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Diabetic Peripheral Neuropathy and Associated Pain: Emerging and Updated Research

      Diabetic peripheral neuropathy (DPN) is estimated to affect 30% to 50% of all adults with diabetes in the United States. Evidence suggests that poor glycemic control and duration of diabetes along with components of metabolic syndrome, including dyslipidemia, obesity, and hypertension, may affect the prevalence of DPN.
      • Grisold A.
      • Callaghan B.C.
      • Feldman E.L.
      Mediators of diabetic neuropathy: Is hyperglycemia the only culprit?.
      DPN is associated with increased risk of falls among older patients with type 2 diabetes, and poorly managed DPN can lead to lower limb amputation.
      • Bruce D.
      • Hunter M.
      • Peters K.
      • et al.
      Fear of falling is common in patients with type 2 diabetes and is associated with increased risk of falls.
      The ideal is to screen for limited sensation and onset of neuropathy using inexpensive tools, including the 10-g Semmes-Weinstein monofilament examination, superficial pain sensation, and vibration testing by the on-off method; however, evidence suggests that, for a variety of systems-oriented reasons, screening is not performed in some health care systems and no treatment of any kind is offered.
      • Tippet A.W.
      Treating peripheral neuropathy.
      Instead, patients are diagnosed with DPN based on patient symptoms of pain and discomfort, and they are treated for their pain. A 2001 report suggested that the likelihood of neuropathy may be easily and inexpensively predicted using the reported operating characteristics for each of these 3 tests, whereas the fourth test, vibration testing using the timed method, introduces some minor complications and extra time.
      • Perkins B.A.
      • Olaleye D.
      • Zinman B.
      • Bril V.
      Simple screening tests for peripheral neuropathy in the diabetes clinic.
      There is no cure for neuropathy; however, the pain and discomfort may be managed and lessened with pharmacotherapy and durable equipment. A recent systematic review found evidence that neuropathy-related pain reduction may be achieved using the serotonin-norepinephrine reuptake inhibitors duloxetine and venlafaxine, the anticonvulsants pregabalin and oxcarbazepine, tricyclic antidepressants, atypical opioids, and botulinum toxin.
      • Waldfogel J.M.
      • Nesbit S.A.
      • Dy S.M.
      • et al.
      Pharmacotherapy for diabetic peripheral neuropathy pain and quality of life: a systematic review.
      Failure to address the pain and discomfort from neuropathy early during the progression of the condition places the patient at risk for falls and subsequent injuries. Many patients experience proximal neuropathy (eg, pain in the thighs, hips, or buttocks), whereas others experience focal neuropathy, resulting in the sudden weakness of one nerve or a group of nerves, causing muscle weakness or pain. The prevalence of diagnosed DPN is higher among patients who are black (22%) and Hispanic (25%) compared with white patients with type 2 diabetes.
      • Lopez J.M.
      • Bailey R.A.
      • Rupnow M.F.
      Demographic disparities among Medicare beneficiaries with type 2 diabetes mellitus in 2011: diabetes prevalence, comorbidities, and hypoglycemia events.
      Furthermore, racial and ethnic minorities may be at increased risk because of underreporting of symptoms and underdiagnosis of chronic pain conditions linked to DPN, particularly when culture, language, and other communication barriers are present.
      • Adams A.S.
      • Parker M.M.
      • Moffet H.H.
      • et al.
      Communication barriers and the clinical recognition of diabetic peripheral neuropathy in a diverse cohort of adults: the DISTANCE study.
      Despite this rather bleak outlook for patients with neuropathy, the current issue of Clinical Therapeutics features research that suggests that there may be optimism regarding reducing neuropathic pain. A review by Parasoglou and Rao
      • Parasoglou P.
      • Rao S.
      Declining skeletal muscle function in diabetic peripheral neuropathy.
      of New York University entitled, “Declining Skeletal Muscle Function in Diabetic Peripheral Neuropathy,” offers an update on the most recent trials of exercise interventions that target DPN and promising magnetic resonance imaging techniques that are providing a foundation for future clinical trials. We also include a review article entitled, “Efficacy of Venlafaxine in Neuropathic Pain: A Narrative Review Towards Optimized Treatment,” by Trouvin and colleagues
      • Trouvin A.P.
      • Perrot S.
      • Lloret-Linares C.
      Efficacy of venlafaxine in neuropathic pain, a narrative review towards optimized treatment.
      from Hopital Cochin, Paris, that addresses the effectiveness of venlafaxine for neuropathic pain. Hidmark and colleagues,
      • Hidmark A.S.
      • Spanidis I.
      • Fleming H.
      • et al.
      Electrical muscle stimulation induces an increase of VEGFR2 on circulating hematopoietic stem cells in diabetes patients.
      based at the Universitat Heidelberg, described the effect of external electric muscle stimulation in reducing neuropathic pain, in their article, “Electrical Muscle Stimulation Induces an Increase of VEGFR2 on Circulating Hematopoietic Stem Cells in Diabetes Patients.”
      Aside from the neuropathic pain that presents in advanced diabetes, an important outcome of type 2 diabetes is the substantially increased risk of cardiovascular (CV) disease.
      • Huxley R.
      • Barzi F.
      • Woodward M.
      excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies.
      As reported in a previous editorial
      • Ryan J.G.
      Evidence for good cardiovascular outcomes among patients with type 2 diabetes, and promising treatment for patients with type 2 diabetes (editorial).
      and a review of the CV effects of glucose-lowering therapies
      • Thompson P.
      • Davis T.M.E.
      Cardiovascular effects of glucose-lowering therapies for type 2 diabetes: new drugs in perspective.
      published in Clinical Therapeutics in conjunction with the American Heart Association’s 2016 Scientific Sessions, several drugs in the sodium/glucose cotransporter 2 (SGLT-2) and glucagon-like peptide 1 classes have good evidence of CV risk reduction.
      The SGLT-2 class has been suggested to reduce CV risk factors by affecting blood pressure, weight, visceral adiposity, hyperinsulinemia, arterial stiffness, albuminuria, circulating uric levels, and oxidative stress.
      • Inzucchi S.E.
      • Zinman B.
      • Wanner C.
      • et al.
      SGLT-2 inhibitors and cardiovascular risk: proposed pathways and review of ongoing outcome trials.
      Several outcome trials have been launched since the major regulatory agencies introduced their requirements that new type 2 diabetes compounds be evaluated to understand effect on CV risk.
      Food and Drug Administration (Center for Drug Evaluation and Research)
      European Medicines Agency
      These trials include the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG Outcome),
      • Zinman B.
      • Inzucchi S.E.
      • Lachin J.M.
      • et al.
      Rationale, design, and baseline characteristics of a randomized, placebo-controlled cardiovascular outcome trial of empagliflozin (EMPA-REG OUTCOME™).
      Canagliflozin Cardiovascular Assessment Study (CANVAS),
      • Neal B.
      • Perkovic V.
      • de Zeeuw D.
      • et al.
      Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS)--a randomized placebo-controlled trial.
      Canagliflozin Cardiovascular Assessment Study: A Study of the Effects of Canagliflozin in Renal Endpoints in Adult Participants With Type 2 Diabetes Mellitus (CANVAS-R),
      • Neal B.
      • Perkovic V.
      • Matthews D.R.
      • et al.
      CANVAS-R Trial Collaborative Group
      Rational, design and baseline characteristics of the CANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R): a randomized, placebo-controlled trial.
      Canagliflozin and Renal Events in Diabetes with an Established Nephropathy Clinical Evaluation Study (CREDENCE),
      • Inzucchi S.E.
      • Zinman B.
      • Wanner C.
      • et al.
      SGLT-2 inhibitors and cardiovascular risk: proposed pathways and review of ongoing outcome trials.
      Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events (DECLARE-TIMI58),
      • Inzucchi S.E.
      • Zinman B.
      • Wanner C.
      • et al.
      SGLT-2 inhibitors and cardiovascular risk: proposed pathways and review of ongoing outcome trials.
      and Ertugliflozin Cardiovascular Outcome Trial.
      • Inzucchi S.E.
      • Zinman B.
      • Wanner C.
      • et al.
      SGLT-2 inhibitors and cardiovascular risk: proposed pathways and review of ongoing outcome trials.
      Of these, results from the EMPA-REG Outcome trial were reported in 2015,
      • Zinman B.
      • Wanner W.
      • Lachin J.M.
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      whereas various preliminary analyses of CANVAS data have also been published before the final CANVAS trial results, expected in 2017 to 2018, including 2 previous reports in Clinical Therapeutics.
      • Bailey R.A.
      • Vijapurkar U.
      • Meininger G.
      • et al.
      Diabetes-related composite quality end-point attainment: canagliflozin versus sitagliptin based on a pooled analysis of 2 clinical trials.
      • Bailey R.A.
      • Schwab P.
      • Xu Y.
      • et al.
      Glycemic control outcomes after canagliflozin initiation: observations in a medicare and commercial managed care population in clinical practice.
      The CV implications of SGLT-2 medications will continue to be reported as analyses of these outcome trials are completed between 2017 and 2021. Meanwhile, we include a third preliminary study of canagliflozin in this month’s issue of Clinical Therapeutics in which electronic medical record data, reflecting real-world evidence, are used for a subgroup analysis of the glycemic outcomes of canagliflozin.
      • Johnson J.F.
      • Parsa R.
      • Bailey R.A.
      Real-world clinical outcomes among patients with type 2 diabetes receiving canagliflozin at a specialty diabetes clinic: subgroup analysis by baseline HbA1c and age.

      References

        • Grisold A.
        • Callaghan B.C.
        • Feldman E.L.
        Mediators of diabetic neuropathy: Is hyperglycemia the only culprit?.
        Curr Opin Endocrinol Diabetes Obes. 2017; 24: 103-111
        • Bruce D.
        • Hunter M.
        • Peters K.
        • et al.
        Fear of falling is common in patients with type 2 diabetes and is associated with increased risk of falls.
        Age Ageing. 2015; 44: 687-690
        • Tippet A.W.
        Treating peripheral neuropathy.
        Wounds: A Compendium of Clinical Research and Practice. 2014; 26 (Accessed May 1, 2017): 65-71
        • Perkins B.A.
        • Olaleye D.
        • Zinman B.
        • Bril V.
        Simple screening tests for peripheral neuropathy in the diabetes clinic.
        Diabetes Care. 2001; 24: 250-256
        • Waldfogel J.M.
        • Nesbit S.A.
        • Dy S.M.
        • et al.
        Pharmacotherapy for diabetic peripheral neuropathy pain and quality of life: a systematic review.
        Neurology. 2017; (Epub ahead of print)
        • Lopez J.M.
        • Bailey R.A.
        • Rupnow M.F.
        Demographic disparities among Medicare beneficiaries with type 2 diabetes mellitus in 2011: diabetes prevalence, comorbidities, and hypoglycemia events.
        Popul Health Manag. 2015; 18: 283-289
        • Adams A.S.
        • Parker M.M.
        • Moffet H.H.
        • et al.
        Communication barriers and the clinical recognition of diabetic peripheral neuropathy in a diverse cohort of adults: the DISTANCE study.
        J Health Commun. 2016; 21: 544-553
        • Parasoglou P.
        • Rao S.
        Declining skeletal muscle function in diabetic peripheral neuropathy.
        Clin Ther. 2017; 39: 1085-1103
        • Trouvin A.P.
        • Perrot S.
        • Lloret-Linares C.
        Efficacy of venlafaxine in neuropathic pain, a narrative review towards optimized treatment.
        Clin Ther. 2017; 39: 1104-1122
        • Hidmark A.S.
        • Spanidis I.
        • Fleming H.
        • et al.
        Electrical muscle stimulation induces an increase of VEGFR2 on circulating hematopoietic stem cells in diabetes patients.
        Clin Ther. 2017; 39: 1132-1144
        • Huxley R.
        • Barzi F.
        • Woodward M.
        excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies.
        BMJ. 2006; 332: 73-78
        • Ryan J.G.
        Evidence for good cardiovascular outcomes among patients with type 2 diabetes, and promising treatment for patients with type 2 diabetes (editorial).
        Clin Ther. 2016; 38: 1274-1278
        • Thompson P.
        • Davis T.M.E.
        Cardiovascular effects of glucose-lowering therapies for type 2 diabetes: new drugs in perspective.
        Clin Ther. 2016; 39
        • Inzucchi S.E.
        • Zinman B.
        • Wanner C.
        • et al.
        SGLT-2 inhibitors and cardiovascular risk: proposed pathways and review of ongoing outcome trials.
        Diabetes & Vascular Disease Res. 2015; 12: 90-100
        • Food and Drug Administration (Center for Drug Evaluation and Research)
        Guidance for industry: diabetes mellitus—evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. 2008; (Accessed May 3, 2017)
        • European Medicines Agency
        Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus. 2012; (Accessed May 3, 2017)
        • Zinman B.
        • Inzucchi S.E.
        • Lachin J.M.
        • et al.
        Rationale, design, and baseline characteristics of a randomized, placebo-controlled cardiovascular outcome trial of empagliflozin (EMPA-REG OUTCOME™).
        Cardiovasc Diabetol. 2014; 13: 102
        • Neal B.
        • Perkovic V.
        • de Zeeuw D.
        • et al.
        Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS)--a randomized placebo-controlled trial.
        Am Heart J. 2013; 166: 217-223
        • Neal B.
        • Perkovic V.
        • Matthews D.R.
        • et al.
        • CANVAS-R Trial Collaborative Group
        Rational, design and baseline characteristics of the CANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R): a randomized, placebo-controlled trial.
        Diabetes Obes Metab. 2017; 19: 387-393
        • Zinman B.
        • Wanner W.
        • Lachin J.M.
        • et al.
        Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
        N Engl J Med. 2015; 373: 2117-2128
        • Bailey R.A.
        • Vijapurkar U.
        • Meininger G.
        • et al.
        Diabetes-related composite quality end-point attainment: canagliflozin versus sitagliptin based on a pooled analysis of 2 clinical trials.
        Clin Ther. 2015; 37: 1045-1054
        • Bailey R.A.
        • Schwab P.
        • Xu Y.
        • et al.
        Glycemic control outcomes after canagliflozin initiation: observations in a medicare and commercial managed care population in clinical practice.
        Clin Ther. 2016; 38: 2046-2057
        • Johnson J.F.
        • Parsa R.
        • Bailey R.A.
        Real-world clinical outcomes among patients with type 2 diabetes receiving canagliflozin at a specialty diabetes clinic: subgroup analysis by baseline HbA1c and age.
        Clin Ther. 2017; 39: 1123-1131