Lower Severe Hypoglycemia Risk: Insulin Glargine Versus NPH Insulin in Type 2 Diabetes!

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The American Journal of Managed Care, January 2008, Volume 14, Issue 1

Hypoglycemia is a common consequence of achieving tight glycemic control for patients

Definitions and Incidence

In addition to causing adverse symptoms and, in some cases, morbidity, hypoglycemia results in significant medical expenditures.23-25 Moderate to severe hypoglycemia contributes to an increased use of healthcare services by insulintreated patients, including hospitalization, emergency room and office visits, and increased short-term disability leave.23,24 Researchers who recently assessed the economic effects of hypoglycemia estimated a mean cost per episode of $1186 and annualized costs of $3241 per patient with a diagnosis of hypoglycemia.23,24 Therapies that can provide effective glycemic control with less potential for hypoglycemia may be expected not only to improve medical outcomes, but also to help limit expenditures for healthcare.

LOWER RATES OF SEVERE HYPOGLYCEMIA WITH INSULIN GLARGINE VS CONVENTIONAL INSULIN

Several randomized clinical trials have demonstrated that the addition of insulin glargine to oral antidiabetic drugs is associated with a significantly lower incidence of hypoglycemia compared with NPH insulin.26-28 In the Treat-to- Target Trial, patients who had inadequately controlled type 2 diabetes with oral therapy received add-on therapy with either basal insulin glargine or NPH insulin. A forced weekly titration algorithm was used for insulin dose, targeting an A1C goal of &#8804;7.0%. Results demonstrated that nearly 25% more patients treated with insulin glargine achieved an A1C value of &#8804;7.0% without nocturnal hypoglycemia compared with those treated with NPH insulin.26 Further, patients in the glargine group had 21% to 48% lower rates for other categories of symptomatic hypoglycemia. There were 3.0 and 5.1 events per patient-year with a blood glucose measurement of <56 mg/dL in the insulin glargine and NPH insulin groups, respectively.26 A post hoc analysis of the severe hypoglycemic events reported in the Treat-to-Target Trial, however, indicated that many episodes reported as severe (defined as requiring third-party assistance and associated with either a glucose level of <56 mg/dL or prompt recovery after oral carbohydrate, IV glucose, or glucagon) were coded on case report forms as of moderate severity by the investigators when characterizing the event (unpublished data, sanofi-aventis U.S., 2003), suggesting that although third-party assistance was provided, it may not have been required. The majority of these events were quickly corrected with carbohydrates. Moreover, several of the severe events were assessed as possibly avoidable. In another clinical trial comparing bedtime NPH with insulin glargine given either at bedtime or in the morning, the rates of severe hypoglycemia (defined as requiring third-party assistance and associated with either a glucose level of <50 mg/dL or prompt recovery after carbohydrate, IV glucose, or glucagon) were 0.12, 0.04, and 0.06 events per patient-year, respectively.28 Most recently, researchers who compared glimepiride plus insulin glargine with glimepiride plus NPH reported a lower rate of symptomatic nocturnal hypoglycemia (defined as events that occurred during sleep [between bedtime and morning rising]) in patients receiving insulin glargine (1.1 vs 3.1 events per patient-year for NPH; P = .001).29 Rates of severe hypoglycemia were 0.1 versus 0.2 events per patientyear (P = .369).

The incidence of severe events was very low in clinical trials; however, meta-analyses can serve to increase statistical power when evaluating such events. A recent meta-analysis by Rosenstock et al combined results from 4 open-label, randomized, parallel, open-group studies comparing insulin glargine with NPH insulin in type 2 diabetes. A significant risk reduction was associated with insulin glargine for severe hypoglycemia (46%, P = .0442) and severe nocturnal hypoglycemia (59%, P = .0231) (Table).27 Furthermore, in the subgroup of patients achieving the target A1C level of &#8804;7.0%, those who were treated with insulin glargine experienced a lower incidence of nocturnal hypoglycemia than those taking NPH insulin (39% vs 49%; P < .01); however, the incidence of all other types of hypoglycemia was similar between groups. The collective results from individual clinical trials as well as a meta-analysis support the contention that insulin glargine results in a lower rate of overall, nocturnal, and severe hypoglycemic events compared with NPH insulin.

Analyses of Clinical Practice Databases

Insurance claims data provide another important source for evaluating not only the incidence of severe hypoglycemic events, but also their economic impact. However, because these data generally are derived from claims for emergency departments, hospitalizations, physician visits, and ambulance calls, the rates are lower than those in other population-based assessments. Bullano et al retrospectively examined pharmacy and medical claims data from a southeastern US managed healthcare plan for patients who initiated therapy with either insulin glargine (n = 310) or NPH insulin (n = 1124).32 The events in this analysis are believed to be severe, as such events are more likely to generate insurance claims. Analysis of hypoglycemia-related claims before (preindex period) and after (postindex period) initiation of insulin revealed that the rate of events (per 100 patients per year) declined from 30 to 10 among patients who initiated therapy with insulin glargine, whereas that for patients starting NPH insulin increased slightly, from 29 to 31. Negative binomial regression was used to predict rates of patient hypoglycemic events at A1C levels between 4% and 17% (Figure). At an A1C level of 7.0%, the rate of events per 100 patients per year was estimated to be 7.3 for insulin glargine and 18.3 for NPH insulin (P = .009); thus, to avoid 1 hypoglycemic event per patient per year, 9 patients would need to be treated with insulin glargine rather than NPH insulin. The mean annual medication cost of insulin glargine was $390, with a mean annual difference in cost between insulin glargine and NPH insulin of $47. Because the mean cost per hypoglycemic event was $1087, it is worthwhile to note that the cost increase associated with treating 9 patients with insulin glargine versus NPH insulin (ie, $423) was $664 less than the cost of treating 1 hypoglycemic event.32

Zhang and Menditto, who conducted a retrospective review of claims from Medicaid recipients in California, also report reductions in hypoglycemia-related claims after introduction of insulin glargine.33 A total of 267 patients using insulin glargine were matched to 534 reference patients to assess short-term costs of diabetes care before and after initiation of therapy with insulin glargine. Hypoglycemia-related inpatient claims decreased in the insulin glargine group, but remained unchanged in the reference group. Hypoglycemiarelated emergency department claims declined similarly in both groups. Initiation of insulin glargine was associated with reduced costs at 6 months from baseline, including inpatient and total costs of diabetes-related care and expenditures from inpatient hypoglycemia-related claims.33 Consistent with these data, a recent analysis of patient-level data from Medicaid programs in 4 states demonstrated lower overall healthcare expenditures in patients using insulin glargine compared with other types of long- or intermediate-acting insulin.34 Thus, analysis of hypoglycemia-related insurance claims in several studies supports not only a lower incidence of severe hypoglycemic events but also a lower overall cost with insulin glargine compared with other therapies.

SUMMARY

Intensive insulin therapy is recommended for patients with type 2 diabetes when glycemic goals are not reached with lifestyle modification and oral agents. Hypoglycemia is an expected outcome when aiming to achieve near-normal glycemic control. Despite the low incidence of severe events in patients with type 2 diabetes, hypoglycemia remains a major barrier to insulin therapy. In addition, severe hypoglycemic events result in increased medical expenditures. Prospective clinical studies have established that insulin glargine results in a lower rate of hypoglycemia compared with NPH insulin in patients with type 2 diabetes. Meta-analysis also supports the observation that the incidence of severe events is lower with insulin glargine than with NPH insulin. Notably, data from real-world practices and medical claims databases also demonstrate that insulin glargine use is associated with a lower incidence of overall and severe hypoglycemia compared with NPH insulin and other therapies. Finally, medical claims data also are consistent with the clinical trial data and indicate a significantly lower incidence of severe hypoglycemia with insulin glargine, which is accompanied by a reduction in healthcare expenditures. The remarkable consistency of relative hypoglycemia risks for insulin glargine and NPH insulin in prospective clinical trials, observational data from endocrinology clinics, and finally in retrospective managed care database analyses may lend credibility to retrospective database analyses regarding severe hypoglycemia in general.

The authors gratefully acknowledge Lisa Bergstrom, PhD, who assisted in the preparation of a first draft of this article based on an author-provided outline.

1. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977-986.

3. UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837-853.

5. Turner RC, Cull CA, Frighi V, Holman RR, for the UK Prospective Diabetes Study Group (UKPDS). Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). JAMA. 1999;281:2005-2012.

7. American College of Endocrinology, American Association of Clinical Endocrinologists. Implementation Conference for ACE Outpatient Diabetes Mellitus Consensus Conference Recommendations: Position Statement. February 2, 2005. www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf. Accessed March 14, 2005.

9. Cryer PE. Hypoglycemia: Pathophysiology, Diagnosis, and Treatment. 1st ed. New York: Oxford University Press; 1997.

11. UK Hypoglycaemia Study Group. Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration. Diabetologia. 2007;50:1140-1147.

13. Hermansen K, Davies M, Derezinski T, Martinez Ravn G, Clauson P, Home P. A 26-week, randomized, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as add-on therapy to oral glucoselowering drugs in insulin-naive people with type 2 diabetes. Diabetes Care. 2006;29:1269-1274.

15. Yale J-F. Nocturnal hypoglycemia in patients with insulin-treated diabetes. Diabetes Res Clin Pract. 2004;65(suppl 1):S41-S46.

17. Gale EA, Tattersall RB. Unrecognised nocturnal hypoglycaemia in insulin-treated diabetics. Lancet. 1979;1:1049-1052.

19. The Diabetes Control and Complications Trial Research Group. Hypoglycemia in the Diabetes Control and Complications Trial. Diabetes. 1997;46:271-286.

21. Wright AD, Cull CA, MacLeod KM, Holman RR. Hypoglycemia in type 2 diabetic patients randomized to and maintained on monotherapy with diet, sulfonylurea, metformin, or insulin for 6 years from diagnosis: UKPDS73. J Diabetes Complications. 2006;20:395-401.

23. Rhoads GG, Orsini LS, Crown W, Wang S, Getahun D, Zhang Q. Contribution of hypoglycemia to medical care expenditures and shortterm disability in employees with diabetes. J Occup Environ Med. 2005;47:447-452.

25. Lundkvist J, Berne C, Bolinder B, Jonsson L. The economic and quality of life impact of hypoglycemia. Eur J Health Econ. 2005;6:197-202.

27. Rosenstock J, Dailey G, Massi-Benedetti M, Fritsche A, Lin Z, Salzman A. Reduced hypoglycemia risk with insulin glargine: a metaanalysis comparing insulin glargine with human NPH insulin in type 2 diabetes. Diabetes Care. 2005;28:950-955.

29. Eliaschewitz FG, Calvo C,Valbuena H, et al. Therapy in type 2 diabetes: insulin glargine vs. NPH insulin both in combination with glimepiride. Arch Med Res. 2006;37:495-501.

31. Fischer JS, McLaughlin T, Loza L, Beauchamp R, Schwartz S, Kipnes M. The impact of insulin glargine on clinical and humanistic outcomes in patients uncontrolled on other insulin and oral agents: an office-based naturalistic study. Curr Med Res Opin. 2004;20:1703-1710.

33. Zhang Q, Menditto L. Incremental cost savings 6 months following initiation of insulin glargine in a Medicaid fee-for-service sample. Am J Ther. 2005;12:337-343.