Diabetes and Cardiometabolic Medicine
Cara Reiter-Brennan
Omar Dzaye
Michael J. Blaha
INTRODUCTION
Epidemiology
In the United States, an estimated one-third of the population will develop type 2 diabetes mellitus (T2DM) over the course of their lifetimes. T2DM, in turn, predisposes to cardiovascular disease.1 Diabetes is one of the leading causes of death worldwide (30%) and cardiovascular disease (CVD)-related deaths account for 70% of all deaths among diabetic patients. T2DM is the most common form of diabetes (>90%), whereas type 1 diabetes mellitus (T1DM) makes up 5% of all diabetic patients2 (Table 98.1).
Risk Factors
The prevalence of T1DM is increased in patients with autoimmune diseases such as Hashimoto thyroiditis, type A gastritis, celiac disease, and adrenal dysfunction. Patients who are human leukocyte antigen (HLA)-DR3 and HLA-DR4 positive have a higher risk of developing T1DM.3
T2DM is strongly associated with metabolic syndrome (MetSyn), which is characterized by insulin resistance (IR). Older age, little physical activity, and obesity (especially high waist-to-hip ratio) all increase the risk of diabetes. Diabetes prevalence is higher in women with previous gestational diabetes mellitus (GDM) and in patients with hypertension or dyslipidemias. Individuals identifying with certain ethnic groups (African American, American, Hispanic/Latino, and American Asian) are also at higher risk of developing diabetes. Genetic disposition is more common in T2DM than in T1DM, with family history being a strong independent risk factor for T2DM.4
TABLE 98.1 Differential Diagnosis of Type 1 and Type 2 Diabetes Mellitus | |||||||||||||||||||||||||||
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PATHOGENESIS
Type 1 Diabetes Mellitus
Current research suggests that T1DM is caused by an autoimmune response, often triggered by a viral infection. The most common antibodies found in T1DM patients are anti-glutamic acid decarboxylase (anti-GAD) antibodies, which target GAD, an enzyme found in the pancreatic cell. These promote the destruction of insulin-producing β-cells in the pancreas, ultimately resulting in absolute insulin deficiency.
T1DM develops because of absolute insulin deficiency as a result of autoimmune β-cell destruction. Without insulin, glucose cannot be absorbed into muscle and adipose tissue. Glycosuria leads to polyurea and hypovolemia, which in turn can cause polydipsia. Decrease of total body water facilitates loss of electrolytes and patients present with hypovolemia, hypokalemia, and hypomagnesemia. As a result, patients experience fatigue, weakness, and muscle cramps. In addition, insulin
deficiency can lead to a catabolic state, promoting muscle wasting. Hyperglycemia may cause osmotic swelling of the lens, which presents itself as blurred vision. Patients with T1DM often experience weight loss because of the catabolic state.
deficiency can lead to a catabolic state, promoting muscle wasting. Hyperglycemia may cause osmotic swelling of the lens, which presents itself as blurred vision. Patients with T1DM often experience weight loss because of the catabolic state.
Type 2 Diabetes Mellitus
T2DM is primarily caused by the defect of insulin secretion from β-cells in the context of increased insulin demand from IR. The condition is made worse by disordered gluconeogenesis, altered skeletal muscle metabolism, and glucotoxicity, resulting in further β-cell decline. Obesity, particularly visceral adiposity, is a strong risk factor for T2DM. Abdominal adipose tissue is metabolically active and is regarded as the primary contributor to worsening IR5 (Figure 98.1).
 FIGURE 98.1 Pathogenesis of type 2 diabetes mellitus (T2DM). Pathogenesis of obesity-related T2DM. The expanded visceral fat mass in upper body obesity elaborates several factors that contribute to tissue insulin resistance. These include an increase in circulating free (nonesterified) fatty acids (FFAs) and other cytokines and proteins that inhibit insulin action, as well as a decrease in factors that enhance insulin signaling, such as adiponectin. These changes result in a block to insulin action in liver and skeletal muscle at the level of the insulin receptor and at postreceptor signaling sites, resulting in a failure of insulin to suppress hepatic glucose production and to promote glucose uptake into muscle. The resulting hyperglycemia is normally countered by increased insulin secretion by pancreatic β-cells. In persons with T2DM, the combination of resistance to insulin action and a genetically determined impairment of the β-cell response to hyperglycemia results in hyperglycemia, and T2DM ensues. (Reprinted with permission from Rubin R, Strayer DS, Rubin E. Rubin’s Pathology: Clinicopathologic foundations of medicine. 6th ed. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2011. Figure 22.5.) |
Most patients present with no or few of the classic symptoms (polyuria, polydipsia, nocturia, blurred vision, and weight loss) and only hyperglycemia identified during routine laboratory testing prompts the diagnosis. Adults with T2DM rarely show signs of hyperosmolar hyperglycemia, a state marked by obtundation, hyperglycemia, and dehydration. Diabetic ketoacidosis (DKA) is also very uncommon but may occur with severe infections like pneumonia or urinary tract infections, or during inadequate insulin therapy.
Common Signs and Symptoms
T1DM is characterized by a sudden onset of disease. Up to 25% of initial presentations of T1DM may be DKA. In comparison, microvascular or macrovascular DM complications may be the first clinical signs in patients with T2DM.
Typical Symptoms of Diabetes
Polyuria
Polydipsia
Polyphagia
Fatigue
Calf cramps
Visual impairment (blurred vision)
Disturbed wound healing
Pruritus
Weight loss (T1DM)
Benign acanthosis nigricans (T2DM)
DIAGNOSIS
Algorithm 98.1 presents the criteria used to diagnose diabetes mellitus: fasting plasma glucose (FPG) levels, 2-hour plasma glucose (2h-PG) levels during an oral glucose tolerance test (OGTT), elevated glycated hemoglobin A1c (HbA1c) levels, or elevated random plasma glucose (RPG) levels in patients with hyperglycemia, or a hyperglycemic crisis. If hyperglycemia is not certain, diabetes can be diagnosed by two abnormal test results from the same sample or two separate test samples. If test results are at the margin of cutoff points, clinicians should observe patients closely and follow up with tests in 3 to 6 months.
In comparison to 2h-PG and FPG, HbA1c has multiple advantages, such as not requiring fasting, greater preanalytic stability, and less day-to-day variations because of illness or other stress factors. However, limitations of HbA1c include lower sensitivity of HbA1c at selected cutoff points and poor correlations between glucose levels and HbA1c levels in select patients. For instance, data from the National Health and Nutritional Examination Survey (NHANES) showed that using the threshold of 6.5% or more (48 mmol/dL), HbA1c only diagnosed 30% of diabetes compared to using collective measures of 2-h PG, FPG, and HbA1c.7 In addition, clinicians should be aware of other conditions affecting hemoglobin glycation, such as HIV treatment, age, race/ethnicity, pregnancy, hemoglobinopathies/anemia, and genetic factors.8
 ALGORITHM 98.1 Diabetes diagnosis. Possible testing modalities for diabetes include measuring fasting plasma glucose (FPG) levels, 2-hour plasma glucose (PG) levels during an oral glucose tolerance test (OGTT), elevated glycated hemoglobin A1c (HbA1C) levels or elevated random plasma glucose (RPG) levels. |
MANAGEMENT OF PATIENTS WITH DIABETES
Lifestyle Intervention
Particularly for patients with T2DM, lifestyle intervention is effective in delaying onset and diabetes complications. Evidence from multiple randomized controlled trials suggests that lifestyle intervention can significantly reduce progression of MetSyn to overt T2DM. In the Diabetes Prevention Program9 nondiabetic subjects who were randomly assigned to participate in an intensive lifestyle modification program were given metformin or a placebo for a mean of 2.8 years. Lifestyle modification programs consisted of healthy, low-calorie, and low-fat diet and 150 min of weekly moderate-intensity exercise in order to achieve a body weight reduction of at least 7%. In this randomized controlled trial, intensive lifestyle intervention was more effective than metformin in delaying the onset of T2DM, and both were more effective than placebo in preventing new T2DM. Modeled after the intervention in the Diabetes Prevention Program, the ADA/EASD 2019 Standards of Care suggest 7% weight loss and 150 min of moderate-intensity physical activity per week, in addition to healthy low-calorie eating patterns.
Glycemic Control
Improved glycemic control reduces progression and, in some instances, even reverses microvascular complications in patients with DM. However, these benefits have to be balanced with the risks of hypoglycemia and cardiovascular effects. Three major outcome trials ACCORD,20 ADVANCE,8 and VADT21 randomizing over 23,000 patients with follow-up of 3 to 5 years compared the cardiovascular effects of intensive glycemic control versus standard care. The trials did not report cardiovascular benefits of tight glycemic control. ACCORD was terminated prematurely after observing increased mortality in individuals of the very intense glycemic control arm (1.41% vs 1.14% per year; 257 vs 203 deaths over a mean 3.5 years of follow-up; hazard ratio [HR] 1.22 [95% confidence interval (CI) 1.01-1.46]).20 In all trials, severe hypoglycemia was more common in the intensive glycemic control group. As hypoglycemia is strongly associated with cardiovascular events and mortality, guidelines advocate for wariness of hypoglycemia and not persist in accomplishing euglycemia in individuals where HbA1c targets cannot be safely achieved.18 In response to the complexity of adequate glycemic control, the 2019 ADA/EASD Standards of Medical Care emphasize the importance of shared decision-making to incorporate the distinct characteristics and preferences of each patient to induce optimal glycemic control.18 In general, for nonpregnant adults, a general target of less than 7% HbA1c is still recommendable. In patients without CVD and long life expectancy, or only treated with lifestyle therapy or metformin, a more stringent HbA1c target (<6.5%) is suitable to prevent microvascular complications. HbA1c levels of 8% are acceptable in patients with short life expectancy, serious comorbidities, or inadequate self-management.8
General Therapeutic Plan According to Guidelines
Type 1 Diabetes Mellitus
Multiple daily injections of either basal or prandial insulin should be the main treatment strategy for patients with T1DM. Alternatively, subcutaneous administration through an insulin pump is equally safe and effective. To reduce hypoglycemia risk, rapid-acting insulin analogs are recommended. Education on matching insulin dosage with carbohydrate intake, preprandial glucose levels, and physical exercise is essential for patients starting insulin therapy.
Type 2 Diabetes Mellitus
The 2019 ADA/EASD Standards of Medical Care recommend an individualized approach to pharmacologic therapy of DM.
When choosing the optimal antidiabetes medication, key comorbidities (atherosclerotic cardiovascular disease [ASCVD], heart failure [HF], and chronic kidney disease [CKD]), effect on body weight, side effects, risk of hypoglycemia, cost, and patient preference should be taken into account (Algorithm 98.2). Although traditionally metformin has been the first-line agent for all patients diagnosed with T2DM, the new 2019 ESC guidelines recommend sodium-glucose cotransporter-2 (SGLT-2) inhibitors or glucagon-like peptide-1 receptor agonist (GLP1-RA) monotherapy to metformin-naive patients with ASCVD or high CVD risk.10 (
e-Figure 98.1) In such patients, if HbA1c target is not reached, metformin can be added. For patients at low CVD risk, metformin should still be the first choice and initiated at the time of diagnosis. If adequate glycemic control is not achieved after 3 months and patients do not have ASCVD or CKD, a combination of metformin with any of the following drugs is possible: SGLT-2 inhibitors, dipeptidyl peptidase 4 (DPP-4) inhibitors, GLP1-RAs, sulfonylureas, or thiazolidinediones (TZDs). Insulin is no longer considered part of initial therapy and should only be used if lifestyle intervention and other antidiabetic medications did not have the desired effect. In the absence of comorbidities, the decision of antidiabetic medications should be based on side effects and patient-specific factors. Multiple large randomized controlled studies have demonstrated the statistically significant cardiovascular benefits of SGLT-2 inhibitors and GLP1-RAs for patients with T2DM. In such cardiovascular outcome trials (CVOTs), SGLT-2 inhibitors demonstrated reduction in HF and CKD and thus should be prescribed in patients at increased risk of HF or CKD if estimated glomerular filtration rate (eGFR) is adequate. Specifically, evidence from CVOTs demonstrated reduction of HF incidence and CKD progression for canagliflozin, dapagliflozin, and empagliflozin. If eGFR is not acceptable or SGLT-2 inhibitors are not tolerated, clinicians should subscribe GLP1-RAs that demonstrated reduction of ASCVD events. GLP1-RAs are currently the most effective antidiabetic agents for weight loss and should be preferred when need for obesity treatment predominates.11 GLP1-RAs are also a viable alternative for patients with high ASCVD risk. Currently, weekly injections with semaglutide and dulaglutide are preferred.12 Worsening of glycemic control in T2DM contributes to progressive β-cell apoptosis during the course of the disease.13 GLP1-RA may preserve β-cell function and thereby play a particularly important role early on in the disease process.14,15 TZDs should be avoided in patients with HF. DPP-4 inhibitors are no longer considered first-line drugs because of the risk of HF associated with some agents and only modest reduction of HbA1c levels. As a result of the complete or almost-complete absence of β-cell function in patients with T1DM, insulin therapy is essential. For patients with T2DM however, insulin is a method of last resort and should only be introduced if treatment goals are not met with lifestyle modification and other antidiabetic medications. Because of the risk of hypoglycemia as well as weight gain, insulin should be avoided as long as possible in patients with T2DM. In addition, cost of insulin has been rising and may pose a significant burden for patients, contributing to therapy nonadherence.16
When choosing the optimal antidiabetes medication, key comorbidities (atherosclerotic cardiovascular disease [ASCVD], heart failure [HF], and chronic kidney disease [CKD]), effect on body weight, side effects, risk of hypoglycemia, cost, and patient preference should be taken into account (Algorithm 98.2). Although traditionally metformin has been the first-line agent for all patients diagnosed with T2DM, the new 2019 ESC guidelines recommend sodium-glucose cotransporter-2 (SGLT-2) inhibitors or glucagon-like peptide-1 receptor agonist (GLP1-RA) monotherapy to metformin-naive patients with ASCVD or high CVD risk.10 (
e-Figure 98.1) In such patients, if HbA1c target is not reached, metformin can be added. For patients at low CVD risk, metformin should still be the first choice and initiated at the time of diagnosis. If adequate glycemic control is not achieved after 3 months and patients do not have ASCVD or CKD, a combination of metformin with any of the following drugs is possible: SGLT-2 inhibitors, dipeptidyl peptidase 4 (DPP-4) inhibitors, GLP1-RAs, sulfonylureas, or thiazolidinediones (TZDs). Insulin is no longer considered part of initial therapy and should only be used if lifestyle intervention and other antidiabetic medications did not have the desired effect. In the absence of comorbidities, the decision of antidiabetic medications should be based on side effects and patient-specific factors. Multiple large randomized controlled studies have demonstrated the statistically significant cardiovascular benefits of SGLT-2 inhibitors and GLP1-RAs for patients with T2DM. In such cardiovascular outcome trials (CVOTs), SGLT-2 inhibitors demonstrated reduction in HF and CKD and thus should be prescribed in patients at increased risk of HF or CKD if estimated glomerular filtration rate (eGFR) is adequate. Specifically, evidence from CVOTs demonstrated reduction of HF incidence and CKD progression for canagliflozin, dapagliflozin, and empagliflozin. If eGFR is not acceptable or SGLT-2 inhibitors are not tolerated, clinicians should subscribe GLP1-RAs that demonstrated reduction of ASCVD events. GLP1-RAs are currently the most effective antidiabetic agents for weight loss and should be preferred when need for obesity treatment predominates.11 GLP1-RAs are also a viable alternative for patients with high ASCVD risk. Currently, weekly injections with semaglutide and dulaglutide are preferred.12 Worsening of glycemic control in T2DM contributes to progressive β-cell apoptosis during the course of the disease.13 GLP1-RA may preserve β-cell function and thereby play a particularly important role early on in the disease process.14,15 TZDs should be avoided in patients with HF. DPP-4 inhibitors are no longer considered first-line drugs because of the risk of HF associated with some agents and only modest reduction of HbA1c levels. As a result of the complete or almost-complete absence of β-cell function in patients with T1DM, insulin therapy is essential. For patients with T2DM however, insulin is a method of last resort and should only be introduced if treatment goals are not met with lifestyle modification and other antidiabetic medications. Because of the risk of hypoglycemia as well as weight gain, insulin should be avoided as long as possible in patients with T2DM. In addition, cost of insulin has been rising and may pose a significant burden for patients, contributing to therapy nonadherence.16 ALGORITHM 98.2 Novel pharmacologic approach to type 2 diabetes mellitus (T2DM). The 2019 ADA/EASD Standards of Medical Care recommend an individualized approach to pharmacologic therapy of diabetes mellitus. Cardiovascular comorbidities (ASCVD, HF, and CKD), body weight, side effects, risk of hypoglycemia, cost, and patient preference should be taken into account. SGLT-2 inhibitors should be preferred if HF or CKD predominates, whereas GLP-1 receptor agonists are the good agents to promote weight loss. ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; CVD, cardiovascular disease; GLP-1, glucagon-like peptide-1; HF, heart failure; SGLT-2, sodium-glucose cotransporter-2. |
Pharmacologic Therapy for Type 1 Diabetes Mellitus
Insulin
For patients with T1DM, multiple daily injections or use of a subcutaneous insulin pump is the safest as well as the most effective method of insulin administration. In general, insulin doses range from 0.4 to 1.0 units/kg/day, with higher doses necessary during pregnancy, illness, and puberty.
Drug Interactions or Major Restrictions. A major disadvantage of insulin therapy is risk of hypoglycemia (Table 98.2). The 2019 ADA/EASD 2019 Standards of Care recommend rapid-acting insulin analogs to reduce risk of hypoglycemia in individuals with T1DM.8 Insulin dosage may be increased when subscribed with diuretics,17 steroids, and oral contraceptives, as these agents inhibit insulin release and elevate peripheral IR. Clinicians should also be aware of reducing insulin dosage in patients with renal impairment, as insulin clearance is compromised. Inhaled insulins are not recommended for patients diagnosed with asthma, chronic obstructive pulmonary disease, or other chronic lung diseases.8
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