated with metformin during pregnancy. Metformin should be discontinued in PCOS patients with a positive pregnancy test, given the lack of benefit associated with its routine use during the same.4 Use of metformin in adolescents with PCOS is associated with improvements in hyperandrogenemia, ovulation, and dyslipidemia and one may maintain a lower threshold for initiating metformin in this population compared to adults.5
PREGNANCY
Maternal hyperglycemia in the first few weeks of pregnancy increases the risk of fetal malformations, spontaneous abortions, and perinatal mortality as well as increased risk of worsening of diabetic retinopathy and nephropathy.6 Therefore, women with diabetes should receive adequate preconception counseling and strive to achieve blood glucose and HbA1c levels as close to normal as possible without undue hypoglycemia. Risk increases compared to the general childbearing population from an HbA1c as low as 6.4% along a continuum. There is a stable degree of anomaly risk of 3.9–5.0% with a periconceptional HbA1c of up to 10.4%, but increases to 10.9% if the HbA1C is 10.4% or higher.7 Multiple daily doses of insulin or insulin pump therapy is preferred to split-dose, premixed insulin therapy, as it allows achievement of target preconceptional levels more rapidly and, in the event of pregnancy allows for easy flexibility and precise adjustment of therapy.8 Insulin pump therapy is considered only when basal bolus therapy fails to achieve desired glycemic control. Rapid-acting insulin analogs are preferred over regular insulin in insulin-treated women wishing to conceive on account of better postprandial glycemia control and lower hypoglycemia risk.8 Women with diabetes successfully using the long-acting insulin analogs insulin detemir or insulin glargine preconceptionally may continue with this therapy before and then during pregnancy although the lack of US Food and Drug Administration (FDA) approval and theoretical mitogenicity of the latter need to be discussed with the patient. Any change in 6the insulin regime should be made well in advance of withdrawing contraceptive measures.8
All pregnant women should be tested with a fasting plasma glucose, HbA1c, or an untimed random plasma glucose at the first prenatal visit (before 13 weeks gestation, or as soon as possible thereafter). In the case of overt diabetes, but not gestational diabetes, a second test (either a fasting plasma glucose, untimed random plasma glucose, HbA1c, or OGTT) must be performed in the absence of symptoms of hyperglycemia and found to be abnormal on another day to confirm the diagnosis. Pregnant women not previously identified with overt diabetes or gestational diabetes should be tested for gestational diabetes by having a 2-hour, 75 g OGTT performed at 24–28 weeks gestation and diagnosed based on the cut-offs in table 1.8
Pregnant women with diabetes should be treated to achieve a preprandial blood glucose less than or equal to 95 mg/dL or if possible less than or equal to 90 mg/dL if the same can be safely achieved without undue hypoglycemia. Blood glucose levels 1 hour after the start of a meal should be less than or equal to 140 mg/dL and less than or equal to 120 mg/dL 2 hours after the start of a meal provided they can be achieved without undue hypoglycemia. Pregnant women with overt diabetes should strive to achieve an HbA1c less than or equal to 7% and if possible less than or equal to 6.5%.8 Self-monitoring of blood glucose in all pregnant women with diabetes before and either 1 or 2 hours after the start of each meal and, as indicated, at bedtime and during the night helps in monitoring treatment. Continuous glucose monitoring is an option in those in whom the above is insufficient to achieve targets.8 An important fact that needs to be conveyed to the mother is that maternal hypoglycemia has no harmful effect on the fetus.9
Medical nutrition therapy and exercise are recommended for all pregnant women with overt or gestational diabetes to achieve appropriate weight gain (Table 2) with the reassurance that limiting maternal weight gain is not associated with a decrease in fetal birth weight.10 Obese women with overt or gestational diabetes should reduce their calorie intake by approximately one-third (compared with their usual intake before pregnancy) while maintaining a minimum intake of 1,600–1,800 kcal/day.8 Calorie restriction is not necessary for underweight or normal-weight women with these conditions as long as fetal growth and weight gain targets are being met. Carbohydrate intake should be limited to 35–45% of 7total calories, distributed in three small- to moderate-sized meals and 2–4 snacks including an evening snack.8 Initial therapy for gestational diabetes consists of medical nutrition therapy and daily moderate exercise of 30 minutes or more. A useful exercise regimen consists of walking briskly for 10 minutes thrice daily 30 minutes after meals.
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Insulin is the agent of choice for treating hyperglycemia in pregnancy with the guiding principles being same as that of preconceptional use. All types of insulin are suitable for use in pregnancy with the exceptions of insulin degludec and insulin glulisine. Glibenclamide is a suitable alternative to insulin therapy for glycemic control in women with gestational diabetes who fail to achieve sufficient glycemic control after a 1-week trial of medical nutrition therapy and exercise except for those women with a diagnosis of gestational diabetes before 25 weeks gestation and for those women with fasting plasma glucose levels more than 110 mg/dL, in which case insulin therapy is preferred.8 Metformin therapy should be used for glycemic control only for those women with gestational diabetes who do not have satisfactory glycemic control despite medical nutrition therapy and who refuse or cannot use insulin or glyburide and are not in the first trimester.8 Gilbenclamide, on account of its high protein binding, crosses the placenta negligibly while metformin crosses the placenta freely but is not deleterious to the fetus.11,12 The use of other oral antidiabetic agents during pregnancy is contraindicated.
Elevated maternal blood glucose during labor and delivery increases the risk of neonatal hypoglycemia and fetal distress as well as birth asphyxia and need to be maintained between 72 mg/dL and 126 mg/dL usually with a glucose potassium insulin infusion.8,13
Women with gestational diabetes should have fasting plasma glucose measured or fasting capillary blood glucose self-monitored for 24–72 hours after delivery to rule out ongoing hyperglycemia. A 2-hour, 75-g OGTT should be undertaken 6–12 weeks after delivery in women with gestational diabetes to rule out prediabetes or diabetes and thereafter repeated periodically. In the absence of overt diabetes, all women with gestational diabetes should have antidiabetic drugs discontinued following delivery but should follow lifestyle modification advice.8
Breastfeeding women with overt diabetes successfully using metformin or glyburide therapy during pregnancy should continue to use these medications, 8and when necessary, during breastfeeding.8 Glipizide can also be used during breastfeeding as it does not enter breast milk significantly and of course, there is no contraindication at all to the use of insulin.8 Breastfeeding is beneficial for both the mother and infant in reducing the future risk of diabetes.14
MENOPAUSE
Estrogen decreases lipoprotein lipase activity and increases hormone sensitive lipase and lipolytic effects of epinephrine besides acting on the hypothalamus to decrease feeding. This effect is lost in menopause predisposing to obesity and leading to an increased risk of the metabolic syndrome and T2DM.15 Postmenopausal women are also at increased risk of developing CVD due to the loss of protective effect of estrogen. Follow-up data from the United Kingdom Prospective Diabetes Study (UKPDS) has shown that intensive glycemic control early in the course of diabetes has long standing benefits on both macrovascular and microvascular complications.16 Put into the present context, this makes intensive management of hyperglycemia in new onset diabetes in postmenopausal women all the more important. The propensity of pioglitazone to increase risk of distal limb fractures restricts their use in postmenopausal women who are already predisposed to osteoporosis.17
WEIGHT GAIN
Weight gain with certain diabetic therapies like sulfonylureas, pioglitazone, and insulin may be bothersome for certain women with T2DM and there are anecdotal reports of women cutting back on insulin doses to avoid gaining weight. Women are naturally more inclined to gain weight compared to men on account of their hormonal makeup and weight reducing or neutral antidiabetic therapies like incretin mimetics, dipeptidyl peptidase 4 inhibitors, metformin, and a glucosidase inhibitors may offer special benefits in this regard.
Although the pathophysiology of T2DM is similar in both genders, its treatment in women is different in certain respects on account of conditions which are an exclusively feminine. Several factors as discussed in this chapter need to be taken into consideration to deliver optimal medical management of hyperglycemia in women with T2DM and enable them to lead healthy and productive lives.
REFERENCES
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- Ehrmann DA, Barnes RB, Rosenfield RL, Cavaghan MK, Imperial J. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care. 1999;22:141–6.
- Legro RS, Arslanian SA, Ehrmann DA, Hoeger KM, Murad MH, Pasquali R, et al. Diagnosis and treatment of polycystic ovary syndrome: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2013;98:4565–92.
- Harwood K, Vuguin P, DiMartino-Nardi J. Current approaches to the diagnosis and treatment of polycystic ovarian syndrome in youth. Horm Res. 2007;68:209–17.
- Inkster ME, Fahey TP, Donnan PT, Leese GP, Mires GJ, Murphy DJ. Poor glycated haemoglobin control and adverse pregnancy outcomes in type 1 and type 2 diabetes: systematic review of observational studies. BMC Pregnancy Childbirth. 2006;6:30.
- Jensen DM, Korsholm L, Ovesen P, Beck-Nielsen H, Moelsted-Pedersen L, Westergaard JG, et al. Peri-conceptionalA1Cand risk of serious adverse pregnancy outcome in 933 women with type 1 diabetes. Diabetes Care. 2009;32:1046–8.
- Blumer I, Hadar E, Hadden DR, Jovanovic L, Mestman JH, Murad MH, et al. Diabetes and pregnancy: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2013;98:4227–49.
- Pregnancy outcomes in the Diabetes Control and Complications Trial. Am J Obstet Gynecol. 1996;174:1343–53.
- Magee MS, Knopp RH, Benedetti TJ. Metabolic effects of 1200-kcal diet in obese pregnant women with gestational diabetes. Diabetes. 1990;39:234–40.
- Langer O, Conway DL, Berkus MD, Xenakis EM, Gonzales O. A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med. 2000;343:1134–8.
- Charles B, Norris R, Xiao X, Hague W. Population pharmacokinetics of metformin in late pregnancy. Ther Drug Monit. 2006;28:67–72.
- Feldberg D, Dicker D, Samuel N, Peleg D, Karp M, Goldman JA. Intrapartum management of insulin-dependent diabetes mellitus (IDDM) gestants. A comparative study of constant intravenous insulin infusion and continuous subcutaneous insulin infusion pump (CSIIP). Acta Obstet Gynecol Scand. 1988;67:333–8.
- O'Reilly M, Avalos G, Dennedy MC, O'Sullivan EP, Dunne FP. Breast-feeding is associated with reduced postpartum maternal glucose intolerance after gestational diabetes. Ir Med J. 2012;105(5 Suppl):31–6.
- Cooke PS, Naaz A. Role of estrogens in adipocyte development and function. Exp Biol Med (Maywood). 2004;229(11):1127–35.
- Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HAW. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577–89.
- Dormandy JA, Charbonnel B, Eckland DJ, et al.; PROactive investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macrovascular Events): a randomised controlled trial. Lancet. 2005;366:1279–89.