Differential Treatment Response to Insulin Intensification Therapy: A Post Hoc Analysis of a Randomized Trial Comparing Premixed and Basal-Bolus Insulin Regimens

Li Xin Shi, Peng Fei Li, Jia Ning Hou, Li Xin Shi, Peng Fei Li, Jia Ning Hou

Abstract

Introduction: Identification of subgroups of patients that may benefit most from certain treatment is important because individual treatment response varies due to multiple contributing factors. The present study used the subgroup identification based on the differential effect search (SIDES) algorithm to identify subgroups with different treatment responses to insulin intensification therapies.

Methods: This was a post hoc analysis of a 24-week, multicenter, open-label, randomized, parallel study comparing prandial premixed therapy (PPT) to basal-bolus therapy (BBT). Patients with type 2 diabetes mellitus were randomized to PPT (insulin lispro mix 50/50 thrice daily with meals) or BBT (glargine at bedtime plus mealtime insulin lispro) insulin intensification therapies. The SIDES algorithm was used to identify the subgroups from at-goal patients [glycated hemoglobin (HbA1c) <7.0% (53.0 mmol/mol) at the end of 24 weeks; n = 182] who could have benefitted from insulin intensification therapies.

Results: Baseline characteristics of overall at-goal patients were comparable between PPT and BBT groups. The SIDES algorithm identified patients with race other than Caucasian (i.e., African-American, Asian, and Hispanic) and baseline fasting blood glucose (FBG) <8.89 mmol/L as a subgroup that could respond better to PPT relative to BBT than the overall at-goal patient population. In this identified subgroup population, the HbA1c mean (standard deviation) changes from baseline to endpoint in PPT and BBT groups were -2.27 (0.88)% versus -2.05 (0.75)%; p = 0.40, respectively; while in the overall at-goal patients, the HbA1c changes were -2.17 (0.79)% versus -2.34 (1.00)%; p = 0.19, respectively.

Conclusions: The preliminary results showed that the subgroup of patients with race other than Caucasian and FBG <8.89 mmol/L may respond better to premixed intensification therapy. This result provides some preliminary information for further investigation in prospective studies.

Funding: Eli Lilly and Company.

Clinical trial registration: Clinicaltrials.gov ID number: NCT00110370.

Keywords: Basal-bolus; Differential treatment response; Premixed insulin; SIDES algorithm; Type 2 diabetes mellitus.

Figures

Fig. 1
Fig. 1
HbA1c at baseline, endpoint, and change from baseline to endpoint (24 weeks of treatment) in both at-goal patients and subgroup of at-goal patients. BBT basal-bolus therapy, HbA1c glycated hemoglobin, n number of patients without missing data, PPT prandial premixed therapy
Fig. 2
Fig. 2
FBG at baseline, endpoint, and change from baseline to endpoint (24 weeks of treatment) in both at-goal patients and subgroup of at-goal patients. BBT basal-bolus therapy, FBG fasting blood glucose, n number of patients without missing data, PPT prandial premixed therapy

References

    1. International Diabetes Federation. IDF diabetes atlas, 7th edn. Brussels (Belgium): International Diabetes Federation, 2013. . Accessed 24 Feb 2015.
    1. Hu FB. Globalization of diabetes: the role of diet, lifestyle, and genes. Diabetes Care. 2011;34:1249–1257. doi: 10.2337/dc11-0442.
    1. Handelsman Y, Bloomgarden ZT, Grunberger G, et al. American Association of Clinical Endocrinologists and American College of Endocrinology—clinical practice guidelines for developing a diabetes mellitus comprehensive care plan—2015. Endocr Pract. 2015;21(Suppl 1):1–87. doi: 10.4158/EP15672.GLSUPPL.
    1. Mosenzon O, Raz I. Intensification of insulin therapy for type 2 diabetic patients in primary care: basal-bolus regimen versus premix insulin analogs: when and for whom? Diabetes Care. 2013;36(Suppl 2):S212–S218. doi: 10.2337/dcS13-2007.
    1. American Diabetes Association Pharmacologic approaches to glycemic treatment. Diabetes Care. 2017;40(Suppl 1):S64–S74. doi: 10.2337/dc17-S011.
    1. Cantrell RA, Alatorre CI, Davis EJ, et al. A review of treatment response in type 2 diabetes: assessing the role of patient heterogeneity. Diabetes Obes Metab. 2010;12:845–857. doi: 10.1111/j.1463-1326.2010.01248.x.
    1. Klonoff DC. Personalized medicine for diabetes. J Diabetes Sci Technol. 2008;2:335–341. doi: 10.1177/193229680800200301.
    1. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38:140–149. doi: 10.2337/dc14-2441.
    1. Lipkovich I, Dmitrienko A, Denne J, Enas G. Subgroup identification based on differential effect search—a recursive partitioning method for establishing response to treatment in patient subpopulations. Stat Med. 2011;30:2601–2621.
    1. Rosenstock J, Ahmann AJ, Colon G, Scism-Bacon J, Jiang H, Martin S. Advancing insulin therapy in type 2 diabetes previously treated with glargine plus oral agents: prandial premixed (insulin lispro protamine suspension/lispro) versus basal/bolus (glargine/lispro) therapy. Diabetes Care. 2008;31:20–25. doi: 10.2337/dc07-1122.
    1. The Criteria Committee of the New York Heart Association. Functional capacity and objective assessment. Nomenclature and criteria for diagnosis of diseases of the heart and great vessels. 9th ed. Boston, MA: Little Brown; 1994.
    1. Hardin DS, Rohwer RD, Curtis BH, et al. Understanding heterogeneity in response to antidiabetes treatment: a post hoc analysis using SIDES, a subgroup identification algorithm. J Diabetes Sci Technol. 2013;7:420–430. doi: 10.1177/193229681300700219.
    1. Mori E, Ikeda M, Nakagawa M, Miyagishi H, Kosaka K. Pretreatment cognitive profile likely to benefit from donepezil treatment in dementia with Lewy bodies: pooled analyses of two randomized controlled trials. Dement Geriatr Cogn Disord. 2016;41:58–68. doi: 10.1159/000447586.
    1. Seibold H, Zeileis A, Hothorn T. Model-based recursive partitioning for subgroup analyses. Int J Biostat. 2016;12:45–63. doi: 10.1515/ijb-2015-0032.
    1. Patel S, Hee SW, Mistry D, et al. Identifying back pain subgroups: developing and applying approaches using individual patient data collected with clinical trials. Southampton (UK): NIHR Journals Library; 2016 Jul. Programme Grants for Applied Research, No. 4.10.
    1. 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) Diabetes Care. 2012;35:1364–1379. doi: 10.2337/dc12-0413.
    1. Jia W, Xiao X, Ji Q, et al. Comparison of thrice-daily premixed insulin (insulin lispro premix) with basal-bolus (insulin glargine once-daily plus thrice-daily prandial insulin lispro) therapy in East Asian patients with type 2 diabetes insufficiently controlled with twice-daily premixed insulin: an open-label, randomised, controlled trial. Lancet Diabetes Endocrinol. 2015;3:254–262. doi: 10.1016/S2213-8587(15)00041-8.
    1. Heise T, Heinemann L, Hovelmann U, et al. Pharmacokinetics and pharmacodynamics compared with once-daily biphasic human insulin and basal-bolus therapy. Diabetes Care. 2009;32:1431–1433. doi: 10.2337/dc09-0097.
    1. Giugliano D, Chiodini P, Maiorino MI, Bellastella G, Esposito K. Intensification of insulin therapy with basal-bolus or premixed insulin regimens in type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Endocrine. 2016;51:417–428. doi: 10.1007/s12020-015-0718-3.
    1. Ma RC, Chan JC. Type 2 diabetes in East Asians: similarities and differences with populations in Europe and the United States. Ann N Y Acad Sci. 2013;1281:64–91. doi: 10.1111/nyas.12098.
    1. Herman WH, Dungan KM, Wolffenbuttel BH, et al. Racial and ethnic differences in mean plasma glucose, hemoglobin A1c, and 1,5-anhydroglucitol in over 2000 patients with type 2 diabetes. J Clin Endocrinol Metab. 2009;94:1689–1694. doi: 10.1210/jc.2008-1940.
    1. Kirk JK, Passmore LV, Bell RA, et al. Disparities in A1C levels between Hispanic and non-Hispanic white adults with diabetes: a meta-analysis. Diabetes Care. 2008;31:240–246. doi: 10.2337/dc07-0382.
    1. Lanting LC, Joung IM, Mackenbach JP, Lamberts SW, Bootsma AH. Ethnic differences in mortality, end-stage complications, and quality of care among diabetic patients: a review. Diabetes Care. 2005;28:2280–2288. doi: 10.2337/diacare.28.9.2280.
    1. Cerf ME. Beta cell dysfunction and insulin resistance. Front Endocrinol (Lausanne) 2013;4:37.
    1. Haffner SM, Howard G, Mayer E, et al. Insulin sensitivity and acute insulin response in African–Americans, non-Hispanic whites, and Hispanics with NIDDM: the Insulin Resistance Atherosclerosis Study. Diabetes. 1997;46:63–69. doi: 10.2337/diab.46.1.63.
    1. Kodama K, Tojjar D, Yamada S, Toda K, Patel CJ, Butte AJ. Ethnic differences in the relationship between insulin sensitivity and insulin response: a systematic review and meta-analysis. Diabetes Care. 2013;36:1789–1796. doi: 10.2337/dc12-1235.
    1. Osei K, Schuster DP. Ethnic differences in secretion, sensitivity, and hepatic extraction of insulin in black and white Americans. Diabet Med. 1994;11:755–762. doi: 10.1111/j.1464-5491.1994.tb00349.x.
    1. Kuroe A, Fukushima M, Usami M, et al. Impaired beta-cell function and insulin sensitivity in Japanese subjects with normal glucose tolerance. Diabetes Res Clin Pract. 2003;59:71–77. doi: 10.1016/S0168-8227(02)00177-8.
    1. Davidson JA, Lacaya LB, Jiang H, et al. Impact of race/ethnicity on the efficacy and safety of commonly used insulin regimens: a post hoc analysis of clinical trials in type 2 diabetes mellitus. Endocr Pract. 2010;16:818–828. doi: 10.4158/EP09285.OR.
    1. Sheu WH, Ji L, Lee WJ, Jabbar A, Han JH, Lew T. Efficacy and safety of premixed insulin analogs in Asian patients with type 2 diabetes: a systematic review. J Diabetes Investig. 2016. doi:10.1111/jdi.12605.
    1. Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA(1c) Diabetes Care. 2003;26:881–885. doi: 10.2337/diacare.26.3.881.
    1. Riddle M, Umpierrez G, DiGenio A, Zhou R, Rosenstock J. Contributions of basal and postprandial hyperglycemia over a wide range of A1C levels before and after treatment intensification in type 2 diabetes. Diabetes Care. 2011;34:2508–2514. doi: 10.2337/dc11-0632.
    1. Garber AJ. Premixed insulin analogues for the treatment of diabetes mellitus. Drugs. 2006;66:31–49. doi: 10.2165/00003495-200666010-00003.
    1. Dunbar JM, Madden PM, Gleeson DT, Fiad TM, McKenna TJ. Premixed insulin preparations in pen syringes maintain glycemic control and are preferred by patients. Diabetes Care. 1994;17:874–878. doi: 10.2337/diacare.17.8.874.
    1. Peyrot M, Barnett AH, Meneghini LF, Schumm-Draeger PM. Insulin adherence behaviours and barriers in the multinational global attitudes of patients and physicians in insulin therapy study. Diabet Med. 2012;29:682–689. doi: 10.1111/j.1464-5491.2012.03605.x.
    1. Peyrot M, Rubin RR, Kruger DF, Travis LB. Correlates of insulin injection omission. Diabetes Care. 2010;33:240–245. doi: 10.2337/dc09-1348.
    1. American Diabetes Association Standards of medical care in diabetes–2013. Diabetes Care. 2013;36(Suppl 1):S11–S66. doi: 10.2337/dc13-S011.
    1. Ho PM, Rumsfeld JS, Masoudi FA, et al. Effect of medication nonadherence on hospitalization and mortality among patients with diabetes mellitus. Arch Intern Med. 2006;166:1836–1841. doi: 10.1001/archinte.166.17.1836.
    1. Bailey CJ, Kodack M. Patient adherence to medication requirements for therapy of type 2 diabetes. Int J Clin Pract. 2011;65:314–322. doi: 10.1111/j.1742-1241.2010.02544.x.

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