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Did You Know: Safety Concerns for Diabetes Medications

When it comes to antidiabetic therapies, professionals should be aware of the following safety concerns:  

Diabetes: Medication Safety Concerns

Authors Tom Palma, RPh, MS, BCPS, and Greg Wiggers, PharmD, PhD

  1. Concentrated Insulin Formulations:  Concentrated insulin such as Humulin R U-500 carries a greater risk for adverse effects such as hypoglycemia and is intended only for patients requiring > 200 units of insulin per day.  Clinicians and patients commonly draw up doses from a U-500 insulin vial with a U-100 insulin syringe or a TB syringe. A conversion step is required to ensure the correct amount of U-500 insulin is drawn into these syringes. If conversion is not done correctly, there is a chance for a potentially serious dosing error.  To reduce confusion and the need for conversion, a U-500 syringe intended specifically for use with U-500 insulin vial has been approved. It is calibrated in 5-unit measures and can deliver 5 to 250 units per injection. Most importantly, there are no conversion steps required.  U-500 insulin vials are to be used only in conjunction with a dedicated U-500 insulin syringe. For patients being discharged from the hospital and/or in the outpatient setting, the U-500 insulin syringe should only be prescribed/dispensed in conjunction with U-500 insulin vials. In order to fully realize risk minimization, all levels of healthcare (prescribing, dispensing, administration, patient education) must be aware of this change in order to safely transition to using the dedicated U-500 syringes.
  2. Metformin and Renal Function:  Lactic acidosis is one rare but serious metabolic complication that can occur due to metformin accumulation, particularly in patients with renal impairment. Previously, criteria for using metformin in patients with renal impairment were based upon gender and serum creatinine, which may often be a poor estimate of actual renal function, especially in older patients or those with extremes of muscle mass or albuminuria. Equations for determining the estimated glomerular filtration rate (eGFR) such as the Modified Diet in Renal Disease (MDRD) and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) take into account age, gender, and race in addition to serum creatinine, providing significantly more accurate estimates of renal function. These types of equations should be used exclusively to determine patients at highest risk of lactic acidosis with metformin use (eg, eGFR <30 mL/minute/1.73 m2), while allowing for increased metformin use in patients with lesser degrees of renal impairment. Although much improved, equations such as MDRD or CKD-EPI still rely on measurement of serum creatinine and may be less accurate in patients with extremes of muscle mass or if kidney function is unstable. The MDRD equation has been validated in patients up to 70 years of age, and the National Institute of Diabetes and Digestive and Kidney Diseases suggests that use of MDRD may also be useful in patients older than 70 years.   Another risk factor for metformin-induced lactic acidosis is iodinated contrast dye imaging. Many injectable contrast dyes are associated with acute kidney injury, which can lead to rapid metformin accumulation and lactic acidosis. Previously it was recommended to withhold metformin in all patients receiving contrast dyes. Current recommendations suggest withholding metformin only in patients with eGFR < 60 mL/minute/1.73 m2, hepatic disease, alcoholism, or heart failure; or in patients who will receive intra-arterial iodinated contrast.
  1.     SGLT-2 Inhibitors and Diabetic Ketoacidosis: (See comment from Dr. George Bakris)  Diabetic ketoacidosis (DKA) is a life-threatening condition usually characterized by ketoacidosis and hyperglycemia (> 250 mg/dL) and can be precipitated by surgery, infections, sepsis, alcohol, severe injury, hypovolemia, pancreatitis, and severe metabolic stress-related conditions (e.g., myocardial infarction or marathon running).DKA has also been associated with use of sodium-glucose cotransporter 2 (SGLT2) inhibitors. In some cases, patients developing DKA while receiving SGLT2 inhibitors have had normal or modestly elevated blood glucose levels (< 250 mg/dL). Clinicians should not exclude DKA diagnosis in patients receiving SGLT2 inhibitor therapy on the basis of normal or modestly elevated blood glucose levels. Patients presenting with nausea/vomiting, abdominal pain, generalized malaise, and/or shortness of breath should be assessed immediately for ketoacidosis.Patients should ensure adequate hydration during SGLT2 therapy. Additionally, to minimize the risk of DKA, the American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology recommend the following:
  •        Stop SGLT2 inhibitor therapy immediately for emergency surgery or any extreme stress event
  •        Consider interrupting therapy for at least 24 hours prior to elective surgery or anticipated severe stressful physical events
  •        Avoid stopping insulin or decreasing the dose excessively
  •        Avoiding excessive alcohol intake and very low carbohydrate/ketogenic diets during SGLT2 inhibitor therapy

Comment from Dr. George Bakris:  Much of what is said in this commentary is true but the key issue with the updates relates to level of kidney function. While it is true the current method of assessing GFR is valid only within a certain age group most endocrinologists and nephrologists understand about these limitations, importance of muscle mass and other issues. The data indicate that lactic acidosis is not a risk if the eGFR is above 60 and hence nothing is done if getting contrast or other test. Key in mind those who got contrast and developed lactic acidosis also had acute reduction in kidney function, i.e. acute kidney injury from contrast which is always followed after such procedures and in specific cases if recovery is prolonged metformin is held for a week or two.

Tom Palma, RPh, MS, BCPS, is a board certified pharmacotherapy specialist who has worked as a clinical content specialist with Wolters Kluwer Clinical Drug Information for the past ten years. He earned both his pharmacy and graduate degree from The Ohio State University.

Greg Wiggers PharmD, PhD, has worked as a clinical content specialist with Wolters Kluwer Clinical Drug Information for the past four years. He earned his PharmD from Northeast Ohio Medical University (NEOMED) and his PhD from Case Western Reserve University.