Sulfonylureas and Basal Insulin: A Logical Combination?

Authors:
Eric A. Dietrich, PharmD, BCPS, and Kyle Davis, PharmD, BCPS

Citation:
Dietrich EA, Davis K. Sulfonylureas and basal insulin: a logical combination? Consultant. 2017;57(12):708,710.

In 2015, 23.1 million Americans had diagnosed diabetes, and an estimated 7.2 million more had undiagnosed diabetes.¹ In recent years, the number of diabetes treatment options has greatly expanded, such that 9 classes of oral medications are now approved by the Food and Drug Administration, in addition to the various insulin formulations and other injectable agents (such as glucagon-like peptide-1 receptor agonists). Combination therapy is often required in order to attain patients’ blood glucose goals, and given the numerous options available, selecting the most appropriate combination therapy can be difficult. Metformin remains a cornerstone of therapy for patients who are able to tolerate it, given its favorable safety and efficacy profile and its low cost. Because of these advantages, metformin is routinely combined with other oral and injectable agents, including basal insulin. Similarly, sulfonylureas (SUs) are a frequent component of combination therapy, given their extensive history of use and low cost. Does it make sense, however, to continue an SU when basal insulin is added to a patient’s antidiabetes regimen?

Patient Case

AM is a 68-year-old woman with a history of type 2 diabetes mellitus, hypertension, hyperlipidemia, and obesity. She is on amlodipine, 10 mg daily; lisinopril, 20 mg daily; atorvastatin, 20 mg daily; metformin, 1000 mg twice daily; and glimepiride, 4 mg daily. Despite her efforts to modify her diet and exercise, and despite her adherence to her metformin and glimepiride therapy, AM’s glycated hemoglobin (HbA_1c) continues to increase, measuring 9.2% at this visit. All of AM’s other laboratory test results and vital signs are within normal limits.

Given this degree of HbA_1c elevation despite therapy with 2 oral agents, it is unlikely that additional oral agents will be able to attain an HbA_1c of less than 7%, indicating that AM will need to begin basal insulin (insulin degludec, detemir, or glargine). During and after the initiation and titration of the basal insulin, should AM continue to receive glimepiride?

The Evidence

SUs lower blood glucose by stimulating the pancreas to increase the production and release of endogenous insulin. While the HbA_1c-lowering effect of SUs initially is robust (1%-2%), often this beneficial effect wanes with time. Given that the pancreas of a person with diabetes is already overworked (thereby leading to the diagnosis of diabetes, as endogenous insulin production is unable to keep up with the body’s demand), further increases in the workload may “burn out” the pancreas more quickly.

Furthermore, at the time of diagnosis, a person with diabetes has on average only 50% of β-cell function remaining. Because diabetes results in a progressive decline in β-cell function, this production capacity will only diminish over time. Because SUs rely on the pancreas’s ability to produce insulin, it seems logical to think that at some point the pancreas simply will run out of any extra “reserve” in insulin production capability, and that the medication will no longer have the same efficacy as it did in the early stages of treatment.

Although SUs have been studied in combination with basal insulin, we believe that this combination is a clash of clinical reasoning. SUs aim to increase insulin production from the pancreas, whereas exogenously administered insulin either supplements or completely replaces inadequate endogenous insulin production. By selecting insulin as a treatment option, one is assuming that the pancreas is incapable of secreting enough insulin to meet the demands of the body. Therefore, adding an agent that exclusively attempts to increase endogenous insulin production seems to carry a high risk for treatment failure, since the uncontrolled HbA_1c (which is the precipitant for adding an additional agent) is likely directly related to a mismatch between insulin supply and demand.

The practicality of such a regimen also should be considered. The ability of SUs to increase insulin release depends on the β-cell function of the patient’s pancreas. Patients with higher remaining β-cell function are better able to produce insulin. However, estimation of β-cell function cannot be readily and accurately performed in the clinical setting, which introduces an element of guesswork into the clinician’s decision. With exogenous insulin, this guesswork is removed, since the efficacy of this treatment can be independent of β-cell function (or can work with endogenous insulin), given that this medication class does not rely on endogenous pancreatic function for efficacy.

Secondly, while a dose-dependent relationship exists between SUs and insulin release, there is not a clear and consistent dose-response such that x mg of an SU leads to y units of insulin being released. Certainly, this relationship differs from patient to patient based on age, duration of diabetes, HbA_1c, current and past medications, and numerous other factors that introduce a wide range of variability in response. Indeed, those patients with higher levels of β-cell function are likely to experience more

insulin release compared with patients with lower levels of β-cell function. With basal insulin, especially given the availability of insulin pens today, the dose can be titrated by single units to allow for a specific and individualized dose to be administered to maximize safety and efficacy.

These concerns about SUs are shared by the American Association of Clinical Endocrinologists and the American College of Endocrinology,² both of whom consider SUs as a last-line diabetes treatment option. While the low cost of this medication class will likely preserve a role for it in the treatment of diabetes, we believe that when a patient receiving an SU requires basal insulin, it makes more sense to simply titrate the basal insulin to the desired effect while tapering down and ultimately discontinuing the SU. The continued use of the SU along with the basal insulin increases the pill burden and does not provide a therapeutic advantage compared with monotherapy with a basal insulin alone.

Clinical Application

Given AM’s elevated HbA_1c despite treatment with metformin and glimepiride, she would be initiated on a basal insulin (insulin degludec, detemir, or glargine) at 10 units nightly. Given the degree of HbA_1c elevation, we would suspect that AM has a significant amount of β-cell function remaining, which would allow the SU to be efficacious or to remain efficacious in the future. As the insulin dosage is titrated upward, the glimepiride dosage would be titrated downward with the goal of eliminating it as the insulin dosage increases. Ideally, this process would occur over the next 2 to 4 weeks. Although her glucose level may temporarily increase upon discontinuation of glimepiride, with close follow-up the insulin dose can be titrated accordingly to ensure her glucose level does not become severely elevated. 

AM should be counseled on proper insulin administration technique, proper insulin storage, and monitoring for symptoms of hypoglycemia. 

Eric A. Dietrich, PharmD, BCPS, is a graduate of the University of Florida College of Pharmacy and completed a 2-year fellowship in family medicine where he was in charge of an anticoagulation clinic. He works for the College of Pharmacy and the College of Medicine at the University of Florida in Gainesville.

Kyle Davis, PharmD, BCPS, is a graduate of the University of Florida College of Pharmacy in Gainesville and completed a 2-year residency in internal medicine at Indiana University in Indianapolis. He is an internal medicine specialist at Wake Forest Baptist Medical Center in Winston-Salem, North Carolina.

References:

1. Statistics about diabetes: overall numbers, diabetes and prediabetes. American Diabetes Association website. http://www.diabetes.org/diabetes-basics/statistics/. Updated July 19, 2017. Accessed November 29, 2017.
2. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm—2017 executive summary. Endocr Pract. 2017;23(2):207-238.