The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.
If you have any questions or comments, please contact us.
PURPOSE - Several observational studies suggest that metformin reduces incidence cancer risk; however, many of these studies suffer from time-related biases and several cancer outcomes have not been investigated due to small sample sizes.
METHODS - We constructed a propensity score-matched retrospective cohort of 84,434 veterans newly prescribed metformin or a sulfonylurea as monotherapy. We used Cox proportional hazard regression to assess the association between metformin use compared to sulfonylurea use and incidence cancer risk for 10 solid tumors. We adjusted for clinical covariates including hemoglobin A1C, antihypertensive and lipid-lowering medications, and body mass index. Incidence cancers were defined by ICD-9-CM codes.
RESULTS - Among 42,217 new metformin users and 42,217 matched-new sulfonylurea users, we identified 2,575 incidence cancers. Metformin was inversely associated with liver cancer (adjusted hazard ratio [aHR] = 0.44, 95% CI 0.31, 0.64) compared to sulfonylurea. We found no association between metformin use and risk of incidence bladder, breast, colorectal, esophageal, gastric, lung, pancreatic, prostate, or renal cancer when compared to sulfonylurea use.
CONCLUSIONS - In this large cohort study that accounted for time-related biases, we observed no association between the use of metformin and most cancers; however, we found a strong inverse association between metformin and liver cancer. Randomized trials of metformin for prevention of liver cancer would be useful to verify these observations.
BACKGROUND - Medications that impact insulin sensitivity or cause weight gain may increase heart failure risk. Our aim was to compare heart failure and cardiovascular death outcomes among patients initiating sulfonylureas for diabetes mellitus treatment versus metformin.
METHODS AND RESULTS - National Veterans Health Administration databases were linked to Medicare, Medicaid, and National Death Index data. Veterans aged ≥18 years who initiated metformin or sulfonylureas between 2001 and 2011 and whose creatinine was <1.4 (females) or 1.5 mg/dL (males) were included. Each metformin patient was propensity score-matched to a sulfonylurea initiator. The outcome was hospitalization for acute decompensated heart failure as the primary reason for admission or a cardiovascular death. There were 126 867 and 79 192 new users of metformin and sulfonylurea, respectively. Propensity score matching yielded 65 986 per group. Median age was 66 years, and 97% of patients were male; hemoglobin A 6.9% (6.3, 7.7); body mass index 30.7 kg/m (27.4, 34.6); and 6% had heart failure history. There were 1236 events (1184 heart failure hospitalizations and 52 cardiovascular deaths) among sulfonylurea initiators and 1078 events (1043 heart failure hospitalizations and 35 cardiovascular deaths) among metformin initiators. There were 12.4 versus 8.9 events per 1000 person-years of use (adjusted hazard ratio 1.32, 95%CI 1.21, 1.43). The rate difference was 4 heart failure hospitalizations or cardiovascular deaths per 1000 users of sulfonylureas versus metformin annually.
CONCLUSIONS - Predominantly male patients initiating treatment for diabetes mellitus with sulfonylurea had a higher risk of heart failure and cardiovascular death compared to similar patients initiating metformin.
© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.
BACKGROUND AND OBJECTIVES - Diabetes is the leading cause of ESRD. Glucose control improves kidney outcomes. Most patients eventually require treatment intensification with second-line medications; however, the differential effects of those therapies on kidney function are unknown.
DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS - We studied a retrospective cohort of veterans on metformin monotherapy from 2001 to 2008 who added either insulin or sulfonylurea and were followed through September of 2011. We used propensity score matching 1:4 for those who intensified with insulin versus sulfonylurea, respectively. The primary composite outcome was persistent decline in eGFR≥35% from baseline (GFR event) or a diagnosis of ESRD. The secondary outcome was a GFR event, ESRD, or death. Outcome risks were compared using marginal structural models to account for time-varying covariates. The primary analysis required persistence with the intensified regimen. An effect modification of baseline eGFR and the intervention on both outcomes was evaluated.
RESULTS - There were 1989 patients on metformin and insulin and 7956 patients on metformin and sulfonylurea. Median patient age was 60 years old (interquartile range, 54-67), median hemoglobin A1c was 8.1% (interquartile range, 7.1%-9.9%), and median creatinine was 1.0 mg/dl (interquartile range, 0.9-1.1). The rate of GFR event or ESRD (primary outcome) was 31 versus 26 per 1000 person-years for those who added insulin versus sulfonylureas, respectively (adjusted hazard ratio, 1.27; 95% confidence interval, 0.99 to 1.63). The rate of GFR event, ESRD, or death was 64 versus 49 per 1000 person-years, respectively (adjusted hazard ratio, 1.33; 95% confidence interval, 1.11 to 1.59). Tests for a therapy by baseline eGFR interaction for both the primary and secondary outcomes were not significant (P=0.39 and P=0.12, respectively).
CONCLUSIONS - Among patients who intensified metformin monotherapy, the addition of insulin compared with a sulfonylurea was not associated with a higher rate of kidney outcomes but was associated with a higher rate of the composite outcome that included death. These risks were not modified by baseline eGFR.
Copyright © 2016 by the American Society of Nephrology.
BACKGROUND - To describe common type 2 diabetes treatment intensification regimens, patients' characteristics and changes in glycated hemoglobin (HbA1c) and body mass index (BMI).
METHODS - We constructed a national retrospective cohort of veterans initially treated for diabetes with either metformin or sulfonylurea from 2001 through 2008, using Veterans Health Administration (VHA) and Medicare data. Patients were followed through September, 2011 to identify common diabetes treatment intensification regimens. We evaluated changes in HbA1c and BMI post-intensification for metformin-based regimens.
RESULTS - We identified 323,857 veterans who initiated diabetes treatment. Of these, 55 % initiated metformin, 43 % sulfonylurea and 2 % other regimens. Fifty percent (N = 89,057) of metformin initiators remained on metformin monotherapy over a median follow-up 58 months (interquartile range [IQR] 35, 74). Among 80,725 patients who intensified metformin monotherapy, the four most common regimens were addition of sulfonylurea (79 %), thiazolidinedione [TZD] (6 %), or insulin (8 %), and switch to insulin monotherapy (2 %). Across these regimens, median HbA1c values declined from a range of 7.0-7.8 % (53-62 mmol/mol) at intensification to 6.6-7.0 % (49-53 mmol/mol) at 1 year, and remained stable up to 3 years afterwards. Median BMI ranged between 30.5 and 32 kg/m(2) at intensification and increased very modestly in those who intensified with oral regimens, but 1-2 kg/m(2) over 3 years among those who intensified with insulin-based regimens.
CONCLUSIONS - By 1 year post-intensification of metformin monotherapy, HbA1c declined in all four common intensification regimens, and remained close to 7 % in subsequent follow-up. BMI increased substantially for those on insulin-based regimens.
BACKGROUND - Type 2 diabetes patients often initiate treatment with a sulfonylurea and subsequently intensify their therapy with insulin. However, information on optimal treatment regimens for these patients is limited.
OBJECTIVE - To compare risk of cardiovascular disease (CVD) and hypoglycemia between sulfonylurea initiators who switch to or add insulin.
DESIGN - This was a retrospective cohort assembled using national Veterans Health Administration (VHA), Medicare, and National Death Index databases.
PARTICIPANTS - Veterans who initiated diabetes treatment with a sulfonylurea between 2001 and 2008 and intensified their regimen with insulin were followed through 2011.
MAIN MEASURES - The association between insulin versus sulfonylurea + insulin and time to CVD or hypoglycemia were evaluated using Cox proportional hazard models in a 1:1 propensity score-matched cohort. CVD included hospitalization for acute myocardial infarction or stroke, or cardiovascular mortality. Hypoglycemia included hospitalizations or emergency visits for hypoglycemia, or outpatient blood glucose measurements <60 mg/dL. Subgroups included age < 65 and ≥ 65 years and estimated glomerular filtration rate ≥ 60 and < 60 ml/min.
KEY FINDINGS - There were 1646 and 3728 sulfonylurea monotherapy initiators who switched to insulin monotherapy or added insulin, respectively. The 1596 propensity score-matched patients in each group had similar baseline characteristics at insulin initiation. The rate of CVD per 1000 person-years among insulin versus sulfonylurea + insulin users were 49.3 and 56.0, respectively [hazard ratio (HR) 0.85, 95 % confidence interval (CI) 0.64, 1.12]. Rates of first and recurrent hypoglycemia events per 1000 person-years were 74.0 and 100.0 among insulin users compared to 78.9 and 116.8 among sulfonylurea plus insulin users, yielding HR (95 % CI) of 0.94 (0.76, 1.16) and 0.87 (0.69, 1.10), respectively. Subgroup analysis results were consistent with the main findings.
CONCLUSIONS - Compared to sulfonylurea users who added insulin, those who switched to insulin alone had numerically lower CVD and hypoglycemia events, but these differences in risk were not statistically significant.
BACKGROUND - Hypoglycemia remains a common life-threatening event associated with diabetes treatment. We compared the risk of first or recurrent hypoglycemia event among metformin initiators who intensified treatment with insulin versus sulfonylurea.
METHODS - We assembled a retrospective cohort using databases of the Veterans Health Administration, Medicare and the National Death Index. Metformin initiators who intensified treatment with insulin or sulfonylurea were followed to either their first or recurrent hypoglycemia event using Cox proportional hazard models. Hypoglycemia was defined as hospital admission or an emergency department visit for hypoglycemia, or an outpatient blood glucose value of less than 3.3 mmol/L. We conducted additional analyses for risk of first hypoglycemia event, with death as the competing risk.
RESULTS - Among 178,341 metformin initiators, 2948 added insulin and 39,990 added sulfonylurea. Propensity score matching yielded 2436 patients taking metformin plus insulin and 12,180 taking metformin plus sulfonylurea. Patients took metformin for a median of 14 (interquartile range [IQR] 5-30) months, and the median glycated hemoglobin level was 8.1% (IQR 7.2%-9.9%) at intensification. In the group who added insulin, 121 first hypoglycemia events occurred, and 466 first events occurred in the group who added sulfonylurea (30.9 v. 24.6 events per 1000 person-years; adjusted hazard ratio [HR] 1.30, 95% confidence interval [CI] 1.06-1.59). For recurrent hypoglycemia, there were 159 events in the insulin group and 585 events in the sulfonylurea group (39.1 v. 30.0 per 1000 person-years; adjusted HR 1.39, 95% CI 1.12-1.72). In separate competing risk analyses, the adjusted HR for hypoglycemia was 1.28 (95% CI 1.04-1.56).
INTERPRETATION - Among patients using metformin who could use either insulin or sulfonylurea, the addition of insulin was associated with a higher risk of hypoglycemia than the addition of sulfonylurea. This finding should be considered by patients and clinicians when discussing the risks and benefits of adding insulin versus a sulfonylurea.
© 2016 Canadian Medical Association or its licensors.
OBJECTIVE - Reported rates of hypoglycemia in patients with type 2 diabetes mellitus are lower with glimepiride as compared to glyburide. The aim of this study was to determine whether physiologic differences in counterregulatory neuroendocrine and metabolic mechanisms during hypoglycemia provide a basis for the observed clinical differences between glimepiride and glyburide.
RESEARCH DESIGN AND METHODS - Non-diabetic volunteers (age 38±2years, BMI 26±1kg/m(2)) were studied in a single-blind fashion during separate 2day randomized protocols consisting of 2h hyperinsulinemic (9pmol/kg/min) euglycemic (4.9±0.1mmol) and hypoglycemic (2.9±0.1mmol/L) clamps. Individuals received biologically equivalent doses of glimepiride (4mg) or glyburide (10mg) 1h prior to each glucose clamp (n=11) as well as a control group of placebo studies. Glucose kinetics were calculated using D-Glucose-6-6d2.
RESULTS - Insulin and C-peptide levels were increased (p<0.05) during euglycemia in both sulfonylurea groups as compared to placebo. However, despite equivalent hypoglycemia, insulin and C-peptide levels were higher (p<0.05) only after glyburide. Glucagon responses and endogenous glucose production (EGP) were decreased (p<0.05) during hypoglycemia following glyburide administration as compared to glimepiride. Glyburide reduced (p<0.05) norepinephrine responses during euglycemic clamps. In addition combined epinephrine and norepinephrine responses during hypoglycemia were reduced (p<0.05) following glyburide as compared to placebo. Leptin levels fell by a greater amount (p<0.05) during hypoglycemia with both sulfonylureas as compared to placebo.
CONCLUSIONS - In summary, glimepiride and glyburide can both similarly increase insulin and C-peptide levels during hyperinsulinemic euglycemia. However, during moderate hyperinsulinemic hypoglycemia (2.9mmol/L) glyburide resulted in increased C-peptide and insulin, but blunted glucagon, sympathetic nervous system and EGP responses. We conclude that glyburide can acutely reduce key neuroendocrine and metabolic counterregulatory defenses during hypoglycemia in healthy individuals.
Copyright © 2015. Published by Elsevier Inc.
BACKGROUND - Therapy for certain medical conditions occurs in a stepwise fashion, where one medication is recommended as initial therapy and other medications follow. Sequential pattern mining is a data mining technique used to identify patterns of ordered events.
OBJECTIVE - To determine whether sequential pattern mining is effective for identifying temporal relationships between medications and accurately predicting the next medication likely to be prescribed for a patient.
DESIGN - We obtained claims data from Blue Cross Blue Shield of Texas for patients prescribed at least one diabetes medication between 2008 and 2011, and divided these into a training set (90% of patients) and test set (10% of patients). We applied the CSPADE algorithm to mine sequential patterns of diabetes medication prescriptions both at the drug class and generic drug level and ranked them by the support statistic. We then evaluated the accuracy of predictions made for which diabetes medication a patient was likely to be prescribed next.
RESULTS - We identified 161,497 patients who had been prescribed at least one diabetes medication. We were able to mine stepwise patterns of pharmacological therapy that were consistent with guidelines. Within three attempts, we were able to predict the medication prescribed for 90.0% of patients when making predictions by drug class, and for 64.1% when making predictions at the generic drug level. These results were stable under 10-fold cross validation, ranging from 89.1%-90.5% at the drug class level and 63.5-64.9% at the generic drug level. Using 1 or 2 items in the patient's medication history led to more accurate predictions than not using any history, but using the entire history was sometimes worse.
CONCLUSION - Sequential pattern mining is an effective technique to identify temporal relationships between medications and can be used to predict next steps in a patient's medication regimen. Accurate predictions can be made without using the patient's entire medication history.
Copyright © 2014 Elsevier Inc. All rights reserved.
IMPORTANCE - Preferred second-line medication for diabetes treatment after metformin failure remains uncertain.
OBJECTIVE - To compare time to acute myocardial infarction (AMI), stroke, or death in a cohort of metformin initiators who added insulin or a sulfonylurea.
DESIGN, SETTING, AND PARTICIPANTS - Retrospective cohort constructed with national Veterans Health Administration, Medicare, and National Death Index databases. The study population comprised veterans initially treated with metformin from 2001 through 2008 who subsequently added either insulin or sulfonylurea. Propensity score matching on characteristics was performed, matching each participant who added insulin to 5 who added a sulfonylurea. Patients were followed through September 2011 for primary analyses or September 2009 for cause-of-death analyses.
MAIN OUTCOMES AND MEASURES - Risk of a composite outcome of AMI, stroke hospitalization, or all-cause death was compared between therapies with marginal structural Cox proportional hazard models adjusting for baseline and time-varying demographics, medications, cholesterol level, hemoglobin A1c level, creatinine level, blood pressure, body mass index, and comorbidities.
RESULTS - Among 178,341 metformin monotherapy patients, 2948 added insulin and 39,990 added a sulfonylurea. Propensity score matching yielded 2436 metformin + insulin and 12,180 metformin + sulfonylurea patients. At intensification, patients had received metformin for a median of 14 months (IQR, 5-30), and hemoglobin A1c level was 8.1% (IQR, 7.2%-9.9%). Median follow-up after intensification was 14 months (IQR, 6-29 months). There were 172 vs 634 events for the primary outcome among patients who added insulin vs sulfonylureas, respectively (42.7 vs 32.8 events per 1000 person-years; adjusted hazard ratio [aHR], 1.30; 95% CI, 1.07-1.58; P = .009). Acute myocardial infarction and stroke rates were statistically similar, 41 vs 229 events (10.2 and 11.9 events per 1000 person-years; aHR, 0.88; 95% CI, 0.59-1.30; P = .52), whereas all-cause death rates were 137 vs 444 events, respectively (33.7 and 22.7 events per 1000 person-years; aHR, 1.44; 95% CI, 1.15-1.79; P = .001). There were 54 vs 258 secondary outcomes: AMI, stroke hospitalizations, or cardiovascular deaths (22.8 vs 22.5 events per 1000 person-years; aHR, 0.98; 95% CI, 0.71-1.34; P = .87).
CONCLUSIONS AND RELEVANCE - Among patients with diabetes who were receiving metformin, the addition of insulin vs a sulfonylurea was associated with an increased risk of a composite of nonfatal cardiovascular outcomes and all-cause mortality. These findings require further investigation to understand risks associated with insulin use in these patients.
BACKGROUND AND OBJECTIVE - We recently reported that kidney function declined faster among initiators of sulfonylureas compared to metformin; however, sulfonylurea use compared to metformin use was also associated with increases in body mass index (BMI) and systolic blood pressure (SBP). We sought to determine if differences between sulfonylureas and metformin on kidney function decline were mediated by differential effects on BMI, SBP, or glucose control.
METHODS - We identified 13,238 veterans who initiated sulfonylurea or metformin treatment (2000–2007) with a baseline estimated glomerular filtration rate (eGFR) >60 mL/minute, and followed them until a study event occurred, non-persistence on treatment, loss of follow-up, or end of the study. The composite outcome was a sustained decline from baseline eGFR of ≥25%, end-stage renal disease, or death. We estimated the association of cumulative measurements of potential mediators including BMI, SBP, and glycated hemoglobin on the study outcome. We determined if controlling for these time-varying covariates accounted for the differences in outcome between sulfonylurea and metformin initiators.
RESULTS - Compared to sulfonylurea use, metformin use was associated with a lower risk for renal function decline or death [adjusted hazard ratio (aHR) 0.82, 95% confidence interval 0.70, 0.97]. This protective association remained significant [aHR 0.83 (0.70–0.98)] when accounting for the cumulative time-varying measurements of the three mediators of interest.
CONCLUSION - Metformin initiation was associated with a lower risk of kidney function decline or death compared to sulfonylureas, which which appeared to be independent of changes in BMI, SBP, and glycated hemoglobin over time.