Elizabeth O. Beale, MBBCh, MMed, MS Jorge H. Mestman, MD
Truth always lags last, limping along the arm of time -Baltasar Gracian
Key Points
• The metabolic syndrome (MS) is a cluster of clinical and metabolic factors linked by resistance to insulin action and associated with an increased risk of cardiovascular disease (CVD), type 2 diabetes, and several other diseases
• Gestational diabetes mellitus (GDM) has many features of MS including a predisposition to developing type 2 diabetes and the presence of risk factors for CVD
• Identification of MS is important so that intervention with lifestyle modification or pharmacotherapy can be initiated to prevent progression to these illnesses
INTRODUCTION
Cardiovascular disease (CVD) is the commonest cause of death and disability in women in the United States (US).1 In 2009, CVD accounted for 25% of all-cause mortality in women.1-2 Another serious illness, type 2 diabetes mellitus, is also very common, occurring in approximately 12.6 million or 10.8% of all women aged 20 years or older.3 About one-third of women are unaware of their diagnosis.3 As many as one in three U.S. adults could have diabetes by 2050 if current trends continue.4 Individuals diagnosed as having type 2 diabetes have large reductions in life expectancy. In 2003, it was estimated that women diagnosed after age 40 in the United States would lose 14.3 life-years and 22.0 quality-adjusted life-years.5 More recently, in 2012, it was reported from Canada that diabetes in women was associated with a loss of life expectancy and health-adjusted life expectancy of 6 years and 5.8 years, respectively.6 Much of this increase in mortality and morbidity is because of an increase in CVD, which is the most common complication attributable to diabetes. The risk for CVD is more serious among women than men. The relative risk for fatal coronary heart disease in women with diabetes is 1.5 that of men. This increased risk may be because of more cardiovascular risk factors in women and disparities in health care that favor men.7 Mortality rates for heart disease are reported to be increasing for women although they have declined for men since the 1980s and recently surpassed those for men.8 Young women, in particular, have shown the greatest rise in coronary deaths and this is reported to be related to an increase in cardiac risk factors including diabetes and the metabolic syndrome (MS).9
Multifactorial risk factor reduction is effective for the primary and secondary prevention of CVD.10-12 Similarly, it has been shown that the progression to type 2 diabetes in at-risk individuals can be significantly delayed or even prevented by early lifestyle and pharmacological intervention.13 Risk factors for CVD and type 2 diabetes tend to cluster together. This clustering of clinical and biochemical abnormalities has been termed “MS.”14 Gestational diabetes mellitus (GDM) can be considered a manifestation of the MS in pregnancy.15 Identification of women with the MS or GDM provides an important opportunity to identify individuals at high risk for CVD and type 2 diabetes and to initiate preventive therapy. In this chapter, we will review the clinical significance of the MS in women, its relationship to GDM, and a clinical approach to identification and management.
PART 1: SCIENTIFIC BACKGROUND
Definitions
In 1988, Reaven proposed that resistance to insulin-stimulated glucose uptake (insulin resistance, IR) and secondary hyperinsu- linemia are involved in the etiology of three major related diseases:
CVD, type 2 diabetes, and hypertension. He coined the term “Syndrome X” to describe a group of abnormalities that increase the risk for CVD: resistance to insulin-stimulated glucose uptake, glucose intolerance, hyperinsulinemia, increased triglyceride (TG), decreased high-density lipoprotein-cholesterol (HDL-C), and hypertension.15 Since then, it has become widely recognized that cardiovascular risk factors tend to cluster although whether resistance to insulin action is central to this “syndrome” is contro- versial.16 Several different names and diagnostic criteria have been proposed, including Insulin Resistance Syndrome, Dysmetabolic Syndrome, Deadly Quartet, and MS. The list of biochemical and clinical features included in the cluster has increased since its first description (Figure 24-1).16
Formal criteria for the diagnosis of the MS have been proposed to assist clinicians to identify patients at high risk of CVD and for study purposes (Table 24-1).16,17 In the United States, the most widely used formal definition for the MS is that developed by the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III.14 The World Health Organization (WHO) also formulated diagnostic criteria with similar goals. The main difference is the inclusion of a measure of IR if glucose intolerance or type 2 diabetes is not present in clinical blood glucose measurements, and measurement of the urinary albumin excretion rate.17 A small increase in urinary albumin excretion termed microalbuminuria is a predictor of increased risk of renal failure and CVD.18 Use of morning urine albumin-to-creatinine ratio is the preferred screening method. Fever, exercise, heart failure, and poor glycemic control can cause transient microalbuminuria.19 In clinical practice, serum insulin measurements are not recommended because of lack of standardization of insulin assays.
Clinical Value of the MS
Although the ATP III criteria for the MS have been promoted as a means of identifying individuals at risk for type 2 diabetes and CVD, some studies have shown that other established risk scores (the Framingham Risk Score and the Diabetes Predicting Model) are superior for this purpose.16 The Framingham Risk Score contains other well-recognized cardiovascular risk factors, not included in the NCEP ATP-III and WHO criteria, namely age, sex, total cholesterol (TC), and cigarette smoking. A high score predicts coronary events within 10 years. Similarly, family history, an important predictor of type 2 diabetes, is included in the Diabetes Predicting Model. It has been suggested that the current definitions of the MS are probably best as a “simple public health concept and an easily identified starting point for clinical interventions known to reduce risk for the increasing problems of type 2 diabetes, CVD, and perhaps some cancers.”20
Prevalence of the MS in the United States
Data suggests the prevalence of the MS in the United States remains high but may be decreasing. The National Health and Nutrition Examination Survey (NHANES) showed age-adjusted prevalence of MS decreased from 26% to 23% from 1999 to 2010. There were, however, a difference in trends in the components of the syndrome with hypertriglyceridemia and hypertension each decreasing from approximately 34% to 24% in association with increased use of drug therapy for these disorders, whereas hyperglycemia increased from 13% to 20% and elevated waist circumference from 45% to 56%. Women, particularly nonwhite women, had the highest increase in prevalence of abdominal obesity.21
Cruz et al.22 studied 126 Latino children living in Los Angeles. Inclusion criteria were age 8-13 years, a family history of type 2 diabetes, and overweight. The MS was defined as the presence three or more of the following: abdominal obesity, low HDL, hypertriglyceridemia, hypertension, and/or impaired glucose tolerance (IGT). The presence of 0, 1, 2, 3 or more features of the MS was 9%, 22%, 38%, and 30%, respectively. The incidence was higher in children of mothers with a history of GDM. In another study of U.S. children and adolescents, MS was present in 39% of 438 overweight, and in 50% of obese children, whereas none was found in normal-weight children.23
Risk Factors for the MS
Efforts have been made to identify pathophysiological precursors to the MS but no single unifying cause has been identified.16 Obesity is the most important risk factor for the MS. In NHANES III, MS was present in 4.6%, 22.4%, and 59.6% of normal-weight, overweight, and obese men, respectively, and a similar distribution was observed in women.24 Not all patients with increased IR are obese, however, and a subset of individuals termed “metabolically obese but normal weight” (MONW) has been identified. These individuals, despite having a normal body mass index (BMI) have an increased waist circumference and metabolic characteristics of the MS.25 Conversely, not all overweight and obese individuals are metabolically unhealthy, but metabolically healthy obesity (MHO) may transition to metabolically unhealthy obesity.26 Accumulating data suggest dysfunctional subcutaneous adipose tissue may underlie much of MS by promoting a proinflammatory state and IR27,28 and markers of inflammation, such as serum levels of high-sensitivity C-reactive protein (hs-CRP) and homocysteine are also predictors of type 2 diabetes and cardiovascular events.29,30 Birth weight is a risk factor for the MS and type 2 diabetes with both high and low birth weight increasing the risk of childhood and adult obesity.31 The “thrifty-phenotype hypothesis” proposes that the survival of the undernourished fetus leads to adaptations in intrauterine developmental programming that ultimately result in IR.31,32
MS and Type 2 Diabetes and Cardiovascular Risk
There is undoubtedly a strong association between the MS and the risk for subsequent development of type 2 diabetes as demonstrated in numerous studies.33 This however can be explained by the inclusion of abnormalities in glucose tolerance as a diagnostic criterion of the MS16 and identification of the MS does not improve predictive value for diabetes. The Diabetes Predicting Model is reported to be superior to the MS in this regard.34 Similarly, while there is a strong association between MS and cardiovascular risk, other models, notably the Framingham Risk Score are reported to be better predictors of CVS risk.33,34
MS and Other Conditions
The MS has also been associated with several other disorders including obstructive sleep apnea35 and several cancers.36 Obesity is proposed to mediate cancer through several mechanisms including IR and inflammation.37
Nonalcoholic fatty liver disease (NAFLD) is now the most common liver disease in the United States, with an overall prevalence of about 5% in the general population and between 25% and 75% in patients with obesity and type 2 diabetes. Nonalcoholic steatohepatitis (NASH) is predicted to become the commonest cause for liver transplantation in the United States between 2020 and 2030.38 NASH occurs most commonly in obese, middle-aged women with type 2 diabetes. IR is considered to be central to the pathogenesis.39
Polycystic ovarian syndrome (PCOS) is a common metabolic disorder in women of reproductive age. In PCOS, IR and hyperin- sulinemia are considered to cause ovarian steroidogenic dysregu- lation that leads to excess ovarian androgen production and anovulation. There is a clear association between PCOS obesity and type 2 diabetes and up to 40% of women with PCOS demonstrate some degree of glucose intolerance.40,41 PCOS is also a risk factor for GDM, CVD, and endometrial cancer.42 Acanthosis nigricans is a velvety thickening and darkening of the skin found especially on the back of the neck and axillae that is associated with IR. It is frequently seen in patients with PCOS.
Similarities Between GDM and the MS
GDM affects between 5% and 20% of pregnant women depending on the diagnostic criteria used and has many of the pathophysiological, clinical, and biochemical features of the MS.15,43 These abnormalities occur with increased frequency relative to non-GDM subjects antepartum, postpartum, and in the long term. As in the MS, IR is central to the pathogenesis of GDM. GDM patients are generally overweight and have a higher prepregnancy weight and BMI than non-GDM controls. They also have higher fasting and postprandial insulin levels, and lower HDL. GDM, like the MS, is predictive of type 2 diabetes. GDM may be considered to be a special presentation of the MS in pregnancy and the tip of the iceberg for a dangerous constellation of factors predisposing the patient to type 2 diabetes and CVD.15
Risk Factors for the Development of GDM
Risk factors for the development of GDM were evaluated in the Nurses’ Health Study. This study followed over 100,000 nurses for an average of 10 years.44 In another study of African-American women, risk factors for the development of GDM included obesity, older age, hypertension, family history of type 2 diabetes, and heart disease.44 In a study of 1113 women who were at 21-28 weeks gestation, waist/hip ratio (WHR) and waist circumference were independently associated with two-hour glucose levels after a glucose tolerance test (GTT). These measurements were independent predictors of gestational glucose intolerance.45 Change in waist circumference at this stage of pregnancy is mainly the result of central fat deposition.
IR in Pregnancy
Pregnancies complicated by GDM are characterized by an inability to increase insulin secretion to compensate for the increase in IR that occurs normally in pregnancy.46,47 A pancreatic beta-cell secretory defect is present in both obese and lean women with GDM. Data demonstrate that overweight women who develop GDM have IR prior to pregnancy as measured by hyperinsulinemic-euglycemic clamp studies. Insulin-mediated glucose disposal decreases progressively in the second and third trimester of pregnancy and is about two-thirds that of normal pregnant women matched for weight. Furthermore, although women with GDM improve their IR postpartum, they never achieve the same degree of insulin-mediated glucose disposal as do normal pregnant women.48
GDM as a Predictor of Type 2 Diabetes
Women with GDM are at a significantly increased risk of developing type 2 diabetes. O’Sullivan49 showed that the 15-year prevalence of type 2 diabetes in women with a history of GDM was approximately 60% for women who were obese and 30% for women who were lean. Mestman et al.50 followed 360 women, mostly Latinas, with GDM for up to five years. Of 51 women with elevated fasting glucose during pregnancy, only four had a normal GTT six weeks postpartum. Of those 118 women with abnormal GTT but normal fasting glucose, 12.7 % developed overt type 2 diabetes and 32.6% abnormal GTT at the end of the study. Kjos et al.51 followed 671 Latino women with GDM and a normal oral glucose tolerance test (OGTT) 4-16 weeks postpartum for up to 7.5 years. There was a 47% cumulative incidence rate of type 2 diabetes five years after delivery. In a meta-analysis, Kim et al.52 concluded that differences in lengths of follow-up, ethnic variation, and the diagnostic criteria used accounted for most of the difference in risk between studies. The greatest risk factor for early-onset type 2 diabetes after pregnancy was early gestational age at the time of diagnosis and elevated fasting glucose.53,54 The greatest long-term risk factor was maternal obesity.55
GDM and Subsequent CVD
Until recently there has been little data to demonstrate an increase in cardiovascular complications in women with GDM.56 Carr et al.57 reported that women who had a personal history of gestational diabetes in addition to a family history of type 2 diabetes had more CVD risk factors and more CVD events at a younger age than women with no prior history of GDM. Shah et al.58 confirmed this increased risk and attributed it mostly to an increased prevalence of type 2 diabetes. Finally, recent work by Kessous et al.59 demonstrated GDM to be an independent risk factor for cardiovascular morbidity over a decade later.
GDM and Dyslipidemia
During pregnancy, GDM induces a state of dyslipidemia characterized by elevated TG concentrations, as seen in other states of increased IR. However, GDM seems to blunt an increase in low-density lipoprotein (LDL) cholesterol.60 As dyslipidemia is a component of the MS it is not surprising that this occurs commonly following GDM.61 Kjos et al.62 evaluated fasting lipids in a large cohort of Latino women with GDM during the first 36 months postpartum. Overall, the prevalence of high-risk LDL was no different from that of control subjects. However, increased TG and decreased HDL were found in subjects who developed diabetes during the study period. These findings were similar to those reported in the San Antonio Heart Study.63 In another study of 56 former gestational diabetic mothers and 48 control mothers 5-6 years postpartum, mean TC, TG, LDL, and glucose were significantly higher in the GDM mothers than in the control mothers.64
GDM as a Predictor for Subsequent Development of the MS
Several studies have reported a greatly increased risk of MS following GDM.65,66 Bo et al.67 reported on the development of MS in a group of 81 women with prior GDM. Prevalence of the MS and its components was two- to fourfold higher in women with prior gestational hyperglycemia and 10-fold higher if pre pregnancy obesity coexisted when compared to normoglycemic controls, suggesting that GDM, especially in combination with prepregnancy obesity, predicts a subsequent syndrome of high cardiovascular risk. Verma et al.68 confirmed this finding. They reported that 27% of 106 patients with GDM and 8.2% of 101 controls developed features of IR by 11 years after delivery. The cumulative hazard for developing MS in the next two years was 26 times higher among GDM subjects with prepregnant obesity, compared with controls. It was concluded that obesity and GDM in a prior pregnancy are significant risk factors for developing MS and cardiovascular risk factors. Pallardo et al.69 in Spain studied 788 Caucasian women with GDM 3-6 months postpartum. Forty- three (3.7%) were diagnosed with overt DM. The area under the postpartum glucose curve was positively associated with BMI, waist circumference, WHR, TGs, and systolic and diastolic blood pressures. It was concluded that postpartum glucose intolerance predicts a high-risk cardiovascular profile that includes risk factors besides type 2 diabetes.
Gestational Hypertension, Glucose Intolerance, and Future MS
Pregnancy-induced hypertension (PIH) has now convincingly been related to glucose intolerance and IR.70 Carr et al. reported that the rate of PIH was 17.0% in individuals with two abnormal values on a three-hour oral glucose tolerance (OGT), 10.8% with one abnormal value, and 4.6% with no abnormal value.57 Pouta et al. reported on the six-year outcome in 45 women hospitalized with PIH. There was more hypertension, increased waist:hip circumference, increased serum insulin, and a lower glucose:insulin ratio in the PIH patients than the previously normotensive women. There was, however, no difference in lipids.71
Diagnosis of MS in Pregnancy
There is no generally recognized formal definition for the MS in pregnancy. In a recent study of 600 pregnant women by Bo the following criteria were used:
1. One abnormal value on the OGTT or GDM or hyperinsulinemia (>2 SD above the mean for the 100 women with negative oral glucose challenge test used as controls)
2. Plus any two of the following:
a. Blood pressure (BP) > 140/90
b. TG > 2 SD above mean from control
c. Low HDL-C < 1.0 mmol/L)
d. BMI > 30
e. Waist > 2 SD
The prevalence of the MS was 0% in women with a normal challenge test; 4.9% in those women with abnormal challenge and normal tolerance test; 20% in those with one abnormal value; and, 18% in gestational diabetes patients. Furthermore, worsening of GTT was directly associated with age, weight, BP, waist circumference, TG, and insulin levels and inversely associated with HDL-C values.72
Consequences of Maternal GDM and Type 2 Diabetes for the Offspring
It is well recognized that type 2 diabetes and GDM are associated with neonatal complications in the offspring, particularly relating to macrosomia and hyperinsulinism. However, it is now also recognized that in utero hyperinsulinism and over nutrition are associated with significant long-term problems for the offspring, notably obesity and type 2 diabetes.73 Freinkel74 hypothesized in his fuel-mediated teratogenesis theory that teratogenesis can occur after organogenesis during the differentiation and proliferation of fetal cells. Such changes could cause long-range effects upon behavioral, anthropometric, and metabolic functions. An increase in obesity in offspring of diabetic mothers that appears to be independent of genetic predisposition has been known for some time.75 Offspring of diabetic women, even those who are of normal birth weight, have a higher mean weight relative to height at 5-19 years of age than do offspring of nondiabetic and prediabetic women.76 Studies in Pima Indians found that type 2 diabetes occurs more often in offspring of diabetic mothers than in offspring of prediabetic or nondiabetic women (45% vs. 8.6% or 1.4%, respectively).77 In a recent study of 126 overweight
Hispanic children with a family history of type 2 diabetes, there was a high prevalence of features of the MS as noted previously. Insulin sensitivity was positively related to HDL and negatively related to TGs and systolic and diastolic blood pressures. Insulin sensitivity significantly decreased as the number of features of the MS increased.22
These observations have major implications for the management of obesity and type 2 diabetes. The data suggest that careful management of maternal metabolism in utero could help break the vicious cycle of obesity; GDM and type 2 diabetes and children of mothers with GDM or type 2 diabetes should be evaluated early to enable detection and management of the MS.78
PART 1 SUMMARY
The MS is a cluster of risk factors for CVD and type 2 diabetes associated with IR. GDM may be considered a special case of the MS occurring in pregnancy. It has similar risk factors, clinical and biochemical features, and long-term consequences. It is important to recognize individuals with MS and GDM so that early intervention can begin to modify these risk factors and delay or even prevent the progression to type 2 diabetes and CVD.
PART 2: MANAGEMENT OF THE MS
Delaying or preventing type 2 diabetes and early detection and treatment of cardiovascular risks factors are the main goals in the management of the MS. Although there is still need for high- quality studies to inform best management, a rational and aggressive approach is strongly recommended following delivery.47,79,80
Postpartum Evaluation of Women With GDM
Women with GDM should be seen 1-4 months (typically about six weeks) postpartum; an assessment of risk factors for future type 2 diabetes is done at this first visit along with a fasting plasma glucose (FPG) or an A1c and preferably a blood sugar level two hours after a glucose load (Figure 24-2).79 The American Diabetes Association criteria for the diagnosis of type 2 diabetes and other forms of glucose intolerance are shown in Table 24-2.81 A recent systematic review and meta-analysis by Bellamy et al.82 reported a relative risk of 4.7 within five years of delivery and 9.3 five years after delivery. In one of the studies included in this review by Feig et al.,83 the incidence of type 2 diabetes in women with previous GDM was 3.7% 9 months postpartum, 4.9% 15 months postpartum, 13.1% 5 years postpartum, and 18.9% 9 years postpartum but only 2% in the non-GDM controls). The strongest association is with waist circumference and BMI.84 Other important risk factors are diagnosis of GDM prior to 24 weeks gestation; use of insulin during pregnancy; auto antibodies; higher glucose levels at diagnosis, during pregnancy, and on OGTT; and neonatal hypoglycemia. High birth weight and parity and a first degree relative with type 2 diabetes are of lesser risk.85,86 Specific ethnic groups (Latinos, Asians, Native Americans, and African Americans) are at increased risk.87 In addition, other risk factors such as cigarette smoking, family history of obesity, and cardiovascular risk factors should be carefully evaluated and updated on a regular basis.
All women regardless of the result of the GTT should be advised about their risk factors for future type 2 diabetes and CVDs. Ways of improving their risk factors through smoking cessation, proper meal plan, regular exercise, and achieving an ideal BMI should be discussed. This set of recommendations should extend to their immediate family. They should be seen at least on a yearly basis. Because the majority of women with GDM have been instructed on glucose self-monitoring, it is reasonable to advise them to measure their fasting glucose on a regular basis, perhaps monthly, and report to the physician if the glucose values are consistently over 100 mg/dL. Those with abnormal glucose metabolism need to be seen more frequently, home glucose self-monitoring encouraged and pharmacological intervention considered, if the goals are not achieved with a proper meal plan and increase in physical activity.79 For completeness of the postpartum evaluation, BMI and BP are recorded and lipid levels measured 6-12 months postdelivery.
TABLE 24-2 Diagnosis of Prediabetes and Diabetes Mellitus. Any One of the following
Measure |
Prediabetes |
Diabetes |
Comment |
A1c |
5.7%-6.4% |
>6.5%a |
The test should be performed in a laboratoryb |
Fasting plasma glucose |
100-125 mg/dL (5.6-6.9 mmol/L) |
>126 mg/dLa (7.0 mmol/L) |
Fasting for at least 8 h |
2-h plasma glucose during an OGTT. |
140-199 mg/dL (7.8-11.0 mmol/L) |
>200 mg/dLa (11.1 mmol/L) |
Glucose load of equivalent of 75 g anhydrous glucose dissolved in water |
Random plasma glucose |
— |
>200 mg/dL (11.1 mmol/L) |
In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis |
aIn the absence of unequivocal hyperglycemia, result should be confirmed by repeat testing.
bUsing a method that is NGSP (National Glycohemoglobin Standardization Program) certified. Source: Adapted from Diabetes Care 2013.81
Prevention or Delaying Onset of Type 2 Diabetes
Several landmark studies in the last few years have demonstrated that progression to type 2 diabetes can be significantly delayed, and perhaps even prevented, by lifestyle modification and drug therapy. Controlled trials have demonstrated that 7%-10% weight loss and exercise of approximately 150 min/ wk is highly effective in delaying the progression to type 2 diabetes in subjects with IGT.13,88-90 In a study from China of 577 patients with IGT, a diet and physical activity program for six years was associated with a 30%-40% risk reduction for type 2 diabetes in both normal- and overweight subjects.88 In the U.S. Diabetes Prevention Program, 3234 subjects with IGT were originally divided into four groups and followed for an average of 2.8 months.13 The study comprised (a) a placebo or control group; (b) a metformin group (850 mg twice a day); (c) a lifestyle modification group with regular nutrition counseling and exercise under professional supervision; and (d) a Troglitazone group that was discontinued when the drug was withdrawn from the market. There was a reduction in progression of 58% in the life modification group as compared to 20% in the placebo group. Similar results were reported in the Finnish Diabetes Prevention Study (522 subjects) in which a life modification approach was used (sustained up to six years).89,90
Potential Drug Therapy
Given the poor long-term success of lifestyle modification, drugs from several different classes have been evaluated for their ability to delay progression from prediabetes to diabetes and have been shown to delay progression to type 2 diabetes. In the Diabetes Prevention Program, the subgroup receiving metformin had a 31% relative reduction in progression to type 2 diabetes at 2.8 years.13 In the Troglitazone in the Prevention of Diabetes (TRIPOD) Study, 235 Hispanic women with previous gestational diabetes were randomized to receive placebo or tro- glitazone. At the end of two years, a 58% relative risk reduction for type 2 diabetes was reported in the women on troglitazone that persisted after a washout period of more than eight months.91 However, currently there is no evidence that the benefit of initiating drug treatment for prediabetes outweighs the risks or is superior to initiation of drug treatment once diabetes has developed. The 2013 American Diabetes Association Clinical Practice Recommendations are that metformin therapy may be considered to prevent diabetes in individuals with IGT, impaired fasting glucose (IFG), and an A1c of 5.7%-6.4%, especially in those with a BMI >35 kg/m,2 <60 years of age, and prior GDM.81
In summary, a consistent lifestyle modification approach is very effective in controlling the progression to type 2 diabetes in high-risk populations: the problem is the well-known inability for patients to adhere to these programs in the long term. Pharmacological therapy in prediabetes appears encouraging, but not enough information is available to recommend it at present.
Treatment of Type 2 Diabetes
For the vast majority of those affected, type 2 diabetes is a chronic disease and lifelong care is required. There are several components to care. A summary of these can be found each year in the American Diabetes Association Clinical Practice Recommendations.81 Key points from these recommendations are discussed here.
Diabetes Self-Management Education and Support
Education of patients regarding their diabetes is fundamental to care. Certified Diabetes Educators are available in most communities and they play an important role in management. Every person with type 2 diabetes should receive diabetes education: they should learn about self-care, self-monitoring of glucose at home, critical glucose values, what to do during sickness, and so forth. Teaching should be ongoing with regular visits to care providers.
Lifestyle Management
Several studies have shown benefit of a modest loss of 7%-10% of body weight through lifestyle intervention in individuals with pre- diabetes.13,88-90 However, the recent Look AHEAD study showed no significant benefit in its primary outcome, a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina during a maximum follow-up of 13.5 years although other benefits, including less use of medication and greater mobility were noted.92 Currently, expert opinion still endorses lifestyle modification for the majority of individuals with type 2 diabetes.81
Meal Plan
Although in daily practice this is a very difficult task, patients should be encouraged to at least not gain weight. The latest recommendations from the American Diabetes Association are based mostly on expert opinion and data from single high-quality clinical trials and poorly controlled or uncontrolled studies.81 This includes the following recommendations: the proportions of macronutrient (carbohydrate, protein, and fat) may be adjusted to meet individual metabolic goals and preferences, monitoring of carbohydrate intake is central to achieving glycemic control, saturated fat intake should be 7% of total calories, intake of trans fat should be minimized to lower LDL, alcohol should be limited to one drink per day or less for adult women and two drinks per day or less for adult men, and extra precautions should be taken to avoid hypoglycemia in those who use alcohol. High-quality studies have not demonstrated benefit from routine supplementation with antioxidants such as vitamins E and C and carotene, and as their long-term safety is unknown these are not recommended. Finally, it is recommended that meals are planned so that an individual’s need for all micronutrients are met.81
Physical Activity
The American Diabetes Association considers there is strong evidence to recommend that adults with diabetes perform at least 150 min/wk of moderate-intensity aerobic physical activity (50%-70% of maximum heart rate), spread over at least 3 d/wk with no more than two consecutive days without exercise and, in the absence of contraindications, they should be encouraged to perform resistance training at least twice per week.81 It is now recommended that health care providers use clinical judgment to determine the extent of evaluation for CVD before initiation of an exercise program in asymptomatic patients as screening for coronary artery disease in such individuals remains of unproven benefit.81
Depression
Depression is common and should be screened for and treated with behavioral therapy and/or medication.as it frequently impairs quality of self-care and medical outcomes.81
Drug Therapy
Drug therapy for diabetes is evolving in several ways. First, instead of recommending a standard approach for all patients there is a move toward a personalized approach that takes into account an individual’s “ABCDE” which refers to their age, body weight, complications (microvascular and macrovascular), duration of diabetes, and life expectancy as well as the expense of therapy.93 Second, there is a move to treat individuals more aggressively with multiple different agents with different modes of action soon after diagnosis rather than with the current standard of starting with a low dose of monotherapy and increasing the dose and number of medications when the patient fails to maintain glycemic control on that regimen.93-95 Glycemic target should also be individualized, with a goal A1c of <7% for most patients but <6.5% may be appropriate if this can be achieved safely. Regular reassessment of diabetic control is essential to keep A1c within target values. Potential side effects of each drug must be discussed with the patient at the onset of therapy.81
Over a variable period, ranging from months to years, the efficacy of noninsulin agents in controlling glycemia diminishes as endogenous insulin production by the pancreas declines. At this time, insulin therapy becomes necessary to maintain normoglyce- mia. Several different insulin formulations are available that differ in time of onset and duration of action. Different administration regimens are used. A patient with type 2 diabetes may use a single nighttime dose of neutral protamine hagedorn insulin (NPH) or Glargine to suppress basal glucose levels and continue with oral agents during the day. Eventually, multiple daily injections may be needed.
Bariatric Surgery
Bariatric surgery is now recognized to be highly effective therapy for type 2 diabetes in many individuals. High cost and safety concerns limit wider use. The American Diabetes Association now recommends that adults with BMI >35 kg/m2 and type 2 diabetes be considered for bariatric surgery especially if the diabetes or associated comorbidities are difficult to control with lifestyle and pharmacological therapy.81
The majority of patients with type 2 diabetes present with identifiable cardiovascular risk factors at the time of diagnosis. In addition to management of hyperglycemia, dyslipidemia, hypertension, and obesity should be aggressively managed to prevent micro- and macrovascular complications.
Treatment of Dyslipidemia
Low HDL levels and high TG are typical of the MS. Small, dense LDL particles, known to be atherogenic are increased, although the total LDL levels may be within normal limits or only slightly elevated. The initial approach to the management of dyslipi- demia is lifestyle modification. Drug therapy is indicated if, after a period of about three months, target values are not achieved.81 Statin therapy is very effective in achieving TC and LDL target values. Statins are in general well tolerated. Liver function tests are recommended at six weeks after initiation of therapy. Muscle aches and cramps are reported in a small group of patients and occasionally the drug has to be discontinued. Fibrates are the most effective agents for lowering TGs (25%-50%); they also raise HDL by 10%-20%. Niacin is also very effective at raising HDL (15%—35%) and lowering TGs (20%-40%). However, it has a tendency to increase IR and worsen glucose levels.81
Treatment of Hypertension
Hypertension should also be treated initially with lifestyle modification. Every person with type 2 diabetes with persistent BP readings of 130/80 or higher should receive pharmacological therapy. ACE-I and ARB’s are generally initial drugs of choice. An annual determination of microalbuminuria, a risk factor for the development of nephropathy and CVD, is recommended. Patients with persistent microalbuminuria should be treated with ACE-I or ARB drugs.81
Aspirin
Aspirin is highly effective in secondary prevention of myocardial infarction and stroke, but its use for primary prevention of CVD is controversial. Consequently, the American Diabetes Association recommends routine use in those with a history of CVD and that it be considered for use in those at high risk for this.81
Cigarette Smoking
Cigarette smoking is the major preventable cause of disease in the United States, causing more than 440,000 deaths annually. It may play a role in the development of diabetes and is a major risk factor for CVD. All patients should be advised not to smoke and counseling, behavior modification techniques, and pharmacotherapy with nicotine or bupropion should be considered as therapy.81 Long-term follow-up should be available to prevent relapse.81
PART 2 SUMMARY
GDM is frequently the first indication of type 2 diabetes and the MS. Because these conditions are asymptomatic at onset, it is imperative for the health care professional to actively investigate for early metabolic abnormalities, to offer counseling with the assistance of other health care professionals, such as nutritionists and diabetic educators, and to extend these recommendations to the entire family. Preconception counseling is an integral part of this approach. It is expected that an active integrated program will prevent the alarming increase in the incidence of obesity, type 2 diabetes, and the MS in our society.
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