Individualizing Insulin Therapy

,; ,

Medical Education Library

Individualizing Insulin Therapy

May 2012 · Vol. 61, No. 05 Suppl: S13-S27

By

Luigi Meneghini, MD, MBA

Timothy Reid, MD

PDF Download

References

1. Rodbard HW, Jellinger PS, Davidson JA, et al. Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control [published correction appears in Endocr Pract. 2009;15(7):768-770]. Endocr Pract. 2009;15(6):540-559.

2. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) [published online ahead of print April 19, 2012]. Diabetes Care. doi:10.2337/dc12-0413.

3. Lalić NM, Micić D, Antić S, et al. Effect of biphasic insulin aspart on glucose and lipid control in patients with type 2 diabetes mellitus. Expert Opin Pharmacother. 2007;8(17):2895-2901.

4. Reynolds LR, Kingsley FJ, Karounos DG, Tannock LR. Differential effects of rosiglitazone and insulin glargine on inflammatory markers, glycemic control, and lipids in type 2 diabetes. Diabetes Res Clin Pract. 2007;77(2):180-187.

5. Rosak C, Jung R, Hofmann U. Insulin glargine maintains equivalent glycemic control and better lipometabolic control than NPH insulin in type 1 diabetes patients who missed a meal. Horm Metab Res. 2008;40(8):544-548.

6. Ampudia-Blasco FJ, Girbes J, Carmena R. A case of lipoatrophy with insulin glargine: long-acting insulin analogs are not exempt from this complication. Diabetes Care. 2005;28(12):2983.-

7. Griffin ME, Feder A, Tamborlane WV. Lipoatrophy associated with lispro insulin in insulin pump therapy: an old complication, a new cause? Diabetes Care. 2001;24(1):174.-

8. Fineberg SE, Huang J, Brunelle R, Gulliya KS, Anderson JH, Jr. Effect of long-term exposure to insulin lispro on the induction of antibody response in patients with type 1 or type 2 diabetes. Diabetes Care. 2003;26(1):89-96.

9. Moyes V, Driver R, Croom A, Mirakian R, Chowdhury TA. Insulin allergy in a patient with type 2 diabetes successfully treated with continuous subcutaneous insulin infusion. Diabet Med. 2006;23(2):204-206.

10. Ghosh S, McCann V, Bartle L, Collier A, Malik I. Allergy to insulin detemir. Diabet Med. 2007;24(11):1307.-

11. Blumer I. Severe, delayed insulin detemir injection site reaction. Diabet Med. 2008;25(8):1008.-

12. Pérez E, González R, Martínez J, Iglesias J, Matheu V. Detemir insulin-induced anaphylaxis. Ann Allergy Asthma Immunol. 2009;102(2):174-175.

13. Mollar-Puchades MA, Villanueva IL. Insulin glulisine in the treatment of allergy to rapid acting insulin and its rapid acting analogs. Diabetes Res Clin Pract. 2009;83(1):e21-e22.

14. Kawasaki F, Kamei S, Tatsumi F, et al. Gallbladder edema in type 1 diabetic patient due to delayed-type insulin allergy. Intern Med. 2009;48(17):1545-1549.

15. Wang C, Ding ZY, Shu SQ, et al. Severe insulin allergy after percutaneous transluminal coronary angioplasty. Clin Ther. 2009;31(3):569-574.

16. Ozaki N, Oiso Y. Immunologic tolerance to the insulin analogue glulisine. Diabetes Care. 2010;33(3):e39.-

17. Koroscil T, Kagzi Y, Zacharias D. Failure of multiple therapies in the treatment of a type 1 diabetic patient with insulin allergy: a case report. Endocr Pract. 2011;17(1):91-94.

18. Tuerk PW, Mueller M, Egede LE. Estimating physician effects on glycemic control in the treatment of diabetes: methods, effects sizes, and implications for treatment policy. Diabetes Care. 2008;31(5):869-873.

19. Hajos TR, Polonsky WH, Twisk JW, Dain MP, Snoek FJ. Do physicians understand type 2 diabetes patients’ perceptions of seriousness; the emotional impact and needs for care improvement? A cross-national survey. Patient Educ Couns. 2011;85(2):258-263.

20. Polonsky WH, Hajos TR, Dain MP, Snoek FJ. Are patients with type 2 diabetes reluctant to start insulin therapy? An examination of the scope and underpinnings of psychological insulin resistance in a large, international population. Curr Med Res Opin. 2011;27(6):1169-1174.

21. Nam S, Chesla C, Stotts NA, Kroon L, Janson SL. Factors associated with psychological insulin resistance in individuals with type 2 diabetes. Diabetes Care. 2010;33(8):1747-1749.

22. Nakar S, Yitzhaki G, Rosenberg R, Vinker S. Transition to insulin in type 2 diabetes: family physicians’ misconception of patients’ fears contributes to existing barriers. J Diabetes Complications. 2007;21(4):220-226.

23. Snoek FJ. Breaking the barriers to optimal glycaemic control—what physicians need to know from patients’ perspectives. Int J Clin Pract Suppl. 2002;(129):80-84.

24. Korytkowski M. When oral agents fail: practical barriers to starting insulin. Int J Obes Relat Metab Disord. 2002;26(Suppl 3):S18-S24.

25. Skovlund SE, Peyrot M. The Diabetes Attitudes, Wishes and Needs (DAWN) program: a new approach to improving outcomes of diabetes care. Diabetes Spectrum. 2005;18(3):136-142.

26. Jenkins N, Hallowell N, Farmer AJ, Holman RR, Lawton J. Initiating insulin as part of the Treating To Target in Type 2 Diabetes (4-T) trial: an interview study of patients’ and health professionals’ experiences. Diabetes Care. 2010;33(10):2178-2180.

27. Levinson W, Gorawara-Bhat R, Lamb J. A study of patient clues and physician responses in primary care and surgical settings. JAMA. 2000;284(8):1021-1027.

28. Rodriguez HP, Anastario MP, Frankel RM, et al. Can teaching agenda-setting skills to physicians improve clinical interaction quality? A controlled intervention. BMC Med Educ. 2008;8:3.-

29. Solomon J. How strategies for managing patient visit time affect physician job satisfaction: a qualitative analysis. J Gen Intern Med. 2008;23(6):775-780.

30. Funnell MM, Anderson RM. Empowerment and self-management of diabetes. Clin Diabetes. 2004;22(3):123-127.

31. Funnell MM, Anderson RM. Are patients or outcomes more important? Rev Endocrinol. 2008;2(8):49-51.

32. Shaefer CF. Clinical inertia: overcoming a major barrier to diabetes management. Insulin. 2006;1(2):61-64.

33. Harris S, Yale JF, Dempsey E, Gerstein H. Can family physicians help patients initiate basal insulin therapy successfully?: randomized trial of patient-titrated insulin glargine compared with standard oral therapy: lessons for family practice from the Canadian INSIGHT trial. Can Fam Physician. 2008;54(4):550-558.

34. Centers for Disease Control and Prevention. National diabetes fact sheet national estimates and general information on diabetes and prediabetes in the United States, 2011. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2011. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. Accessed February 10, 2011.

35. 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.

36. 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 [published correction appears in Diabetes Care. 2007;30(4):1035]. Diabetes Care. 2006;29(6):1269-1274.

37. Davies M, Storms F, Shutler S, Bianchi-Biscay M, Gomis R. ATLANTUS Study Group. 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.

38. Meneghini L, Koenen C, Weng W, Selam JL. The usage of a simplified self-titration dosing guideline (303 Algorithm) for insulin detemir in patients with type 2 diabetes—results of the randomized, controlled PREDICTIVE 303 study. Diabetes Obes Metab. 2007;9(6):902-913.

39. Garber AJ, Wahlen J, Wahl T, et al. Attainment of glycaemic goals in type 2 diabetes with once-, twice-, or thrice-daily dosing with biphasic insulin aspart 70/30 (The 1-2-3 study). Diabetes Obes Metab. 2006;8(1):58-66.

40. Philis-Tsimikas A, Charpentier G, Clauson P, Ravn GM, Roberts VL, Thorsteinsson B. Comparison of once-daily insulin detemir with NPH insulin added to a regimen of oral antidiabetic drugs in poorly controlled type 2 diabetes [published correction appears in Clin Ther. 2006;28(11):1967]. Clin Ther. 2006;28(10):1569-1581.

41. Blonde L, Merilainen M, Karwe V, Raskin P. TITRATE Study Group. Patient-directed titration for achieving glycaemic goals using a once-daily basal insulin analogue: an assessment of two different fasting plasma glucose targets—the TITRATE study. Diabetes Obes Metab. 2009;11(6):623-631.

42. Meneghini L, Mersebach H, Kumar S, Svendsen AL, Hermansen K. Comparison of 2 intensification regimens with rapid-acting insulin aspart in type 2 diabetes mellitus inadequately controlled by once-daily insulin detemir and oral antidiabetes drugs: the step-wise randomized study. Endocr Pract. 2011;17(5):727-736.

43. Lankisch MR, Ferlinz KC, Leahy JL, Scherbaum WA. Orals Plus Apidra and LANTUS (OPAL) study group. Introducing a simplified approach to insulin therapy in type 2 diabetes: a comparison of two single-dose regimens of insulin glulisine plus insulin glargine and oral antidiabetic drugs [published correction appears in Diabetes Obes Metab. 2010;12(5):461]. Diabetes Obes Metab 2008;10(12):1178-1185.

44. Meneghini L. Why and how to use insulin therapy earlier in the management of type 2 diabetes. South Med J. 2007;100(2):164-174.

45. Liebl A, Prager R, Binz K, Kaiser M, Bergenstal R, Gallwitz B. PREFER Study Group. Comparison of insulin analogue regimens in people with type 2 diabetes mellitus in the PREFER Study: a randomized controlled trial. Diabetes Obes Metab. 2009;11(1):45-52.

46. Braun A, Sämann A, Kubiak T, et al. Effects of metabolic control, patient education and initiation of insulin therapy on the quality of life of patients with type 2 diabetes mellitus. Patient Educ Couns. 2008;73(1):50-59.

Table of Contents

Introduction

The Evolution of Insulin Therapy in Diabetes Mellitus

Individualizing Insulin Therapy

Advances in Insulin Therapy: A Review of Insulin Degludec

The modern management of diabetes mellitus (DM) began with the discovery of insulin by Banting and Best in 1921 (see The Evolution of Insulin Therapy in Diabetes Mellitus in this supplement). Since that time, numerous additional classes of glucose-lowering agents have been introduced for the treatment of type 2 DM (T2DM). These medications primarily act by addressing 2 of the key defects of T2DM, insulin resistance and pancreatic β-cell dysfunction. T2DM is a progressive disease process that requires continued adjustment of therapy to maintain treatment goals. Most patients with T2DM will require insulin therapy at some point in their lives.

Role of Insulin in Type 2 Diabetes Mellitus Management

Consensus guidelines developed by the American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) recommend initiating insulin when oral therapy fails to achieve glycemic control, A1C > 9.0% in treatment-naïve patients, or if the patient is symptomatic with glucose toxicity (polyuria, polydipsia, and weight loss) (FIGURE 1).¹

Similar consensus guidelines developed by the American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) advise the initiation of glucose-lowering therapy for most patients with T2DM with the combination of lifestyle modifications, diet, and metformin (FIGURE 2).² For patients who do not achieve or maintain glycemic control over 3 months, or thereabouts, with metformin, a second oral agent should be added. Alternatives include a glucagon-like peptide-1 receptor (GLP-1R) agonist or basal insulin. Insulin should be strongly considered as initial therapy for a patient with significant symptoms of hyperglycemia and/or plasma glucose >300-350 mg/dL or A1C ≥10.0%.

The major role of insulin in the management of patients with T2DM stems from several important attributes. First, insulin is the only treatment that works in patients with advanced β-cell deficiency. It acts directly on tissues to regulate glucose homeostasis, unlike other glucose-lowering agents that require the presence of sufficient endogenous insulin to exert their effects as insulin sensitizers, secretagogues, incretin mimetics, amylin analogs, and other factors. This also means that the mechanism of action of insulin is complementary to those of other glucose-lowering agents. Second, there is less of a ceiling effect with insulin. That is, increasing the dose of insulin results in a progressive lowering of blood glucose in the majority of patients, with the major limitation being the risk for hypoglycemia. Third, the glucose-lowering efficacy of insulin is durable, unlike that of other glucose-lowering agents that depend on endogenous insulin secretion for continued effectiveness. Fourth, insulin improves the lipid profile, particularly triglyceride levels.^2-5 Fifth, regarding the long-term safety and tolerability of insulin, it is well established that weight gain, likely mediated via reduction of glycosuria, and hypoglycemia are typically the most concerning adverse events encountered. Allergic reactions, which were a more common complication of animal-sourced insulins, are infrequent with the insulin analogs.^6-17 Finally, the availability of insulin in different formulations allows for targeting fasting plasma glucose or postprandial glucose, and individualization of therapy (see The Evolution of Insulin Therapy in Diabetes Mellitus in this supplement.)

While both the AACE/ACE and ADA/EASD consensus guidelines provide treatment “algorithms,” both make it clear that these are suggested approaches suitable for the population with T2DM (FIGURE 1, FIGURE 2). The specific treatment approach must be individualized based on patient-specific factors such as age, comorbid conditions, and tolerance of hypoglycemia.

FIGURE 1

Role of insulin in the management of patients with type 2 diabetes mellitus according to the AACE/ACE¹

AACE, American Association of Clinical Endocrinologists; ACE, American College of Endocrinology; AGI, α-glucosidase inhibitor; DPP4, dipeptidyl-peptidase-4 inhibitor; FPG, fasting plasma glucose; GLP-1, glucagon–like peptide-1 agonist; MET, metformin; PPG, postprandial glucose; SU, sulfonylurea; TZD, thiazolidinedione.

Reprinted from American Association of Clinical Endocrinologists. AACE/ACE Diabetes Algorithm for Glycemic Control. Available at https://www.aace.com/sites/default/files/GlycemicControlAlgorithmPPT.pdf. Accessed April 4, 2012, with permission from the American Association of Clinical Endocrinologists.

FIGURE 2

Role of insulin in the management of patients with type 2 diabetes mellitus according to the ADA/EASD²

Moving from the top to the bottom of the figure, potential sequences of antihyperglycemic therapy. In most patients, begin with lifestyle changes; metformin monotherapy is added at, or soon after, diagnosis (unless there are explicit contraindications). If the HbA_1c target is not achieved after ~3 months, consider 1 of the 5 treatment options combined with metformin: an SU, TZD, DPP-4-i, GLP-1-RA, or basal insulin. (The order in the chart is determined by historical introduction and route of administration and is not meant to denote any specific preference.) Choice is based on patient and drug characteristics, with the over-riding goal of improving glycemic control while minimizing side effects. Shared decision making with the patient may help in the selection of therapeutic options. The figure displays drugs commonly used both in the United States and/or Europe. Rapid-acting secretagogues (meglitinides) may be used in place of SUs. Other drugs not shown (α-glucosidase inhibitors, colesevelam, dopamine agonists, pramlintide) may be used where available in selected patients but have modest efficacy and/or limiting side effects. In patients intolerant of, or with contraindications for, metformin, select initial drug from other classes depicted and proceed accordingly. In this circumstance, while published trials are generally lacking, it is reasonable to consider 3-drug combinations other than metformin. Insulin is likely to be more effective than most other agents as a third-line therapy, especially when HbA_1c is very high (eg, ≥ 9.0%). The therapeutic regimen should include some basal insulin before moving to more complex insulin strategies. Dashed arrow line on the left-hand side of the figure denotes the option of a more rapid progression from a 2-drug combination directly to multiple daily insulin doses, in those patients with severe hyperglycemia (eg, HbA_1c, ≥ 10.0–12.0%).