Long-Acting Once-Daily Insulins: Are There Differences in Safety or Efficacy?

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

CITATION:
Dietrich EA, Davis K. Long-acting once-daily insulins: are there differences in safety or efficacy? Consultant. 2018;58(1):36-37.

As of 2015, an estimated 30.2 million (12.2%) Americans aged 18 or older had diabetes.¹ While newer oral and subcutaneous diabetes therapies have emerged over the years, insulin therapy has remained a cornerstone of treatment. As of 2012, a reported 2.9 million US adults used insulin therapy only, and 3.1 million used insulin in combination with oral hypoglycemic agents to manage diabetes.²

The Food and Drug Administration has approved several long-acting once-daily insulin therapies—insulin glargine, insulin detemir, and insulin degludec. Because of their longevity on the market and wide availability, glargine and detemir are the most commonly used long-acting insulin agents. Are there differences in the efficacy or safety among these agents? Should health care providers give preference to one agent over another if possible?

Patient Case

MW is a 68-year-old man who weighs 80 kg and has a history of diabetes and hypertension. His hypertension has been well controlled on combination amlodipine-benazepril (10 mg and 20 mg). He also takes atorvastatin (10 mg once daily), metformin (1000 mg twice daily), and insulin glargine (45 units daily). His most recent hemoglobin A_1c level was 7.2%, and overall he is happy with his regimen and blood glucose control and has not experienced any recent episodes of hypoglycemia.

MW reports that his prescription insurance carrier has sent him a letter stating that, beginning in January (only a few months away), the preferred basal insulin under his plan will become detemir, and that glargine will no longer be covered. MW asks what impact this change of insulin will have on his glucose control and whether he will require additional therapy to maintain control. He is concerned that the detemir may not be as effective as the glargine has been. Does a difference truly exist?

The Evidence

Despite the wide use of detemir and glargine, very little head-to-head data exist comparing the 2 insulins. A 2011 Cochrane Review identified only 4 studies lasting more than 12 weeks that directly compared detemir with glargine.³ In total, 2250 patients were randomly assigned to either of the agents in the studies, which lasted between 24 and 52 weeks. The review’s authors noted that markers of efficacy, such as hemoglobin A_1c level, did not differ statistically between patients taking detemir and those taking glargine. Furthermore, the incidence of hypoglycemia (overall, severe, and nocturnal) did not differ between the groups. Patients taking detemir were more often using twice-daily dosing strategies and required more daily units of insulin compared with patients taking glargine. Despite the requirement for higher daily insulin doses, patients receiving detemir experienced less weight gain than those receiving glargine.³

Pharmacokinetics studies have further demonstrated that relatively little difference exists between detemir and glargine in terms of duration of action, “flatness” of the pharmacologic profile, and overall ability to control glucose when administered at clinically relevant doses (0.35-0.80 units/kg). A review of these pharmacokinetics studies did not find a difference between detemir and glargine and found both to have a suitable pharmacokinetic profile to justify once-daily dosing; furthermore, neither agent had a completely flat pharmacologic profile.⁴

However, clinically, it appears that the duration of action of detemir is related to the dose: Lower doses have a slightly shorter duration of action (< 19 h for doses < 0.4 units/kg), whereas higher doses have a longer duration of action (> 22 h for doses > 0.8 units/kg). Glargine is considered to have a duration of action approaching 24 hours regardless of the dose administered.⁴

Clinical Application

This scenario is commonly encountered in practice around the New Year, as patients change insurance plans and insurance carriers adjust their plans’ formularies. Overall, results of pharmacokinetics studies and clinical studies do not show a significant difference between detemir and glargine in terms of the most meaningful markers of efficacy and safety. However, detemir may be associated with less weight gain but requires higher doses in order to achieve the same level of glucose control as glargine. Importantly, the ability to achieve glycemic goals is not different between the agents, partly owing to the ability to titrate each agent to reach the desired glucose level; while titrations may be needed, there is no reason that adequate glucose control cannot be maintained if a patient is required to switch between these insulin products.

Regarding the doses required, it appears that at higher doses (approaching 0.8 units/kg) the pharmacokinetic profile of detemir fully supports once-daily dosing. However, the ability to administer doses this large may be limited by the administration device (insulin pen or syringe), as well as the ability of a person’s body to consistently absorb such a large volume. Absorption becomes reduced and inconsistent at doses of 0.8 mL (or 80 units for 100 units/mL formulations) and may require a given dose to be provided over multiple injections. While it certainly would be feasible to administer, for example, 70 units and 30 units in 2 separate injections at the same time, we believe that more patients would prefer to administer 50 units every 12 hours; splitting evenly this way also allows more room to titrate the dose before absorption becomes problematic.

At lower doses (< 0.4 units/kg), the kinetic profile of detemir may not fully support once-daily dosing. Therefore, because the starting dose of detemir is between 0.1 and 0.2 units/kg, it may be necessary to dose it twice daily until the dose is sufficiently titrated above 0.4 units/kg. This perhaps represents one advantage of glargine—its pharmacokinetic profile appears to be consistent across doses so that once-daily dosing can be utilized from the start, whereas detemir may require twice-daily dosing initially, then be reduced to once-daily dosing, with a return to twice-daily dosing if the dose becomes too high to administer with a single injection.

Because MW is currently receiving 0.56 units/kg of insulin glargine daily, we would expect this dose of detemir to provide consistent glucose lowering throughout a 24-hour period with once-daily dosing. If his current dose of glargine were smaller (< 0.4 units/kg), we may consider starting with twice-daily dosing of detemir, although it is equally reasonable to start with once-daily dosing and follow the patient’s glucose level closely during the transition period.

Outcome of the Case

MW would be counseled that there should not be a significant difference in efficacy or safety between the agents. A switch from glargine to detemir may require a higher number of units of insulin in order to maintain the same level of glucose control, so MW may require more-frequent visits during the transition period to monitor for safety and the achievement of blood glucose goals.

He also would be counseled to ensure that he checks his fasting blood glucose daily, writes down the values, and brings the log sheet (or his meter, if it has a memory function) with him to his clinic visits. During the first weeks of the transition, a morning fasting glucose measurement and an evening postprandial glucose measurement would be helpful to determine whether the detemir is providing glucose control throughout the entire dosing interval. However, despite requiring more units of insulin, he may experience less weight gain with detemir, which could be seen as an advantage.

MW would start insulin detemir at 45 units once daily, be counseled to check his glucose level at least once daily (although twice daily is preferable), and be scheduled for an in-clinic visit in the next 2 to 4 weeks to review his glucose values in order to determine whether adjustments are required in detemir dosing. 

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. Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2017: Estimates of Diabetes and Its Burden in the United States. Atlanta, GA: Centers for Disease Control and Prevention, US Dept of Health and Human Services; 2017. https://stacks.cdc.gov/view/cdc/46743. Accessed December 11, 2017.
2. Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2014: Estimates of Diabetes and Its Burden in the United States. Atlanta, GA: Centers for Disease Control and Prevention, US Dept of Health and Human Services; 2014. https://stacks.cdc.gov/view/cdc/23442. Accessed December 11, 2017.
3. Swinnen SG, Simon ACR, Holleman F, Hoekstra JB, DeVries JH. Insulin detemir versus insulin glargine for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2011;(7):CD006383. doi:10.1002/14651858.CD006383.pub2
4. Poon K, King AB. Glargine and detemir: safety and efficacy profiles of the long-acting basal insulin analogs. Drug Healthc Patient Saf. 2010;2:213-223. doi:10.2147/DHPS.S7301