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A systematic review and meta-analysis of glycemic control for the prevention of diabetic foot syndrome

      Objective

      The objective of this review was to synthesize the available randomized controlled trials (RCTs) estimating the relative efficacy and safety of intensive vs less intensive glycemic control in preventing diabetic foot syndrome.

      Methods

      We used the umbrella design (systematic review of systematic reviews) to identify eligible RCTs. Two reviewers determined RCT eligibility and extracted descriptive, methodologic, and diabetic foot outcome data. Random-effects meta-analysis was used to pool outcome data across studies, and the I2 statistic was used to quantify heterogeneity.

      Results

      Nine RCTs enrolling 10,897 patients with type 2 diabetes were included and deemed to be at moderate risk of bias. Compared with less intensive glycemic control, intensive control (hemoglobin A1c, 6%-7.5%) was associated with a significant decrease in risk of amputation (relative risk [RR], 0.65; 95% confidence interval [CI], 0.45-0.94; I2 = 0%). Intensive control was significantly associated with slower decline in sensory vibration threshold (mean difference, −8.27; 95% CI, −9.75 to −6.79). There was no effect on other neuropathic changes (RR, 0.89; 95% CI, 0.75-1.05; I2 = 32%) or ischemic changes (RR, 0.92; 95% CI, 0.67-1.26; I2 = 0%). The quality of evidence is likely moderate.

      Conclusions

      Compared with less intensive glycemic control therapy, intensive control may decrease the risk of amputation in patients with diabetic foot syndrome. The reported risk reduction is likely overestimated because the trials were open and the decision to proceed with amputation could be influenced by glycemic control.
      Diabetic foot syndrome arises from either vasculopathic or neuropathic complications of diabetes.
      • McIntosh A.P.
      • Young J.
      • Hutchinson R.
      • Chiverton A.
      • Clarkson R.
      • Foster S.
      • et al.
      Prevention and management of foot problems in type 2 diabetes: clinical guidelines and evidence.
      Prevalence varies from 3% to 30% among patients with diabetes.
      • Borssén B.
      • Bergenheim T.
      • Lithner F.
      The epidemiology of foot lesions in diabetic patients aged 15-50 years.
      Diabetic foot syndrome leads to an ulcer in 10% to 30% of patients.
      • Boulton A.J.
      • Vileikyte L.
      • Ragnarson-Tennvall G.
      • Apelqvist J.
      The global burden of diabetic foot disease.
      • Apelqvist J.
      • Bakker K.
      • van Houtum W.H.
      • Schaper N.C.
      Practical guidelines on the management and prevention of the diabetic foot: based upon the International Consensus on the Diabetic Foot (2007) Prepared by the International Working Group on the Diabetic Foot.
      • Boyko E.J.
      • Ahroni J.H.
      • Smith D.G.
      • Davignon D.
      Increased mortality associated with diabetic foot ulcer.
      It increases the risk of amputation by 8- to 23-fold and increases mortality rates in patients with diabetes.
      • Boulton A.J.
      • Vileikyte L.
      • Ragnarson-Tennvall G.
      • Apelqvist J.
      The global burden of diabetic foot disease.
      • Apelqvist J.
      • Bakker K.
      • van Houtum W.H.
      • Schaper N.C.
      Practical guidelines on the management and prevention of the diabetic foot: based upon the International Consensus on the Diabetic Foot (2007) Prepared by the International Working Group on the Diabetic Foot.
      • Boyko E.J.
      • Ahroni J.H.
      • Smith D.G.
      • Davignon D.
      Increased mortality associated with diabetic foot ulcer.
      Complicated foot ulcers represent a major reason for hospitalization, amputation, and utilization of health care resources.
      • McIntosh A.P.
      • Young J.
      • Hutchinson R.
      • Chiverton A.
      • Clarkson R.
      • Foster S.
      • et al.
      Prevention and management of foot problems in type 2 diabetes: clinical guidelines and evidence.
      It has been postulated that chronic hyperglycemia is associated with microvascular and macrovascular changes that play a role in diabetic foot disease.
      • Patel A.
      • MacMahon S.
      • Chalmers J.
      • Neal B.
      • Billot L.
      • Woodward M.
      • et al.
      Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.
      Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group.
      However, it is yet unclear whether lowering glucose to normal or nearly normal targets (intensive glycemic control) leads to reduction in the incidence of diabetic foot syndrome (ie, prevention of diabetic foot). This hypothesis has been tested in several randomized controlled trials (RCTs) that reported variable findings. The United Kingdom Prospective Diabetes Study (UKPDS)
      Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group.
      concluded that intensive control had a favorable effect on the incidence of microvascular complications and diabetic foot but not on macrovascular disease. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial
      • Ismail-Beigi F.
      • Craven T.
      • Banerji M.A.
      • Basile J.
      • Calles J.
      • Cohen R.M.
      • et al.
      Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial.
      showed similar effect on microvascular events but reported an increase in total and cardiovascular-related mortality and increased weight gain. The Veterans Affairs Cooperative Study on type 2 diabetes mellitus (VA CSDM)
      • Azad N.
      • Emanuele N.V.
      • Abraira C.
      • Henderson W.G.
      • Colwell J.
      • Levin S.R.
      • et al.
      The effects of intensive glycemic control on neuropathy in the VA cooperative study on type II diabetes mellitus (VA CSDM).
      demonstrated that intensive control had no significant effect compared with conventional control, and it did not decrease the overall prevalence of peripheral neuropathy.
      Therefore, we conducted this systematic review and meta-analysis to appraise and to summarize the randomized trial evidence regarding the impact of intensive glycemic control on the incidence of amputation and other diabetic foot syndrome outcomes.

      Methods

      Because glycemic control can be achieved by multiple interventions and in multiple settings and because its effect has been evaluated previously in multiple systematic reviews, we used an umbrella systematic review approach. In brief, this approach starts with identifying relevant systematic reviews that compared intensive glycemic control with less intensive control. Eligible systematic reviews are retrieved (regardless of intervention and regardless of whether diabetic foot was an outcome of interest) and are used to identify relevant RCTs. RCTs are subsequently retrieved and undergo quality appraisal, data extraction, and meta-analysis of relevant outcomes.

       Information sources and search methods

      A comprehensive literature search was conducted by an expert reference librarian with input from study investigators with experience in systematic reviews (V.M.M. and M.H.M.). We searched the electronic databases (MEDLINE, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials [CENTRAL]) for systematic reviews using various combinations of controlled vocabulary supplemented by keywords for the concepts of prevention and diabetic foot. Results were limited to systematic reviews. The full search strategy is reported in the Appendix (online only).
      Two reviewers working independently identified systematic reviews eligible for further review by performing a screen of abstracts and titles. If a systematic review was deemed relevant, the manuscript was obtained and reviewed in full-text versions. The included RCTs from the reviewed systematic reviews were retrieved in full-text versions (all available versions of each study) for further assessment.

       Eligibility criteria

      We included RCTs that enrolled patients with diabetes (of any type) without diabetic foot ulcers, comparing intensive glycemic control against less intensive glycemic control and evaluating the incidence of diabetic foot syndrome. The outcomes of interest were amputation and the incidence of diabetic foot, defined as a new ulcer, gangrene, or other forms of neuropathic or ischemic changes.

       Risk of bias assessment

      We used the Cochrane risk of bias tool to evaluate the methodologic quality of RCTs. Two reviewers independently assessed trial quality by examining several components: generation of allocation sequence (classified as adequate if based on computer-generated random numbers, tables of random numbers, or similar), concealment of allocation (classified as adequate if based on central randomization, sealed envelopes, or similar), blinding (patients, caregivers, or outcome assessors), baseline imbalance, adequacy of follow-up, and source of funding (whether it is only by not-for-profit sources or includes for-profit source). Disagreements between the reviewers were resolved by discussion or arbitrated with a third reviewer (M.H.M.). The quality of evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methods.
      • Murad M.H.
      • Montori V.M.
      • Sidawy A.N.
      • Ascher E.
      • Meissner M.H.
      • Chaikof E.L.
      • et al.
      Guideline methodology of the Society for Vascular Surgery including the experience with the GRADE framework.
      • Murad M.H.
      • Swiglo B.A.
      • Sidawy A.N.
      • Ascher E.
      • Montori V.M.
      Methodology for clinical practice guidelines for the management of arteriovenous access.
      Following this approach, randomized trials are considered to warrant high-quality evidence (ie, high certainty) and observational studies warrant low-quality evidence. Then the evidence grading can be increased (if a large effect is observed) or decreased if other factors are noted, such as studies being at increased risk of bias or imprecise (small with wide confidence intervals [CIs]).

       Data collection and extraction

      The data from RCTs were extracted using a standardized, piloted, and web-based data extraction form and working in duplicates. We abstracted data on patient demographics, baseline characteristics, study design, sample size, intervention type, fasting blood glucose and hemoglobin A1c levels, and diabetic foot outcome measures. The number of events in each trial was extracted, when available, and attributed to the arm to which patients were randomized (ie, the basis of the intention-to-treat approach). When change-from-baseline standard deviations for an outcome were not available, they were imputed from other studies in the review. When a study reported follow-up at different periods, outcomes with the longest follow-up were extracted.

       Statistical analysis and data synthesis

      We estimated the relative risk (RR) and the mean difference with the associated 95% CIs and pooled across studies using a random-effects model, as described by DerSimonian and Kacker.
      • DerSimonian R.
      • Kacker R.
      Random-effects model for meta-analysis of clinical trials: an update.
      We chose the random-effects method as primary analysis because of its conservative summary estimate and incorporation of between- and within-study variance. The analysis was repeated using the fixed-effect method, and discrepancies, if present, were outlined. To assess heterogeneity of treatment effect among trials, we used the I2 statistic; the I2 statistic represents the proportion of heterogeneity of treatment effect across trials that is not attributable to chance or random error. Hence, a value of 50% reflects significant heterogeneity that is due to real differences in study populations, protocols, interventions, or outcomes.
      • Higgins J.P.
      • Thompson S.G.
      • Deeks J.J.
      • Altman D.G.
      Measuring inconsistency in meta-analyses.
      The P value threshold for statistical significance was set at .05 for effect sizes. Analyses were conducted using features on RevMan version 5.1 (The Nordic Cochrane Center, Copenhagen, Denmark). The study was reported in accordance with the recommendations set forth by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) work groups.
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • Mulrow C.
      • Gotzsche P.C.
      • Ioannidis J.P.
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.

      Results

       Search results and study description

      A total of 280 systematic reviews were identified by the electronic search strategy, of which 87 full-text articles met the eligibility for assessment. All RCTs included in eligible systematic reviews, whether their outcomes were pooled in a meta-analysis or not, were retrieved and screened for eligibility. A recent Cochrane systematic review
      • Hemmingsen B.
      • Lund S.S.
      • Gluud C.
      • Vaag A.
      • Almdal T.P.
      • Hemmingsen C.
      • et al.
      Targeting intensive glycaemic control versus targeting conventional glycaemic control for type 2 diabetes mellitus.
      identified two RCTs
      • Griffin S.J.
      • Borch-Johnsen K.
      • Davies M.J.
      • Khunti K.
      • Rutten G.E.
      • Sandbaek A.
      • et al.
      Effect of early intensive multifactorial therapy on 5-year cardiovascular outcomes in individuals with type 2 diabetes detected by screening (ADDITION-Europe): a cluster-randomised trial.
      • Araki A.
      • Iimuro S.
      • Sakurai T.
      • Umegaki H.
      • Iijima K.
      • Nakano H.
      • et al.
      Long-term multiple risk factor interventions in Japanese elderly diabetic patients: the Japanese Elderly Diabetes Intervention Trial—study design, baseline characteristics and effects of intervention.
      published after our search that we added to analysis. A total of nine RCTs, reported in 26 published manuscripts at different follow-up points, met the inclusion criteria.
      Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group.
      • Griffin S.J.
      • Borch-Johnsen K.
      • Davies M.J.
      • Khunti K.
      • Rutten G.E.
      • Sandbaek A.
      • et al.
      Effect of early intensive multifactorial therapy on 5-year cardiovascular outcomes in individuals with type 2 diabetes detected by screening (ADDITION-Europe): a cluster-randomised trial.
      • Araki A.
      • Iimuro S.
      • Sakurai T.
      • Umegaki H.
      • Iijima K.
      • Nakano H.
      • et al.
      Long-term multiple risk factor interventions in Japanese elderly diabetic patients: the Japanese Elderly Diabetes Intervention Trial—study design, baseline characteristics and effects of intervention.
      • Abraira C.
      • Colwell J.
      • Nuttall F.
      • Sawin C.T.
      • Henderson W.
      • Comstock J.P.
      • et al.
      Cardiovascular events and correlates in the Veterans Affairs Diabetes Feasibility Trial. Veterans Affairs Cooperative Study on Glycemic Control and Complications in Type II Diabetes.
      • Duckworth W.
      • Abraira C.
      • Moritz T.
      • Reda D.
      • Emanuele N.
      • Reaven P.D.
      • et al.
      Glucose control and vascular complications in veterans with type 2 diabetes.
      • Gaede P.
      • Lund-Andersen H.
      • Parving H.H.
      • Pedersen O.
      Effect of a multifactorial intervention on mortality in type 2 diabetes.
      • Holman R.R.
      • Dornan T.L.
      • Mayon-White V.
      • Howard-Williams J.
      • Orde-Peckar C.
      • Jenkins L.
      • et al.
      Prevention of deterioration of renal and sensory-nerve function by more intensive management of insulin-dependent diabetic patients. A two-year randomised prospective study.
      • Knatterud G.L.
      • Klimt C.R.
      • Levin M.E.
      • Jacobson M.E.
      • Goldner M.G.
      Effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. VII. Mortality and selected nonfatal events with insulin treatment.
      • Ohkubo Y.
      • Kishikawa H.
      • Araki E.
      • Miyata T.
      • Isami S.
      • Motoyoshi S.
      • et al.
      Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study.
      We excluded several RCTs that are well known in this field. For the lack of planned glycemic control target, we excluded PROspective pioglitAzone Clinical Trial In macroVascular Events [PROactive]
      • Dormandy J.A.
      • Charbonnel B.
      • Eckland D.J.
      • Erdmann E.
      • Massi-Benedetti M.
      • Moules I.K.
      • et al.
      Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial.
      and the Glycemic Durability of Rosiglitazone, Metformin, or Glyburide Monotherapy trial (ADOPT).
      • Kahn S.E.
      • Haffner S.M.
      • Heise M.A.
      • Herman W.H.
      • Holman R.R.
      • Jones N.P.
      • et al.
      Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy.
      For the lack of reporting amputation outcome, we excluded the ACCORD trial,
      • Ismail-Beigi F.
      • Craven T.
      • Banerji M.A.
      • Basile J.
      • Calles J.
      • Cohen R.M.
      • et al.
      Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial.
      the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE),
      • Patel A.
      • MacMahon S.
      • Chalmers J.
      • Neal B.
      • Billot L.
      • Woodward M.
      • et al.
      Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.
      and the RCT by Service et al.
      • Service F.J.
      • Daube J.R.
      • O'Brien P.C.
      • Zimmerman B.R.
      • Swanson C.J.
      • Brennan M.D.
      • et al.
      Effect of blood glucose control on peripheral nerve function in diabetic patients.
      Fig 1 depicts the results of the search strategy, and Table I describes the included studies.
      Figure thumbnail gr1
      Fig 1The process of study selection. RCTs, Randomized controlled trials.
      Table ITrial description and baseline characteristics
      TrialOriginNo. of subjectsFollow-up, monthsDuration of DM, yearsMale, No. (%)Age, yearsTarget in intensive groupFasting glucose, mg/dLHbA1c, %
      At entryAchievedAt entryAchieved
      VADT,
      • Duckworth W.
      • Abraira C.
      • Moritz T.
      • Reda D.
      • Emanuele N.
      • Reaven P.D.
      • et al.
      Glucose control and vascular complications in veterans with type 2 diabetes.
      2009
      United States179167.211.51737 (97)61 ± 9HbA1c <6%I: 9.4

      C: 9.4
      I: 6.9

      C: 8.4
      Steno-2,
      • Gaede P.
      • Lund-Andersen H.
      • Parving H.H.
      • Pedersen O.
      Effect of a multifactorial intervention on mortality in type 2 diabetes.
      2008
      Denmark16046I: 5.5

      C: 6
      118 (74)55HbA1c <6.5%I: 182

      C: 189
      I: 130

      C: 178
      I: 8.4

      C: 8.8
      I: 7.9

      C: 9.0
      Holman,
      • Holman R.R.
      • Dornan T.L.
      • Mayon-White V.
      • Howard-Williams J.
      • Orde-Peckar C.
      • Jenkins L.
      • et al.
      Prevention of deterioration of renal and sensory-nerve function by more intensive management of insulin-dependent diabetic patients. A two-year randomised prospective study.
      1983
      United Kingdom74241967 (64)42 ± 12PPG: 72-126I: 11.7

      C: 11.8
      I: 10.5

      C: 11.4
      UKPDS,
      Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group.
      1998
      United Kingdom420912002516 (60)I: 53 ± 9

      C: 53 ± 9
      FPG <108I: 146

      C: 144
      I: 155

      C: 177
      I: 7.1

      C: 7.1
      I: 8.1

      C: 8.7
      Abraira,
      • Abraira C.
      • Colwell J.
      • Nuttall F.
      • Sawin C.T.
      • Henderson W.
      • Comstock J.P.
      • et al.
      Cardiovascular events and correlates in the Veterans Affairs Diabetes Feasibility Trial. Veterans Affairs Cooperative Study on Glycemic Control and Complications in Type II Diabetes.
      1997 (VA CSDM)
      United States153277.8153 (100)60 ± 6HbA1c <7.5%I: 207

      C: 225
      I: 103

      C: 206
      I: 9.3

      C: 9.5
      I: 7.1

      C: 9.6
      Ohkubo,
      • Ohkubo Y.
      • Kishikawa H.
      • Araki E.
      • Miyata T.
      • Isami S.
      • Motoyoshi S.
      • et al.
      Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study.
      1995
      Japan110728.554 (49)50 ± 16HbA1c <7%I: 165

      C: 170
      I: 125

      C: 170
      I: 9.2

      C: 9.0
      I: 7.1

      C: 9.6
      UGDP,
      • Knatterud G.L.
      • Klimt C.R.
      • Levin M.E.
      • Jacobson M.E.
      • Goldner M.G.
      Effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. VII. Mortality and selected nonfatal events with insulin treatment.
      1978
      United States6191201177 (29)53 ± 11FPG <110C: 143

      I: 138
      C: 166

      I: 122
      ADDITION-Europe,
      • Griffin S.J.
      • Borch-Johnsen K.
      • Davies M.J.
      • Khunti K.
      • Rutten G.E.
      • Sandbaek A.
      • et al.
      Effect of early intensive multifactorial therapy on 5-year cardiovascular outcomes in individuals with type 2 diabetes detected by screening (ADDITION-Europe): a cluster-randomised trial.
      2011
      United Kingdom and Denmark3057645760HbA1c <7%I: 7.0

      C: 7.0
      I:6.6

      C: 6.7
      Araki,
      • Araki A.
      • Iimuro S.
      • Sakurai T.
      • Umegaki H.
      • Iijima K.
      • Nakano H.
      • et al.
      Long-term multiple risk factor interventions in Japanese elderly diabetic patients: the Japanese Elderly Diabetes Intervention Trial—study design, baseline characteristics and effects of intervention.
      2012
      Japan113372184672HbA1c <6.9%1708.5I: 7.7

      C: 7.8
      C, Control; DM, diabetes mellitus; FPG, fasting plasma glucose; HbA1c, hemoglobin A1c; I, intervention; PPG, postprandial glucose.
      The nine trials enrolled 10,897 patients with diabetes. In these trials, patients were observed for a period of 2 years to 10 years (median, 5 years). Mean age ranged from 41 to 72 years; duration of diabetes before enrollment ranged from newly diagnosed to 19 years. The RCTs aimed for different glycemic targets for the intensive and the less intensive control arms. The goal of glycemic control was based on fasting glucose concentration of <126 mg/dL in the older trials and hemoglobin A1c (6%-7.5%) in more recent trials. Most included trials enrolled patients without known history of peripheral vascular disease who are at lower risk for amputation. All the trials that evaluated the outcome of amputation enrolled patients with type 2 diabetes (none with type 1). In Table I, we describe the characteristics of the trials; in Table II, we describe the intervention and control employed in each trial.
      Table IIInterventions used in included trials
      Study IDIntensive armConventional arm
      VADT,
      • Duckworth W.
      • Abraira C.
      • Moritz T.
      • Reda D.
      • Emanuele N.
      • Reaven P.D.
      • et al.
      Glucose control and vascular complications in veterans with type 2 diabetes.
      2009
      Metformin plus rosiglitazone if BMI ≥27; glimepiride plus rosiglitazone if BMI <27; insulin was added if HbA1c >9%. Patients started on the maximal dose.Metformin plus rosiglitazone if BMI ≥27; glimepiride plus rosiglitazone if BMI <27; insulin was added if HbA1c >9%. Patients started on half the maximal dose.
      Steno-2,
      • Gaede P.
      • Lund-Andersen H.
      • Parving H.H.
      • Pedersen O.
      Effect of a multifactorial intervention on mortality in type 2 diabetes.
      2008
      If patients were unable to maintain HbA1c <6.5% by means of diet and increased physical activity alone after 3 months, an oral hypoglycemic agent was started:
      • Overweight patients (BMI >25) received metformin (maximum, 1 g twice daily).
      • Lean patients, or overweight patients who had contraindications to metformin therapy, received gliclazide (maximum, 160 mg twice daily).
      • As the second step, metformin was added to the regimen of lean patients and gliclazide to that of overweight patients if hyperglycemia was not controlled.
      If the HbA1c exceeded 7.0% despite maximal doses of oral agents, the addition of NPH insulin at bedtime was recommended. The insulin dose was adjusted on the basis of the morning fasting blood glucose concentration.
      Treatment according to the 1988 recommendations of the Danish Medical Association
      Holman,
      • Holman R.R.
      • Dornan T.L.
      • Mayon-White V.
      • Howard-Williams J.
      • Orde-Peckar C.
      • Jenkins L.
      • et al.
      Prevention of deterioration of renal and sensory-nerve function by more intensive management of insulin-dependent diabetic patients. A two-year randomised prospective study.
      1983
      Patients used ultralente insulin as basal cover and soluble insulin at mealtimes; mean insulin dose, 0.77 ± 0.30 IU/kgPatients continued their usual therapy; mean insulin dose, 0.81± 0.29 IU/kg
      UKPDS,
      Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group.
      1998
      Treatment with one of the following three agents was initiated:
      • One of the following sulfonylureas: chlorpropamide 100-500 mg, glibenclamide 2.5-20 mg, or glipizide 2.5-40 mg
      • Metformin up to 2550 mg, distributed in two doses a day
      • Insulin started on once-daily ultralente insulin or isophane insulin. If the daily dose was >14 U or premeal or bedtime home blood glucose measurements were >7 mmol/L, a short-acting insulin, usually soluble (regular) insulin, was added (basal/bolus regimen).
      All participants had to continue their assigned treatment as long as possible. Patients were changed to insulin therapy if marked hyperglycemia recurred.
      Patients were treated initially with dietary modification. If marked hyperglycemia or symptoms occurred, patients were secondarily randomized to treatment with sulfonylurea or insulin or metformin therapy. The aim of fasting plasma glucose <15 mmol/L without symptoms was maintained.
      Abraira,
      • Abraira C.
      • Colwell J.
      • Nuttall F.
      • Sawin C.T.
      • Henderson W.
      • Comstock J.P.
      • et al.
      Cardiovascular events and correlates in the Veterans Affairs Diabetes Feasibility Trial. Veterans Affairs Cooperative Study on Glycemic Control and Complications in Type II Diabetes.
      1997 (VA CSDM)
      Phase 1: one injection of intermediate- or long-acting insulin in the evening. Phase 2: continued evening insulin with the addition of glipizide in step increment of 2.5 to 5 mg/wk until HbA1c goal is achieved or the maximum dose is reached. Phase 3: discontinue glipizide and give two insulin injections a day. Phase 4: multiple daily injections.One daily injection of insulin; if goal not achieved, a maximum of two daily insulin injections are given.
      Ohkubo,
      • Ohkubo Y.
      • Kishikawa H.
      • Araki E.
      • Miyata T.
      • Isami S.
      • Motoyoshi S.
      • et al.
      Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study.
      1995
      Administered insulin three or more times daily (rapid-acting insulin at each meal and intermediate-acting insulin at bedtime)One or two daily intermediate-acting insulin injections
      UGDP,
      • Knatterud G.L.
      • Klimt C.R.
      • Levin M.E.
      • Jacobson M.E.
      • Goldner M.G.
      Effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. VII. Mortality and selected nonfatal events with insulin treatment.
      1978
      Insulin variables (U-80 Lente or other insulin)Standard insulin (U-80 Lente Iletin insulin)
      ADDITION-Europe,
      • Griffin S.J.
      • Borch-Johnsen K.
      • Davies M.J.
      • Khunti K.
      • Rutten G.E.
      • Sandbaek A.
      • et al.
      Effect of early intensive multifactorial therapy on 5-year cardiovascular outcomes in individuals with type 2 diabetes detected by screening (ADDITION-Europe): a cluster-randomised trial.
      2011
      Target of HbA1c <7%, but change in antidiabetic medicine with HbA1c >6.5%Standard care
      Araki,
      • Araki A.
      • Iimuro S.
      • Sakurai T.
      • Umegaki H.
      • Iijima K.
      • Nakano H.
      • et al.
      Long-term multiple risk factor interventions in Japanese elderly diabetic patients: the Japanese Elderly Diabetes Intervention Trial—study design, baseline characteristics and effects of intervention.
      2012
      Oral hypoglycemic drugs (sulfonylurea, biguanides, α-glucosidase inhibitors, and pioglitazone) or insulin therapyOral hypoglycemic agents/standard care
      BMI, Body mass index; HbA1c, hemoglobin A1c.
      The standard domains of the risk of bias (Table III) were all adequate and consistent with low risk of bias with the exception of a concern about whether the decision to amputate was associated with the assignment to the intervention. It is plausible that patients with suboptimal control were more likely to be advised to proceed with amputation. Therefore, this evidence likely warrants moderate confidence.
      Table IIIQuality assessment and risk of bias
      Study IDRandomizationAllocation concealmentBlindingBaseline imbalancesLost to follow-up, %Source of funding
      VADT,
      • Duckworth W.
      • Abraira C.
      • Moritz T.
      • Reda D.
      • Emanuele N.
      • Reaven P.D.
      • et al.
      Glucose control and vascular complications in veterans with type 2 diabetes.
      2009
      Yes; permuted-block designYes; study sites did not have access to patient codesYes; patients and caregiversNo6.4Includes for-profit sources
      Steno-2,
      • Gaede P.
      • Lund-Andersen H.
      • Parving H.H.
      • Pedersen O.
      Effect of a multifactorial intervention on mortality in type 2 diabetes.
      2008
      Yes; method unclearYes; sealed envelopesYes; outcome assessorsNo6.8Not-for-profit sources
      Holman,
      • Holman R.R.
      • Dornan T.L.
      • Mayon-White V.
      • Howard-Williams J.
      • Orde-Peckar C.
      • Jenkins L.
      • et al.
      Prevention of deterioration of renal and sensory-nerve function by more intensive management of insulin-dependent diabetic patients. A two-year randomised prospective study.
      1983
      Yes; method unclearYes; sealed envelopesUnclearNo6.8Not-for-profit sources
      UKPDS,
      Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group.
      1998
      Yes; computer generatedYes; sealed envelopesYes; outcome assessorsNoNoneNot-for-profit sources
      Abraira,
      • Abraira C.
      • Colwell J.
      • Nuttall F.
      • Sawin C.T.
      • Henderson W.
      • Comstock J.P.
      • et al.
      Cardiovascular events and correlates in the Veterans Affairs Diabetes Feasibility Trial. Veterans Affairs Cooperative Study on Glycemic Control and Complications in Type II Diabetes.
      1997 (VA CSDM)
      UnclearUnclearUnclearNoNoneNot-for-profit sources
      Ohkubo,
      • Ohkubo Y.
      • Kishikawa H.
      • Araki E.
      • Miyata T.
      • Isami S.
      • Motoyoshi S.
      • et al.
      Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study.
      1995
      UnclearUnclearUnclearNo2.7Not-for-profit sources
      UGDP,
      • Knatterud G.L.
      • Klimt C.R.
      • Levin M.E.
      • Jacobson M.E.
      • Goldner M.G.
      Effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. VII. Mortality and selected nonfatal events with insulin treatment.
      1978
      Yes; tables of random numbersYes; method unclearYes; outcome assessors and data analystNo0Not-for-profit sources
      ADDITION-Europe,
      • Griffin S.J.
      • Borch-Johnsen K.
      • Davies M.J.
      • Khunti K.
      • Rutten G.E.
      • Sandbaek A.
      • et al.
      Effect of early intensive multifactorial therapy on 5-year cardiovascular outcomes in individuals with type 2 diabetes detected by screening (ADDITION-Europe): a cluster-randomised trial.
      2011
      Yes, cluster randomizationYesOutcome assessorsNoUnclearIncludes for-profit sources
      Araki,
      • Araki A.
      • Iimuro S.
      • Sakurai T.
      • Umegaki H.
      • Iijima K.
      • Nakano H.
      • et al.
      Long-term multiple risk factor interventions in Japanese elderly diabetic patients: the Japanese Elderly Diabetes Intervention Trial—study design, baseline characteristics and effects of intervention.
      2012
      AdequateYesOutcome assessorsNo9Not-for-profit sources

       Meta-analysis

      Compared with less intensive glycemic control, intensive control was associated with a statistically significant decrease in risk of amputation of diabetic foot (RR, 0.65; 95% CI, 0.45-0.94; I2 = 0%). Results are depicted in Fig 2.
      Figure thumbnail gr2
      Fig 2The risk of amputation. Group A, intensive control arm. Group B, conventional control arm. CI, Confidence interval.
      Two studies reported on sensory nerve function,
      • Holman R.R.
      • Dornan T.L.
      • Mayon-White V.
      • Howard-Williams J.
      • Orde-Peckar C.
      • Jenkins L.
      • et al.
      Prevention of deterioration of renal and sensory-nerve function by more intensive management of insulin-dependent diabetic patients. A two-year randomised prospective study.
      • Ohkubo Y.
      • Kishikawa H.
      • Araki E.
      • Miyata T.
      • Isami S.
      • Motoyoshi S.
      • et al.
      Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study.
      in which a measurement of the changes in vibration threshold from baseline was used. The pooled result showed, when using the fixed-effect model, that compared with conventional control, intensive control caused a significant decrease (ie, less increase) in vibration threshold (mean difference, −8.27; 95% CI, −9.75 to −6.79), which means a better sensory nerve function outcome. The risk of neuropathic changes (RR, 0.89; 95% CI, 0.75-1.05; I2 = 32%) and ischemic changes (RR, 0.92; 95% CI, 0.67-1.26; I2 = 0%) associated with intensive glycemic control was not statistically significant (Supplementary Figs 1 and 2, online only). Ischemic changes were a heterogeneous outcome defined differently across trials (gangrene, ischemic ulcer, new-onset claudication, new diagnosis of peripheral artery disease). In metaregression, there was no significant association between the relative effect on amputation and the baseline risk for amputation in the control arms of the RCTs (P > .05). The small number of RCTs did not allow additional subgroup analyses or statistical evaluation for publication bias.

      Discussion

      We conducted a systematic review and meta-analysis comparing intensive glycemic control with less intensive glycemic control for the prevention of diabetic foot. Intensive control was associated with decreased risk of amputation, better sensory nerve function, and potentially overall diabetic foot incidence. The quality of evidence is likely moderate, considering that these are open trials and the decision to proceed with amputation may be associated with diabetes control, thus biasing the results toward favoring intensive glycemic control. Further, we were not able to assess certain confounders, such as baseline comparators of limb perfusion (eg, ankle-brachial index or toe-brachial index), medication use such as antiplatelet therapy, and personal habits of consistent foot hygiene. Most included trials enrolled patients without known history of peripheral vascular disease. The effect of diabetes control in patients with established peripheral vascular disease may be different, as these patients may be less responsive to intensive glucose control.
      The observed RR reduction of 35% may indeed be too optimistic, considering the impact of other interventions, such as statins, smoking cessation, and blood pressure control. Intensive glycemic control may not improve patients' quality of life measures
      Quality of life in type 2 diabetic patients is affected by complications but not by intensive policies to improve blood glucose or blood pressure control (UKPDS 37). U.K. Prospective Diabetes Study Group.
      • Pitale S.
      • Kernan-Schroeder D.
      • Emanuele N.
      • Sawin C.
      • Sacks J.
      • Abraira C.
      Health-related quality of life in the VA Feasibility Study on glycemic control and complications in type 2 diabetes mellitus.
      and can be associated with increased treatment burden (more drugs, higher doses, more side effects, higher cost, more laboratory testing and visits to physicians). Thus, clinicians need to assess the capacity of the patient and the patient's caregivers to implement these complex programs.
      • Montori V.M.
      Treat the numbers or treat the patient?.
      Weight gain and hypoglycemia are common side effects associated with intensive control of type 2 diabetes.
      Our results are consistent with those of a recent systematic review
      • Hemmingsen B.
      • Lund S.S.
      • Gluud C.
      • Vaag A.
      • Almdal T.P.
      • Hemmingsen C.
      • et al.
      Targeting intensive glycaemic control versus targeting conventional glycaemic control for type 2 diabetes mellitus.
      of RCTs conducted by the Cochrane Collaboration. Our results are also consistent with a systematic review of observational prospective epidemiologic studies
      • Adler A.I.
      • Erqou S.
      • Lima T.A.
      • Robinson A.H.
      Association between glycated haemoglobin and the risk of lower extremity amputation in patients with diabetes mellitus—review and meta-analysis.
      that found a 1.26 RR (95% CI, 1.16-1.36) for each percentage point increase in hemoglobin A1c to be associated with lower extremity amputation. The estimated RR was 1.44 (95% CI, 1.25-1.65) for type 2 diabetes and 1.18 (95% CI, 1.02-1.38) for type 1 diabetes; however, the difference was not statistically significant (P = .09).
      • Adler A.I.
      • Erqou S.
      • Lima T.A.
      • Robinson A.H.
      Association between glycated haemoglobin and the risk of lower extremity amputation in patients with diabetes mellitus—review and meta-analysis.
      The strengths of this review stem from the comprehensive literature search that follows an explicit protocol and bias protection measures undertaken by reviewers (such as selecting studies, evaluating quality of the studies, and extracting outcome data by two independent reviewers). The weaknesses stem from inability to evaluate patient-level covariates that are needed to conduct meaningful subgroup analyses, such as cardiovascular risk factor control, use of statins and aspirin, age, and other comorbidities (eg, lower extremity edema). Such analyses may demonstrate differential benefit of an approach of intensive glycemic control.
      The Society for Vascular Surgery is planning to develop clinical practice guidelines for the management of diabetic foot syndrome. A panel of experts will use data from this report and other sources of evidence and incorporate additional relevant aspects, such as patients' values and preferences, resource allocation, and clinical context, to develop clinical recommendations. A key factor in the recommendation for strict diabetes control is the need for it to be balanced with the potential for important hypoglycemia, the patient's capacity to achieve the glycemic control, and the risk of other outcomes, such as stroke and cardiovascular events, that can be associated with strict control of type 2 diabetes.

      Conclusions

      Compared with less intensive glycemic control therapy, intensive control decreases the risk of amputation in patients with diabetic foot syndrome. The reported risk reduction is likely overestimated because the trials were open and the decision to proceed with amputation could be influenced by glycemic control.

      Author contributions

      Conception and design: RH, BF, TE, JD, AT, LP, GP, MN, VM, MM
      Analysis and interpretation: RH, MM
      Data collection: RH, BF, TE, JD, AT, LP, GP, MN, MM
      Writing the article: RH, LP, GP, VM, MM
      Critical revision of the article: RH, BF, TE, JD, AT, LP, GP, MN, MM
      Final approval of the article: RH, BF, TE, JD, AT, LP, GP, MN, MM
      Statistical analysis: MM
      Obtained funding: MM
      Overall responsibility: MM

      Appendix (online only).

       Data sources and search strategies

      A comprehensive search of several databases from each database's earliest inclusive dates to October 2011 (any language, any population) was conducted. The databases included Ovid Medline In-Process & Other Non-Indexed Citations, Ovid MEDLINE, Ovid Embase, Ovid Cochrane Database of Systematic Reviews, and Scopus. The search strategy was designed and conducted by an experienced librarian with input from the study's principle investigator. Controlled vocabulary supplemented with keywords was used to search for the topic: diabetes control, limited to systematic reviews.

       The actual search strategy

       Ovid

      Databases: Embase 1988 to 2011 Week 41, Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) 1948 to Present, EBM Reviews—Cochrane Database of Systematic Reviews 2005 to October 2011.
      Tabled 1
      #SearchesResults
      1exp Diabetes Mellitus/pc [Prevention & Control]33286
      2(control or controls or controlling).ti,ab.3743841
      31 and 28728
      4(diabetes adj3 (control or controls or controlling)).ti,ab.15376
      5exp “systematic review”/44283
      6(systematic* adj2 review*).mp.106172
      73 or 422638
      85 and 7148
      96 and 7323
      10from 9 keep 203-323121
      11from 7 keep 22621-2263818
      128 or 10 or 11271
      13remove duplicates from 12234
      14limit 13 to (book or book series or editorial or erratum or letter or note or addresses or autobiography or bibliography or biography or comment or dictionary or directory or interactive tutorial or interview or lectures or legal cases or legislation or news or newspaper article or overall or patient education handout or periodical index or portraits or published erratum or video-audio media or webcasts) [Limit not valid in Embase,Ovid MEDLINE(R),Ovid MEDLINE(R) In-Process,CDSR; records were retained]22
      1513 not 14212
      1611 or 15230

       Scopus

      • 1)
        TITLE-ABS-KEY((control w/3 diabetes) or (controls w/3 diabetes) or (controlling w/3 diabetes))
      • 2)
        TITLE-ABS-KEY(systematic* w/2 review*)
      • 3)
        1 and 2
      • 4)
        PMID(0*) OR PMID(1*) OR PMID(2*) OR PMID(3*) OR PMID(4*) OR PMID(5*) OR PMID(6*) OR PMID(7*) OR PMID(8*) OR PMID(9*)
      • 5)
        3 and not 4
      • 6)
        DOCTYPE(le) OR DOCTYPE(ed) OR DOCTYPE(bk) OR DOCTYPE(er) OR DOCTYPE(no) OR DOCTYPE(sh)
      • 7)
        5 and not 6
      Figure thumbnail fx1
      Supplementary Fig 1 (online only)The risk of neuropathic and ischemic changes. CI, Confidence interval; IV, information value.
      Figure thumbnail fx2
      Supplementary Fig 2 (online only)Neuropathy; changes in vibration threshold (fixed-effect model). CI, Confidence interval; IV, information value; SD, standard deviation.

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      Linked Article

      • Regarding “A systematic review and meta-analysis of glycemic control for the prevention of diabetic foot syndrome”
        Journal of Vascular SurgeryVol. 64Issue 1
        • Preview
          We read the paper of Hasan et al1 with great interest. However, the methods and conclusion differ from our meta-analysis published in 2011 on the same subject.2 Indeed, our work showed that glycemic control reduced neither peripheral vascular events (risk ratio [RR], 0.98; 95% confidence interval [CI], 0.84-1.13) nor amputations (or mortality due to amputations; RR, 0.84; 95% CI, 0.54-1.29). The meta-analysis of Hasan et al included multifactorial intervention trials (such as Steno-23), whereas ours included only trials in which glycemic control was analyzed alone.
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