Patients Are Increasingly at Risk for Insulin-Drug Interactions

Health Care Professionals Should Be Aware of Classes of Medications and Conditions That May Affect Blood Glucose Levels.

Nearly half of American adults have diabetes or prediabetes, and every 21 seconds, another individual is given a diagnosis of diabetes,¹ leading to almost 1.5 million diagnoses every year.

More than half of Americans take prescription medications regularly for a variety of conditions, 4 on average, according to Consumer Reports.² Rising prescription drug use means that patients on insulin are increasingly at risk for drug—drug interactions.

Insulin, a hormone produced in pancreatic β cells, regulates blood sugar. With sufficient insulin in the body, blood sugar does not spike. After a meal or a snack, the pancreas secretes insulin and signals the body to absorb glucose. In individuals with type 1 diabetes, insulin production is impaired. In those with type 2 diabetes, fat, liver, and muscle cells do not respond properly to insulin. This is known as insulin resistance.³

Because the body produces insulin regularly, drug interactions with insulin differ from other drug—drug interactions. Practitioners should be aware of classes of medications and conditions that may affect blood glucose levels. By predicting the effect that a medication will have on patients’ blood glucose levels, prescribers can tailor insulin therapy appropriately.

Managing Diabetes

An individual’s glycated hemoglobin (A1C) level reflects average glycemia over about 3 months and has strong predictive value for diabetes complications. A reasonable A1C goal for many nonpregnant adults is 7% or lower.⁴ That said, some providers suggest more stringent A1C goals, such as <6.5% for certain patients in the absence of significant hypoglycemia or other adverse effects. Less stringent A1C goals (eg, <8%) may be appropriate for patients who have a history of or are at risk for severe hypoglycemia.⁴

Basal insulin is initiated in patients usually with metformin with or without another noninsulin agent.⁵ The American Diabetes Association recommends pharmacologic approaches to glycemic treatment in its Standards of Medical Care in Diabetes—2018. The Figure describes the basic steps that clinicians need to follow to initiate and tailor treatment.⁵

Glucocorticoids

Glucocorticoids, or steroids, are the most frequently prescribed class of anti-inflammatory drugs for chronic inflammatory diseases. In addition to acting on glucocorticoid receptors, glucocorticoids cause varying degrees of β-cell dysfunction, including the reduction of insulin sensitivity.⁶ Glucocorticoids activate various genes involved in hepatic carbohydrate metabolism, causing hyperglycemia and increasing endogenous glucose production. Their ability to induce hyperglycemia depends on several factors, such as dose and duration of use.⁷

Steroids’ effects are usually dose dependent, reversible, and transient. As steroid doses are reduced, their effect on endocrine metabolism returns to baseline and drug-induced hyperglycemia resolves.

Practitioners should increase normal insulin by 10% to 20% if a patient is known to have diabetes and is hyperglycemic and on steroid therapy.⁸ Additionally, clinicians should adjust insulin doses based on changes in steroid doses to prevent hyperglycemia and/or hypoglycemia. They should adjust insulin to half the percentage in steroid change. For example, if a patient’s steroid dose is reduced by 50%, the insulin dose should be reduced by 25%.⁸ So, in a patient on 25 units of basal insulin daily and 20 mg of prednisone, reduction of the steroid dose to 10 mg of prednisone daily, a 50% reduction, should be accompanied by a basal insulin reduction of 25%. The patient will be on 19 units of basal insulin daily.

Stress Hyperglycemia

Acute illness or injury may result in glucose intolerance, hyperglycemia, and insulin resistance. Results from numerous studies show a strong association between stress hyperglycemia and poor clinical outcomes, including infections, increased duration of hospitalization, morbidity, mortality, and overall complications.

Patients who are acutely ill and hospitalized may have an increased stress response mediated by the hypothalamic-pituitary-adrenal (HPA) axis. In certain cases, this response can lead to chronic hyperglycemia, which contributes to microvascular complications (eg, diabetic nephropathy, neuropathy, and retinopathy).⁹ Catecholamine, cortisol, and epinephrine all increase and result in multiple effects aimed at restoring homeostasis during stress. The HPA axis and proinflammatory cytokines act synergistically to induce stress hyperglycemia.¹⁰ Chronic hyperglycemia needs to be managed by a primary care provider in an ambulatory care setting.

For patients with stress hyperglycemia, results from randomized controlled studies do not support intensive insulin therapy. In fact, mild to moderate stress hyperglycemia is protective during critical illness and times of stress.¹⁰

Clinicians should increase insulin cautiously in patients who are acutely ill and monitor blood glucose periodically. Treating the illness will lower blood glucose levels to baseline, but patients who have severe stress hyperglycemia (blood glucose exceeding 220 mg/dL) may benefit from insulin adjustment.¹⁰

Common medications used in patients with diabetes may require insulin adjustments (Table).^11-17

Conclusion

Patients with diabetes often take antipsychotics, β-blockers, corticosteroids, and thiazide diuretics. Clinicians must weigh the pros and cons of these medications in patients with diabetes. They are not contraindicated, but clinicians should adjust insulin in the context of these medications. Being aware of medications and conditions that may cause hyperglycemia or hypoglycemia helps ensure patient safety and provides better health outcomes.

Mohammed Waleed is a 2019 PharmD candidate at the University of Connecticut School of Pharmacy in Storrs.

References

• Statistics about diabetes. American Diabetes Association website. diabetes.org/diabetes-basics/statistics/. Updated March 22, 2018. Accessed July 27, 2018.
• Carr T. Too many meds? America’s love affair with prescription medication. Consumer Reports website. consumerreports.org/prescription-drugs/too-many-meds-americas-love-affair-with-prescription-medication/. Published August 3, 2017. Accessed July 27, 2018.
• Campbell A. What does insulin do? Diabetes Self-Management website. diabetesselfmanagement.com/blog/what-does-insulin-do/. Published December 5, 2016. Accessed July 27, 2018.
• American Diabetes Association. Standards of medical care in diabetes-2018 abridged for primary care providers. Clin Diabetes. 2018;36(1):14-37. doi: 10.2337/cd17-0119.
• American Diabetes Association. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2018. Diabetes Care. 2018;41(suppl 1):S73-S85. doi: 10.2337/dc18-S008.
• Di Dalmazi G, Pagotto U, Pasquali R, Vicennati V. Glucocorticoids and type 2 diabetes: from physiology to pathology. J Nutr Metab. 2012;2012:525093. doi: 10.1155/2012/525093.
• van Raalte DH, Ouwens DM. Diamant M. Novel insights into glucocorticoid&#8208;mediated diabetogenic effects: towards expansion of therapeutic options? Eur J Clin Invest. 2009;39(2):81-93. doi: 10.1111/j.1365-2362.2008.02067.x
• Tamez-Pérez HE, Quintanilla-Flores DL, Rodríguez-Gutiérrez R, González-González JG, Tamez-Peña AL. Steroid hyperglycemia: prevalence, early detection and therapeutic recommendations: a narrative review. World J Diabetes. 2015;6(8)1073-1081. doi: 10.4239/wjd.v6.i8.1073.
• Di Carli MF, Janisse J, Grunberger G, Ager J. Role of chronic hyperglycemia in the pathogenesis of coronary microvascular dysfunction in diabetes. J Am Coll Cardiol. 2003;41(8):1387-1393.
• Marik PE, Bellomo R. Stress hyperglycemia: an essential survival response! Crit Care Med. 2013;41(6):e93-e94. doi: 10.1097/CCM.0b013e318283d124.
• Repaske DR. Medication-induced diabetes mellitus. Pediatr Diabetes. 2016;17(6):392-397. doi: 10.1111/pedi.12406.
• Gale EAM. Drug-induced diabetes. Diapedia website. diapedia.org/other-types-of-diabetes-mellitus/41040851133/drug-induced-diabetes. Updated August 13, 2014. Accessed July 27, 2018.
• Marino MT. Drugs that can worsen diabetes control. Diabetes Self-Management website. diabetesselfmanagement.com/managing-diabetes/blood-glucose-management/drugs-that-can-worsen-diabetes-control/. Published April 14, 2009. Accessed July 27, 2018.
• Chou HW, Wang JL, Chang CH, Lee JJ, Shau WY, Lai MS. Risk of severe dysglycemia among diabetic patients receiving levofloxacin, ciprofloxacin, or moxifloxacin in Taiwan. Clin Infect Dis. 2013;57(7):971-980. doi: org/10.1093/cid/cit439.
• Alcohol. American Diabetes Association website. diabetes.org/food-and-fitness/food/what-can-i-eat/making-healthy-food-choices/alcohol.html. Updated October 16, 2017. Accessed July 27, 2018.
• Rehman A, Setter SM, Vue MH. Drug-induced glucose alterations part 2: drug-induced hyperglycemia. Diabetes Spect. 2011;24(4):234-238. doi: 10.2337/diaspect.24.4.234.
• Casqueiro J, Casqueiro J, =Alves C. Infections in patients with diabetes mellitus: a review of pathogenesis. Indian J Endocrinol Metab. 2012;16(suppl 1):S27-S36. doi: 10.4103/2230-8210.94253.