Impact of glycemic control strategies on the progression of diabetic peripheral neuropathy in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Cohort

Rodica Pop-Busui, Jiang Lu, Maria Mori Brooks, Stewart Albert, Andrew D Althouse, Jorge Escobedo, Jenifer Green, Pasquale Palumbo, Bruce A Perkins, Fred Whitehouse, Teresa L Z Jones, BARI 2D Study Group, Rodica Pop-Busui, Jiang Lu, Maria Mori Brooks, Stewart Albert, Andrew D Althouse, Jorge Escobedo, Jenifer Green, Pasquale Palumbo, Bruce A Perkins, Fred Whitehouse, Teresa L Z Jones, BARI 2D Study Group

Abstract

Objective: The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial demonstrated similar long-term clinical effectiveness of insulin-sensitizing (IS) versus insulin-providing (IP) treatments for type 2 diabetes on cardiovascular outcomes in a cohort with documented coronary artery disease. We evaluated the effects of randomized glycemic control strategy (IS vs. IP) on the prevalence and incidence of diabetic peripheral neuropathy (DPN).

Research design and methods: DPN (defined as Michigan Neuropathy Screening Instrument [MNSI] clinical examination score>2) was assessed at baseline and yearly for 4 years. DPN prevalence and incidence were compared by intention-to-treat modeling by logistic generalized estimating equation models for prevalence and Kaplan-Meier estimates and Cox regression models for incidence rates.

Results: Results are reported for 2,159 BARI 2D participants (70% males) with valid baseline and at least one follow-up MNSI score (mean age 62±9 years, mean HbA1c 7.7±1.6%, diabetes duration 10±9 years). There were no differences in the prevalence of DPN between the IS and the IP groups throughout the 4 years of follow-up. In 1,075 BARI 2D participants with no DPN at baseline, the 4-year cumulative incidence rate of DPN was significantly lower in the IS (66%) than in the IP (72%) strategy group (P=0.02), which remained significant after adjusting for the in-trial HbA1c (P=0.04). In subgroup analyses, IS strategy had a greater benefit in men (hazard ratio 0.75 [99% CI 0.58-0.99], P<0.01).

Conclusions: Among patients with type 2 diabetes followed for up to 4 years during BARI 2D, a glycemic control therapy with IS significantly reduced the incidence of DPN compared with IP therapy and may add further benefit for men.

Trial registration: ClinicalTrials.gov NCT00006305.

Figures

Figure 1
Figure 1
A: Four-year incidence rates of DPN in the IS vs. IP treatment group in BARI 2D. B: Per-protocol 4-year incidence rates of DPN in the IS vs. IP treatment group in BARI 2D.
Figure 2
Figure 2
Subgroup analysis for 4-year DPN incidence. *Adjusted for in-trial HbA1c as a time-varying covariate; ^95% CI for overall, 99% CI for subgroups. BL, baseline; Trig, triglyceride level.

References

    1. Tesfaye S, Boulton AJ, Dyck PJ, et al. Toronto Diabetic Neuropathy Expert Group Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care 2010;33:2285–2293
    1. Boulton AJ, Vileikyte L, Ragnarson-Tennvall G, Apelqvist J. The global burden of diabetic foot disease. Lancet 2005;366:1719–1724
    1. The 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. N Engl J Med 1993;329:977–986
    1. Effect of intensive diabetes treatment on nerve conduction in the Diabetes Control and Complications Trial. Ann Neurol 1995;38:869–880
    1. Callaghan BC, Little AA, Feldman EL, Hughes RA. Enhanced glucose control for preventing and treating diabetic neuropathy. Cochrane Database Syst Rev 2012;6:CD007543.
    1. Azad N, Emanuele NV, Abraira C, et al. The effects of intensive glycemic control on neuropathy in the VA cooperative study on type II diabetes mellitus (VA CSDM). J Diabetes Complications 1999;13:307–313
    1. UK Prospective Diabetes Study (UKPDS) Group Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837–853
    1. Frye RL, August P, Brooks MM, et al. BARI 2D Study Group A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med 2009;360:2503–2515
    1. Pop-Busui R, Lu J, Lopes N, Jones TL, BARI 2D Investigators Prevalence of diabetic peripheral neuropathy and relation to glycemic control therapies at baseline in the BARI 2D cohort. J Peripher Nerv Syst 2009;14:1–13
    1. Brooks MM, Frye RL, Genuth S, et al. Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial Investigators Hypotheses, design, and methods for the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial. Am J Cardiol 2006;97(12A):9G–19G
    1. Herman WH, Pop-Busui R, Braffett BH, et al. DCCT/EDIC Research Group Use of the Michigan Neuropathy Screening Instrument as a measure of distal symmetrical peripheral neuropathy in type 1 diabetes: results from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications. Diabet Med 2012;29:937–944
    1. Martin CL, Albers J, Herman WH, et al. DCCT/EDIC Research Group Neuropathy among the diabetes control and complications trial cohort 8 years after trial completion. Diabetes Care 2006;29:340–344
    1. Feldman EL, Stevens MJ, Thomas PK, Brown MB, Canal N, Greene DA. A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy. Diabetes Care 1994;17:1281–1289
    1. Albers JW, Herman WH, Pop-Busui R, et al. Diabetes Control and Complications Trial /Epidemiology of Diabetes Interventions and Complications Research Group Effect of prior intensive insulin treatment during the Diabetes Control and Complications Trial (DCCT) on peripheral neuropathy in type 1 diabetes during the Epidemiology of Diabetes Interventions and Complications (EDIC) Study. Diabetes Care 2010;33:1090–1096
    1. Wang Y, Schmeichel AM, Iida H, Schmelzer JD, Low PA. Enhanced inflammatory response via activation of NF-kappaB in acute experimental diabetic neuropathy subjected to ischemia-reperfusion injury. J Neurol Sci 2006;247:47–52
    1. Cameron NE, Cotter MA. Pro-inflammatory mechanisms in diabetic neuropathy: focus on the nuclear factor kappa B pathway. Curr Drug Targets 2008;9:60–67
    1. Cheng HT, Dauch JR, Oh SS, Hayes JM, Hong Y, Feldman EL. p38 mediates mechanical allodynia in a mouse model of type 2 diabetes. Mol Pain 2010;6:28.
    1. Doupis J, Lyons TE, Wu S, Gnardellis C, Dinh T, Veves A. Microvascular reactivity and inflammatory cytokines in painful and painless peripheral diabetic neuropathy. J Clin Endocrinol Metab 2009;94:2157–2163
    1. Hur J, Sullivan KA, Pande M, et al. The identification of gene expression profiles associated with progression of human diabetic neuropathy. Brain 2011;134:3222–3235
    1. Haffner SM, Greenberg AS, Weston WM, Chen H, Williams K, Freed MI. Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation 2002;106:679–684
    1. Agarwal R. Anti-inflammatory effects of short-term pioglitazone therapy in men with advanced diabetic nephropathy. Am J Physiol Renal Physiol 2006;290:F600–F605
    1. Isoda K, Young JL, Zirlik A, et al. Metformin inhibits proinflammatory responses and nuclear factor-kappaB in human vascular wall cells. Arterioscler Thromb Vasc Biol 2006;26:611–617
    1. Sobel BE, Hardison RM, Genuth S, et al. BARI 2D Investigators Profibrinolytic, antithrombotic, and antiinflammatory effects of an insulin-sensitizing strategy in patients in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. Circulation 2011;124:695–703
    1. Ghosh S, Patel N, Rahn D, et al. The thiazolidinedione pioglitazone alters mitochondrial function in human neuron-like cells. Mol Pharmacol 2007;71:1695–1702
    1. Hwang J, Kleinhenz DJ, Rupnow HL, et al. The PPARgamma ligand, rosiglitazone, reduces vascular oxidative stress and NADPH oxidase expression in diabetic mice. Vascul Pharmacol 2007;46:456–462
    1. Haneda M, Koya D, Kikkawa R. Cellular mechanisms in the development and progression of diabetic nephropathy: activation of the DAG-PKC-ERK pathway. Am J Kidney Dis 2001;38(Suppl. 1):S178–S181
    1. Martens FM, Visseren FL, de Koning EJ, Rabelink TJ. Short-term pioglitazone treatment improves vascular function irrespective of metabolic changes in patients with type 2 diabetes. J Cardiovasc Pharmacol 2005;46:773–778
    1. Yamagishi S, Ogasawara S, Mizukami H, et al. Correction of protein kinase C activity and macrophage migration in peripheral nerve by pioglitazone, peroxisome proliferator activated-gamma-ligand, in insulin-deficient diabetic rats. J Neurochem 2008;104:491–499
    1. Wiggin TD, Kretzler M, Pennathur S, Sullivan KA, Brosius FC, Feldman EL. Rosiglitazone treatment reduces diabetic neuropathy in streptozotocin-treated DBA/2J mice. Endocrinology 2008;149:4928–4937
    1. Wu MS, Johnston P, Sheu WH, et al. Effect of metformin on carbohydrate and lipoprotein metabolism in NIDDM patients. Diabetes Care 1990;13:1–8
    1. Detaille D, Guigas B, Chauvin C, et al. Metformin prevents high-glucose-induced endothelial cell death through a mitochondrial permeability transition-dependent process. Diabetes 2005;54:2179–2187
    1. El-Mir MY, Detaille D, R-Villanueva G, et al. Neuroprotective role of antidiabetic drug metformin against apoptotic cell death in primary cortical neurons. J Mol Neurosci 2008;34:77–87
    1. Wile DJ, Toth C. Association of metformin, elevated homocysteine, and methylmalonic acid levels and clinically worsened diabetic peripheral neuropathy. Diabetes Care 2010;33:156–161
    1. Qiang X, Satoh J, Sagara M, et al. Gliclazide inhibits diabetic neuropathy irrespective of blood glucose levels in streptozotocin-induced diabetic rats. Metabolism 1998;47:977–981
    1. Kim B, Feldman EL. Insulin resistance in the nervous system. Trends Endocrinol Metab 2012;23:133–141
    1. Xu H, Barnes GT, Yang Q, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003;112:1821–1830
    1. Hirsch IB, Brownlee M. Beyond hemoglobin A1c—need for additional markers of risk for diabetic microvascular complications. JAMA 2010;303:2291–2292

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe