Effects of biphasic, basal-bolus or basal insulin analogue treatments on carotid intima-media thickness in patients with type 2 diabetes mellitus: the randomised Copenhagen Insulin and Metformin Therapy (CIMT) trial

Louise Lundby-Christensen, Allan Vaag, Lise Tarnow, Thomas P Almdal, Søren S Lund, Jørn Wetterslev, Christian Gluud, Trine W Boesgaard, Niels Wiinberg, Hans Perrild, Thure Krarup, Ole Snorgaard, Birthe Gade-Rasmussen, Birger Thorsteinsson, Michael Røder, Elisabeth R Mathiesen, Tonny Jensen, Henrik Vestergaard, Christoffer Hedetoft, Leif Breum, Elsebeth Duun, Simone B Sneppen, Oluf Pedersen, Bianca Hemmingsen, Bendix Carstensen, Sten Madsbad, Louise Lundby-Christensen, Allan Vaag, Lise Tarnow, Thomas P Almdal, Søren S Lund, Jørn Wetterslev, Christian Gluud, Trine W Boesgaard, Niels Wiinberg, Hans Perrild, Thure Krarup, Ole Snorgaard, Birthe Gade-Rasmussen, Birger Thorsteinsson, Michael Røder, Elisabeth R Mathiesen, Tonny Jensen, Henrik Vestergaard, Christoffer Hedetoft, Leif Breum, Elsebeth Duun, Simone B Sneppen, Oluf Pedersen, Bianca Hemmingsen, Bendix Carstensen, Sten Madsbad

Abstract

Objective: To assess the effect of 3 insulin analogue regimens on change in carotid intima-media thickness (IMT) in patients with type 2 diabetes.

Design and setting: Investigator-initiated, randomised, placebo-controlled trial with a 2 × 3 factorial design, conducted at 8 hospitals in Denmark.

Participants and interventions: Participants with type 2 diabetes (glycated haemoglobin (HbA1c) ≥ 7.5% (≥ 58 mmol/mol), body mass index >25 kg/m(2)) were, in addition to metformin versus placebo, randomised to 18 months open-label biphasic insulin aspart 1-3 times daily (n=137) versus insulin aspart 3 times daily in combination with insulin detemir once daily (n=138) versus insulin detemir alone once daily (n=137), aiming at HbA1c ≤ 7.0% (≤ 53 mmol/mol).

Outcomes: Primary outcome was change in mean carotid IMT (a marker of subclinical cardiovascular disease). HbA1c, insulin dose, weight, and hypoglycaemic and serious adverse events were other prespecified outcomes.

Results: Carotid IMT change did not differ between groups (biphasic -0.009 mm (95% CI -0.022 to 0.004), aspart+detemir 0.000 mm (95% CI -0.013 to 0.013), detemir -0.012 mm (95% CI -0.025 to 0.000)). HbA1c was more reduced with biphasic (-1.0% (95% CI -1.2 to -0.8)) compared with the aspart+detemir (-0.4% (95% CI -0.6 to -0.3)) and detemir (-0.3% (95% CI -0.4 to -0.1)) groups (p<0.001). Weight gain was higher in the biphasic (3.3 kg (95% CI 2.7 to 4.0) and aspart+detemir (3.2 kg (95% CI 2.6 to 3.9)) compared with the detemir group (1.9 kg (95% CI 1.3 to 2.6)). Insulin dose was higher with detemir (1.6 IU/kg/day (95% CI 1.4 to 1.8)) compared with biphasic (1.0 IU/kg/day (95% CI 0.9 to 1.1)) and aspart+detemir (1.1 IU/kg/day (95% CI 1.0 to 1.3)) (p<0.001). Number of participants with severe hypoglycaemia and serious adverse events did not differ.

Conclusions: Carotid IMT change did not differ between 3 insulin regimens despite differences in HbA1c, weight gain and insulin doses. The trial only reached 46% of planned sample size and lack of power may therefore have affected our results.

Trial registration number: NCT00657943.

Keywords: ULTRASONOGRAPHY.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Figures

Figure 1
Figure 1
Flow of participants through trial.
Figure 2
Figure 2
Changes from baseline and differences between treatments in mean carotid intima-media thickness (IMT) (mean (95% CI)) during 18 months treatment with three insulin regimens: biphasic (green), aspart (Asp)+detemir (Det) (red) and detemir (blue), from the random-effects model with baseline as covariate using multiply imputed data, adjusted for stratification variables.
Figure 3
Figure 3
Changes (mean (95% CI)) during 18 months treatment with three insulin regimens: biphasic (green), aspart+detemir (red) and detemir (blue) in glycated haemoglobin (HbA1c) (A), fasting plasma glucose (B), insulin dose (C) and weight (D). Numbers on the right hand side of the graphs indicate the absolute/relative changes from trial entry to end-of-trial.

References

    1. 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;55:1577–96. 10.1007/s00125-012-2534-0
    1. Abraira C, Colwell JA, Nuttall FQ et al. . Veterans Affairs Cooperative Study on glycemic control and complications in type II diabetes (VA CSDM). Results of the feasibility trial. Veterans Affairs Cooperative Study in Type II Diabetes. Diabetes Care 1995;18:1113–23. 10.2337/diacare.18.8.1113
    1. Hemmingsen B, Lund SS, Gluud C et al. . Intensive glycaemic control for patients with type 2 diabetes: systematic review with meta-analysis and trial sequential analysis of randomised clinical trials. BMJ 2011;343:d6898 10.1136/bmj.d6898
    1. Ceriello A, Colagiuri S. International Diabetes Federation guideline for management of postmeal glucose: a review of recommendations. Diabet Med 2008;25:1151–6. 10.1111/j.1464-5491.2008.02565.x
    1. Esposito K, Ciotola M, Carleo D et al. . Post-meal glucose peaks at home associate with carotid intima-media thickness in type 2 diabetes. J Clin Endocrinol Metab 2008;93:1345–50. 10.1210/jc.2007-2000
    1. Holman RR, Farmer AJ, Davies MJ et al. . Three-year efficacy of complex insulin regimens in type 2 diabetes. N Engl J Med 2009;361:1736–47. 10.1056/NEJMoa0905479
    1. Yki-Järvinen H, Kauppila M, Kujansuu E et al. . Comparison of insulin regimens in patients with non-insulin-dependent diabetes mellitus. N Engl J Med 1992;327:1426–33. 10.1056/NEJM199211123272005
    1. Yki-Järvinen H, Ryysy L, Nikkila K et al. . Comparison of bedtime insulin regimens in patients with type 2 diabetes mellitus. A randomized, controlled trial. Ann Intern Med 1999;130:389–96. 10.7326/0003-4819-130-5-199903020-00002
    1. Giugliano D, Maiorino MI, Bellastella G et al. . Efficacy of insulin analogs in achieving the hemoglobin A1c target of <7% in type 2 diabetes: meta-analysis of randomized controlled trials. Diabetes Care 2011;34:510–17. 10.2337/dc10-1710
    1. Liebl A, Prager R, Binz K et al. . Comparison of insulin analogue regimens in people with type 2 diabetes mellitus in the PREFER Study: a randomized controlled trial. Diabetes Obes Metab 2009;11:45–52. 10.1111/j.1463-1326.2008.00915.x
    1. Liebl A, Prusty V, Valensi P et al. . Ten years of experience with biphasic insulin aspart 30: from drug development to the latest clinical findings. Drugs 2012;72:1495–520. 10.2165/11635490-000000000-00000
    1. Rosenstock J, Ahmann AJ, Colon G et al. . 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;31:20–5. 10.2337/dc07-1122
    1. Vaag A, Lund SS. Insulin initiation in patients with type 2 diabetes mellitus: treatment guidelines, clinical evidence and patterns of use of basal vs premixed insulin analogues. Eur J Endocrinol 2012;166:159–70. 10.1530/EJE-11-0022
    1. Lorenz MW, Markus HS, Bots ML et al. . Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation 2007;115:459–67. 10.1161/CIRCULATIONAHA.106.628875
    1. Sibal L, Agarwal SC, Home PD. Carotid intima-media thickness as a surrogate marker of cardiovascular disease in diabetes. Diabetes Metab Syndr Obes 2011;4:23–34. 10.2147/DMSO.S8540
    1. Lorenz MW, Polak JF, Kavousi M et al. . Carotid intima-media thickness progression to predict cardiovascular events in the general population (the PROG-IMT collaborative project): a meta-analysis of individual participant data. Lancet 2012;379:2053–62. 10.1016/S0140-6736(12)60441-3
    1. Lundby-Christensen L, Tarnow L, Boesgaard TW et al. . Metformin versus placebo in combination with insulin analogues in patients with type 2 diabetes mellitus—the randomised, blinded Copenhagen Insulin and Metformin Therapy (CIMT) trial. BMJ Open 2016;6:e008376 10.1136/bmjopen-2015-008376
    1. Lundby Christensen L, Almdal T, Boesgaard T et al. . Study rationale and design of the CIMT trial: the Copenhagen Insulin and Metformin Therapy trial. Diabetes Obes Metab 2009;11:315–22. 10.1111/j.1463-1326.2008.00959.x
    1. Lundby-Christensen L, Almdal TP, Carstensen B et al. . Carotid intima-media thickness in individuals with and without type 2 diabetes: a reproducibility study. Cardiovasc Diabetol 2010;9:40 10.1186/1475-2840-9-40
    1. Espeland MA, O'leary DH, Terry JG et al. . Carotid intimal-media thickness as a surrogate for cardiovascular disease events in trials of HMG-CoA reductase inhibitors. Curr Control Trials Cardiovasc Med 2005;6:3 10.1186/1468-6708-6-3
    1. Molenberghs G, Kenward MG. Missing data in clinical studies. West Sussex: John Wiley & Sons Ltd, 2007.
    1. Jakobsen JC, Wetterslev J, Winkel P et al. . Thresholds for statistical and clinical significance in systematic reviews with meta-analytic methods. BMC Med Res Methodol 2014;14:120 10.1186/1471-2288-14-120
    1. Bibra Hv, Siegmund T, Ceriello A et al. . 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;41:109–15. 10.1055/s-0028-1112136
    1. Lonn EM, Bosch J, Diaz R et al. . Effect of insulin glargine and n-3FA on carotid intima-media thickness in people with dysglycemia at high risk for cardiovascular events: the glucose reduction and atherosclerosis continuing evaluation study (ORIGIN-GRACE). Diabetes Care 2013;36:2466–74. 10.2337/dc12-2129
    1. Gerstein HC, Bosch J, Dagenais GR et al. . Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med 2012;367:319–28. 10.1056/NEJMoa1203858
    1. Cavalot F, Pagliarino A, Valle M et al. . Postprandial blood glucose predicts cardiovascular events and all-cause mortality in type 2 diabetes in a 14-year follow-up: lessons from the San Luigi Gonzaga Diabetes Study. Diabetes Care 2011;34:2237–43. 10.2337/dc10-2414
    1. Ceriello A, Hanefeld M, Leiter L et al. . Postprandial glucose regulation and diabetic complications. Arch Intern Med 2004;164:2090–5. 10.1001/archinte.164.19.2090
    1. Esposito K, Giugliano D, Nappo F et al. . Regression of carotid atherosclerosis by control of postprandial hyperglycemia in type 2 diabetes mellitus. Circulation 2004;110:214–19. 10.1161/01.CIR.0000134501.57864.66
    1. Barbieri M, Rizzo MR, Marfella R et al. . Decreased carotid atherosclerotic process by control of daily acute glucose fluctuations in diabetic patients treated by DPP-IV inhibitors. Atherosclerosis 2013;227:349–54. 10.1016/j.atherosclerosis.2012.12.018
    1. Hemmingsen B, Lund SS, Gluud C et al. . Targeting intensive glycaemic control versus targeting conventional glycaemic control for type 2 diabetes mellitus. Cochrane Database Syst Rev 2013;11:CD008143 10.1002/14651858.CD008143.pub3
    1. Raz I, Wilson PW, Strojek K et al. . Effects of prandial versus fasting glycemia on cardiovascular outcomes in type 2 diabetes: the HEART2D trial. Diabetes Care 2009;32:381–6. 10.2337/dc08-1671
    1. Després JP, Lamarche B, Mauriège P et al. . Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med 1996;334:952–7. 10.1056/NEJM199604113341504
    1. Hemmingsen B, Lund SS, Wetterslev J et al. . Oral hypoglycaemic agents, insulin resistance and cardiovascular disease in patients with type 2 diabetes. Eur J Endocrinol 2009;161:1–9. 10.1530/EJE-09-0167
    1. Falholt K, Cutfield R, Alejandro R et al. . The effects of hyperinsulinemia on arterial wall and peripheral muscle metabolism in dogs. Metabolism 1985;34:1146–9. 10.1016/0026-0495(85)90161-1
    1. Nigro J, Osman N, Dart AM et al. . Insulin resistance and atherosclerosis. Endocr Rev 2006;27:242–59. 10.1210/er.2005-0007
    1. Montagnani M, Golovchenko I, Kim I et al. . Inhibition of phosphatidylinositol 3-kinase enhances mitogenic actions of insulin in endothelial cells. J Biol Chem 2002;277:1794–9. 10.1074/jbc.M103728200
    1. Adler AI, Neil HA, Manley SE et al. . Hyperglycemia and hyperinsulinemia at diagnosis of diabetes and their association with subsequent cardiovascular disease in the United Kingdom Prospective Diabetes Study (UKPDS 47). Am Heart J 1999;138Pt 1):S353–9. 10.1016/S0167-0115(99)90005-4
    1. Whitlock G, Lewington S, Sherliker P et al. . Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies. Lancet 2009;373:1083–96. 10.1016/S0140-6736(09)60318-4
    1. Holman RR, Thorne KI, Farmer AJ et al. . Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes. N Engl J Med 2007;357:1716–30. 10.1056/NEJMoa075392
    1. Savović J, Jones HE, Altman DG et al. . Influence of reported study design characteristics on intervention effect estimates from randomized, controlled trials. Ann Intern Med 2012;157: 429–38. 10.7326/0003-4819-157-6-201209180-00537
    1. Wood L, Egger M, Gluud LL et al. . Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study. BMJ 2008;336:601–5. 10.1136/
    1. Preiss D, Lloyd SM, Ford I et al. . Metformin for non-diabetic patients with coronary heart disease (the CAMERA study): a randomised controlled trial. Lancet Diabetes Endocrinol 2014;2:116–24. 10.1016/S2213-8587(13)70152-9

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