The effects of cannabis and cannabinoids on the endocrine system.

With the increase in cannabis use due to policy changes and areas of decriminalization, it is important to recognize the potential impact of these substances on endocrine processes. Cannabinoids have many effects by activating the endocannabinoid system. This system plays a role in the normal functioning of nearly every organ and consists of the body's natural endocannabinoids, the cannabinoid receptors, and the enzymes and processes that regulate endocannabinoids. Exogenous cannabinoids such as Δ9-tetrahydrocannabinol (THC) are known to act through cannabinoid type 1 and 2 receptors, and have been shown to mimic endocannabinoid signaling and affect receptor expression. This review summarizes the known impacts of cannabis on thyroid, adrenal, and gonadal function in addition to glucose control, lipids, and bone metabolism, including: reduced female fertility, increased risk of adverse pregnancy outcomes, reduced sperm counts and function, lower thyroid hormone levels with acute use, blunting of stress response with chronic use, increased risk of prediabetes but lower risk of diabetes, suggested improvement of high density lipoproteins and triglycerides, and modest increase in fracture risk. The known properties of endocannabinoids, animal data, population data, and the possible benefits and concerns of cannabinoid use on hormonal function are discussed. The interconnectivity of the endocrine and endocannabinoid systems suggests opportunities for future therapeutic modalities which are an area of active investigation.

Generalizability of heterogeneous treatment effects based on causal forests applied to two randomized clinical trials of intensive glycemic control.

Purpose Machine learning is an attractive tool for identifying heterogeneous treatment effects (HTE) of interventions but generalizability of machine learning derived HTE remains unclear. We examined generalizability of HTE detected using causal forests in two similarly designed randomized trials in type II diabetes patients. Methods We evaluated published HTE of intensive versus standard glycemic control on all-cause mortality from the Action to Control Cardiovascular Risk in Diabetes study (ACCORD) in a second trial, the Veterans Affairs Diabetes Trial (VADT). We then applied causal forests to VADT, ACCORD, and pooled data from both studies and compared variable importance and subgroup effects across samples. Results HTE in ACCORD did not replicate in similar subgroups in VADT, but variable importance was correlated between VADT and ACCORD (Kendall's tau-b 0.75). Applying causal forests to pooled individual-level data yielded seven subgroups with similar HTE across both studies, ranging from risk difference of all-cause mortality of -3.9% (95% CI -7.0, -0.8) to 4.7% (95% CI 1.8, 7.5). Conclusions Machine learning detection of HTE subgroups from randomized trials may not generalize across study samples even when variable importance is correlated. Pooling individual-level data may overcome differences in study populations and/or differences in interventions that limit HTE generalizability.

Pentoxifylline in diabetic kidney disease (VA PTXRx): protocol for a pragmatic randomised controlled trial.

INTRODUCTION: Diabetic kidney disease (DKD) is the most frequent cause of end-stage renal disease (ESRD) in the USA and worldwide. Recent experimental and clinical data suggest that the non-specific phosphodiesterase inhibitor pentoxifylline (PTX) may decrease progression of chronic kidney disease. However, a large-scale randomised clinical trial is needed to determine whether PTX can reduce ESRD and death in DKD. METHODS AND ANALYSIS: Veterans Affairs (VA) PTXRx is a pragmatic, randomised, placebo-controlled multicentre VA Cooperative Study to test the hypothesis that PTX, when added to usual care, leads to a reduction in the time to ESRD or death in patients with type 2 diabetes with DKD when compared with usual care plus placebo. The study aims to enrol 2510 patients over a 4-year period with an additional up to 5-year follow-up to generate a total of 646 primary events. The primary objective of this study is to compare the time until ESRD or death (all-cause mortality) between participants randomised to PTX or placebo. Secondary endpoints will be: (1) health-related quality of life, (2) time to doubling of serum creatinine, (3) incidence of hospitalisations for congestive heart failure, (4) incidence of a three-point major adverse cardiovascular events composite (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke), (5) incidence of peripheral vascular disease, (6) change in urinary albumin-to-creatinine ratio from baseline to 6 months and (7) rate of annual change in estimated glomerular filtration rate (eGFR) during the study period. ETHICS AND DISSEMINATION: This study was approved by the VA Central Institutional Review Board (cIRB/18-36) and will be conducted in compliance with the Declaration of Helsinki and the Guidelines for Good Clinical Practice. The Hines Cooperative Studies Programme will finalise the study results, which will be published in accordance with the Consolidated Standards of Reporting Trials statement in a peer-reviewed scientific journal. TRIAL REGISTRATION NUMBER: NCT03625648.

Eye Outcomes in Veteran Affairs Diabetes Trial (VADT) After 17 Years.

OBJECTIVE: The objective of this study was to assess the long-term role of intensive glycemic control (INT) compared with standard glycemic control in accumulated eye procedures in patients with advanced diabetes. RESEARCH DESIGN AND METHODS: We compared the effect of treatment assignment on the accumulated number of eye procedures during the intervention period of the Veteran Affairs Diabetes Trial (VADT) (2000-2008) (median follow-up 5.6 years), the interim VADT follow-up study (2000-2013), and the full 17 years of VADT follow-up (2000-2017). We further analyzed data using various cardiovascular markers in two models. Model I included total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, systolic and diastolic blood pressure, and BMI. Model II included these covariates plus age and diabetic retinopathy (DR) severity score at baseline of the original trial. RESULTS: The final analysis of the data showed a mild but nonsignificant increase in number of procedures and in retinal or retinal plus cataract surgery during the three periods of the study. CONCLUSIONS: We found no significant benefit of INT during the original trial period in eye-related procedures, such as various procedures for DR, or during the 17 years of follow-up in cataract surgery. However, after adjusting data for some known vascular markers, the increase in the number of eye procedures with INT becomes more prevalent. This finding indicates that INT might not have a protective role in events requiring surgery in individuals with advanced diabetes.

SARS-CoV-2 (COVID-19) and the Endocrine System.

As SARS-CoV-2 (COVID-19) overtakes the world, causing moderate to severe disease in about 15% of infected patients, COVID-19 is also found to have widespread effects throughout the body with a myriad of clinical manifestations including the endocrine system. This manuscript reviews what is known about the impact of COVID-19 on the pathophysiology and management of diabetes (both outpatient and inpatient) as well as pituitary, adrenal, thyroid, bone, and gonadal function. Findings in this area are evolving, and long-term effects of infection remain an active area of further research.

Intensive Glucose Control in Patients with Type 2 Diabetes - 15-Year Follow-up.

BACKGROUND: We previously reported that a median of 5.6 years of intensive as compared with standard glucose lowering in 1791 military veterans with type 2 diabetes resulted in a risk of major cardiovascular events that was significantly lower (by 17%) after a total of 10 years of combined intervention and observational follow-up. We now report the full 15-year follow-up. METHODS: We observationally followed enrolled participants (complete cohort) after the conclusion of the original clinical trial by using central databases to identify cardiovascular events, hospitalizations, and deaths. Participants were asked whether they would be willing to provide additional data by means of surveys and chart reviews (survey cohort). The prespecified primary outcome was a composite of major cardiovascular events, including nonfatal myocardial infarction, nonfatal stroke, new or worsening congestive heart failure, amputation for ischemic gangrene, and death from cardiovascular causes. Death from any cause was a prespecified secondary outcome. RESULTS: There were 1655 participants in the complete cohort and 1391 in the survey cohort. During the trial (which originally enrolled 1791 participants), the separation of the glycated hemoglobin curves between the intensive-therapy group (892 participants) and the standard-therapy group (899 participants) averaged 1.5 percentage points, and this difference declined to 0.2 to 0.3 percentage points by 3 years after the trial ended. Over a period of 15 years of follow-up (active treatment plus post-trial observation), the risks of major cardiovascular events or death were not lower in the intensive-therapy group than in the standard-therapy group (hazard ratio for primary outcome, 0.91; 95% confidence interval [CI], 0.78 to 1.06; P = 0.23; hazard ratio for death, 1.02; 95% CI, 0.88 to 1.18). The risk of major cardiovascular disease outcomes was reduced, however, during an extended interval of separation of the glycated hemoglobin curves (hazard ratio, 0.83; 95% CI, 0.70 to 0.99), but this benefit did not continue after equalization of the glycated hemoglobin levels (hazard ratio, 1.26; 95% CI, 0.90 to 1.75). CONCLUSIONS: Participants with type 2 diabetes who had been randomly assigned to intensive glucose control for 5.6 years had a lower risk of cardiovascular events than those who received standard therapy only during the prolonged period in which the glycated hemoglobin curves were separated. There was no evidence of a legacy effect or a mortality benefit with intensive glucose control. (Funded by the VA Cooperative Studies Program; VADT ClinicalTrials.gov number, NCT00032487.).

Facial Growth of Patients With Complete Unilateral Cleft Lip and Palate Treated With Alveolar Bone Grafting at 6 Years.

OBJECTIVE: To investigate the effect that alveolar bone grafting (ABG) around 6 years of age has on facial growth by assessing craniofacial growth outcomes. DESIGN: Retrospective cohort study. SETTING: North American cleft centers. PARTICIPANTS: A total of 33 children with complete unilateral cleft lip and palate who were consecutively treated with secondary ABG around 6 years of age were compared to 148 participants from 4 centers with late secondary ABG. METHODS: Preorthodontic standardized lateral cephalometric radiographs were analyzed and traced according to the Americleft Study protocol. Sixteen angular and 2 proportional measurements were performed. The outcomes of all ABG were assessed using the Standardized Way to Assess Graft scale. Measurement means from the study center (SC) were compared to 4 North American centers using analysis of variance and Welch modified t tests, and P < .05 was considered statistically significant. RESULTS: For the SC, the mean age (SD) at the time of bone graft was 5.85 (0.71) years and the mean age at the time of the lateral cephalogram was 13.4 (1.8) years. The sagittal maxillary prominence of the SC was comparable to the 4 other centers. The mean SNA (78.1 [4.3]) for the SC was significantly higher compared to one center that used primary bone grafting ( P = .03). The soft tissue mean ANB (3.52 [4.09]) for the SC was significantly lower compared to 3 of the centers. CONCLUSIONS: Early secondary ABG around 6 years of age did not result in reduced midface projection as assessed by SNA and thus did not compromise anterior maxillary growth.

Effects of Severe Hypoglycemia on Cardiovascular Outcomes and Death in the Veterans Affairs Diabetes Trial.

OBJECTIVE: To determine the risk factors for severe hypoglycemia and the association between severe hypoglycemia and serious cardiovascular adverse events and cardiovascular and all-cause mortality in the Veterans Affairs Diabetes Trial (VADT). RESEARCH DESIGN AND METHODS: This post hoc analysis of data from the VADT included 1,791 military veterans (age 60.5 ± 9.0 years) with suboptimally controlled type 2 diabetes (HbA1c 9.4 ± 2.0%) of 11.5 ± 7.5 years disease duration with or without known cardiovascular disease and additional cardiovascular risk factors. Participants were randomized to intensive (HbA1c <7.0%) versus standard (HbA1c <8.5%) glucose control. RESULTS: The rate of severe hypoglycemia in the intensive treatment group was 10.3 per 100 patient-years compared with 3.7 per 100 patient-years in the standard treatment group (P < 0.001). In multivariable analysis, insulin use at baseline (P = 0.02), proteinuria (P = 0.009), and autonomic neuropathy (P = 0.01) were independent risk factors for severe hypoglycemia, and higher BMI was protective (P = 0.017). Severe hypoglycemia within the past 3 months was associated with an increased risk of serious cardiovascular events (P = 0.032), cardiovascular mortality (P = 0.012), and total mortality (P = 0.024). However, there was a relatively greater increased risk for total mortality in the standard group compared with the intensive group (P = 0.019). The association between severe hypoglycemia and cardiovascular events increased significantly as overall cardiovascular risk increased (P = 0.012). CONCLUSIONS: Severe hypoglycemic episodes within the previous 3 months were associated with increased risk for major cardiovascular events and cardiovascular and all-cause mortality regardless of glycemic treatment group assignment. Standard therapy further increased the risk for all-cause mortality after severe hypoglycemia.

Profiling Heparin-Induced Thrombocytopenia (HIT) Antibodies in Hospitalized Patients With and Without Diabetes.

Heparin (H) anticoagulation in populations characterized by elevated platelet factor 4 (PF4) frequently elicits PF4/H antibodies, presenting a risk of heparin-induced thrombocytopenia. Recent studies have shown that anti-PF4/H enzyme-linked immunosorbent assays (ELISAs) detect antibodies in individuals never exposed to heparin. Platelet factor 4/H cross-reactive antibodies may result from PF4-mediated defense responses to injury or infection. This study questioned whether patients with diabetes are more likely to develop the endogenous cross-reactive antibodies. A comparison of healthy volunteers versus hospitalized patients with or without diabetes showed no significant differences in the prevalence of PF4/H ELISA-positive results. However, the group of patients who had both diabetes and an infectious condition had higher median antibody titer compared to other patients with or without diabetes regardless of reason for hospitalization. Higher PF4/H titers were also associated with patients with diabetes who were not on any medical therapy. In the future, determining whether PF4/H cross-reactive antibodies sensitize patients to respond adversely to heparin anticoagulation or predispose patients to other complications may be relevant to diabetes care.

Increasing SBP variability is associated with an increased risk of developing incident diabetic foot ulcers.

OBJECTIVE: SBP variability may be a target for mitigating end-organ damage associated with vascular disease. We evaluated the relationship between increased SBP variability and risk of incident diabetic foot ulceration. METHODS: Using a nested case-control design, we followed patients diagnosed with diabetes and treated within the US Department of Veterans Affairs Healthcare system for development of a diabetic foot ulcer (event) between 2006 and 2010. Each case was randomly matched to up to five controls based on age, sex, race/ethnicity, and calendar time. SBP variability was computed using at least three blood pressure measurements from the year preceding the event. The association between SBP variability and foot ulceration was examined using conditional logistic regression. Potential protective effects of calcium channel blockers, which blunt SBP variability, were also explored. RESULTS: The study sample included 51 111 cases and 129 247 controls. Compared with those in quartile 1 (lowest variability), patients in quartiles 2-4 had higher adjusted odds ratios for diabetic foot ulcer development: 1.11 (95% CI 1.07-1.16), 1.20 (95% CI 1.15-1.25), 1.29 (95% CI 1.24-1.34) (P for trend <0.001). Calcium channel blockers were associated with reduced risks of ulceration for those without peripheral vascular disease (OR = 0.87, 95% CI 0.84-0.90, P < 0.001) or neuropathy (OR = 0.85, 95% CI 0.82-0.89, P < 0.001) in adjusted subgroup analyses. CONCLUSION: This study describes a graded relationship between SBP variability and risk of diabetic foot ulceration, providing a potential new and modifiable target to reduce this common complication.

Long-term follow-up of intensive glycaemic control on renal outcomes in the Veterans Affairs Diabetes Trial (VADT).

AIMS/HYPOTHESIS: We conducted an analysis of data collected during the Veterans Affairs Diabetes Trial (VADT) and the follow-up study (VADT-F) to determine whether intensive (INT) compared with standard (STD) glycaemic control during the VADT resulted in better long-term kidney outcomes. METHODS: VADT randomly assigned 1791 veterans from 20 Veterans Affairs (VA) medical centres who had type 2 diabetes mellitus and a mean HbA1c of 9.4 ± 2% (79.2 mmol/mol) at baseline to receive either INT or STD glucose control for a median of 5.6 years (randomisation December 2000 to May 2003; intervention ending in May 2008). After the trial, participants received routine care through their own physicians within the VA. This is an interim analysis of the VADT-F (June 2008 to December 2013). We collected data using VA and National databases and report renal outcomes based on serum creatinine, eGFR and urine albumin to creatinine ratio (ACR) in 1033 people who provided informed consent to participate in the VADT-F. RESULTS: By the end of the VADT-F, significantly more people who received INT treatment during the VADT maintained an eGFR >60 ml min-1 1.73 m-2 (OR 1.34 [95% CI 1.05, 1.71], p = 0.02). This benefit was most evident in those who were classified as at moderate risk (INT vs STD, RR 1.3, p = 0.03) or high risk (RR 2.3, p = 0.04) of chronic kidney disease on the Kidney Disease Improving Global Outcomes (KDIGO-CKD) at the beginning of VADT. At the end of VADT-F, significantly more people from the INT group improved to a low KDIGO risk category (RR 6.1, p = 0.002). During the VADT-F there were no significant differences between INT and STD for average HbA1c, blood pressure or lipid levels. CONCLUSIONS/INTERPRETATION: After just over 11 years of follow-up, there was a 34% greater odds of maintaining an eGFR of >60 ml min-1 1.73 m-2 and of improving the KDIGO category in individuals with type 2 diabetes who had received INT for a median of 5.6 years. VADT clinical trials.gov number: NCT 00032487.

BIOTIN INTERFERENCE WITH ROUTINE CLINICAL IMMUNOASSAYS: UNDERSTAND THE CAUSES AND MITIGATE THE RISKS.

OBJECTIVE: The objectives of this report are to review the mechanisms of biotin interference with streptavidin/biotin-based immunoassays, identify automated immunoassay systems vulnerable to biotin interference, describe how to estimate and minimize the risk of biotin interference in vulnerable assays, and review the literature pertaining to biotin interference in endocrine function tests. METHODS: The data in the manufacturer's "Instructions for Use" for each of the methods utilized by seven immunoassay system were evaluated. We also conducted a systematic search of PubMed/MEDLINE for articles containing terms associated with biotin interference. Available original reports and case series were reviewed. Abstracts from recent scientific meetings were also identified and reviewed. RESULTS: The recent, marked, increase in the use of over-the-counter, high-dose biotin supplements has been accompanied by a steady increase in the number of reports of analytical interference by exogenous biotin in the immunoassays used to evaluate endocrine function. Since immunoassay methods of similar design are also used for the diagnosis and management of anemia, malignancies, autoimmune and infectious diseases, cardiac damage, etc., biotin-related analytical interference is a problem that touches every area of internal medicine. CONCLUSION: It is important for healthcare personnel to become more aware of immunoassay methods that are vulnerable to biotin interference and to consider biotin supplements as potential sources of falsely increased or decreased test results, especially in cases where a lab result does not correlate with the clinical scenario. ABBREVIATIONS: FDA = U.S. Food & Drug Administration FT3 = free tri-iodothyronine FT4 = free thyroxine IFUs = instructions for use LH = luteinizing hormone PTH = parathyroid hormone SA/B = streptavidin/biotin TFT = thyroid function test TSH = thyroid-stimulating hormone.

Visit-to-visit systolic blood pressure variability and microvascular complications among patients with diabetes.

AIMS: To examine the relationship between systolic blood pressure (SBP) variability and the risk of microvascular complications in a non-elderly diabetic population. METHODS: This is a retrospective cohort study of individuals aged ≤60years treated for diabetes in 2003 in the US Department of Veterans Affairs healthcare system. Individuals were followed for five years for any new diagnosis of diabetic nephropathy, retinopathy, or neuropathy. In each year of follow-up, individuals were classified into quartiles based on their SBP variability. RESULTS: We identified 208,338 patients with diabetes without diabetic nephropathy, retinopathy, or neuropathy at baseline. Compared to individuals with the least SBP variability (Quartile 1), those with most variability (Quartile 4) had 81% (OR=1.81; 95% CI, 1.72-1.91), 17% (OR=1.17; 95% CI, 1.13-1.21), 30% (OR=1.30; 95% CI, 1.25-1.35), and 19% (OR=1.19; 95% CI, 1.15-1.23) higher incidence of nephropathy, retinopathy, neuropathy, and any complication, respectively, after adjusting for mean SBP, demographic and clinical factors. CONCLUSIONS: We found a significant graded relationship between SBP variability and the incidence of each complication and of any combined endpoint. This is the first study showing a significant association between SBP variability and the risk of diabetic retinopathy and neuropathy.

Incidence, Severity, and Outcomes of AKI Associated with Dual Renin-Angiotensin System Blockade.

BACKGROUND AND OBJECTIVES: The benefit of dual blockade of the renin-angiotensin system is limited by adverse effects. We performed a secondary analysis of the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) Study to describe the effect of increased intensity of renin-angiotensin system blockade on the incidence, risk factors, and outcomes of AKI. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In the VA NEPHRON-D Study, we randomized 1148 veterans receiving outpatient care with type 2 diabetes mellitus, eGFR of between 30 and 89.9 ml/min per 1.73 m2, and urinary albumin excretion of at least 300 µg/mg creatinine (or a urinary total protein of at least 0.5 mg/mg creatinine) to either combination therapy with losartan and lisinopril or monotherapy with losartan. We identified hospitalized AKI events and their outcomes during a median follow-up of 2.2 years through systematic reporting of serious adverse events. RESULTS: The incidence of AKI was 12.2 (95% confidence interval, 10.5 to 14.0) versus 6.7 (95% confidence interval, 5.6 to 8.2) per 100 patient-years in the combination arm versus monotherapy arms (P<0.001). Individuals with AKI were more likely to develop the primary study end point of death, ESRD, or decline in kidney function (hazard ratio, 1.78; 95% confidence interval, 1.34 to 2.26; P<0.001). Patients with AKI in the combination arm had greater recovery of kidney function (75.9% versus 66.3%; P=0.04), lower 30-day mortality (4.7% versus 15.0%; P<0.01), and lower hazard for development of the primary study end point (hazard ratio, 0.60; 95% confidence interval, 0.37 to 0.98). CONCLUSIONS: Dual renin-angiotensin system blockade was associated with an increased risk of AKI compared with monotherapy, but AKI in the setting of monotherapy was associated with lower rates of recovery of kidney function, higher mortality, and higher risk of progression of kidney disease.

Association of Blood Glucose Control and Lipids With Diabetic Retinopathy in the Veterans Affairs Diabetes Trial (VADT).

OBJECTIVE: This study examined whether lipids modify the relationship between intensive glucose control (INT) and diabetic retinopathy (DR). RESEARCH DESIGN AND METHODS: The incidence and progression of DR were assessed in 858 of 1,791 participants with 7-field stereoscopic fundus photographs at baseline and 5 years later. RESULTS: Odds of DR progression were lower by ∼40% in those with baseline total cholesterol (TC) ≥200 mg/dL (P = 0.007), LDL-C ≥120 mg/dL (P < 0.02), or HDL-C ≥40 mg/dL (P < 0.007) in the INT arm versus standard glycemic treatment. Odds of DR progression were reduced by ∼40% in those who had TC ≤140 mg/dL (P ≤ 0.024), triglycerides (TG) ≤120 mg/dL (P = 0.004), or HDL-C ≥45 mg/dL (P = 0.01) at the fifth year. Odds of DR progression were lower by ∼40-50% with reductions of TC by ≥40 mg/dL (P < 0.0001), of LDL-C of ≥40 mg/dL (P < 0.004), and of TG by ≥60 mg/dL (P = 0.004) at the fifth year. Odds of DR progression increased by 80% with increases in TC of ≥20 mg/dL (P < 0.0001) and by 180% with increases in LDL-C by ≥60 mg/dL (P < 0.004). After adjusting for covariants, those with higher TC at baseline and lower TC during and at the fifth year and higher HDL-C throughout study had significantly decreased odds of DR progression in INT. CONCLUSIONS: INT was associated with decreased odds of progression but not with onset of retinopathy in those with worse lipid levels at baseline and more improved lipid levels during the study. Higher HDL-C was consistently associated with better response to INT throughout the study.

A primer on concentrated insulins: what an internist should know.

The common insulin concentration in most preparations of insulin is 100 units per mL or U-100. Human regular U-500 insulin was the first concentrated insulin introduced and it has been available in the United States since the 1950s. Humulin R is the only human regular U-500 available on the market. Human regular U-500 is five times more concentrated than U-100 and because of its pharmacodynamic properties, works as both a basal and a bolus insulin. Human regular U500 allows for delivery of a larger insulin dose with a smaller volume leading to better absorption compared to U-100 and has traditionally been used in patients with moderate to severe insulin resistance. More recently other forms of concentrated insulin have become available and the newer concentrated insulin preparations can be used in diabetic patients with or without insulin resistance. Our intent is to provide primary care physicians with a review of the pharmacology and current literature on concentrated insulins as well as recommendations for patient selection, dose initiation, and dose adjustment.

Systolic blood pressure variability and lower extremity amputation in a non-elderly population with diabetes.

OBJECTIVE: Systolic blood pressure (SBP) variability is emerging as a new risk factor for cardiovascular diseases, diabetic nephropathy, and other atherosclerotic conditions. Our objective is to examine whether it has any prognostic value for lower-extremity amputations. RESEARCH DESIGN AND METHODS: This is a nested case-control study of a cohort of patients with diabetes aged<60 years and treated in the US Department of Veterans Healthcare system in 2003. They were followed over five years for any above-ankle (major) amputations. For each case with a major amputation (event), we randomly selected up to five matched controls based on age, sex, race/ethnicity, and calendar time. SBP variability was computed using three or more blood pressure measures taken during the one-year period before the event. Patients were classified into quartiles according to their SBP variability. RESULTS: The study sample included 1038 cases and 2932 controls. Compared to Quartile 1 (lowest variability), Quartile 2 had 1.4 times (OR=1.44, 95% CI=1.00-2.07) and Quartiles 3 and 4 (highest) had 2.5 times (OR for Quartile 3=2.62, 95% CI=1.85-3.72; OR for Quartile 4=2.50, 95% CI=1.74-3.59) higher risk of major amputation (P for trend<0.001). This gradient relationship held in both normotensive and hypertensive groups as well as for individuals without prior peripheral vascular disease. CONCLUSIONS: This is the first study to show a significant graded relationship between SBP variability and risk of major amputation among non-elderly persons with diabetes.

Geographic Variation in Rosiglitazone Use Surrounding FDA Warnings in the Department of Veterans Affairs.

BACKGROUND: Geographic variation in the use of prescription drugs, particularly those deemed harmful by the FDA, may lead to variation in patient exposure to adverse drug events. One such drug is the glucose-lowering drug rosiglitazone, for which the FDA issued a safety alert on May 21, 2007, following the publication of a meta-analysis that suggested a 43% increase in the risk of myocardial infarction with the use of rosiglitazone. This alert was followed by a black box warning on August 14, 2007, that was updated 3 months later. While large declines have been documented in rosiglitazone use in clinical practice, little is known about how the use of rosiglitazone and other glucose-lowering drugs varied within the Department of Veterans Affairs (VA), surrounding the FDA alerts. Understanding this variation within integrated health care systems is essential to formulating policies that enhance patient protection and quality of care. OBJECTIVE: To document variation in the use of rosiglitazone and other glucose- lowering drugs across 21 Veterans Integrated Service Networks (VISNs). METHODS: We conducted a retrospective analysis of drug use patterns for all major diabetes drugs in a national cohort of 550,550 veterans with diabetes from 2003 to 2008. This included the time periods when rosiglitazone was added to (November 2003) and removed from (October 2007) the VA national formulary (VANF). We employed multivariable logistic regression models to statistically estimate the association between a patient's location and the patient's odds of using rosiglitazone. RESULTS: Aggregate rosiglitazone use increased monotonically from 7.7%, in the quarter it was added to the VANF (November 4, 2003), to a peak of 15.3% in the quarter when the FDA issued the safety alert. Rosiglitazone use decreased sharply afterwards, reaching 3.4% by the end of the study period (September 30, 2008). The use of pioglitazone, another glucose-lowering drug in the same class as rosiglitazone, was low when the FDA issued the safety alert (0.4%) but increased sharply afterwards, reaching 3.6% by the end of the study period. Insulin use increased monotonically; metformin use remained relatively flat; and sulfonylurea use exhibited a general declining trend throughout the study period. Statistically significant geographic variation was observed in rosiglitazone use throughout the study period. The prevalence range, defined as the range of minimum to maximum use across VISNs was 3.7%-12.4% in the first quarter (January 1 to March 31, 2003); 1.0%-5.5% in the last quarter of study period (July 1 to September 30, 2008); and reached a peak of 9.6%-25.5% in the quarter when the FDA safety alert was issued (April 1 to March 31, 2007). In 5 VISNs, peak rosiglitazone use occurred before the FDA issued the safety alert. The odds ratio of using rosiglitazone in a given VISN varied from 0.55 (95% CI = 0.52-0.59; VISN 10) to 1.58 (95% CI = 1.50-1.66; VISN 15), with VISN 1 being the reference region. The variation was higher in the periods after the FDA issued the safety alert. Much less variation was observed in the use of pioglitazone, metformin, sulfonylurea, and insulin. CONCLUSIONS: Our results show statistically significant variation in the way VISNs within the VA responded to the FDA alerts, suggesting a need for mechanisms that disseminate information and guidelines for drug use in a consistent and reliable manner. Further study of regions that adopted ideal practices earlier may provide lessons for regional leadership and practice culture within integrated health care systems.