Management of Hypoglycemia: Insulin Degludec vs Insulin Glargine

Although mortality rates and other outcomes in diabetes have vastly improved in recent decades, insulin-treated patients continue to face substantial challenges related to hypoglycemia. According to the results of 1 international study, roughly 80% of patients with type 1 diabetes and 50% of patients with type 2 diabetes treated with insulin reported hypoglycemia during a 1-month period.¹ These episodes can impede A1C goal attainment and lead to severe consequences.

“When someone experiences hypoglycemia, they can have symptoms of tremor, shakiness, palpitations, sweating, and confusion. In some cases, the condition can also lead to coma or death,” Elizabeth R. Seaquist, MD, professor of medicine and director of the Division of Endocrinology and Diabetes at the University of Minnesota, told Endocrinology Advisor. A 2006 study, for example, identified hypoglycemia as the cause of death in 10% of individuals younger than 40 years with type 1 diabetes.²

The use of insulin pumps, continuous glucose monitors, and patient education programs have been found to reduce hypoglycemia in insulin-treated patients, and newer insulin products have also shown promise in this regard. “We have come a long way with basal insulin products,” says Kevin M. Pantalone, DO, staff endocrinologist and director of clinical research at the Cleveland Clinic in Ohio. “The new basal insulin analogues have been designed to afford flatter insulin-action profiles and a longer half-life, with the aim to simultaneously reduce the risk of hypoglycemia.”

The SWITCH 1 (ClinicalTrials.gov identifier: NCT02034513) and SWITCH 2 (ClinicalTrials.gov identifier: NCT02030600) trials used a randomized, double-blind, crossover design to compare the effects of insulin degludec and insulin glargine U100 in patients with type 1 and type 2 diabetes.^3,4 The results were recently published in JAMA; the same issue of the journal includes an editorial coauthored by Dr Seaquist.⁵ In interviews with Endocrinology Advisor, she and Dr Pantalone offered further thoughts on the findings.

Endocrinology Advisor: What are some of the most common problems related to the risk for hypoglycemia in patients treated with insulin?

​Dr Seaquist: If people have frequent hypoglycemia, they may not know their blood sugar is low before they become confused or unconscious. Patients are afraid they will be unable to detect low blood sugars and sometimes let their blood sugars run higher than optimal. 

Dr Pantalone: Hypoglycemia often leads patients to skip doses of insulin or eat to avoid hypoglycemia. These behaviors further complicate the physician’s ability to help patients requiring insulin to achieve their A1C target.

Endocrinology Advisor: Dr Seaquist, you mentioned in your editorial that previous findings call into question the common practice of managing hypoglycemia by increasing the hemoglobin A1C target?

​Dr Seaquist: Studies done in both type 1 and type 2 diabetes have shown that the hypoglycemia risk is the same for people with the lowest and highest A1C values. This raises questions about whether raising the A1C target will be enough to avoid hypoglycemia. 

Endocrinology Advisor: What are the main findings and potential clinical implications of the SWITCH 1 and SWITCH 2 trials?

Dr Seaquist: In both studies, the primary endpoint was the rate of overall severe hypoglycemia, which investigators defined as an episode requiring assistance from another person, or symptomatic hypoglycemia, in which blood glucose was found to be <56 mg/dL during the 16-week maintenance phase (which followed a 16-week titration phase) in each treatment period. Insulin degludec was associated with a lower rate of hypoglycemia than insulin glargine U100, while being comparable in terms of overall glycemic control, in both SWITCH 1 (2200.9 vs 2462.7 episodes per 100 patient-years of exposure; rate ratio, 0.89; 95% CI, 0.85-0.94; P <.001) and SWITCH 2 (185.6 vs 265.4 episodes per 100 patient years of exposure; rate ratio, 0.70; 95% CI, 0.61-0.80; P <.001). These results indicate that regardless of type 1 or type 2 diabetes status, patients will have fewer episodes of hypoglycemia when treated with insulin degludec than insulin glargine U100.

Dr Pantalone: Although these findings are certainly helpful to clinicians and patients, it remains unclear how they will translate into clinical practice, where insulin therapy is often used with less aggressive glycemic targets or not titrated as quickly. Patient access to these new basal insulin products is also affected by insurance formularies. Medication cost can also be a barrier to using these new products, particularly for older patients on Medicare who live on a fixed income. In any event, the new basal insulin analogues represent an improvement to what was previously available and will be additional options for clinicians to prescribe to patients, particularly those at a high risk for or currently struggling with hypoglycemia.

Endocrinology Advisor: Dr Seaquist, as a limitation of these trials, you mentioned they did not count asymptomatic hypoglycemia episodes. Can you say more about that and how it might influence conclusions drawn from these results?

​Dr Seaquist: Asymptomatic hypoglycemia occurs frequently in patients receiving insulin. One reason these episodes may be asymptomatic is that they occur frequently enough to drop the glucose level at which the symptoms are elicited, which will increase the risk of having severe hypoglycemia. It would be important to know whether 1 of these insulins reduced asymptomatic episodes more than the other, because that would suggest overall outcomes with respect to serious hypoglycemia might be reduced by that insulin.

Endocrinology Advisor: What should be next steps in terms of research in this area?

​Dr Seaquist: A study in which patients wore continuous glucose monitors would be very informative, as would a study on the quality of life and fear of hypoglycemia in patients randomly assigned to treatment with 1 of these insulins. ​

Disclosures: Dr Seaquist has received funding from Eli Lilly, Locemia, Medtronic, Sanofi, and Zucera. Dr Chow, coauthor of the editorial, has received funding from Eli Lilly.

References

1. KhuntiK, Alsifri S, Aronson R, et al. Rates and predictors of hypoglycaemia in 27585 people from 24 countries with insulin-treated type 1 and type 2 diabetes. Diabetes Obes Metab. 2016;18(9):907-915. doi: 10.1111/dom.12689
2. Skrivarhaug T, Bangstad HJ, Stene LC, et al. Long-term mortality in a nationwide cohort of childhood-onset type 1 diabetic patients in Norway. Diabetologia. 2006;49(2):298-305. doi: 10.1007/s00125-005-0082-6
3. Lane W, Bailey TS, Gerety G, et al; SWITCH 1. Effect of insulin degludec vs insulin glargine u100 on hypoglycemia in patients with type 1 diabetes: the SWITCH 1 randomized clinical trial. JAMA. 2017;318(1):33-44. doi: 10.1001/jama.2017.7115
4. Wysham C, Bhargava A, Chaykin L, et al. Effect of insulin degludec vs insulin glargine u100 on hypoglycemia in patients with type 2 diabetes: the SWITCH 2 randomized clinical trial. JAMA. 2017;318(1):45-56. doi:10.1001/jama.2017.7117
5. Seaquist ER, Chow L. Hypoglycemia in diabetes: does insulin type matter? JAMA. 2017;318(1):31-32. doi:10.1001/jama.2017.8075