FPG ≥126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 ha
2-h PG ≥200 mg/dL (11.1 mmol/L) during an OGTT. The test should be performed as described by the WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in watera
Hemoglobin A1C ≥6.5 % (48 mmol/mol). The test should be performed in a laboratory using a method that is NGSP certified and standardized to the DCCT assaya
In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥200 mg/dL (11.1 mmol/L)
1. Testing should be considered in all adults who are overweight (BMI ≥25 kg/m2 or ≥23 kg/m2 in Asian Americans) and have additional risk factors: |
Physical inactivity |
First-degree relative with diabetes |
High-risk race/ethnicity (e.g., African American, Latino, Native American, Asian American, Pacific Islander) |
Women who delivered a baby weighing >9 lb or were diagnosed with gestational diabetes mellitus |
Hypertension (≥140/90 mmHg or on therapy for hypertension) |
HDL cholesterol level <35 mg/dL (0.90 mmol/L) and/or a triglyceride level > 250 mg/dL (2.83 mmol/L) |
Women with polycystic ovary syndrome |
Categories of increased risk for diabetes (prediabetes) on previous testing |
Impaired fasting glucose, 100 mg/dL (5.6 mmol/L) to 125 mg/dL (6.9 mmol/L) or |
Impaired glucose tolerance, 2-h plasma glucose 140 mg/dL (7.8 mmol/L) to 199 mg/dL (11.0 mmol/L) or |
A1C 5.7–6.5 % (39–46 mmol/mol) |
Other clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosis nigricans) |
History of cardiovascular disease |
2. For all patients, testing should begin at age 45 years |
3. If results are normal, testing should be repeated at a minimum of 3-year intervals, with consideration of more frequent testing depending on initial results (e.g., those with prediabetes should be tested yearly) and risk status |
The constellation of menopause and diabetes poses unique challenges. Some diabetic women anecdotally report sensations similar to hot flashes with highs or lows of blood glucose [4]. Our patient checks her blood glucose regularly and has not observed a relationship between the feelings she interprets as hot flashes and excursions of blood glucose. Her symptoms sound like typical menopausal hot flashes. Upon further questioning, the patient reveals that VMS are annoying during the day, but are also associated with nighttime awakenings. She feels that sleep disruption contributes to her fatigue during the day and interferes with her effectiveness at work. She is definitely interested in exploring options to reduce VMS as well as improve her sleep.
As patients diagnosed with type 2 diabetes may have diabetes for years prior to their diagnosis, a comprehensive diabetes medical evaluation should be initiated that includes assessment of current lifestyle patterns and for existence of microvascular (retinopathy, nephropathy, and neuropathy) and macrovascular (coronary heart disease, cerebrovascular disease, and peripheral arterial disease) complications of diabetes [5]. This provides a baseline for future clinical management and, in this case, facilitates decisions about treatment of VMS. Although the diagnosis of diabetes has been confirmed in this patient, it would be reasonable to repeat the A1C level to confirm the level of diabetic control on metformin therapy over the past 3 months [5]. Additional laboratory testing should include annual fasting lipid profile, liver function tests, spot urinary albumin-to-creatinine ratio, serum creatinine, and estimated glomerular filtration rate [5]. For diabetic women > age 50, thyroid-stimulating hormone determination is also recommended [5]. Depression affects 20–25 % of people with diabetes [5]. Our patient does not complain of depression or appear depressed, but an office-based screening (such as with the patient health questionnaire 2 PHQ-2) is recommended [5].
Our patient’s husband notes that she snores more than in the past. The prevalence of obstructive sleep apnea (OSA) in patients with type 2 diabetes may be as high as 23 %; in a study of obese patients with type 2 diabetes, it exceeded 80 % [5]. Referral to a sleep specialist for evaluation including full overnight polysomnography with cardiac rhythm monitoring is recommended by the American College of Physicians as the preferred diagnostic tool for sleep breathing disturbances [6]. Management of sleep apnea with continuous positive airway pressure significantly improves quality of life and blood pressure control [5, 7, 8].
Although this patient has no symptoms of coronary heart disease or past history of CVD events, cardiovascular disease is a major contributor to morbidity and mortality associated with diabetes in women [9]. Formal assessment of CVD risk with the American College of Cardiology/American Heart Association 10-year CVD risk calculator [10] could facilitate decision-making regarding level of CVD risk and appropriate choice of therapy for VMS relief [11] (further discussed under management) as well as regarding CVD preventive strategies [12, 13].
Diabetes increases the risk for osteoporotic fractures regardless of bone mineral density. The added risk is attributed to low bone turnover, low bone quality, and increased risk of falls [14] (osteoporosis risk assessment and treatment options are covered elsewhere in this volume). Providers should assess fracture history and risk factors in older patients with diabetes and recommend measurement of BMD if appropriate for the patient’s age and sex [5]. Fracture prevention strategies for people with diabetes are currently the same as for the general population [5]. For patients with type 2 diabetes with fracture risk factors, thiazolidinediones and sodium–glucose cotransporter 2 inhibitors should be avoided as their use has been associated with a higher risk of fractures [5, 14].
Diabetes is associated with increased cancer risk. In recent meta-analyses, elevated risk of breast (20 %), colorectal (27 %), and endometrial (97 %) cancers were found in women with diabetes [15]. Patients with diabetes mellitus should be encouraged to undergo recommended age-appropriate and country-specific cancer screenings [16] and to reduce modifiable cancer risk factors (smoking, obesity, and physical inactivity) [5]. (Case XXX includes a detailed discussion of recommended cancer screening for all postmenopausal women.)
Management
Our patient, complaining of bothersome vasomotor symptoms (VMS), also presented with obesity, recent diagnosis of type 2 diabetes, and hypertension. As with many patients with type 2 diabetes, our patient also had dyslipidemia with HDL < 50 mg/dL, LDL > 100 mg/dL, and triglycerides > 200 mg/dL. The choice of therapy for relief of VMS in patients with CVD risk factors such as diabetes, obesity, hypertension, and dyslipidemia must be dictated by the adage, “First, do no harm.” Because randomized clinical trials show increased rates of heart attacks and strokes with oral menopausal hormone therapy (MHT) in women of advanced age, increasing time since menopause, and with established CVD, MHT use is generally not recommended for women in the high CVD risk category [11]. For a woman with diabetes mellitus and additional CVD risk factors (as the patient under discussion), a conservative approach seems merited, as adequately powered clinical trial evidence of CVD outcomes of MHT use in women with diabetes is lacking. Of note, women meeting criteria for the metabolic syndrome at trial initiation in the Women’s Health Initiative randomized clinical trial of combined (estrogen plus progestin) hormone therapy in women with a uterus were found to be at increased risk of CHD outcomes when assigned to oral hormone therapy with daily conjugated equine estrogens 0.625 mg combined with medroxyprogesterone acetate 2.5 mg [17].
As experienced clinicians are aware, the diagnosis of diabetes mellitus represents a clinical continuum, and not all women with diabetes mellitus present with multiple CVD risk factors. The Endocrine Society Clinical Practice Guideline on Treatment of Symptoms of Menopause [11] allows that some women with diabetes mellitus, after formal evaluation of CVD risk, who fall into the “low”- or “intermediate”-risk category [10], might be candidates for low-dose transdermal estradiol therapy with micronized progesterone (for endometrial protection in women with a uterus), as these hormonal preparations are less metabolically active and possibly less likely than oral menopausal hormone therapies to contribute to risk of venous thrombosis and stroke [18]. From the standpoint of effect of MHT on glucose control in women with diabetes mellitus, a number of small, short-duration randomized controlled trials showed either improvement or neutral effects [19].
Aggressive cardiovascular risk factor management is paramount [12]. In addition to treating hypertension to blood pressure goal of <140/90 mmHg, for patients with diabetes mellitus aged 40–75 years with additional atherosclerotic CVD risk factors (such as our obese, hypertensive, dyslipidemic patient), consider using high-intensity statin and lifestyle therapy [13]. Although elevated LDL-C level is not usually the major lipid abnormality in patients with type 2 diabetes mellitus (they are more likely to have low HDL-C and elevated levels of triglycerides), as demonstrated in clinical trials, statin therapy reduces the risk for major coronary events independent of baseline LDL-C and other lipid values [12]. According to the American Heart Association and the American Diabetes Association Scientific Statement on prevention of CVD in adults with type 2 diabetes mellitus, patients between 40 and 75 years of age with LDL-C between 70 and 189 mg/dL should be treated with a moderate-intensity statin [12]. Statin therapy of high intensity should be given to individuals with diabetes mellitus between 40 and 75 years of age with a ≥7.5 % estimated risk of arteriosclerotic CVD [12]. Lipid levels should be measured at least annually to assess compliance with therapy [12].
It is essential to remember to emphasize a healthy lifestyle—including diet and exercise—to achieve weight loss. In the Diabetes Prevention Program, weight reduction of just 5–7 % was associated with a 58 % reduction in evolution to diabetes for those with prediabetes [5]. Depending upon degree of weight loss (>7 %), the duration of diabetes (<5 years), the baseline A1C (<8 %), and medical therapy (<2 oral medications for diabetes mellitus), the metabolic disturbances characteristic of type 2 diabetes mellitus can improve and, in some patients, result in remission of diabetes [20, 21].
For women with diabetes, current recommendations for prevention and treatment of osteoporosis should be followed, as there are no specific guidelines for women with diabetes [14]. Good glycemic control to reduce complications of diabetes and efforts to prevent falls are important ongoing measures. In the midst of all the other surveillance required by a patient with diabetes mellitus, do not forget to maintain country-specific recommendations for cancer screening and detection.
Outcome
This patient’s VMS reflected her postmenopausal status, and because of her history of diabetes mellitus and CVD risks, a non-hormonal strategy was agreed upon as a conservative first-line approach. Given that poor nocturnal sleep was a dominant symptom, gabapentin was chosen from among the various available non-hormonal options available for relief of VMS [22]; non-hormonal options for treatment of menopausal VMS are covered in detail elsewhere in this volume. As a side effect of gabapentin therapy includes drowsiness, bedtime administration is preferred [22]. For our patient, therapy was initiated at a dose of 300 mg orally taken at bedtime. Although the patient reported some improvement by the end of the first month of gabapentin therapy, because of persistent nocturnal VMS, the bedtime dose was increased to 600 mg orally. After another month of therapy, the patient reported improvement in both VMS as well as sleep disruption.
Motivated by her daughter’s upcoming wedding, after enrolling in an intensive lifestyle program at the local YMCA, the patient lost 20 pounds (approximately 10 % of her baseline weight). Concordant with the weight loss, her blood glucose progressively normalized, and the metformin was eventually discontinued. Her blood pressure is now adequately controlled on a lower dose of a calcium channel blocker and angiotensin-converting enzyme inhibitor. Metabolic improvements were attained within 3 months of weight loss with triglyceride levels now below 150 mg/dl and an increase HDL cholesterol level. Although diabetes appears to be in remission, the patient has elected to continue statin therapy given her age, hypertension, and predisposition to diabetes.
Continuation of the gabapentin therapy (rather than a switch to transdermal estrogen therapy) was preferred by the patient. The patient reported subjective improvement in sleep with control of nighttime VMS, although a formal sleep study did demonstrate characteristics of obstructive sleep apnea. Continuous positive airway pressure (CPAP) was advised, with additional improvement in nocturnal sleep and symptoms of daytime fatigue.
Clinical Pearls/Pitfalls
VMS symptoms can be more bothersome in an obese postmenopausal woman compared to those of normal weight. In some trials, weight loss is associated with improvement in VMS.
In the setting of diabetes and presence of additional CVD risk factors, a non-hormonal approach to treatment of VMS is most prudent.
Diabetes mellitus in women portends an increased risk of CVD; aggressive measures to control risk factors are indicated.
Weight loss via diet and lifestyle can be associated with remarkable improvement in metabolic risks including in some patients, remission of type 2 diabetes.
Sleep apnea should be a consideration in the setting of symptoms of daytime fatigue and poor nighttime sleep, particularly in an obese, diabetic, postmenopausal woman.
Given that type 2 diabetes mellitus augments risks for osteoporotic fractures and some cancers, follow general recommendations for screening and preventive strategies.
Case 2: A 55-Year-Old Suffering from Severe Diaphoresis, Hypertensive (Focus on Differential Diagnosis of Menopause-Like Picture)
A 55-year-old postmenopausal woman presents with complaint of episodes of intense sweating. She describes the episodes as coming on suddenly associated with a perceptible increase in heart rate. They last usually a few to no more than 10–15 min. She started noticing them shortly after she stopped menstruating at age 52. To her, they seem similar to the episodes described by her friends with hot flashes. Shortly after menopause, she was also diagnosed with hypertension. Her doctor told her that hypertension was incredibly common with half of all his menopausal patients over age 50 years having elevated blood pressure. Given that she was otherwise healthy and bothered by these episodic symptoms, her doctor started her on a course of transdermal estrogen therapy. After several months of a trial of menopausal hormone therapy (continuous transdermal estrogen with cyclic progesterone), she returned to his office noting no improvement in sweating episodes. He refers her to you for additional evaluation and treatment.
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