Diabetes Risks from Prescription and Nonprescription Drugs. Samuel Dagogo-Jack

pain syndromes). A vast literature abounds, however, on the potential adverse effects of numerous medications on glucose metabolism. There is, thus, genuine clinical concern that certain medications used for treatment of comorbid conditions and other indications (such as hormone replacement, contraception, infections) might worsen glycemic control in diabetic patients or trigger diabetes in others. These concerns influence therapeutic decisions in a manner that sometimes emphasizes avoidance of possible dysglycemia over effective control of the comorbid conditions. The same concerns may also weigh against the otherwise appropriate use of necessary medications.

      The purpose of this concise book is to provide clinicians with actionable knowledge regarding the effects of various medications on glucose regulation and diabetes risk. Beginning with a brief overview of diabetes pathophysiology, the different drugs have been organized by class, and the scientific evidence for the diabetes risk and possible mechanisms have been presented for each drug. The agents discussed include widely prescribed medication classes: antibiotics, antidepressants, antihypertensives, bronchodilators, sex hormones (androgens, estrogens, and oral contraceptives), glucocorticoids, lipid-lowering agents, nonsteroidal anti-inflammatory drugs, acetaminophen, and thyroid hormone. Although less widely prescribed than the foregoing list, atypical antipsychotics, HIV antiretrovirals, immunomodulatory agents used in transplant medicine, gonadotropin-releasing hormone analogs, and human growth hormone also have been included because of the interest generated by their link to diabetes risk. In addition to medications used in ambulatory practice, this work includes a discussion of total parenteral nutrition (TPN)–induced hyperglycemia, which is associated with increased morbidity and mortality among hospitalized patients. For completeness, because of the possible intersection between these addictive agents and the global diabetes epidemic, an account of the growing link between the use of recreational drugs (alcohol, nicotine, marijuana, opioids, cocaine, amphetamine-like drugs and other psychostimulants) and glucose abnormalities has been included.

      With some medications, the data presented should help debunk myths, clarify misperceptions, and provide reassurance to practicing clinicians. Wherever the evidence supports increased diabetes risk, clear suggestions are given on how to reduce the risk. Also covered in this book are diabetes management guidelines for special situations, including new-onset diabetes after transplant and TPN-induced hyperglycemia. The final chapter provides a general approach to the prevention or attenuation of diabetes risk, focusing on risk stratification, lifestyle modification, and a critical appraisal of the medications that have been demonstrated, in clinical trials, to prevent or delay diabetes. Also introduced is the emerging concept of diabetes pharmacoprophylaxis in high-risk individuals receiving treatment with potentially diabetogenic agents.

      The knowledge gained from reading this book should enable clinicians to become well informed regarding the impact of a wide variety of commonly used medications on glucose homeostasis and the risks of drug-induced diabetes or exacerbation of preexisting diabetes. With such knowledge, clinicians will be better positioned to design and select therapeutic regimens that embody the best risk–benefit profile with regard to glycemia and concurrent management of the primary or comorbid conditions.

       1: Overview of Diagnosis, Classification, and Pathophysiology of Diabetes

      DOI: 10.2337/9781580406192.01

      Diabetes

      Diabetes refers to a group of metabolic disorders that result in hyperglycemia. These disorders have different underlying processes but their common manifestation is hyperglycemia, regardless of underlying process. More than 29 million Americans have diabetes and approximately 8 million of these individuals are undiagnosed. Diabetes is a major public health problem because of the long-term complications (such as blindness, amputations, kidney failure, heart disease, and stroke) that could occur if the condition is inadequately controlled. Fortunately, the complications of diabetes can be prevented by maintaining excellent glycemic control, using comprehensive diabetes management.^1,2

      Diagnosis of Diabetes and Prediabetes

      The diagnosis of diabetes (Figure 1.1) can be established using any of the following American Diabetes Association criteria:

      • Plasma glucose of ≥126 mg/dL after an overnight fast. A repeat test on a different day is required to confirm the diagnosis of diabetes.³

      • Symptoms of diabetes and a random (nonfasting) plasma glucose of ≥200 mg/dL.

      • A standard oral glucose tolerance test (OGTT) showing a plasma glucose level of ≥200 mg/dL at 2 h after ingestion of a 75-g glucose load, provided all testing protocols are followed.

      • A hemoglobin A1c level of >6.5%.

      In the absence of unequivocal hyperglycemia with typical symptoms, abnormal test results should be confirmed by repeat testing.³

      Figure 1.1—Fasting plasma glucose (FPG), oral glucose tolerance test (OGTT), random blood glucose (RBG), and HbA_1c criteria for diagnosis of diabetes and prediabetes.

      Prediabetes

      The term prediabetes is used to describe persons with impaired glucose tolerance (IGT) or impaired fasting glucose (IFG). IGT is defined by a 2-h OGTT plasma glucose level >140 mg/dL but <200 mg/dL, and IFG is defined by a fasting plasma glucose level of ≥100 mg/dL but <126 mg/dL.³ Approximately 86 million Americans have prediabetes, and studies have shown that people with prediabetes tend to develop type 2 diabetes (T2D) at a rate of ~10% per year. Recently, it was observed that initially normoglycemic offspring of parents with T2D develop incident prediabetes at a rate of ~10% per year.⁴ Lifestyle modifications (dietary restriction and exercise) and certain medications can prevent the development of diabetes in people with prediabetes.⁵

      Classification of Diabetes

      Type 1 diabetes (T1D) accounts for <10% of all cases of diabetes, occurs in younger people, and is caused by absolute insulin deficiency resulting from an immune-mediated destruction of the insulin-producing cells of the pancreas, known as β-cells. T2D accounts for >90% of all cases of diabetes (Figure 1.2). Usually a disease of adults, T2D is being diagnosed increasingly in younger age-groups. Obesity, insulin resistance, and relative insulin deficiency are characteristic findings. Insulin resistance refers to a decreased ability of insulin to drive the uptake of glucose from the blood into the cells and to produce the other appropriate metabolic effects of insulin. People with insulin resistance alone do not develop diabetes, because their pancreatic β-cells compensate by increasing insulin secretion to levels that can maintain normoglycemia. Therefore, a second defect—an inability to maintain compensatory hyperinsulinemia—is required to precipitate T2D. Other specific types of diabetes include those that result from surgical resection or diseases of the exocrine pancreas (such as cystic fibrosis), glandular disorders (e.g., Cushing’s syndrome, acromegaly), and monogenic syndromes (e.g., maturity-onset diabetes of the young). Gestational diabetes occurs during the second half of pregnancy and tends to resolve once the baby and placenta have been delivered (although the mother remains at high risk for future T2D).³

      Figure 1.2—The two major types of diabetes mellitus.

      The Genetic Basis of Diabetes

      Interactions between genetic and environmental factors are well recognized in the pathogenesis of T1D and T2D (Figure 1.3). In T1D, the expression of inherited disease susceptibility markers of the major histocompatibility (HLA) gene family predisposes individuals to islet β-cell damage, classically through autoimmune-mediated mechanisms. The environmental triggers for such autoimmune destruction of the β-cells are believed to include certain viruses.⁶ A family history of diabetes in first-degree relatives (parents, siblings, and offspring) is one of the strongest risk factors for the development of diabetes. The genetic transmission of diabetes risk from parents to offspring