Drug Interaction Potential of Antidiabetic Medications

Diabetes occurs comorbidly with many other medical conditions, such as hypertension, dyslipidemia and central nervous system disorders.¹ The “multifactorial pharmacotherapy” necessitated by these conditions leads to a higher risk of adverse drug effects and interactions.¹ Specific issues of concern are cytochrome P-450 (CYP) enzyme interactions, altered absorption properties, and transporter activities. Added to the complex picture of potential drug interaction risk are nutritional factors, herbal supplements, and other parameters such as the patient’s age and gender.¹

A recent literature review by May and Schindler² examines the pharmacokinetic and pharmacodynamic properties of antidiabetic drugs and their clinically relevant interactions.

The authors define a drug interaction as “either an increase or decrease of a medical diagnostic or therapeutic effect of a specific drug caused by another substance, which may be another drug, plant, or a dietary supplement.”  They divide interactions into two categories: pharmacokinetic and pharmacodynamic.

Pharmacokinetic Interactions

Pharmacokinetic interactions “influence absorption, distribution, metabolism, or excretion of a drug (ADME rule) and thus lead to increased or reduced plasma levels of a drug,” with each drug affecting the metabolic pathway of the other concomitantly taken drug.¹ This leads to either increased or decreased plasma levels of one or both, compared with the plasma levels if each drug were taken separately.²

The mechanism of pharmacokinetic interaction often involves inhibition, induction, or degradation of liver enzymes,³ typically based on oxidative metabolism by the CYP enzyme system or an interaction with the drug transported P-glycoprotein. Other mechanisms involve altered plasma binding; displacement from plasma protein binding; and abnormalities in absorption and excretion, which can can also lead to pharmacokinetic drug interactions. For example, altered gastric pH or formation of insoluble complexes within the gastrointestinal tract caused by certain foods or nutritional supplements can result in altered absorption rates. In patients with diabetes, this can reduce and delay metformin absorption when drug intake coincides with food ingestion. This process causes significant differences in the plasma concentration of several drugs.¹

Herbal supplements “represent a complex problem when taken concomitantly with a pharmacological treatment” because they are usually available over the counter, are unregulated, and can contain a multitude of bioactive substances.¹ For this reason, antidiabetic drugs metabolized by hepatic enzymes should be carefully monitored in patients taking these supplements.¹ Common herb-drug interactions can be found in Table 1.

Polypharmacy is common in patients with diabetes⁴ and tends to increase in patients over age 65, who may be taking as many as five or more different prescribed drugs.⁵ Adverse effects may include cognitive impairment and falls due to dizziness, weight change, and heart disease. These effects increase as the number of drugs increases. Moreover, liver and renal capacity decreases with age, with resulting impairments in the ability to metabolize and eliminate drugs. For this reason, a highly individualized approach to drug therapy is required in this population.¹