Cost-Benefit Analysis of Insulin Analogs in Type 2 Diabetes

According to a 2016 study, the mean price of insulin increased nearly 3-fold between 2002 and 2013, with 2013 expenditures per patient of approximately $228.20 (95% CI, $183.98-$273.42) for human insulin and $507.89 (95% CI, $422.34-$593.44) for insulin analogs.¹ In terms of their relative benefits in clinical practice, there is a dearth of evidence to support the substantially higher cost of insulin analogs vs human insulin.

In a retrospective cohort study published July 2018 in JAMA, the authors aimed to elucidate this issue by comparing outcomes of patients with type 2 diabetes who received treatment at Kaiser Permanente of Northern Calfiornia.² The sample consisted of 23,561 patients who initiated human neutral protamine Hagedorn (NPH) insulin and 1928 patients who initiated basal insulin analogs between 2006 and 2015.

The results show no significant difference between groups regarding the risk for hypoglycemia-related ED visits or hospital admissions (primary outcome), or improvement in glycemic control (secondary outcome), within 1 year of initiating treatment. In a propensity-matched analysis of 4428 patients, the adjusted hazard ratio associated with insulin analogs was 1.16 (95% CI, 0.71-1.78) for the primary outcome.

In a related editorial published in the same issue of JAMA, researchers wrote that the “clinical value of using basal analogs as front-line insulins for type 2 diabetes is unclear,” and “reemphasizing NPH insulin as a front-line insulin option for most patients with type 2 diabetes could begin to bend the insulin cost curve for patients and insurers.”³

They noted the need for high-quality evidence comparing insulin analogs with NPH insulin. “Newer, even higher-priced basal insulin analogs are now being promoted despite their minor absolute benefits vs current widely used analog options, so questions about value will remain pressing into the foreseeable future,” they concluded.

For an additional perspective on the implications of the new findings, Endocrinology Advisor interviewed David C. Klonoff, MD, FACP, FRCPE, Fellow AIMBE, clinical professor of medicine at the University of California, San Francisco, and medical director of the Diabetes Research Institute at Mills-Peninsula Medical Center in San Mateo.

Endocrinology Advisor: What are your thoughts about the results from Lipka et al and the points raised in

Dr Klonoff: Despite the editorial authors’ conclusion that “reemphasizing NPH insulin as a front-line insulin option…could begin to bend the insulin cost curve for patients and insurers.” There is a substantial body of literature, including prospective randomized controlled trials as well as retrospective studies, that have consistently come to the opposite conclusion. These studies have concluded that compared with NPH insulin, glargine is associated with less hypoglycemia and better glycemic control.

The first article to show this outcome was published in 2003 by Riddle et al.⁴ Subsequently, an article by Porcellati et al showed less hypoglycemia and lower A1c with long-acting basal insulin vs NPH, and the abstract of a review article by Tricco comparing long-acting basal insulins with NPH concludes that “long acting insulin analogs are probably superior to intermediate acting insulin analogs, although the difference is small for hemoglobin A1c.”^5,6 This is a reasonable, balanced statement that emphasizes that for long-acting basal insulins compared with NPH, the hemoglobin A1c difference is small, but the literature shows that the decreased hypoglycemia outcomes, especially for nocturnal hypoglycemia, are considerable.

Furthermore, for the 2 new ultralong-acting basal insulins that have recently become available, substantial evidence has demonstrated even lower risk for hypoglycemia and similar mean control compared with glargine therapy. A recent review article by Woo concluded that there is less hypoglycemia and similar overall control with the use of newer analog ultralong-acting basal insulins than with basal glargine insulin when these 2 options for basal control are compared.⁷ Russell-Jones and colleagues showed less nocturnal hypoglycemia with degludec than with glargine insulin, and Dailey and Lavernia reported less nocturnal hypoglycemia with glargine-300 than with glargine insulin.^8.9 

Although most studies have shown less hypoglycemia, but not necessarily less severe hypoglycemia, with long-acting basal insulin compared with NPH insulin, this difference is because most of the studies were not powered to detect severe hypoglycemia. Readers of Lipska’s retrospective database analyses must be careful to recognize that the treatments administered to the NPH group and the glargine group during a 7-year period might or might not have been the same, and patients might have been allocated to glargine if they were felt to be at higher risk for hypoglycemia than those who were allocated to NPH. In retrospective data analyses such as this one, there is no way to know whether the patients and the treatments were the same in both groups.

Endocrinology Advisor: What are some other points for clinicians to consider regarding basal insulins compared with NPH?

Dr Klonoff: Note that long-acting basal insulins offer the advantage that the dose can be increased, and the additional effect is spread over many hours [for] when basal insulin is needed. When the dose of a more rapidly acting basal insulin such as NPH is increased, it is more likely that the additional insulin will be concentrated over a shorter number of hours, which will make hypoglycemia more likely at the time when the extra insulin is taking effect.

Endocrinology Advisor: In conclusion, what are your thoughts about the idea of a renewed role for NPH insulin as a first-line insulin option for patients with type 2 diabetes, based on the available evidence?

Dr Klonoff: In the face of strong evidence to the contrary, it is premature to [assume this would] “bend the insulin cost curve.” It is likely, based on currently available evidence from a wealth of randomized control trials, that that if this proposed substitution of NPH for glargine and longer-acting insulins were to take place, that this approach would likely result in bending the benefits curve downward and the adverse effect curve upward.

References

1. Hua X, Carvalho N, Tew M, Huang ES, Herman WH, Clarke P https://jamanetwork.com/journals/jama/fullarticle/2510902. JAMA. 2016; 315(13):1400-1402.
2. Lipska KJ, Parker MM, Moffet HH, Huang ES, Karter AJ. Association of initiation of basal insulin analogs vs neutral protamine Hagedorn insulin with hypoglycemia-related emergency department visits or hospital admissions and with glycemic control in patients with type 2 diabetes. JAMA. 2018;320(1):53-62.
3. Crowley MJ, Maciejewski ML. Revisiting NPH insulin for type 2 diabetes: is a step back the path forward? JAMA. 2018;320(1):38-39.
4. Riddle MC, Rosenstock J, Gerich J; Insulin Glargine 4002 Study Investigators. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care. 2003;26(11):3080-3086.
5. Porcellati F, Rossetti P, Pampanelli S, et al. Better long-term glycaemic control with the basal insulin glargine as compared with NPH in patients with Type 1 diabetes mellitus given meal-time lispro insulin. Diabet Med. 2004;21(11):1213-1220.
6. Tricco AC,Ashoor HM, Antony J, et al. Safety, effectiveness, and cost effectiveness of long acting versus intermediate acting insulin for patients with type 1 diabetes: systematic review and network meta-analysis. BMJ. 2014;349:g5459.
7. Woo VC. A review of the clinical efficacy and safety of insulin degludec and glargine 300 u/ml in the treatment of diabetes mellitus. Clin Ther. 2017; 39(8S2):S12-S33.
8. Russell-Jones D, Gall MA, Niemeyer M, Diamant M, Del Prato S. Insulin degludec results in lower rates of nocturnal hypoglycaemia and fasting plasma glucose vs. insulin glargine: A meta-analysis of seven clinical trials. Nutr Metab Cardiovasc Dis. 2015;25(10):898-905.
9. Dailey G, Lavernia F. A review of the safety and efficacy data for insulin glargine 300 units/ml, a new formulation of insulin glargine. Diabetes Obes Metab. 2015;17(12):1107-1114.