Individualizing Insulin Therapy in the Management of Type 2 Diabetes Etie Moghissi, MD, FACE,a Allen B. King, MD, FACEb a
Department of Medicine, University of California Los Angeles, Los Angeles, Calif; bCA Diabetes Care Center, Salinas, Calif.
ABSTRACT It is recognized that reducing hyperglycemia early on in disease progression has long-term benefits for patients with diabetes. Insulin therapy has greater potential to reduce hyperglycemia than other therapies; however, there is often a significant delay in insulin initiation and intensification. Insulin replacement therapy in type 2 diabetes should no longer be viewed as the treatment of last resort. With the development of modern insulin analogs, the field has evolved. Large clinical trials have improved our understanding of the potential benefits and risks associated with intensive glycemic control in different patient populations and highlighted the need for individualization of glycemic targets and treatment strategies. Current treatment guidelines recognize the important role of insulin therapy both early on and throughout the progression of type 2 diabetes. Ó 2014 Elsevier Inc. All rights reserved. The American Journal of Medicine (2014) 127, S3-S10 KEYWORDS: Diabetes management; Glycemic target; Individualizing therapy; Insulin; Type 2 diabetes
An estimated 382 million people are living with diabetes, half of whom are undiagnosed.1 In the United States alone, more than 29 million individuals have diabetes.2 The most prevalent form, type 2 diabetes, is characterized by insulin resistance and impaired insulin production. Because of the progressive nature of type 2 diabetes, the majority of patients eventually require insulin therapy to maintain adequate glycemic control.3 There is growing awareness that insulin output, relative to insulin sensitivity, is deficient early in the course of the disease and continues to worsen throughout the disease progression. Therefore, insulin therapy is relevant throughout all stages of type 2 diabetes. This article discusses some of the background studies and
Funding: The publication of this manuscript was funded by Novo Nordisk Inc. Conflict of Interest: EM has served on advisory boards for Amylin/ BMS, Janssen, Merck, Novo Nordisk, and Sanofi, and is on the speakers’ bureau for Boehringer Ingelheim, Novo Nordisk, Takeda, and Janssen. ABK has served on advisory boards for Sanofi, Novo Nordisk, and Lilly, for which he is also on the speakers’ bureau and has conducted commercially sponsored research. Authorship: The authors take full responsibility for the content of this manuscript. Writing support was provided by Watermeadow Medical. Requests for reprints should be addressed to Etie Moghissi, MD, FACE, 4644 Lincoln Blvd, Suite 409, Marina del Rey, CA 90292. E-mail address: [email protected] 0002-9343/$ -see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2014.07.002
trials that shaped the current guidelines and the resulting recommendations regarding insulin use in the management of patients with type 2 diabetes, the evolving role of insulin therapy, and the tailoring of treatment goals to individual patients.
INDIVIDUALIZING THERAPY AND GOALS FOR PATIENTS WITH TYPE 2 DIABETES Evolution of Insulin Therapy in Type 2 Diabetes: The Lessons Learned from Outcome Studies The first step in the treatment of patients with type 2 diabetes is setting glycemic targets. The current standard of care involves individualizing these targets on the basis of patient characteristics.4,5 The individualized targets should take into account not only clinical conditions, such as relevant comorbid conditions, age, duration of diabetes, and history of severe hypoglycemia, but also the patient-specific psycho-socioeconomic context. This includes the psychologic aspects, economic considerations, available support systems, and social functioning of the patient. Ultimately, the goal of any treatment should be to provide the patient with the greatest possible improvement in both short- and long-term quality of life.5 Large-scale outcome trials
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performed over recent decades have demonstrated the merits of this approach and helped to shape current treatment guidelines. Details of some of the pivotal studies follow. In 1998, the UK Prospective Diabetes Study (UKPDS) demonstrated the link between tight control of glycated hemoglobin (HbA1c) and incidence of microvascular complications in patients with type 2 diabetes.6 Treatment was insulin/sulfonylurea or metformin for overweight patients (those over 120% of ideal body weight). Intensive glycemic control (median HbA1c 7.0%) over an average 10-year period in newly diagnosed patients led to a 25% reduction in overall microvascular complications compared with conventional glycemic control (median HbA1c 7.9%). Another study, the Diabetes Control and Complications Trial (DCCT), also showed a clear reduction in microvascular complications in intensively treated patients with type 1 diabetes (mean achieved HbA1c w7.0%) compared with the standard group (mean achieved HbA1c w9.0%). Over an average of 6.5 years, the development of diabetic retinopathy in those patients with no retinopathy at baseline was reduced by 76%, and its progression was reduced by 54% in those with mild retinopathy at baseline; in this group, the development of proliferative or severe nonproliferative retinopathy was also reduced by 47%. Overall, nephropathy was reduced by 54% and neuropathy by 60%.7 Thus, the link between tight glycemic control and reduced incidence of microvascular disease associated with diabetes was established. Although these trials clearly demonstrated the benefits of intensive glycemic control on microvascular outcomes, the effects on macrovascular events were inconclusive. Of note, follow-up studies of the UKPDS cohort suggested a continued benefit in those patients who had been in the intensive treatment arm, years after intensive treatment had ceased—the so-called legacy effect.8 These findings were similar to those of the DCCT follow-up study (the Epidemiology of Diabetes Interventions and Complications trial), although that study involved patients with type 1 diabetes. Despite a convergence in HbA1c levels between treatment groups at 1 year after the initial study end, patients who were originally randomized to intensive therapy showed a statistically significant risk reduction for any diabetesrelated end point and for myocardial infarction and death from any cause at 10 years. Thus, these follow-up studies revealed that when good glycemic control is established early in type 2 diabetes, the prognostic benefits endure. Although an increased risk of cardiovascular disease associated with type 2 diabetes is well established,9,10 it remains less clear how intensive glycemic control affects the incidence of cardiovascular events. Both the UKPDS and the DCCT (preefollow-up studies) showed a trend toward a reduction in cardiovascular events in the intensive treatment arms, but the reductions did not reach statistical significance; however, the follow-up studies did suggest a benefit in the longer term. Three subsequent trials sought to clarify the effect of intensive glycemic control on cardiovascular outcomes in older patients with type 2 diabetes at
relatively high risk of cardiovascular disease. Unlike the UKPDS, these trials were performed in older patients (aged 60-66 years) with established diabetes. The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE) and the Veteran Affairs Diabetes Trial (VADT) showed that intensive glycemic control (ADVANCE target HbA1c 6.5%, VADT target HbA1c 6.5% is advised for patients with concurrent illness at risk of hypoglycemia, and the algorithm suggests that in these cases, HbA1c goals should be individualized. Basal insulin is recommended as an option in both second- and third-line therapy, or as a part of the multiple dual therapy options for newly diagnosed patients with an entry HbA1c 7.5%. For symptomatic patients with an entry HbA1c >9.0%, insulin with or without other agents is recommended from the start of treatment. In regard to insulin initiation, the AACE recommends initiating basal insulin with a dose of 0.1 to 0.2 U/kg in patients with an HbA1c 8%. The AACE’s “algorithm for adding/intensifying insulin” then recommends insulin titration every 2 to 3 days to reach
Figure 1 Antihyperglycemic therapy in type 2 diabetes: general recommendations (ADA/EASD position statement). Reproduced with permission from Inzucchi et al.4 DPP-4-i ¼ dipeptidyl peptidase-4 inhibitor; Fx ¼ bone fracture; GLP-1-RA ¼ glucagon-like peptide-1 receptor agonist; GI ¼ gastrointestinal; HbA1c ¼ glycated hemoglobin; HF ¼ heart failure; SU ¼ sulfonylurea; TZD ¼ thiazolidinedione.
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the glycemic target, with different advice based on whether the patient is on a fixed or flexible regimen; in the case of the latter, the dose adjustment is calculated according to fasting plasma glucose. Should the glycemic target still not be met, 2 different means of intensification are offered (Figure 3). One recommendation is the addition of prandial insulin, up to a total daily dose of 0.3 to 0.5 U/kg, and the algorithm details how to titrate both the basal and prandial insulins according to regimen type and incidence of hypoglycemia. Of note, the alternative route recognizes the value of adding an incretin-based therapy and suggests adding a glucagon-like peptide-1 receptor agonist or a dipeptidyl peptidase-4 inhibitor to the basal insulin.
FUTURE PROSPECTS FOR INSULIN THERAPY IN TYPE 2 DIABETES Historically, as we have learned about the prognostic benefits of glycemic control and the practicalities of using insulin, our attitude toward insulin therapy in type 2 diabetes has progressively shifted from regarding it as “treatment of last resort” to a mainstay of therapy that should not be delayed. One concept that takes this to the extreme is that of “correcting” glycemia, using intensive insulin therapy for a brief period at the time of diagnosis. It is thought this may help to restore beta-cell function and insulin sensitivity. In a
pilot study, 16 newly diagnosed patients received intensive insulin therapy for 2 to 3 weeks, after which insulin was discontinued. A statistically significant decrease in fasting plasma glucose values (from 239.6 mg/dL to 126.1 mg/dL) was seen, and these improvements were maintained at 1 year (fasting plasma glucose 120.7 mg/dL).34 A more recent study also demonstrated a sustained benefit in glycemic control after intensive insulin therapy. Multiple daily insulin injections or continuous subcutaneous insulin infusion was compared with glicazide or metformin treatment in newly diagnosed patients with type 2 diabetes, and treatment was continued until 2 weeks of normoglycemia had been achieved. After 1 year, remission rates were significantly higher in the groups that had received initial insulin therapy, at 51% and 45% in the continuous subcutaneous insulin infusion and multiple daily insulin injection groups, respectively, compared with 27% in the oral therapy group.35 These studies support the theory that newly diagnosed patients may see a long-term benefit from a short period of intensive insulin therapy. However, intensive insulin therapy requires close monitoring and support from specialist care providers, and despite promising results, the place for such an approach is yet to be established under current treatment guidelines. In addition to changes in the way insulin is used in type 2 diabetes, the continual development of basal insulins has
Figure 2 Sequential insulin strategies in type 2 diabetes (ADA/EASD position statement 2012). Reproduced with permission from Inzucchi et al.4
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Figure 3 Algorithm for adding/intensifying insulin (EASD Comprehensive Diabetes Management Algorithm 2013). Reproduced with permission from Garber et al.20 BG ¼ blood glucose; DPP4-i ¼ dipeptidyl peptidase-4 inhibitor; FBG ¼ fasting blood glucose; GLP-1-RA ¼ glucagon-like peptide-1 receptor agonist; HbA1c ¼ glycated hemoglobin; NPH ¼ neutral protamine Hagedorn; TDD ¼ total daily dose; T2D ¼ type 2 diabetes.
transformed the treatment of diabetes. More information on currently available insulin options and others still in development is given in this supplement.32
CONCLUSIONS The importance of individualizing treatment in patients with type 2 diabetes is established. The benefits of insulin therapy, alone or in combination with other oral antidiabetic drugs, in the early stages of the disease are clear. Tight glycemic control has been shown to have a sustained positive effect on microvascular end points, and when hyperglycemia is targeted early, significant improvements in macrovascular outcomes are apparent in the long-term. Insulin therapy can make glycemic goals more readily achievable, and early therapy may partially restore beta-cell function. However, such aggressive treatment is not appropriate in all patients,
particularly those with concurrent illnesses. Current treatment guidelines issued by the ADA/EASD and AACE acknowledge this, and the ADA/EASD position statement in particular emphasizes the importance of individualized therapy. Advances in insulin dosing regimens, such as treating-totarget with simple patient-led algorithms and stepwise addition of bolus insulin, together with the development of modern insulin analogs, have enabled therapy to be better tailored to the individual patient, and a range of therapy options now exist. Insulin therapy plays a crucial role in the management of type 2 diabetes and should no longer be viewed as a treatment of last resort.
ACKNOWLEDGMENTS The authors thank Liam Sebag-Montefiore and Gabrielle Parker of Watermeadow Medical for writing and editing assistance, supported by Novo Nordisk.
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References 1. International Diabetes Federation. IDF Diabetes Atlas, 6th edn. Brussels, Belgium: International Diabetes Federation, 2013. Available at http://www.idf.org/diabetesatlas. Accessed August 8, 2014. 2. Centers for Disease Control and Prevention. Last updated 2013. Available at: http://www.cdc.gov/diabetes/pubs/statsreport14/nationaldiabetes-report-web.pdf. Accessed August 8, 2014. 3. 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. Endocr Pract. 2009;15:540-559. 4. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia 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). Diabetologia. 2012;55:1577-1596. 5. Ismail-Beigi F, Moghissi E, Tiktin M, et al. Individualizing glycemic targets in type 2 diabetes mellitus: implications of recent clinical trials. Ann Intern Med. 2011;154:554-559. 6. UK Prospective Diabetes Study (UKPDS) Group. Intensive bloodglucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853. 7. 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. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329:977-986. 8. Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577-1589. 9. Selvin E, Marinopoulos S, Berkenblit G, et al. Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus. Ann Intern Med. 2004;141:421-431. 10. Stettler C, Allemann S, Juni P, et al. Glycemic control and macrovascular disease in types 1 and 2 diabetes mellitus: meta-analysis of randomized trials. Am Heart J. 2006;152:27-38. 11. Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129-139. 12. Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560-2572. 13. Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545-2559. 14. Riddle MC, Rosenstock J, Gerich J. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care. 2003;26:3080-3086. 15. Blonde L, Merilainen M, Karwe V, Raskin P. 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;11:623-631. 16. Hermansen K, Fontaine P, Kukolja KK, et al. Insulin analogues (insulin detemir and insulin aspart) versus traditional human insulins (NPH insulin and regular human insulin) in basal-bolus therapy for patients with type 1 diabetes. Diabetologia. 2004;47:622-629. 17. Philis-Tsimikas A, Charpentier G, Clauson P, et al. Comparison of once-daily insulin detemir with NPH insulin added to a regimen of oral antidiabetic drugs in poorly controlled type 2 diabetes. Clin Ther. 2006;28:1569-1581. 18. Meneghini L, Koenen C, Weng W, Selam JL. The usage of a simplified self-titration dosing guideline (303 Algorithm) for insulin detemir in
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patients with type 2 diabeteseresults of the randomized, controlled PREDICTIVE 303 study. Diabetes Obes Metab. 2007;9:902-913. Davies M, Storms F, Shutler S, et al. Improvement of glycemic control in subjects with poorly controlled type 2 diabetes: comparison of two treatment algorithms using insulin glargine. Diabetes Care. 2005;28: 1282-1288. Garber AJ, Abrahamson MJ, Barzilay JI, et al. AACE comprehensive diabetes management algorithm 2013. Endocr Pract. 2013;19:327-336. Pennartz C, Schenker N, Menge BA, et al. Chronic reduction of fasting glycemia with insulin glargine improves first- and second-phase insulin secretion in patients with type 2 diabetes. Diabetes Care. 2011;34: 2048-2053. Holman RR, Farmer AJ, Davies MJ, et al. Three-year efficacy of complex insulin regimens in type 2 diabetes. N Engl J Med. 2009;361: 1736-1747. Hollander P, Cooper J, Bregnhoj J, Pedersen CB. A 52-week, multinational, open-label, parallel-group, noninferiority, treat-to-target trial comparing insulin detemir with insulin glargine in a basal-bolus regimen with mealtime insulin aspart in patients with type 2 diabetes. Clin Ther. 2008;30:1976-1987. Davidson MB, Raskin P, Tanenberg RJ, et al. A stepwise approach to insulin therapy in patients with type 2 diabetes mellitus and basal insulin treatment failure. Endocr Pract. 2011;17:395-403. Meneghini L, Mersebach H, Kumar S, et al. 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;17:727-736. Rosenstock J, Rodbard HW, Bain SC, et al. One-year sustained glycemic control and weight reduction in type 2 diabetes after addition of liraglutide to metformin followed by insulin detemir according to HbA1c target. J Diabetes Complications. 2013;27:492-500. Barnett AH, Charbonnel B, Donovan M, Fleming D, Chen R. Effect of saxagliptin as add-on therapy in patients with poorly controlled type 2 diabetes on insulin alone or insulin combined with metformin. Curr Med Res Opin. 2012;28:513-523. Buse JB, Bergenstal RM, Glass LC, et al. Use of twice-daily exenatide in Basal insulin-treated patients with type 2 diabetes: a randomized, controlled trial. Ann Intern Med. 2011;154:103-112. Vilsboll T, Rosenstock J, Yki-Jarvinen H, et al. Efficacy and safety of sitagliptin when added to insulin therapy in patients with type 2 diabetes. Diabetes Obes Metab. 2010;12:167-177. Buse JB, Rosenstock J, Sesti G, et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet. 2009;374:39-47. Drucker DJ, Buse JB, Taylor K, et al. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, openlabel, non-inferiority study. Lancet. 2008;372:1240-1250. Sorli C. New developments in insulin therapy for type 2 diabetes. Am J Med. 2014;127:S39-S48. King AB, Clark D, Wolfe GS. Weight versus pre-insulin-treatment assessment of insulin sensitivity to determine the starting basal insulin dose: a faster way to get to goal? J Diabetes Sci Technol. 2013;7: 1098-1099. Ryan EA, Imes S, Wallace C. Short-term intensive insulin therapy in newly diagnosed type 2 diabetes. Diabetes Care. 2004;27: 1028-1032. Weng J, Li Y, Xu W, et al. Effect of intensive insulin therapy on betacell function and glycaemic control in patients with newly diagnosed type 2 diabetes: a multicentre randomised parallel-group trial. Lancet. 2008;371:1753-1760.
Department of Medicine, University of California Los Angeles, Los Angeles, Calif; bCA Diabetes Care Center, Salinas, Calif.
ABSTRACT It is recognized that reducing hyperglycemia early on in disease progression has long-term benefits for patients with diabetes. Insulin therapy has greater potential to reduce hyperglycemia than other therapies; however, there is often a significant delay in insulin initiation and intensification. Insulin replacement therapy in type 2 diabetes should no longer be viewed as the treatment of last resort. With the development of modern insulin analogs, the field has evolved. Large clinical trials have improved our understanding of the potential benefits and risks associated with intensive glycemic control in different patient populations and highlighted the need for individualization of glycemic targets and treatment strategies. Current treatment guidelines recognize the important role of insulin therapy both early on and throughout the progression of type 2 diabetes. Ó 2014 Elsevier Inc. All rights reserved. The American Journal of Medicine (2014) 127, S3-S10 KEYWORDS: Diabetes management; Glycemic target; Individualizing therapy; Insulin; Type 2 diabetes
An estimated 382 million people are living with diabetes, half of whom are undiagnosed.1 In the United States alone, more than 29 million individuals have diabetes.2 The most prevalent form, type 2 diabetes, is characterized by insulin resistance and impaired insulin production. Because of the progressive nature of type 2 diabetes, the majority of patients eventually require insulin therapy to maintain adequate glycemic control.3 There is growing awareness that insulin output, relative to insulin sensitivity, is deficient early in the course of the disease and continues to worsen throughout the disease progression. Therefore, insulin therapy is relevant throughout all stages of type 2 diabetes. This article discusses some of the background studies and
Funding: The publication of this manuscript was funded by Novo Nordisk Inc. Conflict of Interest: EM has served on advisory boards for Amylin/ BMS, Janssen, Merck, Novo Nordisk, and Sanofi, and is on the speakers’ bureau for Boehringer Ingelheim, Novo Nordisk, Takeda, and Janssen. ABK has served on advisory boards for Sanofi, Novo Nordisk, and Lilly, for which he is also on the speakers’ bureau and has conducted commercially sponsored research. Authorship: The authors take full responsibility for the content of this manuscript. Writing support was provided by Watermeadow Medical. Requests for reprints should be addressed to Etie Moghissi, MD, FACE, 4644 Lincoln Blvd, Suite 409, Marina del Rey, CA 90292. E-mail address: [email protected] 0002-9343/$ -see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2014.07.002
trials that shaped the current guidelines and the resulting recommendations regarding insulin use in the management of patients with type 2 diabetes, the evolving role of insulin therapy, and the tailoring of treatment goals to individual patients.
INDIVIDUALIZING THERAPY AND GOALS FOR PATIENTS WITH TYPE 2 DIABETES Evolution of Insulin Therapy in Type 2 Diabetes: The Lessons Learned from Outcome Studies The first step in the treatment of patients with type 2 diabetes is setting glycemic targets. The current standard of care involves individualizing these targets on the basis of patient characteristics.4,5 The individualized targets should take into account not only clinical conditions, such as relevant comorbid conditions, age, duration of diabetes, and history of severe hypoglycemia, but also the patient-specific psycho-socioeconomic context. This includes the psychologic aspects, economic considerations, available support systems, and social functioning of the patient. Ultimately, the goal of any treatment should be to provide the patient with the greatest possible improvement in both short- and long-term quality of life.5 Large-scale outcome trials
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performed over recent decades have demonstrated the merits of this approach and helped to shape current treatment guidelines. Details of some of the pivotal studies follow. In 1998, the UK Prospective Diabetes Study (UKPDS) demonstrated the link between tight control of glycated hemoglobin (HbA1c) and incidence of microvascular complications in patients with type 2 diabetes.6 Treatment was insulin/sulfonylurea or metformin for overweight patients (those over 120% of ideal body weight). Intensive glycemic control (median HbA1c 7.0%) over an average 10-year period in newly diagnosed patients led to a 25% reduction in overall microvascular complications compared with conventional glycemic control (median HbA1c 7.9%). Another study, the Diabetes Control and Complications Trial (DCCT), also showed a clear reduction in microvascular complications in intensively treated patients with type 1 diabetes (mean achieved HbA1c w7.0%) compared with the standard group (mean achieved HbA1c w9.0%). Over an average of 6.5 years, the development of diabetic retinopathy in those patients with no retinopathy at baseline was reduced by 76%, and its progression was reduced by 54% in those with mild retinopathy at baseline; in this group, the development of proliferative or severe nonproliferative retinopathy was also reduced by 47%. Overall, nephropathy was reduced by 54% and neuropathy by 60%.7 Thus, the link between tight glycemic control and reduced incidence of microvascular disease associated with diabetes was established. Although these trials clearly demonstrated the benefits of intensive glycemic control on microvascular outcomes, the effects on macrovascular events were inconclusive. Of note, follow-up studies of the UKPDS cohort suggested a continued benefit in those patients who had been in the intensive treatment arm, years after intensive treatment had ceased—the so-called legacy effect.8 These findings were similar to those of the DCCT follow-up study (the Epidemiology of Diabetes Interventions and Complications trial), although that study involved patients with type 1 diabetes. Despite a convergence in HbA1c levels between treatment groups at 1 year after the initial study end, patients who were originally randomized to intensive therapy showed a statistically significant risk reduction for any diabetesrelated end point and for myocardial infarction and death from any cause at 10 years. Thus, these follow-up studies revealed that when good glycemic control is established early in type 2 diabetes, the prognostic benefits endure. Although an increased risk of cardiovascular disease associated with type 2 diabetes is well established,9,10 it remains less clear how intensive glycemic control affects the incidence of cardiovascular events. Both the UKPDS and the DCCT (preefollow-up studies) showed a trend toward a reduction in cardiovascular events in the intensive treatment arms, but the reductions did not reach statistical significance; however, the follow-up studies did suggest a benefit in the longer term. Three subsequent trials sought to clarify the effect of intensive glycemic control on cardiovascular outcomes in older patients with type 2 diabetes at
relatively high risk of cardiovascular disease. Unlike the UKPDS, these trials were performed in older patients (aged 60-66 years) with established diabetes. The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE) and the Veteran Affairs Diabetes Trial (VADT) showed that intensive glycemic control (ADVANCE target HbA1c 6.5%, VADT target HbA1c 6.5% is advised for patients with concurrent illness at risk of hypoglycemia, and the algorithm suggests that in these cases, HbA1c goals should be individualized. Basal insulin is recommended as an option in both second- and third-line therapy, or as a part of the multiple dual therapy options for newly diagnosed patients with an entry HbA1c 7.5%. For symptomatic patients with an entry HbA1c >9.0%, insulin with or without other agents is recommended from the start of treatment. In regard to insulin initiation, the AACE recommends initiating basal insulin with a dose of 0.1 to 0.2 U/kg in patients with an HbA1c 8%. The AACE’s “algorithm for adding/intensifying insulin” then recommends insulin titration every 2 to 3 days to reach
Figure 1 Antihyperglycemic therapy in type 2 diabetes: general recommendations (ADA/EASD position statement). Reproduced with permission from Inzucchi et al.4 DPP-4-i ¼ dipeptidyl peptidase-4 inhibitor; Fx ¼ bone fracture; GLP-1-RA ¼ glucagon-like peptide-1 receptor agonist; GI ¼ gastrointestinal; HbA1c ¼ glycated hemoglobin; HF ¼ heart failure; SU ¼ sulfonylurea; TZD ¼ thiazolidinedione.
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the glycemic target, with different advice based on whether the patient is on a fixed or flexible regimen; in the case of the latter, the dose adjustment is calculated according to fasting plasma glucose. Should the glycemic target still not be met, 2 different means of intensification are offered (Figure 3). One recommendation is the addition of prandial insulin, up to a total daily dose of 0.3 to 0.5 U/kg, and the algorithm details how to titrate both the basal and prandial insulins according to regimen type and incidence of hypoglycemia. Of note, the alternative route recognizes the value of adding an incretin-based therapy and suggests adding a glucagon-like peptide-1 receptor agonist or a dipeptidyl peptidase-4 inhibitor to the basal insulin.
FUTURE PROSPECTS FOR INSULIN THERAPY IN TYPE 2 DIABETES Historically, as we have learned about the prognostic benefits of glycemic control and the practicalities of using insulin, our attitude toward insulin therapy in type 2 diabetes has progressively shifted from regarding it as “treatment of last resort” to a mainstay of therapy that should not be delayed. One concept that takes this to the extreme is that of “correcting” glycemia, using intensive insulin therapy for a brief period at the time of diagnosis. It is thought this may help to restore beta-cell function and insulin sensitivity. In a
pilot study, 16 newly diagnosed patients received intensive insulin therapy for 2 to 3 weeks, after which insulin was discontinued. A statistically significant decrease in fasting plasma glucose values (from 239.6 mg/dL to 126.1 mg/dL) was seen, and these improvements were maintained at 1 year (fasting plasma glucose 120.7 mg/dL).34 A more recent study also demonstrated a sustained benefit in glycemic control after intensive insulin therapy. Multiple daily insulin injections or continuous subcutaneous insulin infusion was compared with glicazide or metformin treatment in newly diagnosed patients with type 2 diabetes, and treatment was continued until 2 weeks of normoglycemia had been achieved. After 1 year, remission rates were significantly higher in the groups that had received initial insulin therapy, at 51% and 45% in the continuous subcutaneous insulin infusion and multiple daily insulin injection groups, respectively, compared with 27% in the oral therapy group.35 These studies support the theory that newly diagnosed patients may see a long-term benefit from a short period of intensive insulin therapy. However, intensive insulin therapy requires close monitoring and support from specialist care providers, and despite promising results, the place for such an approach is yet to be established under current treatment guidelines. In addition to changes in the way insulin is used in type 2 diabetes, the continual development of basal insulins has
Figure 2 Sequential insulin strategies in type 2 diabetes (ADA/EASD position statement 2012). Reproduced with permission from Inzucchi et al.4
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Figure 3 Algorithm for adding/intensifying insulin (EASD Comprehensive Diabetes Management Algorithm 2013). Reproduced with permission from Garber et al.20 BG ¼ blood glucose; DPP4-i ¼ dipeptidyl peptidase-4 inhibitor; FBG ¼ fasting blood glucose; GLP-1-RA ¼ glucagon-like peptide-1 receptor agonist; HbA1c ¼ glycated hemoglobin; NPH ¼ neutral protamine Hagedorn; TDD ¼ total daily dose; T2D ¼ type 2 diabetes.
transformed the treatment of diabetes. More information on currently available insulin options and others still in development is given in this supplement.32
CONCLUSIONS The importance of individualizing treatment in patients with type 2 diabetes is established. The benefits of insulin therapy, alone or in combination with other oral antidiabetic drugs, in the early stages of the disease are clear. Tight glycemic control has been shown to have a sustained positive effect on microvascular end points, and when hyperglycemia is targeted early, significant improvements in macrovascular outcomes are apparent in the long-term. Insulin therapy can make glycemic goals more readily achievable, and early therapy may partially restore beta-cell function. However, such aggressive treatment is not appropriate in all patients,
particularly those with concurrent illnesses. Current treatment guidelines issued by the ADA/EASD and AACE acknowledge this, and the ADA/EASD position statement in particular emphasizes the importance of individualized therapy. Advances in insulin dosing regimens, such as treating-totarget with simple patient-led algorithms and stepwise addition of bolus insulin, together with the development of modern insulin analogs, have enabled therapy to be better tailored to the individual patient, and a range of therapy options now exist. Insulin therapy plays a crucial role in the management of type 2 diabetes and should no longer be viewed as a treatment of last resort.
ACKNOWLEDGMENTS The authors thank Liam Sebag-Montefiore and Gabrielle Parker of Watermeadow Medical for writing and editing assistance, supported by Novo Nordisk.
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