Effects of analogue insulin in multiple daily injection therapy of type 2 diabetes on postprandial glucose control and cardiac function compared to human insulin: a randomized controlled long-term study

Helene von Bibra, Thorsten Siegmund, Iris Kingreen, Markus Riemer, Tibor Schuster, Petra-Maria Schumm-Draeger, Helene von Bibra, Thorsten Siegmund, Iris Kingreen, Markus Riemer, Tibor Schuster, Petra-Maria Schumm-Draeger

Abstract

Background: The prevention of cardiovascular disease, including diastolic cardiac dysfunction with its high prevalence and ominous prognosis, is a therapeutic challenge for patients with type 2 diabetes. Both short and long-acting insulin analogues (AI) have been shown to reduce glucose variability and provide potential benefit for cardiovascular disease although the effects on cardiac function have not yet been evaluated. This long-term, prospective, randomized controlled trial in patients with type 2 diabetes (T2D) tested the hypothesis that a multiple daily injection regimen (MDI) with AI improves postmeal glucose excursions in comparison to human insulin (HI) and that the effects of AI improve diastolic cardiac function.

Methods: For 36 months, MDI treatment in 109 T2D patients was adapted every 3 months (targets: fasting glucose ≤ 110 mg/dl, postmeal glucose ≤ 150 mg/dl) in both groups: AI (insulin detemir and insulin aspart, n = 61) and HI (NPH-insulin and regular HI, n = 48). Diastolic cardiac function (myocardial velocity E' using tissue Doppler imaging and the mitral inflow ratio E/A) and vascular function were assessed before and 2 h after a standardized breakfast (48 g carbohydrates). At baseline, both groups were comparable with regards to demographic, cardiac and metabolic data. Analysis of data included traditional statistics as well as the use of a multiple imputation technique shown in brackets [ ].

Results: At 36 months, the primary endpoint, postmeal glucose, decreased by 20 ± 62 mg/dl, p = 0.038 [p = 0.021] with AI and increased insignificantly with HI (inter-group p = 0.032 [p = 0.047]) to postmeal glucose levels of 161 ± 39 with AI vs. 195 ± 54 mg/dl with HI (inter-group p = 0.002 [p = 0.010]) whereas the levels of fasting glucose and HbA1c were comparable. With AI, postmeal E' improved by 0.6 ± 1.4 cm/s, p = 0.009 [p = 0.002] and fasting E' by 0.4 ± 1.4 cm/s, p = 0.069 [p = 0.013], however, E' remained unchanged with HI. These changes were consistent with those of the traditional parameter E/A.

Conclusions: MDI with AI results in better postmeal glucose control compared to HI. The treatment with AI is associated with improved diastolic cardiac function. ClinicalTrials.gov (NTC00747409).

Trial registration: ClinicalTrials.gov NCT00747409.

Figures

Fig. 1
Fig. 1
Trial profile for the long-term RCT study MDI with analogue (AI) versus human insulin (HI) in type 2 diabetes

References

    1. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106:3143–3421.
    1. Stahrenberg R, Edelmann F, Mende M, Kockskämper A, Düngen HD, Scherer M, et al. Association of glucose metabolism with diastolic function along the diabetic continuum. Diabetologia. 2010;53:1331–1340. doi: 10.1007/s00125-010-1718-8.
    1. Fontes-Carvalho R, Ladeiras-Lopes R, Bettencourt P, Leite-Moreira A. Diastolic dysfunction in the diabetic continuum: association with insulin resistance, metabolic syndrome and type 2 diabetes. Cardiovasc Diabetol. 2015;14:4–12. doi: 10.1186/s12933-014-0168-x.
    1. von Bibra H, Hansen A, Dounis V, Bystedt T, Malmberg K, Rydén L. Insulin based improved metabolic control augments myocardial diastolic function and perfusion in patients with type 2 diabetes mellitus. Heart. 2004;90:1483–1484. doi: 10.1136/hrt.2003.020842.
    1. von Bibra H, Siegmund T, Ceriello A, Volozhyna M, Schumm-Draeger PM. Optimized postprandial glucose control is associated with improved cardiac/vascular function—comparison of three insulin regimens in well controlled type 2 diabetes. Horm Metab Res. 2009;41:109–115. doi: 10.1055/s-0028-1112136.
    1. von Bibra H, St John Sutton M. Diastolic dysfunction in diabetes and the metabolic syndrome: promising potential for diagnosis and prognosis. Diabetologia. 2010;53:1033–1045. doi: 10.1007/s00125-010-1682-3.
    1. Norhammar A, Tenerz A, Nilsson G, Hamsten A, Efendic S, Rydén L. Glucose metabolism in patients with acute myocardial infarction and no previous diagnosis of diabetes mellitus: a prospective study. Lancet. 2003;359:2140–2144. doi: 10.1016/S0140-6736(02)09089-X.
    1. Ceriello A. Postprandial hyperglycemia and diabetes complications: is it time to treat? Diabetes. 2005;54:1–7. doi: 10.2337/diabetes.54.1.1.
    1. Okada K, Hibi K, Gohbara M, Kataoka S, Takano K, Akiyama E. Association between blood glucose variability and coronary plaque instability in patients with acute coronary syndromes. Cardiovasc Diabetol. 2015;14:111–122. doi: 10.1186/s12933-015-0275-3.
    1. Kuroda M, Shinke T, Sakaguchi K, Otake H, Takaya T, Hirota Y, et al. Association between daily glucose fluctuation and coronary plaque properties in patients receiving adequate lipid-lowering therapy assessed by continuous glucose monitoring and optical coherence tomography. Cardiovasc Diabetol. 2015;14:78–88. doi: 10.1186/s12933-015-0236-x.
    1. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10 year follow-up of intensive glucose control in type 2 diabetes. NEJM. 2008;359:1577–1589. doi: 10.1056/NEJMoa0806470.
    1. Raskin P, Guthrie RA, Leiter L, Riis A, Jovanovic L. Use of insulin aspart, a fast acting insulin analog, as the mealtime insulin in the management of patients with type 1 diabetes. Diabetes Care. 2000;23:583–588. doi: 10.2337/diacare.23.5.583.
    1. Pollock RF, Valentine WJ, Pilgaard T, Nishimura H. The cost effectiveness of rapid-acting insulin aspart compared with human insulin in type 2 diabetes patients: an analysis from the Japanese third-party payer perspective. J Med Econ. 2011;14:36–46. doi: 10.3111/13696998.2010.541045.
    1. Evans M, Schumm-Dreaeger P-M, Vora J, King AB. A review of modern insulin analogue pharmacodynamic profiles in type 2 diabetes: improvements and limitations. Diabetes Obes Metab. 2011;13:677–684. doi: 10.1111/j.1463-1326.2011.01395.x.
    1. Mann JI, Hermansen K, Karamanos B, Hermansen K, Karamanos B, Karlström B, Diabetes and Nutrition Study Group (DNSG) of the European Association for the Study of Diabetes (EASD) et al. Evidence-based nutritional approaches to the treatment and prevention of diabetes mellitus. Nutr Metab Cardiovasc Dis. 2004;14:373–394. doi: 10.1016/S0939-4753(04)80028-0.
    1. Lang RM, Bierig M, Devereux R, Flachskampf F, Foster E, Pellikka P, American Society of Echocardiography’s Nomenclature and Standards Committee. Task Force on Chamber Quantification. American College of Cardiology Echocardiographic Committee. American Heart Association. European Association of Echocardiography. European Society of Cardiology et al. Recommendations for chamber quantification. Eur J Echocardiogr. 2006;7:79–108. doi: 10.1016/j.euje.2005.12.014.
    1. von Bibra H, Thrainsdottir IS, Hansen A, Dounis V, Malmberg K, Rydén L. Tissue Doppler imaging for the detection and quantitation of myocardial dysfunction in patients with type 2 diabetes mellitus: a methodological study. Diab Vasc Dis Res. 2005;2:483–487.
    1. von Bibra H, Paulus W. St John Sutton M, Leclerque C, Schuster T, Schumm-Draeger PM. Quantification of diastolic dysfunction via the age dependence of diastolic function—impact of insulin resistance with and without type 2 diabetes. Int J Cardiol. 2015;182:368–74. doi: 10.1016/j.ijcard.2014.12.005.
    1. Henry RM, Kostense PJ, Spjikerman AM, Dekker JM, Nijpels G, Heine RJ, et al. Arterial stiffness increases with deteriorating glucose tolerance status: the Hoorn Study. Circulation. 2003;107:2089–2095. doi: 10.1161/01.CIR.0000065222.34933.FC.
    1. Pfützner A, Kunt T, Hohberg C, Mondok A, Pahler S, Konrad T, et al. Fasting intact proinsulin is a highly specific predictor of insulin resistance in type 2 diabetes. Clin Lab. 2004;50:567–73.
    1. Rubin DB. Multiple imputation for nonresponse in surveys. New York: John Wiley and Sons Inc.; 1987.
    1. Donders ART, van der Heyden GJMG, Stijnen T, Moons KGM. Review: a gentle introduction to imputation of missing values. J Clin Epidemiol. 2006;59:1087–1091. doi: 10.1016/j.jclinepi.2006.01.014.
    1. Bretzel RG, Arnolds S, Medding J, Linn T. A direct efficacy and safety comparison of insulin aspart, human soluble insulin and human premix insulin [70/30] in patients with type 2 diabetes. Diabetes Care. 2004;27:1023–1027. doi: 10.2337/diacare.27.5.1023.
    1. Chapman TM, Perry CM. Insulin detemir: a review of its use in the management of type 1 and type 2 diabetes mellitus. Drugs. 2004;64:2577–2595. doi: 10.2165/00003495-200464220-00008.
    1. Borlaug BA, Paulus WJ. Heart failure with preserved ejection fraction: pathophysiology, diagnosis and treatment. Eur Heart J. 2011;32:670–679. doi: 10.1093/eurheartj/ehq426.
    1. von Bibra H, St John Sutton M. Impact of diabetes on postinfarction heart failure and left ventricular remodeling. Curr Heart Fail Rep. 2011;8:242–251. doi: 10.1007/s11897-011-0070-8.
    1. Taegtmeyer H, McNulty P, Young ME. Adaptation and maladaptation of the heart in diabetes: Part I: general concepts. Circulation. 2002;105:1727–1733. doi: 10.1161/01.CIR.0000012466.50373.E8.
    1. von Bibra H, Wulf G, St John Sutton M, Schuster T, Pfützner A, Heilmeyer P. Low-carbohydrate/high-protein diet improves diastolic cardiac function and the metabolic syndrome in overweight-obese patients with type 2 diabetes. IJC Metab Endocr. 2014;2:11–18. doi: 10.1016/j.ijcme.2013.12.001.
    1. Tschöpe C, Paulus WJ. Is echocardiographic evaluation of diastolic function useful in determining clinical care?—Doppler echocardiography yields dubious estimates of left ventricular diastolic pressure. Circulation. 2009;120:810–820. doi: 10.1161/CIRCULATIONAHA.109.869628.
    1. Shimabukuro M, Higa N, Asahi T. Impaired glucose tolerance, but not impaired fasting glucose, underlies left ventricular diastolic dysfunction. Diabetes Care. 2011;34:686–690. doi: 10.2337/dc10-1141.
    1. Hwang YC, Jee JH, Kang M, Rhee EJ, Sung J, Lee MK. Metabolic syndrome and insulin resistance are associated with abnormal left ventricular diastolic function and structure independent of blood pressure and fasting plasma glucose level. Int J Cardiol. 2012;179:107–111. doi: 10.1016/j.ijcard.2011.02.039.
    1. Ichikawa R, Daimon M, Miyazaki T, Kawata T, Miyazaki S, Maruyama M, et al. Influencing factors on cardiac structure and function beyond glycemic control in patients with type 2 diabetes. Cardiovasc Diabetol. 2013;12:38–46. doi: 10.1186/1475-2840-12-38.
    1. Witteles RM, Fowler MB. Insulin-resistant cardiomyopathy—clinical evidence, mechanisms, and treatment options. J Am Coll Cardiol. 2008;51:93–102. doi: 10.1016/j.jacc.2007.10.021.
    1. Hammer S, Snel M, Lamb HJ, Jazet IM, van der Meer RW, Pijl H, et al. Prolonged caloric restriction in obese patients with type 2 diabetes mellitus decreases myocardial triglyceride content and improves myocardial function. J Am Coll Cardiol. 2008;52:1006–1012. doi: 10.1016/j.jacc.2008.04.068.
    1. Monnier L, Mas E, Ginet C, Michel F, Villon L, Cristol JP, et al. Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. JAMA. 2006;295:1681–1687. doi: 10.1001/jama.295.14.1681.
    1. von Bibra H, St John Sutton M, Schuster T, Ceriello A, Siegmund T, Schumm-Draeger PM. Oxidative stress after a carbohydrate meal contributes to the deterioration of diastolic cardiac function in non-hypertensive insulin-treated patients with moderately well controlled type 2 diabetes. Horm Metab Res. 2013;45:449–455. doi: 10.1055/s-0033-1333752.
    1. von Bibra H, Diamant M, Scheffer PG, Siegmund T, Schumm-Draeger PM. Rosiglitazone, but not glimepiride, improves myocardial diastolic function in association with a reduction of oxidative stress and inflammation in patients with type 2 diabetes mellitus. Diab Vasc Dis Res. 2008;5:310–318. doi: 10.3132/dvdr.2008.045.
    1. Rider OJ, Francis JM, Ali MK, Petersen SE, Robinson M, Robson MD, et al. Beneficial cardiovascular effects of bariatric surgical and dietary weight loss in obesity. J Am Coll Cardiol. 2009;54:718–726. doi: 10.1016/j.jacc.2009.02.086.
    1. Solomon TP, Haus JM, Kelly KR. A low-glycemic index diet combined with exercise reduces insulin resistance, postprandial hyperinsulinemia, and glucose-dependent insulinotropic polypeptide responses in obese, prediabetic humans. Am J Clin Nutr. 2010;92:1359–1368. doi: 10.3945/ajcn.2010.29771.
    1. Standards of medical care in diabetes-2015: summary of revisions. Diabetes Care. 2015;38 Suppl:S4.
    1. Pitocco D, Zaccardia F, Di Stasio E. Oxidative stress, nitric oxide, and diabetes. Rev Diabet Stud. 2010;7:15–25. doi: 10.1900/RDS.2010.7.15.
    1. Paulus W, Tschöpe C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol. 2013;62:263–271. doi: 10.1016/j.jacc.2013.02.092.
    1. Boudina S, Abel ED. Mitochondrial uncoupling: a key contributor to reduced cardiac efficiency in diabetes. Physiology. 2006;21:250–258. doi: 10.1152/physiol.00008.2006.
    1. Phan TT, Abozguia K, Shivu GN, Mahadevan G, Ahmed I, Williams L, et al. Heart failure with preserved ejection fraction is characterized by dynamic impairment of active relaxation and contraction of the left ventricle on exercise and associated with myocardial energy deficiency. J Am Coll Cardiol. 2009;54:4002–4009. doi: 10.1016/j.jacc.2009.05.012.
    1. Scognamiglio R, Negut C, de Kreutzenberg S, Tiengo A, Avogaro A. Effects of different insulin regimens on postprandial myocardial perfusion defects in type 2 diabetic patients. Diabetes Care. 2006;29:95–100. doi: 10.2337/diacare.29.01.06.dc05-0955.
    1. Reznik Y, Cohen O, Aronson R, Conget I, Runzis S, Castaneda J, Lee SW, OpT2mise Study Group Insulin pump treatment compared with multiple daily injections for treatment of type 2 diabetes (OpT2mise): a randomised open-label controlled trial. Lancet. 2014;384(9950):1265–1272. doi: 10.1016/S0140-6736(14)61037-0.
    1. Taylor R. Type 2 diabetes—etiology and reversibility. Diabetes Care. 2013;36:1047–1055. doi: 10.2337/dc12-1805.
    1. Meloni AR, DeYoung MB, Han J, Best JH, Grimm M. Treatment of patients with type 2 diabetes with exenatide once weekly versus oral glucose-lowering medications or insulin glargine: achievement of glycemic and cardiovascular goals. Cardiovasc Diabetol. 2013;12:48–61. doi: 10.1186/1475-2840-12-48.
    1. Nishimura R, Tanaka Y, Koiwai K, Inoue K, Hach T, Salsali A, et al. Effect of empagliflozin monotherapy on postprandial glucose and 24-hour glucose variability in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled, 4-week study. Cardiovasc Diabetol. 2015;14:11–23. doi: 10.1186/s12933-014-0169-9.
    1. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. NEJM. 2008;358:580–591. doi: 10.1056/NEJMoa0706245.

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