Higher Risk Of Lower Extremity Amputation Research Articles

The relationship between lower extremity amputation and body mass index.

Non-traumatic lower extremity amputation (LEA) is associated with significant morbidity and mortality. Diabetes mellitus (DM) and peripheral vascular disease (PVD) are associated with increased risk for LEA. As such, DM and PVD account for 54% of all LEA's, performed in the United States annually. As obesity is highly associated with both DM and PVD, our study sought to explore the relationship between LEA and obesity defined by BMI. Using the National Inpatient Sample (NIS) database, a retrospective review of patients who underwent non-traumatic LEA (LEA) between 2008 and 2014 was performed. The International Classification of Diseases 9th edition (ICD-9) codes were utilized to determine the diagnoses, comorbidities, and procedures. Patient BMIs were classified as follows: Non-obese [BMI <30], Obesity class I [BMI 30-34.9], Obesity class II [BMI 35-39.9], and Obesity class III [BMI ≥40]. Predictors for LEA were compared between groups using chi-square test and binary logistic regression to identify possible underlying factors associated with LEA. We also conducted a multivariate analysis to measure the effect of multiple variables on LEA. We identified 16,259 patients with non-traumatic LEA and a mean age of 59.9 years. Rate of amputation in females was lower than males at 0.35% vs 0.87% respectively (p < 0.001). Of patients that underwent amputation there was a V-shape trend based on BMI, with 30.4% in non-obese patients, 18.2% in obesity class I, 17.3% in obesity class II, and 34.1% in obesity class III. The incidence of diabetes increased with obesity class, while the incidence of PVD decreased. Interestingly, of those with DM there was an inverse relationship between amputation rate and BMI class, with LEA rates in non-obese versus obesity class III patients were 1.63% vs 0.98% respectively (p < 0.001). Similarly, patients who had both diabetes and PVD showed a downward trend in LEA rate as obesity class increased; non-obese patients had a LEA rate of 8.01%, while obesity class III had 4.65% (p < 0.001). Patients in higher income bracket have lower odds of LEA (OR 0.77, p < 0.001) compared to the lowest income patients. Also, patients with comorbidities such as PVD (OR 10.78), diabetes (OR 5.02), renal failure (OR 1.41), and hypertension (OR 1.36) had higher odds to get an LEA (p < 0.001). Individuals with obesity class III are almost at half the odds (OR 0.52) to get an LEA compared to non-obese (p < 0.001). Higher BMI and female gender are protective factors against lower extremity amputation. Factors that predisposing to LEA include lower household income and certain comorbidities such as PVD, diabetes, renal failure, and hypertension. These findings warrant further research to identify patients at high risk for LEA and help develop management guidelines for targeted populations.

PDG82 Machine Learning to Identify Diabetes Patients with Canagliflozin Prescriptions at High-Risk of Lower Extremity Amputation Using Real-Word DATA

PDG82 Machine Learning to Identify Diabetes Patients with Canagliflozin Prescriptions at High-Risk of Lower Extremity Amputation Using Real-Word DATA

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.

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.

Risk of Foot Ulcer and Lower Extremity Amputation among Participants in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC)

We examined whether prior intensive glycemic control during the DCCT reduced the risk of diabetic foot ulcer (DFU) and lower extremity amputation (LEA) among participants with type 1 diabetes in the EDIC study. DFU and LEA occurrence were determined by physical examination during annual EDIC follow-up visits that began about one year following DCCT completion. We also assessed DFU and LEA risk by neurovascular measurements, diabetes characteristics, and clinical factors. Data were available from 23 years of EDIC follow-up. Recurrent DFU was defined if reported on a different limb in subsequent years or the same limb in non-consecutive years. Multivariable Cox models were used to estimate the association of intensive glycemic control and other time-updated risk factors with incident or total (incident + recurrent) DFU or incident LEA. Incident DFU was observed in 86 of the 699 former intensive and 109 of the 7former conventional treatment participants (HR 0.78, 95% CI 0.59 to 1.03). Total DFU numbered 117 in intensive (7.3/1000 person-years (p-y)) and 153 in conventional treatment participants (9.6/1000 p-y) for a significant risk reduction (HR 0.76, 95% CI 0.60 to 0.97, p=0.03). Incident LEA occurred in 15 intensive (1.0/1000 p-y) compared to 21 conventional treatment participants (1.4/1000 p-y, HR 0.70, 95% CI 0.36 to 1.36, p=0.30). Greater HbA1c, lower eGFR, albuminuria, confirmed clinical neuropathy, lower nerve conduction velocity, abnormal cardiovascular autonomic function, proliferative retinopathy, and macular edema were independently associated (p&amp;lt;0.05) with higher risk of incident DFU and LEA. Current smoking was associated with higher risk of LEA only. Ankle-brachial index measured continuously was not associated with risk of either outcome. We conclude that intensive glycemic control decreases the risk of DFU, the most important antecedent in the causal pathway to LEA. Disclosure E.J. Boyko: None. L. Zelnick: None. B. Braffett: None. R. Pop-Busui: Research Support; Self; AstraZeneca. C.C. Cowie: None. G.M. Lorenzi: Advisory Panel; Self; Intarcia Therapeutics, Inc.. R. Gubitosi-Klug: None. B. Zinman: Consultant; Self; Novo Nordisk A/S, Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Sanofi, Merck &amp; Co., Inc., Abbott. I. de Boer: Research Support; Self; Medtronic, Abbott. Consultant; Self; Boehringer Ingelheim GmbH, Ironwood Pharmaceuticals, Inc..

HbA1c and Lower-Extremity Amputation Risk in Low-Income Patients With Diabetes

OBJECTIVEDiabetes confers a very high risk of lower-extremity amputation (LEA); however, few studies have assessed whether blood glucose control can reduce LEA risk among patients with diabetes, especially in practice settings where low-income patients predominate.RESEARCH DESIGN AND METHODSWe performed a prospective cohort study (2000–2009) on patients with diabetes that included 19,808 African Americans and 15,560 whites. The cohort was followed though 31 May 2012. Cox proportional hazards regression models were used to estimate the association of HbA1c with LEA risk.RESULTSDuring a mean follow-up of 6.83 years, 578 LEA incident cases were identified. The multivariable-adjusted hazard ratios of LEA associated with different levels of HbA1c at baseline (<6.0% [reference group], 6.0–6.9, 7.0–7.9, 8.0–8.9, 9.0–9.9, and ≥10.0%) were 1.00, 1.73 (95% CI 1.07–2.80), 1.65 (0.99–2.77), 1.96 (1.14–3.36), 3.02 (1.81–5.04), and 3.30 (2.10–5.20) (P trend <0.001) for African American patients with diabetes and 1.00, 1.16 (0.66–2.02), 2.28 (1.35–3.85), 2.38 (1.36–4.18), 2.99 (1.71–5.22), and 3.25 (1.98–5.33) (P trend <0.001) for white patients with diabetes, respectively. The graded positive association of HbA1c during follow-up with LEA risk was observed among both African American and white patients with diabetes (all P trend <0.001). With stratification by sex, age, smoking status, blood pressure, LDL cholesterol, BMI, use of glucose-lowering agents, and income, this graded association of HbA1c with LEA was still present.CONCLUSIONSThe current study conducted in a low-income population suggests a graded association between HbA1c and the risk of LEA among both African American and white patients with type 2 diabetes.

Diabetes-related lower-extremity amputation incidence and risk factors: a prospective seven-year study in Costa Rica

To analyze the incidence and determinants of lower-extremity amputation (LEA) in people with diabetes in a low-income community in Costa Rica. Data on LEA incidence were collected during a seven-year follow-up (2001-2007) in a diabetes patient cohort (n = 572). Risk factors were analyzed using the Cox proportional hazards regression model and baseline variables from the year 2000 (socio- demographic characteristics, comorbidity, metabolic control, treatment, and chronic microvascular complications). LEA incidence was 6.02 per 1 000 person-years (8.65 in men and 4.50 in women). Known risk factors (sex, years of diabetes, elevated glycated hemoglobin [HbA1c], retinopathy, insulin therapy, and prior amputation) were highly significant. Those most likely to undergo LEA among Costa Rican diabetic patients were men with 10 or more years of diabetes and average HbA1c > 8% who used insulin and had diabetic retinopathy. Patients on insulin therapy were at greatest risk, especially those with a previous amputation. Diabetic patients with the above-mentioned profile should be considered to be at very high risk of LEA and followed closely by the health care system.

The Management of Diabetic Neuropathy in CKD

Diabetic nephropathy is the leading cause of end stage renal disease (ESRD) requiring renal replacement therapy in the U.S.1A The progression of diabetes to advanced stages of chronic kidney disease is associated with the progression of multiple other micro and macrovascular complications of diabetes including diabetic neuropathies1. Diabetic peripheral neuropathy is a common complication of diabetes associated with high morbidity, poor quality of life and high risk of lower-extremity amputation. Similarly, cardiac autonomic neuropathy is associated with life-threatening consequences, such as silent myocardial ischemia and high mortality 2-4. In this review we will examine the characteristics of cardiac autonomic neuropathy and diabetic peripheral neuropathy in diabetic patients with stage 4-5 chronic kidney disease (CKD) or end stage renal disease (ESRD) undergoing dialysis. We will describe the evidence supporting the available therapeutic options and the challenges associated with providing adequate care for these patients and discuss future directions for investigation.

Efficacy of Low-Density Lipoprotein Apheresis in Patients with Peripheral Arterial Occlusive Disease Undergoing Hemodialysis Treatment

Background: Low-density lipoprotein (LDL) apheresis is effective in the treatment of peripheral arterial occlusive disease (PAOD). In the present study, we attempted to determine whether LDL apheresis is effective even for PAOD patients undergoing hemodialysis, who tend to be refractory to any treatment, and if so, to determine the mechanism of its efficacy. Methods: Serum levels of lipids and vascular growth factors, leg symptom, and endothelium-dependent vasodilation were investigated before and after 10 sessions of LDL apheresis in 11 PAOD patients undergoing hemodialysis. Results: Serum levels of total cholesterol, LDL cholesterol, and triglyceride exhibited drastic reduction, which completely disappeared 4 weeks after the final apheresis. Resting leg pain was improved in 6 cases even 4 weeks after final apheresis. Endothelium-dependent vasodilation was significantly increased 4 weeks after final apheresis (1.6 ± 0.6 to 4.7 ± 1.0%, p < 0.05). Levels of vascular growth factors, hepatocyte growth factor and vascular endothelial growth factor were not changed during treatment. Conclusions: These findings suggested that LDL apheresis is effective even in PAOD patients undergoing hemodialysis. Our findings suggest that its mechanisms of efficacy include improvement of vascular endothelial dysfunction, in addition to drastic but acute reduction of lipid levels. Since PAOD patients undergoing hemodialysis tend to be resistant to any treatment and are at high risk for lower-extremity amputation, LDL apheresis could be a useful strategy for treatment of them.

Amputation prevention by vascular surgery and podiatry collaboration in high-risk diabetic and nondiabetic patients. The Operation Desert Foot experience.

To describe a unique multidisciplinary outpatient intervention for patients at high risk for lower-extremity amputation. Patients with foot ulcers and considered to be high risk for lower-extremity amputation were referred to the High Risk Foot Clinic of Operation Desert Foot at the Carl T. Hayden Veterans Affairs' Medical Center in Phoenix, Arizona, where patients received simultaneous vascular surgery and podiatric triage and treatment. Some 124 patients, consisting of 90 diabetic patients and 34 nondiabetic patients, were initially seen between 1 October 1991 and 30 September 1992 and followed for subsequent rate of lower-extremity amputation. In a mean follow-up period of 55 months (range 3-77), only 18 of 124 patients (15%) required amputation at the level of the thigh or leg. Of the 18 amputees, 17 (94%) had type 2 diabetes. The rate of avoiding limb loss was 86.5% after 3 years and 83% after 5 years or more. Furthermore, of the 15 amputees surviving longer than 2 months, only one (7%) had to undergo amputation of the contralateral limb over the following 12-65 months (mean 35 months). Compared with nondiabetic patients, patients with diabetes had a 7.68 odds ratio for amputation (95% CI 5.63-9.74) (P < 0.01). A specialized clinic for prevention of lower-extremity amputation is described. Initial and contralateral amputation rates appear to be far lower in this population than in previously published reports for similar populations. Relative to patients without diabetes, patients with diabetes were more than seven times as likely to have a lower-extremity amputation. These data suggest that aggressive collaboration of vascular surgery and podiatry can be effective in preventing lower-extremity amputation in the high-risk population.

Identifying diabetic patients at high risk for lower-extremity amputation in a primary health care setting. A prospective evaluation of simple screening criteria.

To evaluate prospectively a risk categorization scheme for lower-extremity problems that incorporates the Semmes-Weinstein 5.07 monofilament and a simple exam to stratify patients who were followed in a primary-care setting into risk groups for plantar ulceration and lower-extremity amputation. Patients with diabetes in a well-defined American-Indian population were stratified into four risk categories based on sensation status to the 5.07 monofilament, the presence of foot deformity, and a history of lower-extremity events (amputation or ulceration): category 0, sensate; category 1, insensate; category 2, insensate with deformity; and category 3, history of lower extremity events. Patients were followed prospectively for lower extremity events and changes in sensation status. We gave screening exams to 358 (88%) of 406 individuals with diabetes in the community. The distribution of patients for risk categories 0, 1, 2, and 3 was 74.3, 8.4, 4.5, and 13%, respectively. Over a 32-mo follow-up period, 41 patients developed ulcerations, and incidence rates correlated positively with increasing risk category (P less than 0.00001). All 14 amputations occurred in risk groups 2 and 3. These data suggest that the risk categorization described here may have a role in identifying patients at risk for lower extremity events who are followed in a primary-care setting.