Risk Of Lower Extremity Amputation Research Articles

SGLT2 Inhibitors: the Star in the Treatment of Type 2 Diabetes?

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a novel class of oral hypoglycemic agents which increase urinary glucose excretion by suppressing glucose reabsorption at the proximal tubule in the kidney. SGLT2 inhibitors lower glycated hemoglobin (HbA1c) by 0.6–0.8% (6–8 mmol/mol) without increasing the risk of hypoglycemia and induce weight loss and improve various metabolic parameters including blood pressure, lipid profile and hyperuricemia. Recent cardiovascular (CV) outcome trials have shown the improvement of CV and renal outcomes by treatment with the SGLT2 inhibitors, empagliflozin, canagliflozin, and dapagliflozin. The mechanisms by which SGLT2 inhibitors improve CV outcome appear not to be glucose-lowering or anti-atherosclerotic effects, but rather hemodynamic effects through osmotic diuresis and natriuresis. Generally, SGLT2 inhibitors are well-tolerated, but their adverse effects include genitourinary tract infection and dehydration. Euglycemic diabetic ketoacidosis is a rare but severe adverse event for which patients under SGLT2 inhibitor treatment should be carefully monitored. The possibility of an increase in risk of lower-extremity amputation and bone fracture has also been reported with canagliflozin. Clinical trials and real-world data have suggested that SGLT2 inhibitors improve CV and renal outcomes and mortality in patients with type 2 diabetes (T2DM), especially in those with prior CV events, heart failure, or chronic kidney disease. Results of recent trials including individuals without diabetes may change the positioning of this drug as ″a drug for cardiorenal protection″. This review summarizes the potential of SGLT2 inhibitors and discusses their role in the treatment of T2DM.

Sodium-Glucose Cotransporter-2 Inhibitors and the Risk of Amputation: What Is Currently Known?

Diabetes mellitus is a major cause of morbidity and mortality in the United States. Twelve medication classes on the market reduce serum glucose including sodium-glucose cotransporter-2 (SGLT2) inhibitors. Potential benefits of these agents include improved glycemic control, weight loss, reduction in blood pressure, and possible reduction in cardiovascular events in patients with elevated cardiovascular risk. Recently, several adverse events have been identified including increased possible risk of amputation associated with SGLT2 inhibitor therapy. We conducted a review of published literature and identified 32 trials reviewing incidence of SGLT2 inhibitor-related amputation. The potential increased risk for amputation is mostly of the lower extremities. Of the SGLT2 inhibitors currently available, canagliflozin has the highest association with an increased risk of lower extremity amputation and is the only agent with a Food and drug Administration Black Box Warning. Most canagliflozin amputation occurred in a single study. Risk factors for amputation with SGLT2 inhibitors may include those who have a history of amputations, susceptible to foot ulcers and those with baseline cardiovascular disease. For at-risk patients who desire an agent from this drug class, empagliflozin or dapagliflozin should be considered, as studies have not found a significant increase in amputations when compared with placebo or in retrospective reviews. Despite the increased risk of amputation found with canagliflozin, providers can use SGLT2 inhibitors with frequent monitoring to safely manage diabetes in low-risk patients. Patient education on associated risks is warranted. Diabetes educators can inform patients of risk factors to assist with monitoring.

SGLT2 INHIBITORS ARE NOT ASSOCIATED WITH RISKS FOR AMPUTATION-A SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS

Sodium glucose cotransporter-2(SGLT2) inhibitors are an insulin-independent class of oral anti-hyperglycemic medication with promising cardiovascular and renal outcome benefits. One of its safety concerns is a perceived increase in the risk of lower extremity amputation, mainly put forth by the

Leukocyte Telomere Length, DNA Oxidation, and Risk of Lower-Extremity Amputation in Patients With Long-standing Type 1 Diabetes.

Telomere shortening and DNA oxidation are associated with premature vascular aging, which may be involved in lower-extremity amputation (LEA). We sought to investigate whether leukocyte telomere length (LTL) and plasma 8-hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of DNA oxidation, were associated with LEA in subjects with type 1 diabetes at high vascular risk. LTL (quantitative PCR) and plasma 8-OHdG concentrations (immunoassay method) were assessed at baseline in the GENEDIAB (Génétique de la Néphropathie Diabétique) type 1 diabetes cohort. Logistic and Cox proportional hazards regression models were fitted to estimate odds ratio (OR) (at baseline) and hazard ratio (HR) (during follow-up), with related 95% CI, by increasing biomarker tertiles (T1, T2, T3). Among 478 participants (56% male, mean ± SD age 45 ± 12 years and diabetes duration 29 ± 10 years), 84 patients had LEA at baseline. Baseline history of LEA was associated with shorter LTL (OR for T2 vs. T1 0.62 [95% CI 0.32-1.22] and for T3 vs. T1 0.41 [0.20-0.84]) but not with plasma 8-OHdG (1.16 [0.56-2.39] and 1.24 [0.61-2.55], respectively). New cases of LEA occurred in 34 (12.3%) participants during the 10-year follow-up. LTL were shorter (HR T2 vs. T1 0.25 [95% CI 0.08-0.67] and T3 vs. T1 0.29 [0.10-0.77]) and plasma 8-OHdG higher (2.20 [0.76-7.35] and 3.11 [1.07-10.32]) in participants who developed LEA during follow-up compared with others. No significant interaction was observed between biomarkers on their association with LEA. We report the first independent association between LTL shortening and excess risk of LEA in type 1 diabetes. High plasma 8-OHdG was also associated with incident LEA but partly dependent on cofounding variables.

Calendula mother tincture vs normal saline for ulcer dressing as an add-on to Individualized Homoeopathic Intervention in the management of Diabetic Foot Ulcer: A Randomized Controlled Pilot Study

Background: Despite standard management, healing rate of Diabetic Foot Ulcers (DFUs) remains low, posing risk of lower extremity amputation. Objectives: This study was undertaken to evaluate if Calendula Q has added benefit over individualized homoeopathic intervention (IHI). The primary objective was to achieve complete epithelialisation within 20 weeks and secondary objective was to assess the changes in quality of life using DFU Scale-short form (DFU-SF) questionnaire. Materials and Methods: A randomised controlled pilot study with a 20-week intervention was conducted from 2014-2017. 277 cases were screened and 60 cases were enrolled and randomised to Group I: IHI + Calendula Q dressing (n= 30) and Group II: IHI + normal saline (NS) dressing (n = 30), along with standard conventional medication for glycaemic control. Results: The mean time (Group I= 12 weeks, Group II= 11 weeks) of ulcer healing in both groups showed no statistically significant difference, thus calendula Q used for dressing did not have any added benefits (p= 0.0521). Arsenicum album (n= 14, 23.3%), Lycopodium (n= 8, 13.3%), Silicea (n= 7, 11.7%), Sulphur (n= 6, 10%), Phosphorus (n= 5, 10%) and Sepia (n=5, 10%) were found to be effective medicines. Conclusion: IHI, along with wound hygiene and conventional diabetic management, proved to be effective, irrespective of whether Calendula Q or normal saline was used for wound hygiene, thus leading to early, complete epithelialisation of Wagner's first and second stages of DFUs. Further studies comparing IHI with standard care are warranted.

Effect of contact with podiatry in a team approach context on diabetic foot ulcer and lower extremity amputation: systematic review and meta-analysis

Multidisciplinary team (MDT) approach has been shown to reduce diabetic foot ulcerations (DFUs) and lower extremity amputations (LEAs), but there is heterogeneity between team members and interventions. Podiatrists have been suggested as “gatekeepers” for the prevention and management of DFUs. The purpose of our study is to review the effect of podiatric interventions in MDTs on DFUs and LEAs. We conducted a systematic review of available literature. Data’s heterogeneity about DFU outcomes made it impossible for us to include it in a meta-analysis, but we identified 12 studies fulfilling inclusion criteria that allowed for them to be included for LEA outcomes. With the exception of one study, all reported favourable outcomes for MDTs that include podiatry. We found statistical significance in favour of an MDT approach including podiatrists for our primary outcome (total LEAs (RR: 0.69, 95% CI 0.54–0.89, I2 = 64%, P = 0.002)) and major LEAs (RR: 0.45, 95% CI 0.23–0.90, I2 = 67%, P < 0.02). Our systematic review, with a standard search strategy, is the first to specifically address the relevant role of podiatrists and their interventions in an MDT approach for DFU management. Our observations support the literature that MDTs including podiatrists have a positive effect on patient outcomes but there is insufficient evidence that MDTs with podiatry management can reduce the risk of LEAs. Our study highlights the necessity for intervention descriptions and role definition in team approach in daily practice and in published literature.

Mortality and Contralateral Amputation Rates Following an Index Major Lower Extremity Amputation

Introduction: High mortality and contralateral amputation rates following an index (first) major lower extremity amputation (LEA) as a consequence of diabetes and/ or peripheral arterial disease (PAD) are well documented. However, risks for a contralateral amputation, and for mortality in relation to the indication for an amputation have not been previously described. In this retrospective cohort study, we aim to investigate mortality and contralateral major LEA rates, and to describe the relationship between risk of mortality, contralateral LEA and contralateral amputation free survival with the indication for major LEA. Methods: Consecutive patients that underwent an index major LEA over a 6- year period in Leeds Teaching Hospitals NHS Trust (LTHT), were identified. Patients were excluded if they had bilateral amputation at the index procedure, were undergoing a contralateral LEA as their first procedure in the study period or if the indication for an amputation was not as a complication of diabetes or PAD. Results: 204 consecutive patients met the inclusion criteria. The overall median survival was 38 months, 33 months in those with diabetes and 47 months in those without. Mortality and indication for amputation (sepsis vs ischaemia) showed a trend towards a significant relationship. Male sex and proximal amputations were independently associated with contralateral LEA. Age at the time of amputation, male sex and proximal amputation were independently associated with amputation free survival. There was no significant relationship between indication of amputation and the risk of contralateral LEA and amputation free survival. Conclusion: Mortality rates following an index LEA remain high. Clinical factors associated with mortality and contralateral LEA suggest that further optimisation of this challenging patient group may improve outcomes. To our knowledge, this is the first study to suggest that indication for amputation in patients with diabetes and/ or PAD may influence mortality, and this warrants further assessment in future studies. Disclosure: Nothing to disclose

Clinical Outcomes in Patients With Type 2 Diabetes Mellitus and Peripheral Artery Disease: Results From the EXSCEL Trial.

Recent trials have identified anti-diabetes mellitus agents that lower major adverse cardiovascular event (MACE) rates, although some increase rates of lower-extremity amputation (LEA). Patients with peripheral artery disease (PAD) have greater incidence of diabetes mellitus and risk for LEA, prompting this investigation of clinical outcomes in patients with diabetes mellitus and PAD in the EXSCEL trial (Exenatide Study of Cardiovascular Event Lowering). EXSCEL evaluated the effects of once-weekly exenatide (a GLP-1 [glucagon-like peptide-1] receptor agonist) versus placebo on the rates of the primary composite MACE end point (cardiovascular death, myocardial infarction, or stroke) among patients with type 2 diabetes mellitus. In this post hoc analysis, we assessed the association of baseline PAD with rates of MACE, LEA, and the effects of exenatide versus placebo in patients with and without PAD. EXSCEL included 2800 patients with PAD (19% of the trial population). These individuals had higher unadjusted and adjusted rates of MACE compared with patients without PAD (13.6% versus 11.4%, respectively) as well as a higher adjusted hazard ratio (adjusted hazard ratio, 1.13 [95% CI, 1.00-1.27]; P=0.047). Patients with PAD had higher all-cause mortality (adjusted hazard ratio 1.38 [95% CI, 1.20-1.60]; P<0.001) and more frequent LEA (adjusted hazard ratio 5.48 [95% CI, 4.16-7.22]; P<0.001). Patients treated with exenatide or placebo had similar rates of MACE and LEA, regardless of PAD status. EXSCEL participants with PAD had higher rates of all-cause mortality and LEA compared with those without PAD. There were no differences in MACE or LEA rates with exenatide versus placebo. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT01144338.

Association between glucose variation and lower extremity amputation incidence in individuals with type 2 diabetes: a nationwide retrospective cohort study.

Elevated glucose level is one of the risk factors for lower extremity amputation (LEA), but whether glycaemic variability confers independent risks of LEA remains to be elucidated. This study aimed to investigate the association between visit-to-visit glycaemic variability and minor and major LEA risks during 8years of follow-up in type 2 diabetic individuals aged 50years and older. This retrospective cohort study included 27,574 ethnic Chinese type 2 diabetic individuals aged ≥50years from the National Diabetes Care Management Program in Taiwan. Glycaemic variability measures were presented as the CVs of fasting plasma glucose (FPG-CV) and of HbA1c (A1c-CV). The effect of glycaemic variability on the incidence of LEA events was analysed using Cox proportional hazards models. After a median follow-up of 8.9years, 541 incident cases of LEA with a crude incidence density rate of 2.4 per 1000 person-years were observed. After multivariate adjustment, FPG-CV and A1c-CV were found to be significantly associated with minor LEA, with corresponding HRs of 1.53 (95% CI 1.15, 2.04) and 1.34 (95% CI 1.02, 1.77) for the third tertiles of FPG-CV and A1c-CV, respectively. In addition, these associations were stronger amongst older adults with longer diabetes duration (≥3years) than amongst those with shorter duration (<3years) (pinteraction < 0.01). Our study suggests that visit-to-visit variations in HbA1c and FPG are important predictors of minor LEA amongst older adults with type 2 diabetes, particularly for those with more than 3years of diabetes duration.

Amputations in patients with diabetic foot ulcer: a retrospective study from a single centre in the Northern Territory of Australia.

Lower extremity amputations (LEAs) in diabetic patients are common in the indigenous population. There is no published data from the Northern Territory. All patients with diabetic foot ulcer, presenting for the first time to the multi-disciplinary foot clinic at Royal Darwin Hospital, between January 2003 and June 2015, were included. These patients were followed until 2017, or death. LEA rates over the follow-up period and the risk factors were studied. Of the 513 included patients, 62.8% were males and 48.2% were indigenous. The majority (93.6%) had type 2 diabetes with median diabetes duration of 7.0 years (interquartile range 3-12). During the follow-up period of 5.8 years (interquartile range 3.1-9.8), a total of 435 LEAs (16.6% major; 34.7% minor) occurred in 263 patients (mean age 57.0 ± 11.8 years). In multivariate analysis, the following variables were associated with LEAs (adjusted odds ratio (95% confidence interval)): prior LEA (4.49 (1.69-11.9)); peripheral vascular disease (2.67 (1.27-5.59)); forefoot ulcer (7.72 (2.61-22.7)); Wagner grade 2 (3.71 (1.87-7.36)); and Wagner grade 3 (17.02 (3.77-76.72)). Indigenous patients were 1.8 times more likely to have LEAs than non-indigenous patients. Indigenous amputees were approximately 9 years younger than their non-indigenous counterparts. Half of patients presenting with diabetic foot ulcer had LEA during follow-up. Prior LEAs, peripheral vascular disease, forefoot ulcers and higher Wagner grades were independent risk factors for LEA. Indigenous patients were at higher risk for LEAs and were younger at the time of amputation.

67-OR: Plasma Copeptin and Risk for Lower Extremity Amputation in People with Type 1 and Type 2 Diabetes

Recently, an increased risk of lower extremity amputation (LEA) was observed with canagliflozin, a SGLT2 inhibitor, in the CANVAS trial although observational studies showed conflicting results. This association could be related to the contraction of plasma volume induced by SGLT2 inhibition. In this case, copeptin, a surrogate marker of vasopressin, should be associated with LEA. Our aim was to analyze the association between LEA and plasma copeptin in 4 cohorts of patients with type 1 and type 2 diabetes (T1D, T2D). Analysis were done in 2 pooled cohorts of patients with type 2 diabetes (DIABHYCAR, SURDIAGENE, n=4532) and 2 pooled cohorts of patients with type 1 diabetes (GENESIS, GENEDIAB, n=712). Cox regression model was fitted to compute hazard ratio (HR) and 95% CI for incident LEA by tertiles of copeptin at baseline. C-statistic, integrated discrimination improvement (IDI) and continuous net reclassification improvement (cNRI) were used to assess the prognostic value of copeptin in LEA discrimination. Mean follow-up was 5.3 years for DT2 and 6.3 for DT1. Incidence of LEA was 1.6% (T1), 2.6% (T2) and 3.3% (T3) for DT2 (p&amp;lt;0.001) and 3.9% (T1), 3.3% (T2) and 10% (T3) for DT1 (p=0.003). In a Cox multivariable analysis model (adjusted for cohort, sex, diabetes duration, hypertension, previous cardiovascular and peripheral arterial disease and glomerular filtration rate), HR for LEA was 1.91 (1.13-3.24; p=0.016) in DT2 and 2.76 (1.05-7.66; p=0.04) in DT1, both for T3 vs. T1. Plasma copeptin yielded incremental information for the risk of LEA in DT2: C-statistic change 0.012 (p=0.005), IDI: 0.007 (0.005-0.025, p=0.05), cNRI: 0.13 (0.03-0.29, p=0.03). Plasma copeptin is significantly associated with an increased risk of LEA in patients with T1D and T2D. Mechanisms underlying this association are not known but could be related to hydration status. Our results suggest a potential role of contraction volume effect of SGLT2 inhibitor in the higher risk of LEA possibly associated with this class. Disclosure L. Potier: Advisory Panel; Self; Merck Sharp &amp; Dohme Corp. Consultant; Self; Sanofi. R. Roussel: Advisory Panel; Self; Merck Sharp &amp; Dohme Corp., Sanofi. Consultant; Self; Abbott, AstraZeneca, Eli Lilly and Company, Medtronic, Novo Nordisk A/S, Physiogenex. Research Support; Self; Janssen Pharmaceuticals, Inc. K. Mohammedi: None. P. Saulnier: None. M. Marre: Advisory Panel; Self; Servier. Board Member; Self; Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S. S. Hadjadj: Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck &amp; Co., Inc., Novo Nordisk A/S, Sanofi, Servier. Research Support; Self; Bayer AG, Janssen Research &amp; Development. Speaker's Bureau; Self; Abbott, Valbiotis. G. Velho: None.

A Lack of Decline in Major Nontraumatic Amputations in Texas: Contemporary Trends, Risk Factor Associations, and Impact of Revascularization.

Nontraumatic major lower extremity amputations (LEAs) have been reported to be declining nationally; however, trends in Texas have been less well described. We evaluated demographic and clinical risk factors and revascularization associations for LEAs by using inpatient hospital discharge data in Texas from 2005 to 2014. Inpatient hospital discharge data were obtained from the Texas Center for Health Statistics. Multivariate logistic regression analyses were performed to evaluate clinical, ethnic, and socioeconomic risk factors associated with LEA. The impact of revascularization (surgical and/or endovascular) on LEA was analyzed. Between 2005 and 2014, of 19,939,716 admissions, 46,627 were for nontraumatic major LEAs. Over time, LEAs were constant, and revascularization rates during index admission declined. The majority of LEAs occurred in males and in individuals aged 60-79 years. Risk factors associated with LEA included diabetes, peripheral arterial disease, chronic kidney disease, and male sex (P < 0.001). Insurance status, hyperlipidemia, coronary artery disease, and stroke/transient ischemic attack were associated with lower odds of amputation (P < 0.001). Hispanic (odds ratio [OR] 1.51 [95% CI 1.48, 1.55], P < 0.001) and black (OR 1.97 [95% CI 1.92, 2.02], P < 0.001) ethnicities were associated with a higher risk for amputation when compared with non-Hispanic whites. Revascularization, either surgical or endovascular (OR 0.52 [95% CI 0.5, 0.54], P < 0.001), was also associated with lower odds for amputation. Amputation rates in Texas have remained constant, whereas revascularization rates are declining. A higher risk for LEA was seen in minorities, including Hispanic ethnicity, which is the fastest growing demographic in Texas. Revascularization and having insurance were associated with lower odds for amputation.

Excess risk of lower extremity amputations in people with type 1 diabetes compared with the general population: amputations and type 1 diabetes

ObjectiveThis study investigates how the excess risk of lower extremity amputations (amputations) in people with type 1 diabetes mellitus (DM) differs from the general population by diabetes duration, glycemic control,...

Using the Society for Vascular Surgery Wound, Ischemia, and foot Infection classification to identify patients most likely to benefit from revascularization

BackgroundThe Society of Vascular Surgery Wound Ischemia foot Infection (WIfI) classification system for chronic limb-threatening ischemia was intended to predict 1-year major lower extremity amputation (LEA) risk and to identify which patients benefit most from revascularization. We aimed to identify which WIfI presentations benefited most from revascularization to explore whether a cluster analysis could identify a more data-driven WIfI score, and to quantify which component of the WIfI score was most strongly associated with 1-year LEA after revascularization. MethodsComposite multi-institutional nested cohort data from centers who previously validated WIfI were reviewed retrospectively. We collected each patient's WIfI component grades and whether LEA was performed. To examine the benefit of revascularization, the predicted LEA rates were subtracted from observed LEA rates. We used k-means cluster analysis to model predicted vs observed LEA rates after revascularization. Multivariable linear regression analysis was performed to quantify which WIfI score component(s) best predicted LEA. ResultsData from 10 centers, accumulated between 2005 and 2015 were collated (2878 limbs at risk; 314 LEAs performed). The subset of patients who underwent revascularization comprised the study base (1654 limbs; 169 LEAs). Of 64 potential WIfI grade combinations, 15 were never reported and were excluded from the analysis. By original WIfI stages, the observed LEA rate after revascularization was: stage 1, 10.8% (14/130); stage 2, 4.9% (5/103); stage 3, 5.1% (25/487); and stage 4, 13.4% (125/934). Based on the difference between predicted and observed LEA risk for those who underwent revascularization, the WIfI scores were placed into quartiles from greatest to no benefit of revascularization. Cluster analysis identified four clusters with the following 1-year LEA rates: cluster 1, 4.4% (46/1038); cluster 2, 14.8% (66/447); cluster 3, 28.1% (36/128); and cluster 4, 51.2% (21/41). The between sum of squares/total sum of squares was 93.9%. Multiple linear regression revealed the wound grade most strongly predicted LEA (F-value, 17.25; P < .001). Ischemia (F-value, 6.51; P = .001) and infection (F-value, 5.7; P = .003) were similarly associated with LEA risk. Interaction terms between each component of the WIfI score were not statistically significant. ConclusionsWIfI can identify which patients with chronic limb-threatening ischemia are most likely to benefit from revascularization and may provide improved prognostication, risk stratification, and equitable outcome assessments. After revascularization, wound severity is most strongly associated with LEA risk. Ischemic and infectious grades confer additive, but not synergistic, risk. Future cluster analyses comparing specific WIfI presentations treated with and without revascularization will be required to further refine WIfI.

Sodium-glucose co-transporter-2 inhibitor use and risk of lower-extremity amputation: Evolving questions, evolving answers.

To examine whether sodium-glucose co-transporter-2 (SGLT2) inhibitors are associated with a higher risk of lower-extremity amputation than dipeptidyl-peptidase-4 (DPP-4) inhibitors and sulphonylureas. We conducted a retrospective cohort study, using the MarketScan Commercial Claims and Encounters Database (2013-2015), to compare the incidence of lower-extremity amputation (LEA) between initiators of SGLT2 inhibitors and initiators of two second-line drugs, DPP-4 inhibitors and sulphonylureas (SUs). We estimated crude incidence rates (IRs) and adjusted hazard ratios (aHR), with 95% confidence intervals (CIs), before and after propensity-score weighting. We additionally conducted sensitivity analyses using a comparator group of all non-metformin, non-SGLT2 inhibitor glucose-lowering drugs, as previous studies used this approach. In a cohort of 328 150 individuals aged 18 to 64 years, the IR of LEA ranged from 1.5 to 2.4 per 1000 person-years. In as-treated analysis, the estimated hazard of LEA was increased among SGLT2 inhibitor initiators compared to DPP-4 inhibitor initiators (aHR 1.69, 95% CI 1.20-2.38), but not compared to SU initiators (aHR 1.02, 95% CI 0.67-1.55) or non-metformin, non-SGLT2 inhibitor initiators (aHR 1.02, 95% CI 0.54-1.93). Results were consistent in intention-to-treat analysis and across a number of sensitivity analyses. Among commercially insured patients in the United States, our results suggest that initiation of SGLT2 inhibitors may increase the risk of LEA compared to initiation of DPP-4 inhibitors. Contrasting results when comparing SGLT2 inhibitor initiators to DPP-4 inhibitor and SU initiators highlight the importance of choosing appropriate comparator drugs when addressing comparative effectiveness and safety questions that can inform clinical decision-making.

Sodium-glucose co-transporter-2 inhibitor use and risk of lower-extremity amputation: Evolving questions, evolving answers

Sodium-glucose co-transporter-2 inhibitor use and risk of lower-extremity amputation: Evolving questions, evolving answers

Effect of Intensive Glycemic Control on Risk of Lower Extremity Amputation

Diabetes mellitus is a major risk factor for peripheral arterial disease and lower extremity amputation (LEA). We evaluated the effects of intensive glucose control (IGC) on risk of LEA in patients with type 2 diabetes during a randomized-controlled multicenter trial. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial randomized patients with type 2 diabetes to IGC (HbA1c target < 6.0%) or standard glycemic control (SGC; HbA1c target 7.0% to 7.9%). Using analysis of mean HbA1c, we examined relationships between glycemic control and incident/recurrent LEA during the clinical trial/follow-up. Mean post-randomization HbA1c over the course of the trial and post-trial follow-up was 7.3% ± 0.9% (6.8% ± 0.8% in the IGC arm, 7.7% ± 0.7% in the SGC arm). There were 124 participants who had at least 1 LEA during the study period; 73 were randomized to the SGC arm and 51 to the IGC arm (p= 0.049). Randomization to IGC was associated with decreased LEA rate (HR 0.69, 95% CI 0.483 to 0.987, p= 0.042). In multivariable models, mean HbA1c was a powerful predictor of LEA (HR 2.07 per 1% increase in HbA1c, 95% CI 1.67 to 2.57, p < 0.0001). Post-randomization mean HbA1c remained a strong predictor of LEA after controlling for other important covariates and competing risk of death (HR 1.94 per 1% increase in HbA1c, 95% CI 1.52 to 2.46, p < 0.0001). In patients with type 2 diabetes, IGC was associated with a reduction in the risk for LEA. After 3.7 years of IGC, there was an enduring protective effect against LEA. Improved glycemic control was a strong predictor of decreased risk for subsequent LEA. This study suggests that tight glycemic control, even over a short time period, has potential to reducerisk of limb loss.

Cardiovascular outcomes of sodium glucose cotransporter-2 inhibitors in patients with type 2 diabetes.

To determine the association between cardiovascular diseases (CVD) and SGLT2 inhibitors compared to sulfonylureas and dipeptidyl peptidase-4 (DPP4) inhibitors and to examine within-class effects of SGLT2 inhibitors. A retrospective cohort analysis was conducted using Truven Health MarketScan. New users of SGLT2 inhibitors, sulfonylureas or DPP-4 inhibitors were included. Primary outcome was incident CVD, defined as non-fatal myocardial infarction or non-fatal stroke; secondary outcomes were hospitalization because of heart failure and lower extremity amputation. Proportional hazards models, after propensity score matching, were used to obtain hazard ratios (HR) and 95% confidence intervals (CI). In fully adjusted models, use of SGLT2 inhibitors was associated with a decreased risk of developing CVD compared with use of sulfonylureas (HR, 0.50; 95% CI, 0.45, 0.55) and DPP-4 inhibitors (HR, 0.57; 95% CI, 0.52, 0.62), respectively. Analyses revealed no evidence of within-class effects: dapagliflozin vs sulfonylureas (HR, 0.55; 95% CI, 0.43, 0.70) or DPP-4 inhibitors (HR, 0.57; 95% CI, 0.46, 0.70); and canagliflozin vs sulfonylureas (HR, 0.61; 95% CI, 0.54, 0.69) or DPP-4 inhibitors (HR, 0.66; 95% CI, 0.54, 0.71). Additionally, SGLT2 inhibitors were associated with lower risk of hospitalization because of heart failure compared to both sulfonylureas and DPP-4 inhibitors, as well as lower risk of lower extremity amputation compared to sulfonylureas. Using population-based data, incident use of SGLT-2 inhibitors was associated with a decreased incidence of CVD compared to use of sulfonylureas and DPP-4 inhibitors. These findings were consistent between dapagliflozin and canagliflozin, suggesting that CVD reduction is a class effect for SGLT2 inhibitors. In addition, SGLT2 inhibitors portended lower risk of hospitalization because of heart failure (vs sulfonylureas and DPP-4 inhibitors) and lower risk of lower extremity amputation (vs sulfonylureas).

Preventing Major Amputations in Patients with Critical Limb Ischemia.

This review summarizes the risks of lower extremity amputation associated with critical limb ischemia (CLI) and discusses current therapies that can prevent amputation in CLI. CLI remains an under-recognized condition associated with high rates of major amputation and disparities in care. Optimal medical therapy can reduce the risk of major adverse cardiovascular and limb events, but revascularization combined with close wound care remains the cornerstone of amputation prevention. Endovascular revascularization has become more common over time and has been associated with a reduction in amputation rates. Ongoing clinical trials will help inform best practices for revascularization strategies and techniques. Vascular care is inconsistent across the USA, with significant variation in access to care revascularization rates and rates of major amputation. Major amputation can be prevented in patients with CLI when optimal medical therapy, lifestyle modification, and revascularization are provided in a multidisciplinary setting.

Trends in Rates of Lower Extremity Amputation Among Patients With End-stage Renal Disease Who Receive Dialysis

Patients with end-stage renal disease (ESRD) who receive dialysis are at high risk of lower extremity amputation. Recent studies indicate decreasing rates of lower extremity amputation in non-ESRD populations, but contemporary data for patients with ESRD who receive dialysis are lacking. To assess rates of lower extremity amputation among patients with ESRD who receive dialysis during a recent 15-year period; to analyze whether those rates differed by age, sex, diabetes, or geographic region; and to determine 1-year mortality rates in this population after lower extremity amputation. This retrospective study of 3 700 902 records obtained from a US national registry of patients with ESRD who receive dialysis assessed cross-sectional cohorts for each calendar year from 2000 through 2014. Adult patients with prevalent ESRD treated with hemodialysis or peritoneal dialysis covered by Medicare Part A and B on January 1 of each cohort year were included. Data analysis was conducted from August 2017 to April 2018. Age, sex, diabetes, and hospital referral region. Annual rates per 100 person-years of nontraumatic major (above- or below-knee) and minor (below-ankle) amputations. For each annual cohort, there were fewer women (47.5% in 2000, 46.2% in 2005, 44.9% in 2010, and 44.0% in 2014) than men, more than half the patients were white individuals (58.1% in 2000, 56.9% in 2005, 56.9% in 2010, and 56.7% in 2014), and a small proportion were employed (13.9% in 2000, 15.1% in 2005, 16.1% in 2010, and 16.5% in 2014). The rate of lower extremity amputations for patients with ESRD who receive dialysis decreased by 51.0% from 2000 to 2014, driven primarily by a decrease in the rate of major amputations (5.42 [95% CI, 5.28-5.56] in 2000 vs 2.66 [95% CI, 2.59-2.72] per 100 person-years in 2014). Patients with diabetes had amputation rates more than 5 times as high as patients without diabetes. Patients younger than 65 years had higher adjusted amputation rates than older patients, and men had consistently higher adjusted amputation rates than women. Adjusted 1-year mortality rates after lower extremity amputation for patients with ESRD who receive dialysis decreased from 52.2% (95% CI, 50.9%-53.4%) in 2000 to 43.6% (95% CI, 42.5%-44.8%) in 2013. In general, amputation rates decreased among all regions from 2000 to 2014, but regional variability persisted across time despite adjustment for differences in patient demographics and comorbid conditions. Although rates of lower extremity amputations among US patients with ESRD who receive dialysis decreased by 51% during a recent 15-year period, mortality rates remained high, with nearly half of patients dying within a year after lower extremity amputation. Our results highlight the need for more research on ways to prevent lower extremity amputation in this extremely high-risk population.