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Long-Acting Insulins for the Treatment of Type 2 Diabetes

Sandra Leal, PharmD, CDE
Published Online: Wednesday, October 1, 2008   [ Request Print ]


Dr. Leal is clinical pharmacy superisor at El Rio Health Center in Tucson, Arizona.


Editorial support provided through the sanofi-aventis US Group.

Many studies have demonstrated the link between sustained high blood glucose and microvascular and cardiovascular complications,1-3 as well as the benefit of achieving glycemic control in reducing these complications.4-6 Although most patients with type 2 diabetes start therapy with oral antidiabetic drugs (OADs), disease progression usually requires the addition of insulin to help patients reach American Diabetes Association guideline–recommended glycemic goals (Table).7 Compared with neutral protamine Hagedorn (NPH) insulin, the only currently available conventional intermediate- or long-acting insulin- newer, long-acting analogs (eg, glargine and detemir) have significant advantages. This article provides pharmacists an overview and comparison of long-acting insulins to help counsel patients regarding the role of basal insulin in the treatment of type 2 diabetes.

What Is Basal Insulin Replacement?

Basal insulin therapy approximates the physiologic pattern of interprandial pancreatic secretion of insulin to suppress hepatic glucose production between meals and overnight. An ideal basal insulin regimen supplies a low level of insulin for 24 hours with little variation and no pronounced peaks in activity.

When Should Basal Insulin Be Initiated?

When glycemic goals are not achieved with OADs after 3 to 6 months at maximal doses, basal insulin can be added to existing OADs. Insulin addition to OAD therapy has been shown to reduce blood glucose significantly without increased risk of hypoglycemia and is associated with minimal weight gain.1 Large trials have demonstrated the benefits of early, intensive insulin therapy in reducing diabetes-related complications, 2 and algorithms exist that indicate the appropriate time for initiation of therapy (Figure).8-11

What Types of Basal Insulins Are Available?

The intermediate- and long-acting insulin formulations used to provide basal insulin fall into 2 categories: conventional (human insulin) and insulin analogs.

Conventional (Human) Basal Insulin Formulation

NPH has peak activity at 4 to 10 hours and a duration of action of 10 to 16 hours12; 2 injections are required for 24-hour coverage in most patients. Early in therapy, when patients still secrete significant amounts of endogenous insulin, once-daily peak intermediate insulin may be sufficient.

In 2 large randomized trials, similar improvements in glycated hemoglobin A1C (A1C) levels were observed with NPH and insulin glargine in patients with type 2 diabetes, with significantly less nocturnal hypoglycemia in the insulin glargine group.13,14 In a randomized trial in 505 patients with type 2 diabetes, similar efficacy was observed with NPH and insulin detemir in reducing A1C levels, with no significant difference in nocturnal hypoglycemia observed between groups.15

Newer Basal Insulin Analog Formulations

Basal insulin analogs were developed through molecular alterations of human insulin with pharmacokinetic and pharmacodynamic properties that closely approach physiologic insulin secretion. Currently, 2 basal insulin analogs are available: insulin glargine and insulin detemir.

Insulin glargine is dosed once daily for 24-hour basal insulin coverage. It has a relatively constant pharmacokinetic profile compared with NPH, and no pronounced peak in activity. The sustained activity of insulin glargine over 24 hours closely approximates that of continuous subcutaneous insulin infusion, as well as physiologic insulin secretion.16 A study evaluating the efficacy and safety of insulin glargine as an add-on to OAD therapy demonstrated significant (P<.0001) improvement in glycemic control and a low rate of hypoglycemia in 7893 patients with type 2 diabetes.17 In another trial, patients with type 2 diabetes on OADs received a single bedtime dose of insulin glargine or human NPH insulin; at the end of the study, average A1C levels were below 7% in each group, and the glarginetreated group experienced significantly (P<.05) fewer nocturnal hypoglycemic episodes.14

Insulin detemir provides basal insulin coverage with once- or twice-daily dosing.18 In a pharmacokinetic study, peak activity with insulin detemir occurred 5 to 8 hours after dosing, and the duration of action ranged between 11 and 13 hours.19 Results from a trial demonstrated that insulin detemir (plus mealtime insulin) was as effective as NPH insulin (plus mealtime insulin) in reducing A1C in patients with type 2 diabetes, with no significant difference in nocturnal hypoglycemic episodes.20 The majority of patients in this study required twice-daily dosing with insulin detemir to achieve glycemic control.20 Another study found that twice-daily insulin detemir or NPH produced similar reductions in A1C (1.8% and 1.9% reductions for insulin detemir and NPH insulin, respectively). Patients treated with insulin detemir experienced significantly (P<.001) less hypoglycemia in this study.21

What Are the Advantages of the Newer Basal Insulin Analogs?

The efficacy of insulin detemir and insulin glargine is similar to that of NPH. The pharmacokinetics of these insulin analogs allow for fewer daily injections, which may lead to greater patient acceptance and adherence. For example, insulin glargine is dosed once daily, providing 24-hour basal insulin coverage. This allows mealtime flexibility and reduces the need for betweenmeal snacks to avoid "lows." Basal insulin analogs also may be associated with less hypoglycemia in patients with type 2 diabetes. Another benefit is a more predictable pattern of absorption, compared with conventional human insulin, which allows more options for injection sites.

How Should Basal Insulin Be Dosed?

Basal insulin can be initiated using simple regimens that allow the dose to be adjusted to reach glycemic targets. Although the degree of dose adjustment will vary among individuals, ideal titration should occur in a straightforward and consistent manner in a combined effort between patients and their health care team. In the Treat-to-Target trial, a simple treatment algorithm was used successfully to reach recommended goals for A1C in patients with type 2 diabetes.14 In this trial, a single bedtime dose of insulin glargine or human NPH insulin was added to existing OAD therapy using a titration algorithm. Although titration of insulin may seem daunting to some patients, they can be assured that patient-managed titration has been proven effective. Accordingly, a recent trial demonstrated that patient-managed titration was more effective than physician- managed titration in reducing A1C levels.10 When initiating any insulin regimen, glucose monitoring and sufficient supervision of dose adjustments are imperative to achieve glycemic goals.

Conclusion

Basal insulin replacement is a practical and effective way to initiate insulin in patients who have diabetes and inadequately controlled glucose. Compared with conventional insulin, basal insulin analogs are similarly able to achieve glycemic control in patients with type 2 diabetes, but have the advantage of less hypoglycemia. Patients should be counseled on the need for adding basal insulin to their treatment regimen, and reassured that titration to glucose targets based on simple algorithms is effective. Pharmacists can educate and motivate patients to gain the greatest benefit from treatment.

References

  1. Wright A, Burden ACF, Paisey RB, Cull CA, Holman RR, for the U.K.Prospective Diabetes Study Group. Sulfonylurea inadequacy: efficacy of addition of insulin over 6 years in patients with type 2 diabetes in the U.K. Prospective Diabetes Study (UKPDS 57). Diabetes Care. 2002;25(2):330-336.
  2. Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA. 2002;287(19):2563-2569.
  3. Khaw K-T, Wareham N, Luben R, et al. Glycated haemoglobin, diabetes, and mortality in men in Norfolk cohort of European Prospective Investigation of Cancer and Nutrition (EPIC-Norfolk). BMJ. 2001;322(7277):1-6.
  4. Stratton IM, Adler AI, Neil HAW, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321(7258):405-412.
  5. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med. 2000;342(6):381-389.
  6. The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560-2572.
  7. American Diabetes Association. Standards of medical care in diabetes--2008. Diabetes Care. 2008;31 Suppl 1:S12-S54.
  8. Texas Diabetes Council. Glycemic control algorithm for type 2 diabetes mellitus in children¹ and adults. www.dshs.state.tx.us/diabetes/. Accessed April 25, 2006.
  9. Vinik AI. Benefits of early initiation of insulin therapy to long-term goals in type 2 diabetes mellitus. Insulin. 2006;1(1):2-12.
  10. Davies M, Storms F, Shutler S, Bianchi-Biscay M, Gomis R. Improvement of glycemic control in subjects with poorly controlled type 2 diabetes: comparison of two treatment algorithms using insulin glargine. Diabetes Care. 2005;28(6):1282-1288.
  11. Texas Diabetes Council. Glycemic control algorithm for type 2 diabetes mellitus in children and adults (Report 45-11265):1-2. www.dshs.state.tx.us/diabetes/.
  12. American Diabetes Association. Resource Guide: Insulin. Diabetes Forecast. 2006;(suppl):RG14-RG20.
  13. Rosenstock J, Schwartz SL, Park GD, Donley DW, Edwards MB. Basal insulin therapy in type 2 diabetes: 28-week comparison of insulin glargine (HOE 901) and NPH insulin. Diabetes Care. 2001;24(4):631-636.
  14. 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.
  15. Haak T, Tiengo A, Draeger E, Suntum M, Waldhausl W. Lower within-subject variability of fasting blood glucose and reduced weight gain with insulin detemir compared to NPH insulin in patients with type 2 diabetes. Diabetes Obes Metab. 2005;7(1):56-64.
  16. Lepore M, Pampanelli S, Fanelli C, et al. Pharmacokinetics and pharmacodynamics of subcutaneous injection of long-acting human insulin analog glargine, NPH insulin, and ultralente human insulin and continuous subcutaneous infusion of insulin lispro. Diabetes. 2000;49(12):2142-2148.
  17. Kennedy L, Herman WH, Strange P, Harris A. Impact of active versus usual algorithmic titration of basal insulin and point-of-care versus laboratory measurement of HbA1C on glycemic control in patients with type 2 diabetes: The Glycemic Optimization with Algorithms and Labs at Point of Care (GOAL A1C) trial. Diabetes Care. 2006;29(1):1-8.
  18. Levemir (insulin detemir [rDNA origin] injection) [package insert]. Princeton, NJ: Novo Nordisk; 2005.
  19. Danne T, Lupke K, Walte K, Von Schuetz W, Gall MA. Insulin detemir is characterized by a consistent pharmacokinetic profile across age-groups in children, adolescents, and adults with type 1 diabetes. Diabetes Care. 2003;26(11):3087-3092.
  20. Rašlová K, Bogoev M, Raz I, Leth G, Gall MA, Hâncu N. Insulin detemir and insulin aspart: a promising basal-bolus regimen for type 2 diabetes. Diabetes Res Clin Pract. 2004;66(2):193-201.
  21. 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 glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetes Care. 2006;29(6):1269-1274.
  22. 2008 resource guide. Insulin. Diabetes Forecast. 2008;61(1):RG11-RG14.
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