Sulfonylurea Users Research Articles

Metformin vs sulfonylurea use and risk of dementia in US veterans aged ≥65 years with diabetes.

To determine whether metformin is associated with a lower incidence of dementia than sulfonylureas. This was a retrospective cohort study of US veterans ≥65 years of age with type 2 diabetes who were new users of metformin or a sulfonylurea and had no dementia. Follow-up began after 2 years of therapy. To account for confounding by indication, we developed a propensity score (PS) and used inverse probability of treatment weighting (IPTW) methods. Cox proportional hazards models estimated the hazard ratio (HR) of incident dementia. We identified 17,200 new users of metformin and 11,440 new users of sulfonylureas. Mean age was 73.5 years and mean HbA1c was 6.8%. Over an average follow-up of 5 years, 4,906 cases of dementia were diagnosed. Due to effect modification by age, all analyses were conducted using a piecewise model for age. Crude hazard ratio [HR] for any dementia in metformin vs sulfonylurea users was 0.67 (95% confidence interval [CI] 0.61-0.73) and 0.78 (95% CI 0.72-0.83) for those <75 years of age and ≥75 years of age, respectively. After PS IPTW adjustment, results remained significant in veterans <75 years of age (HR 0.89; 95% CI 0.79-0.99), but not for those ≥75 years of age (HR 0.96; 95% CI 0.87-1.05). A lower risk of dementia was also seen in the subset of younger veterans who had HbA1C values ≥7% (HR 0.76; 95% CI 0.63-0.91), had good renal function (HR 0.86; 95% CI 0.76-0.97), and were white (HR 0.87; 95% CI 0.77-0.99). After accounting for confounding by indication, metformin was associated with a lower risk of subsequent dementia than sulfonylurea use in veterans <75 years of age. Further work is needed to identify which patients may benefit from metformin for the prevention of dementia.

Hypoglycaemia seriousness and weight gain as determinants of cardiovascular disease outcomes among sulfonylurea users.

Certain treatments for type 2 diabetes mellitus cause hypoglycaemia and weight gain, and thus might counteract the benefits of intensive glucose control. We quantify the association of cardiovascular disease (CVD) outcomes with hypoglycaemia and weight gain among patients with type 2 diabetes treated with sulfonylureas. This cohort study included patients from January 2009 through December 2014 who were selected from within a deidentified nationwide electronic health records repository, including multiple provider networks and electronic medical records systems. Hypoglycaemia measures from structured data fields and free text clinical notes were categorized as serious or non-serious. Covariate adjusted Poisson regression analysis was used to assess the association between frequency of hypoglycaemia (by severity), or magnitude of weight change, and incidence of acute myocardial infarction (AMI), congestive heart failure (CHF) and stroke. Among 143 635 eligible patients, we observed 5669 cases of AMI, 14 109 incident cases of CHF and 7017 cases of stroke. Overall incidence rates were 1.53, 4.26 and 1.92 per 100 person-years for AMI, CHF and stroke, respectively. The associations between overall hypoglycaemia and each of the CVD outcomes were positive, with stronger associations observed for serious hypoglycaemia and attenuated or null associations observed for non-serious hypoglycaemia. Weight change exhibited a U-shaped association with increased risks associated with both weight loss and weight gain relative to stable weight. This study provides evidence of increased CVD risk associated with hypoglycaemia, especially with serious hypoglycaemia events. While associations were attenuated with non-serious hypoglycaemia, the results were suggestive of a potential increased risk.

Lack of chemopreventive efficacy of metformin in rodent models of urinary bladder, head and neck, and colon/intestine cancer.

Metformin is a biguanide employed in treating type II diabetes. Its potential efficacy for treating cancer has been demonstrated epidemiologically (lower cancer incidence in metformin users compared with users of sulfonylureas or insulin) and mechanistically, primarily in cell culture. Metformin decreases the levels of insulin-like growth factor 1 and secondarily inhibits the mammalian target of rapamycin pathway to exhibit anticancer effects. The current study examined its cancer preventive efficacy in multiple standard in situ arising cancer models. Metformin was administered orally by gavage or in the diet, at human equivalent doses, in numerous cancer models. In the hydroxybutyl(butyl)nitrosamine-induced model of invasive urinary bladder cancer, metformin (50 or 150 mg/kg body weight/day, intragastric) was ineffective despite high urinary concentrations of metformin. Metformin (250 or 500 ppm in diet) failed to decrease the incidence or invasiveness of squamous cell cancer of the tongue in a 4-nitroquinoline-1-(4NQO)-induced model. Finally, in the Min mouse model of gastrointestinal cancer, metformin (400 or 1,200 ppm in diet) was ineffective. Notably, a slight increase in intestinal tumor multiplicity was observed at the higher dose. Therefore, metformin lacked efficacy in multiple standard cancer models in non-diabetic rodents. This lack of efficacy may discourage any large phase clinical cancer trials in non-diabetic individuals in the absence of clear phase-II studies.

Cardiovascular events associated with second-line anti-diabetes treatments: analysis of real-world Korean data.

To compare the risks of cardiovascular disease (CVD) and all-cause mortality associated with sulfonylurea (SU), dipeptidyl peptidase-4 inhibitor (DPP4i) and thiazolidinedione (TZD) as add-on medications to metformin (MET) therapy in people with Type 2 diabetes. We identified 40 263 individuals who used SU (n = 11 582), DPP4i (n = 26 623) or TZD (n = 2058) in addition to MET between January 2013 and June 2015 from the database of the Korean National Health Insurance, the single-payer healthcare system in South Korea. Cox proportional hazard models were used to estimate hazard ratios for major CVD event (coronary artery disease, heart failure, stroke or transient ischaemic attack) development and all-cause mortality by second-line anti-diabetes medication type. Age, sex, duration of MET monotherapy, calendar year and comorbid conditions were adjusted as potential confounders. The observed numbers of CVD events (total observed person-time) were 485 (18 778 person-years) for MET + SU, 744 (40 374 person-years) for MET + DPP4i and 60 (3014 person-years) for MET + TZD users. Compared with MET + SU users, the fully adjusted hazard ratios for CVD events were 0.79 [95% confidence interval (CI): 0.71-0.89] for MET + DPP4i users and 0.85 (95% CI: 0.65-1.11) for MET + TZD users. The corresponding hazard ratios for all-cause mortality were 0.84 (95% CI: 0.66-1.07) for MET + DPP4i users and 0.67 (95% CI: 0.35-1.28) for MET + TZD users. Analysis of Korea National Health Insurance database showed that MET + DPP4i treatment for diabetes had a lower CVD risk than MET + SU treatment.

Glucose-Lowering Drugs Linked to Increased Fracture Risk in Patients With Diabetes

Researchers in Denmark have concluded that use of glucose-lowering sulfonylureas and glitazones within 90 days increased the risk for hip fractures in elderly patients with type 2 diabetes. Current use of sulfonylureas was also associated with an increased risk of other fractures including vertebral and forearm. “Current use of sulfonylureas and glitazones was associated with increased risk of a hip fracture, and the risk remained increased after adjustment for comorbidities and previous admissions due to falls and hypoglycemic events,” the researchers concluded (Bone 2017:95;136–42). “By contrast, hip fracture risk was not increased in ever users of glucose-lowering drugs among patients with incident type 2 diabetes.” Previous research has shown that patients with type 2 diabetes are at 1.4-fold increased risk for hip fracture, but there are conflicting data on the effect of sulfonylureas. Researchers led by Jakob Starup-Linde, PhD, selected 5244 patients from a cohort of diabetes patients (n = 501,724) entered into the Danish National Patient Register and the Register of Medicinal Product Statistics from January 1996 to December 2011. Patients with type 1 diabetes were excluded. Researchers followed the cohort from the time of diabetes diagnosis to time of fracture or date of death, emigration, or end of study. Mean follow-up was 5.5 years for patients with a hip fracture and 6.4 years for patients who did not have a fracture. Mean follow-up was 5.2 years for patients with a fracture at a major osteoporotic site, 5 years for any fracture, 5.2 years for vertebral fractures, and 5.2 years for forearm fractures. Compared with non-diabetic patients, major osteoporotic fractures and any fractures were more common than hip fractures in patients with type 2 diabetes. Patients who suffered a hip fracture were significantly older than those without a hip fracture, and women with type 2 diabetes were at greater risk for hip fracture than men. “The most plausible reason for an increased risk of fracture within sulfonylurea users are hypoglycemic events,” Dr. Starup-Linde, from the department of endocrinology and internal medicine, Aarhus University Hospital, Denmark, told Caring. “Sulfonylureas are known to cause hypoglycemia by increasing beta cell insulin release. Hypoglycemia may lead to falls and thereby fractures.” Previous and current use of sulfonylureas were associated with an increased risk for hip fracture in the unadjusted model (HR, 1.08). Current use of sulfonylureas increased the risk for hip fracture in all models. However, ever use of sulfonylurea use was associated with a lower fracture risk in the adjusted (HR, 0.81) and propensity adjusted (HR, 0.91) models. Ever use of glitazones was associated with a higher risk of a hip fracture in the unadjusted model (HR, 0.28) but the effect was neutral in the adjusted models. Current use of glitazones was associated with a lower risk of hip fracture in the unadjusted model, but researchers said glitazones were a strong risk factor for fracture in the 90-day propensity adjusted models (HR, 2.07). When researchers examined the effect of new use of a glucose-lowering drug, sulfonylureas (HR, 1.91) and glitazones (HR, 7.18) were associated with an increased risk for hip fracture. Current use of sulfonylureas was associated with an increased risk for any fracture (HR, 1.44), major osteoporotic fracture (HR, 1.54), vertebral fracture (HR, 1.47; 95% CI, 1.24–1.74), and forearm fracture (HR, 1.55). Current use of glitazones was associated with an increased risk for any fracture (HR, 3.01), major osteoporotic fracture (HR, 3.71), vertebral fracture (HR, 4.53), and forearm fracture (HR, 4.89). In contrast, current use of metformin, dipeptidyl peptidase IV-inhibitors, or peptide-1 receptor agonists was associated with reduced risk for decreased risk of any fracture, major osteoporotic fracture, vertebral fracture, and forearm fracture. “To the best of our knowledge, this is the largest study on incident hip and osteoporotic fractures among incident cases of type 2 diabetes,” the researchers wrote. “The present investigation is limited by the lack of information on bone mass, body mass index, lifestyle habits as smoking and daily alcohol consumption, vitamin D status, and other biochemical parameters. These factors are important to consider when interpreting the risk of fracture.” Jason Harris is a freelance medical writer based in Philadelphia.

Time-Varying Risk for Breast Cancer Following Initiation of Glucose-Lowering Therapy in Women with Type 2 Diabetes: Exploring Detection Bias.

To explore detection bias in the association between glucose-lowering therapies and breast cancer in a cohort of women with type 2 diabetes. This was a retrospective, population-based cohort study. We identified new users of metformin, sulfonylureas, thiazolidinediones and insulin during the index period of January 1, 2003, to December 31, 2010. The main outcome was incident breast cancer, and patients were followed up from drug exposure index date until death, diagnosis of another type of cancer, termination of medical insurance or December 31, 2010. To explore detection bias, we split follow-up time into 2 discrete time periods of 0 to 3 months and 3 months to 6 years after drug index date. We performed time-varying Cox regression analyses, including duration of cumulative drug exposure and ever/never drug exposure for each glucose-lowering therapy into our model. The reference was no use of the same drug-exposure category. There were 22,169 women with type 2 diabetes, with a mean (SD) age of 53.0 (9.2) years and mean (SD) follow up of 2.2 (1.5) years. Hazard ratios for breast cancer in the first 3 months following initiation of metformin, sulfonylurea or thiazolidinedione were 0.66 (0.43 to 1.02), 0.74 (0.44 to 1.25) and 0.67 (0.38 to 1.18), respectively. In the later period of 3 months to 6 years following drug start, hazard ratios (95% CI) for breast cancer were 1.00 (0.98 to 1.02), 1.01 (0.98 to 1.03) and 0.98 (0.95 to 1.01) for metformin, sulfonylurea and thiazolidinedione cumulative exposure, respectively. Our findings suggest that no detection bias exists for glucose-lowering therapies and breast cancer in this population.

Maturity-onset diabetes of the young (MODY) in Brazil: Establishment of a national registry and appraisal of available genetic and clinical data.

Maturity-Onset Diabetes of the Young (MODY) comprises a heterogeneous group of monogenic forms of diabetes caused by mutations in at least 14 genes, but mostly by mutations in Glucokinase (GCK) and hepatocyte nuclear factor-1 homeobox A (HNF1A). This study aims to establish a national registry of MODY cases in Brazilian patients, assessing published and unpublished data. 311 patients with clinical characteristics of MODY were analyzed, with unpublished data on 298 individuals described in 12 previous publications and 13 newly described cases in this report. 72 individuals had GCK mutations, 9 described in Brazilian individuals for the first time. One previously unpublished novel GCK mutation, Gly178Ala, was found in one family. 31 individuals had HNF1A mutations, 2 described for the first time in Brazilian individuals. Comparisons of GCK probands vs HNF1A: age 16±11 vs 35±20years; age at diagnosis 11±8 vs 21±7years; BMI 19±6 vs 25±6kg/m2; sulfonylurea users 5 vs 83%; insulin users 5 vs 17%; presence of arterial hypertension 0 vs. 33%, all p<0.05. No differences were observed in lipids and C-peptide. Most MODY cases in Brazil are due to GCK mutations. In agreement with other studied populations, novel mutations are common. Only 14% of patients with familial diabetes carry a HNF1A mutation. Diagnosis of other rare forms of MODY is still a challenge in Brazilian population, as well as adequate strategies to screen individuals for molecular diagnosis.

Cancer risk of sulfonylureas in patients with type 2 diabetes mellitus: A systematic review.

Increasing evidence suggests that oral hypoglycemic agents used in type 2 diabetes mellitus (T2DM) may affect cancer risk. Sulfonylureas (SUs) are the most frequently used antidiabetic medications for T2DM. Whether using SUs has any effect on cancer has received considerable attention. The aim of this study was to assess the effects of SUs on cancer risk in T2DM patients. Published studies were identified in PubMed, EMBASE, and the Cochrane Register of Clinical Studies, and ClinicalTrials.gov was searched for additional information to identify randomized controlled trials (RCTs), cohort studies, and case-control studies. The abstracts and full text were screened, data collected, and the risk of bias assessed for each individual study. Seventy-seven studies (33 RCTs, 27 cohort studies, and 17 case-control studies) were analyzed. The RCTs did not report a difference in the risk of malignant tumor between SU-treated T2DM patients and controls (odds ratio [OR] 0.96; 95% confidence interval [CI] 0.78-1.18); cohort studies showed that cancer risk was higher in patients using SUs than metformin (relative risk 1.60 [95%CI 1.37-1.87]; adjusted hazard ratio 1.13 [95%CI 1.06-1.19]), and case-control studies suggested a trend for increased cancer risk in those using SUs compared with non-SU users (adjusted OR 1.13; 95%CI 0.93-1.37). The available evidence clearly shows that SUs can significantly increase the risk of cancer compared with metformin. Although the evidence suggests the possibility that SU users may have a higher risk of cancer than those using alternative medications in addition to metformin, it remains inadequate to enable definitive conclusions to be drawn.

Genetic variations in TCF7L2 influence therapeutic response to sulfonylureas in Indian diabetics

Sulfonylureas are widely used to treat type 2 diabetes, with considerable inter-individual variation in the hypoglycaemic response to sulfonylureas. Genetic variants in the gene encoding for transcription factor-7-like 2 (TCF7L2) have been associated with type 2 diabetes. This study aimed to study the effect of variations in TCF7L2 on therapeutic response to sulfonylureas in Type 2 diabetes mellitus patients. The effect of TCF7L2 rs12255372, rs7903146 and rs4506565 genotypes on glycaemic response was observed in 250 diabetic patients treated with sulfonylureas and sulfonylureas along with metformin. The genotyping tests were done by allele-specific multiplex PCR. Glycated haemoglobin (HbA1c) levels were used as phenotypic marker. 60% of sulfonylurea users did not achieve a target HbA1c levels of ⩽6.5% (48mmol/mol) (which denotes good control in diabetics). Genotype influenced response to sulfonylureas, with more treatment failure in the TT homozygotes in case of rs12255372 and rs4506565. The GG genotype at rs12255372 favourably influences treatment success with sulfonylurea therapy in patients with type 2 diabetes (p⩽0.05). At rs12255372, 70.5% GT or TT genotype failed to achieve therapeutic target, an absolute difference of 19% compared to GG homozygotes. Our preliminary data show that genetic variation at rs12255372 has a direct correlation with therapeutic success with sulfonylureas in type 2 diabetes, hence paving the way for better treatment outcomes in diabetics.

Risk factors associated with treatment discontinuation and down-titration in type 2 diabetes patients treated with sulfonylureas

Objectives: Sulfonylurea therapy among patients with type 2 diabetes mellitus (T2DM) can be disrupted due to adverse events, including hypoglycemia. A retrospective study using the MarketScan claims database quantified the frequency of sulfonylurea discontinuation or down-titration and identified associated risk factors.Research design and methods: Adult patients with an index sulfonylurea prescription between 2008 and 2012 and 1 year continuous enrollment pre- and post-index were included. Therapy changes assessed over 1 year post-index included discontinuation and down-titration. Discontinuation occurred if the date of a fill was >90 days from the end date of the preceding fill. Down-titration occurred when a fill had a lower equivalent dose than the fill on the index date. Kaplan–Meier methods estimated the probability of either discontinuation or down-titration over 12 months, and Cox regression models identified associated risk factors.Results: A total of 104,082 sulfonylurea users were included in the study and the probability of either discontinuation or down-titration at 3, 6 and 12 months was 23.2%, 38.9%, and 52.3%, respectively. Major risk factors associated with therapy changes included post-index hypoglycemia (discontinuation hazard ratio [HR] = 1.78 [1.68, 1.89]; down-titration HR =2.79 [2.40, 3.23]) and concomitant use of insulin (discontinuation HR =1.48 [1.40, 1.57]; down-titration HR =1.82 [1.56, 2.11]). Other risk factors included younger age, female gender, use of second generation sulfonylureas, prior cardiovascular comorbidity and liver disease.Limitations: The study was not able to assess unreported, potentially mild cases of hypoglycemia, nor was it able to evaluate the association between changes in therapy and HbA1c levels or body weight.Conclusions: More than half of T2DM patients who initiated sulfonylurea therapy discontinued or down-titrated within 1 year. Insulin use and hypoglycemia were associated with sulfonylurea therapy change.

Urinary albumin excretion with sitagliptin compared to sulfonylurea as add on to metformin in type 2 diabetes patients with albuminuria: A real-world evidence study

AimTo compare the change in urinary albumin to creatinine ratio (UACR) in type 2 diabetes (T2DM) patients with albuminuria who initiate sitagliptin to those who initiate a sulfonylurea (SU) as add-on to metformin monotherapy. MethodA cohort of T2DM patients with albuminuria (UACR >30mg/g) who initiated sitagliptin or SU as add-on dual therapy to metformin between 2008 and 2014 was extracted from the computerized medical records of a large managed care organization in Israel. Patients with albuminuria and UACR measurements available at treatment initiation and 120–365days afterwards were included. Propensity scores were calculated based on 17 factors, including demography, comorbidities, baseline levels of HbA1c, UACR, BMI, eGFR, and ACE/ARB use, and patients were matched in a 1:1 ratio. Changes in UACR were compared between the matched pairs using generalized estimating equations. ResultsA total of 282 eligible pairs (sitagliptin:SU) were identified. During a mean follow-up of 9months, median UACR changes were −35% (IQR=−73% to 5%) and −31% (IQR=−72% to 21%) in the sitagliptin and SU groups, respectively. Mean absolute HbA1c reductions among sitagliptin and SU groups were 0.9% and 1.0%, respectively. The magnitude of UACR reduction generally increased with greater magnitude of HbA1c reduction in both treatment groups. However, after controlling for HbA1c reduction and the interaction between HbA1c reduction and UACR reduction, sitagliptin users demonstrated a trend toward an increased likelihood of UACR reduction compared to SU users (odds ratio=1.20; 95% confidence interval: 0.99–1.47, P=0.063). ConclusionOur results suggest that both sitagliptin and SU reduce albuminuria as an add-on therapy to metformin, but that sitagliptin may provide greater reductions in albuminuria independent of glycemic control when compared to SU. Larger population studies are required to further explore this.

Hypoglycemia Incidence Rates and Associated Health Care Costs in Patients with Type 2 Diabetes Mellitus Treated with Second-Line Linagliptin or Sulfonylurea After Metformin Monotherapy.

Hypoglycemia poses a significant clinical and economic burden to patients with type 2 diabetes mellitus (T2DM). Minimizing the risk of hypoglycemia is an important component when managing patients with T2DM. Understanding hypoglycemia rates and the associated economic consequences can help to inform health care decision makers. To assess hypoglycemia incidence rates and associated costs in patients who initiated second-line treatment with the antidiabetic agents linagliptin or a sulfonylurea (SU) after metformin. A large U.S. administrative claims database was used to identify patients with T2DM (during the identification period July 2011-October 2013) who initiated linagliptin or a SU after metformin use. The date of the first prescription for linagliptin or a SU during the identification period was designated as the index date. Linagliptin users were matched to SU users based on demographic and clinical characteristics identified within a 12-month period before the index date using propensity scores (1:3 ratio, caliper: ±0.001). Rates and costs (2013 U.S. dollars) of hypoglycemia resulting in any health care resource use were quantified during a variable follow-up period (i.e., end of the study, end of the 12-month follow-up, treatment regimen change, or disenrollment, whichever came first). Hypoglycemia rates per 100 person-years were compared using univariate Poisson regression, and hazard of hypoglycemia was obtained from multivariate Cox proportional hazards regression. Mean monthly hypoglycemia-related costs, all-cause costs, and T2DM-related costs were computed for patients with hypoglycemia and compared using t-tests. Propensity-score matching resulted in a sample of 11,536 patients (linagliptin = 2,884; SU = 8,652) with a mean age of 56 years and 59% male. The rate of hypoglycemia (per 100 person-years) was lower in the linagliptin than the SU user groups (2.51 vs. 3.63; P= 0.049). Linagliptin users had a 33% lower risk of hypoglycemia compared with SU users (HR = 0.67; 95% CI = 0.47-0.97; P= 0.031). Among patients who had hypoglycemia, linagliptin users showed numerically lower mean monthly hypoglycemia-related costs compared with SU users ($300 vs. $890; P= 0.092), which was primarily driven by differences in hypoglycemia-related costs in the hospital setting. A similar theme was observed with monthly all-cause costs (linagliptin users, $1,971 vs. SU users, $3,758; P= 0.092). Linagliptin use was associated with a lower incidence rate of hypoglycemia compared with SU use in patients initiating second-line therapy after metformin monotherapy. Among patients who experienced hypoglycemia, linagliptin users appeared to have lower monthly hypoglycemia-related and all-cause costs than SU users. Careful consideration of newer treatment alternatives may be prudent for optimal T2DM management, especially with regard to hypoglycemia. Funding for the research study and resultant publication was provided by Boehringer Ingelheim. Shetty is an employee of Boehringer Ingelheim. Cai was an employee of Boehringer Ingelheim at the time of the study. Raju and D'Souza are employees of Xcenda, which received research funding from Boehringer Ingelheim for the conduct of this study and for the preparation of this manuscript. All authors contributed to concept and study design. Raju took the lead in data analysis, along with D'Souza, and all authors contributed equally to data interpretation. The manuscript was written by Raju, D'Souza, Cai, and Shetty and revised primarily by Raju, along with Shetty and D'Souza.

Risk of fractures and diabetes medications: a nationwide cohort study.

The effects of diabetes medications on risk of fracture were investigated using the South Korea nationwide claims database. We demonstrated that the use of dipeptidyl peptidase-4 inhibitor could be associated with decreased risk of fracture. Thiazolidinedione use was associated with about 60% increased risk of fracture in real clinical practice. The effects of diabetes medication on fracture have important clinical health consequences, since most diabetes patients are at high risk of fracture. We aimed to investigate the effect of diabetes medication on fracture risk. The nationwide medical claim database in South Korea was investigated. Among 2,886,555 subjects with antidiabetes prescriptions, 207,558 subjects aged 50years and older, who initiated diabetes medication from 2008 to 2011, were analyzed. The subjects were classified based on diabetes medication classes: non-user (insufficient exposure), metformin (MET), sulfonylurea (SU), alpha-glucosidase inhibitor (AGI), MET + SU, MET + thiazolidinedione (TZD), MET + dipeptidyl peptidase-4 inhibitor (DPP4-I), and SU + TZD. A total of 5996 fractures were observed. The fracture rate varied significantly across type of diabetes medications, with MET + DPP4-I combination group having the lowest rate and SU + TZD combination group having the highest rate. Compared to non-users, MET + DPP4-I inhibitor combination group had significantly reduced composite fracture risk (hazard ratio (HR) = 0.83, P = 0.025) and significantly reduced vertebral fracture risk (HR = 0.73, P = 0.013) in the unadjusted analysis. Compared to MET + SU users, MET + DPP4-I users showed a trend of lower non-vertebral fracture risk (HR = 0.82, P = 0.086) after adjusting for all confounding variables. Patients using TZD had significantly increased risk of fracture (HR = 1.59, P < 0.001) compared with patients not using TZDs adjusting for all confounding variables. The results of this nationwide study showed a trend that DPP4 inhibitor might have a protective effect on bone metabolism compared with SU, when added to MET. Clinicians should take these results into consideration when prescribing diabetes medication, especially in elderly patients or those at high risk or fracture.

Comparative safety of diabetes medications and risk of incident invasive breast cancer: a population-based cohort study.

Growing evidence suggests that certain commonly used diabetes medications have the potential to differentially alter breast cancer risk. We evaluated the influence of metformin, insulin, and sulfonylureas on risk of incident invasive breast cancer. We conducted a retrospective cohort study of women ≥40 years of age enrolled in a health plan between 1996 and 2011. Ever, current (≤12 months), and duration (<1, 1-2.9, ≥3 years) of diabetes medication use were obtained from pharmacy databases and modeled as time varying. Multivariable Cox proportional hazards models adjusting for potential confounders including screening mammography and body mass index were used to estimate hazard ratios (HRs) and 95% Confidence Intervals (CIs). Among 10,050 women with diabetes, 57 % used metformin, 43 % used sulfonylureas, 32 % used insulin, and 301 were diagnosed with breast cancer over median follow-up of 6.7 years. Results suggested no significant decreased risk of breast cancer among metformin users (HR 0.86; 95% CI 0.65-1.12). We found no association between increased breast cancer risk and long-acting insulin (HR 0.95; 95% CI 0.51-1.77), but reduced risk with short-/rapid-acting insulin (HR 0.69; 95% CI 0.50-0.94), and suggestion of a dose-response with increasing duration of short-/rapid-acting insulin use (HR 0.87; 95% CI 0.76-1.00). Estimates for sulfonylurea users suggested increased risk with ever use (HR 1.18; 95% CI 0.90-1.53) and with longer durations of use (≥3 years: HR 1.23; 95% CI 0.88-1.73), but confidence intervals included 1.0. Our results provide little support for the previously hypothesized decreased risk of breast cancer with metformin use or for an increased risk with insulin use. Implications for possible residual confounding by screening mammography and comorbidity should be considered in breast cancer pharmacoepidemiology studies.

Abstract P260: Large-scale Meta-analysis of Diverse Ancestry Genome-wide Association Studies to Identify Pharmacogenomic Interactions of Sulfonylureas and ECG Phenotypes

Introduction: Sulfonylureas are a commonly-used class of diabetes medication that can prolong the QT-interval, which is a leading cause of drug withdrawals from the market given the possible risk of life-threatening arrhythmias. Previously, we conducted a meta-analysis of genome-wide association studies of sulfonylurea-genetic interactions on QT interval among 9 European-ancestry (EA) cohorts using cross-sectional data, with null results. To improve our power to identify novel drug-gene interactions, we have included repeated measures of medication use and QT interval and expanded our study to include several additional cohorts, including African-American (AA) and Hispanic-ancestry (HA) cohorts with a high prevalence of sulfonylurea use. To identify potentially differential effects on cardiac depolarization and repolarization, we have also added two phenotypes - the JT and QRS intervals, which together comprise the QT interval. Hypothesis: The use of repeated measures and expansion of our meta-analysis to include diverse ancestry populations will allow us to identify novel pharmacogenomic interactions for sulfonylureas on the ECG phenotypes QT, JT, and QRS. Methods: Cohorts with unrelated individuals used generalized estimating equations to estimate interactions; cohorts with related individuals used mixed effect models clustered on family. For each ECG phenotype (QT, JT, QRS), we conducted ancestry-specific (EA, AA, HA) inverse variance weighted meta-analyses using standard errors based on the t-distribution to correct for small sample inflation in the test statistic. Ancestry-specific summary estimates were combined using MANTRA, an analytic method that accounts for differences in local linkage disequilibrium between ethnic groups. Results: Our study included 65,997 participants from 21 cohorts, including 4,020 (6%) sulfonylurea users, a substantial increase from the 26,986 participants and 846 sulfonylureas users in the previous meta-analysis. Preliminary ancestry-specific meta-analyses have identified genome-wide significant associations (P &lt; 5х10–8) for each ECG phenotype, and analyses with MANTRA are in progress. Conclusions: In the setting of the largest collection of pharmacogenomic studies to date, we used repeated measurements and leveraged diverse ancestry populations to identify new pharmacogenomic loci for ECG traits associated with cardiovascular risk.

Sulfonylurea use and the risk of hospital readmission in patients with type 2 diabetes.

BackgroundHospital inpatient care for patients with diabetes was estimated to cost $76 billion in 2012. Substantial expense resulted from those patients having multiple hospitalizations. The objective was to compare the risk for diabetes–related hospital readmission in patients with type 2 diabetes treated with sulfonylureas (SUs) compared to those treated with other oral antihyperglycemic agents (AHAs).MethodsA retrospective cohort analysis was conducted using two-year panels, from 1999 to 2010, from the Medical Expenditure Panel Survey. The study included patients with type 2 diabetes taking an oral AHA who experienced a diabetes-related hospitalization. A Cox proportional hazard regression predicting time to readmission was used to estimate and compare the risks of readmission for SU-monotherapy versus other-AHA-monotherapy patients. Covariates included age, gender, marital status, cardiovascular disease, kidney disease, and eye disease, along with a propensity score to control for selection bias. The lack of clinical data on disease severity and progression limited our ability to estimate causal relationships between drug use and risk of hospital readmission.ResultsFrom 1999 to 2010, an estimated 13.5 million patients experienced a diabetes-related hospital admission and subsequent AHA treatment. While 23.2 % (n = 746,579) of patients in the SU monotherapy cohort had a readmission, only 16.1 % (n = 881,984) in the other-AHA monotherapy group were readmitted. Average readmission expenditure for readmitted SU users (in 2010 dollars) was $11,148 (±$1,558) compared to $7,673 (±$763) for users of other oral AHAs. The estimated readmission hazard ratio was 1.29 (95 % CI: 1.01–1.65; p-value = 0.04) for SU monotherapy users. If a patient’s first hospital admission was during the time period 2008–2010, a readmission was significantly less likely (HR 0.49, 95 % CI: 0.31–0.78; p = 0.003) relative to 2004–2007.ConclusionsAmong patients with type 2 diabetes, SU use was associated with an approximately 30 % increased risk for readmission compared to other-AHA use, while each readmission for an SU user cost on average 45 % more than one for an other-AHA patient. Because of the rapidly rising prevalence of diabetes in the U.S. and the large number of patients with prediabetes, preventing hospital readmissions will continue to be an important cost-saving strategy in the future.

Prescription Patterns of Antidiabetic Treatment in the Elderly. Results from Southern Italy

The treatment of diabetes in the elderly is a major challenge both in terms of clinical management and of public health. Evidence about prescribing patterns in the elderly diabetic population is limited. The aim was to describe trends in antidiabetic drug (AD) utilization patterns in the elderly in Southern Italy with a focus on drugs for cardiovascular prevention and pharmaceutical costs. The data used for this study were obtained from pharmacy records of Caserta Local Health Authority, a province in Southern Italy with 1 million of inhabitants, comprising urban and rural areas. Subjects above 65 years who received at least one dispensing of antidiabetic between January 2010 and December 2014 were selected. Prevalence and incidence rates (%) of AD use were calculated for each calendar year and stratified by class therapy and age group. Sub-analyses by cardiovascular co-medication therapy and pharmaceutical cost analysis were performed. The prevalence rate decreases from 22.0% in 2010 to 17.5% in 2014 (p<0.001). Proportion of subjects treated with monotherapy increases over the study period (33.9% in 2010; 38.6% in 2014; p<0.001). In particular, increases the proportion of users of metformin (18.2% in 2010; 23.7% in 2014; p<0.001), while the proportion of users of sulfonylureas dropped (11.0% in 2010; 7.2% in 2014; p< 0.001). About 90% of elderly diabetic patients are treated with drugs for cardiovascular prevention. The per/patient/yearly drug costs were 2,349 €: 28.5% for AD therapy and 71.5% for other treatments. Trend in drug utilization patterns showed a tendency towards treatment recommendations in older adults.

Abstract 11983: Oral Therapies for Type 2 Diabetes in Combination With Long-acting Insulin and the Risks of Myocardial Infarction and Stroke

Introduction/Hypothesis: The use of oral therapies in combination with insulin for the treatment of type 2 diabetes is common, but the cardiovascular risks or benefits are largely unknown. Among users of long-acting insulin, we conducted a population-based case-control study to evaluate the incident myocardial infarction (MI) and incident stroke risks associated with sulfonylurea and metformin use. We hypothesized that sulfonylurea use would be associated with elevated risk and metformin use with decreased risk. Methods: Cases were enrollees of Group Health Cooperative (GHC) with type 2 diabetes who used long-acting insulin at the time of diagnosis with a first MI (n=413) or first stroke (n=247) from 1995-2010. Controls (n=443) were randomly sampled GHC enrollees with type 2 diabetes who used long-acting insulin, matched to cases on age, sex, and calendar year. Sulfonylureas and metformin use was classified as current, past, or never using electronic pharmacy records. MI and stroke diagnoses and potential confounding variables were validated by medical record review. Analyses were adjusted for matching variables and cardiovascular risk factors, including smoking, duration of diabetes, blood pressure, and cholesterol. Results: Current use of sulfonylureas compared with never use was associated with a higher risk of MI (OR 1.67; 95% CI, 1.10-2.55) but not stroke (OR 1.22; 95% CI, 0.74-2.00). Current use of metformin compared with never use was associated with a lower risk of stroke (OR 0.54; 95% CI, 0.31-0.95) but not MI (OR 0.77; 95% CI 0.44-1.33). Past use of sulfonylureas and past use of metformin were not associated with either outcome. Findings were robust to sensitivity analyses that tested assumptions about eligibility criteria and medication adherence. An unmeasured confounder associated with a 2-fold increased MI risk would have to be present in 70% more current users than never users of sulfonylureas to render the sulfonylurea-MI odds ratio null. Conclusions: The use of sulfonylureas in combination with long-acting insulin may increase the risk of MI compared with insulin alone. Our study adds to a growing body of evidence that metformin may be an effective cardiovascular disease prevention therapy, even when used with insulin.

Thiazolidinediones and Parkinson Disease: A Cohort Study.

Thiazolidinediones, a class of medications indicated for the treatment of type 2 diabetes mellitus, reduce inflammation and have been shown to provide a therapeutic benefit in animal models of Parkinson disease. We examined the association between treatment with thiazolidinediones and the onset of Parkinson disease in older individuals. We performed a cohort study of 29,397 Medicare patients enrolled in state pharmaceutical benefits programs who initiated treatment with thiazolidinediones or sulfonylureas during the years 1997 through 2005 and had no prior diagnosis of Parkinson disease. New users of thiazolidinediones were propensity score matched to new users of sulfonylureas and followed to determine whether they were diagnosed with Parkinson disease. We used Cox proportional hazards models to compare time to diagnosis of Parkinson disease in the propensity score-matched populations. To assess the association with duration of use, we performed several analyses that required longer continuous use of medications. In the primary analysis, thiazolidinedione users had a hazard ratio for a diagnosis of Parkinson disease of 1.09 (95% confidence interval: 0.71, 1.66) when compared with sulfonylurea users. Increasing the duration-of-use requirements to 10 months did not substantially change the association; the hazard ratios ranged from 1.00 (95% confidence interval: 0.49, 2.05) to 1.17 (95% confidence interval: 0.60, 2.25). Thiazolidinedione use was not associated with a longer time to diagnosis of Parkinson disease than was sulfonylurea use, regardless of duration of exposure.

No evidence for a decreased risk of thyroid cancer in association with use of metformin or other antidiabetic drugs: a case-control study

BackgroundUse of metformin has been associated with a decreased cancer risk. We aimed to explore whether use of metformin or other antidiabetic drugs is associated with a decreased risk for thyroid cancer.MethodsWe conducted a case-control analysis (1995 to 2014) using the U.K.-based Clinical Practice Research Datalink (CPRD). Cases had a first-time diagnosis of thyroid cancer, six controls per case were matched on age, sex, calendar time, general practice, and number of years of active history in the database prior to the index date. We assessed odds ratios (ORs) with 95 % confidence intervals (95 % CI), adjusted for body mass index (BMI), smoking, and diabetes mellitus.ResultsIn 1229 cases and 7374 matched controls, the risk of thyroid cancer associated with ever use of metformin yielded an adjusted OR of 1.48, 95 % CI 0.86–2.54. The relative risk estimate was highest in long-term (≥30 prescriptions) users of metformin (adjusted OR 1.83, 95 % CI 0.92–3.65), based on a limited number of 26 exposed cases. No such association was found in users of sulfonylurea, insulin, or thiazolidinediones (TZD). Neither a diabetes diagnosis (adjusted OR 1.17, 95 % CI 0.89–1.54), nor diabetes duration >8 years (adjusted OR 1.22, 95 % CI 0.60–2.51) altered the risk of thyroid cancer.ConclusionIn our observational study with limited statistical power, neither use of metformin nor of other antidiabetic drugs were associated with a decreased risk of thyroid cancer.