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Aims: The objective of this umbrella review and meta‐analysis was to evaluate the effect of diabetes on risk of dementia, as well as the mitigating effect of antidiabetic treatments. Materials and Methods: We conducted a systematic umbrella review on diabetes and its treatment, and a meta‐analysis focusing on treatment. We searched MEDLINE/PubMed, Embase, PsycINFO, CINAHL and the Cochrane Library for systematic reviews and meta‐analyses assessing the risk of cognitive decline/dementia in individuals with diabetes until 2 July 2023. We conducted random‐effects meta‐analyses to obtain risk ratios and 95% confidence intervals estimating the association of metformin, thiazolidinediones, pioglitazone, dipeptidyl peptidase‐4 inhibitors, α‐glucosidase inhibitors, meglitinides, insulin, sulphonylureas, glucagon‐like peptide‐1 receptor agonists (GLP1RAs) and sodium‐glucose cotransporter‐2 inhibitors (SGLT2is) with risk of dementia from cohort/case‐control studies. The subgroups analysed included country and world region. Risk of bias was assessed with the AMSTAR tool and Newcastle‐Ottawa Scale. Results: We included 100 reviews and 27 cohort/case‐control studies (N = 3 046 661). Metformin, thiazolidinediones, pioglitazone, GLP1RAs and SGLT2is were associated with significant reduction in risk of dementia. When studies examining metformin were divided by country, the only significant effect was for the United States. Moreover, the effect of metformin was significant in Western but not Eastern populations. No significant effect was observed for dipeptidyl peptidase‐4 inhibitors, α‐glucosidase inhibitors, or insulin, while meglitinides and sulphonylureas were associated with increased risk. Conclusions: Metformin, thiazolidinediones, pioglitazone, GLP1RAs and SGLT2is were associated with reduced risk of dementia. More longitudinal studies aimed at determining their relative benefit in different populations should be conducted. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Recent trials of glucose-lowering drugs (GLDs) have drawn attention to renal outcomes. Our goal was to understand how patients with diabetic kidney disease (DKD) are treated in general practices in the United States. STUDY DESIGN: Retrospective cohort study using a national-level claims data set and electronic health records. METHODS: Patients (≥ 18 years) with type 2 diabetes, whose estimated glomerular filtration rates (eGFRs) were between 15 and 89 mL/min/1.73 m² between 2016 and 2018, were selected. Use of different GLDs during a 12-month period was examined across all eGFR levels. RESULTS: Of the 25,486 sample patients, 69.2%, 18.9%, 9.6%, and 2.3% had an eGFR in the ranges of 60 to 89, 45 to 59, 30 to 44, and 15 to 29 mL/min/1.73 m², respectively. Metformin was used by nearly 33% of patients with an eGFR of 30 to 44 mL/min/1.73 m² and by 10% of patients with an eGFR less than 30 mL/min/1.73 m². Less than 10% (across all eGFR levels) of patients used glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors. Use of insulin was more frequent among patients with a lower eGFR (P < .05). The findings were similar in subgroups with different hemoglobin A1c levels (< 7% and ≥ 7%). CONCLUSIONS: Real-world treatment of DKD in the United States is suboptimal. Inappropriate use of some GLD classes, especially in advanced DKD stages, was found along with lower than expected use of modern agents that are considered safe and effective to treat glycemic outcomes. Efforts may be needed to improve understanding of safety, glycemic efficacy, and overall clinical value of GLDs across DKD stages. [ABSTRACT FROM AUTHOR]

Objectives: Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) offer cardiovascular benefits, whereas thiazolidinediones (TZDs) and sulfonylureas (SUs) increase cardiovascular risk. The objective of this study was to describe the use of SGLT-2is, GLP-1RAs, TZDs, and SUs before and after a heart failure (HF)-related hospitalization in nursing home (NH) residents with type 2 diabetes (T2D)., Design: This was a cohort study using a 20% sample of Medicare claims linked with Minimum Data Set resident assessments., Setting and Participants: The study population was long-stay NH residents with T2D and an HF-related hospitalization between January 1, 2013, and August 31, 2018. For individuals with multiple HF hospitalizations, 1 hospitalization was randomly selected., Methods: We ascertained diabetes medications using Medicare Part D claims during the 120 days before and after hospital discharge (or skilled nursing facility discharge, where applicable). We calculated (1) the proportion of study participants who received a medication class of interest during pre- and posthospitalization periods; (2) the proportion of continuous users; and (3) the proportion of posthospitalization users who were new users., Results: A total of 12,990 NH residents with T2D and an HF-related hospitalization were included (mean age 78 years, 66% female, 19% Black). Before hospitalization, 1.5% received TZDs, 14.1% received SUs, 1.2% received GLP-1RAs, and 0.3% received SGLT-2is. Among prehospitalization users of TZDs, SUs, GLP-1RAs, and SGLT-2is, 49%, 62%, 60%, and 40% continued the medications, respectively. Among posthospitalization users of TZDs, SUs, GLP-1RAs, and SGLT-2is, 37%, 10%, 28%, and 11%, respectively, were new users., Conclusions: Among NH residents with hospitalized HF, GLP-1RAs and SGLT-2is were seldom used. TZDs and SUs were still used by many residents with T2D after HF hospitalizations., Implementations: Barriers may exist in the use of newer diabetes medications to prevent heart failure in NH residents with T2D, which warrants further studies in older adults with multimorbidity., (Copyright © 2023 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Data on trends of diabetes medications use are sparse, outdated, and limited to prescription data. We determined trends in diabetes medication use among US individuals with diabetes during 2008-2015. Methods: We used 2008-2015 Medical Expenditure Panel Survey to examine diabetes medication utilization among individuals aged ≥18 years with diabetes. Prescription medications were classified based on therapeutic class and subclass using Multum Lexicon database. Results: From 2008 to 2015, use of any diabetes medication (81.4% vs. 87%), metformin (47.8% vs. 59.0%), and insulin (23.0% vs. 31.0%) increased, whereas, use of sulfonylurea (36.0% vs. 29.0%) and thiazolidinedione (21% vs. 9.0%) declined. A linear increase was observed in the uptake of dipeptidyl peptidase-4 (DPP-4) inhibitors from 6.2% in 2008 to 12.4% in 2015; glucagon-like peptide-1 (GLP-1) receptor agonists from 2.5% in 2008 to 4.4% in 2015 and sodium glucose transporter-2 (SGLT2) inhibitors from 0.8% in 2014 (the first SGLT2 inhibitors approval year) to 4.4% in 2015. Monotherapy use increased from 50.6% to 56.4% during 2008-2015, while triple therapy use declined. Conclusions: Metformin, insulin and sulfonylureas remained the top-three prescribed classes of diabetes medications. Increased use of DPP-4 inhibitors, GLP-1 receptor agonists and SGLT2 inhibitors was offset by decline in TZDs use. [ABSTRACT FROM AUTHOR]

Objective: 1) To examine trends in the use of diabetes medications and 2) to determine whether physicians individualize diabetes treatment as recommended by the American Diabetes Association (ADA).Research Design and Methods: We conducted a retrospective, cross-sectional analysis of 2003-2016 National Health and Nutrition Examination Survey (NHANES) data. We included people ≥18 years who had ever been told they had diabetes, had an HbA1c >6.4%, or had a fasting plasma glucose >125 mg/dL. Pregnant women and patients aged <20 years receiving only insulin were excluded. We assessed trends in use of ADA's seven preferred classes from 2003-2004 to 2015-2016. We also examined use by hypoglycemia risk (sulfonylureas, insulin, and meglitinides), weight effect (sulfonylureas, thiazolidinediones [TZDs], insulin, and meglitinides), cardiovascular benefit (canagliflozin, empagliflozin, and liraglutide), and cost (brand-name medications and insulin analogs).Results: The final sample included 6,323 patients. The proportion taking any medication increased from 58% in 2003-2004 to 67% in 2015-2016 (P < 0.001). Use of metformin and insulin analogs increased, while use of sulfonylureas, TZDs, and human insulin decreased. Following the 2012 ADA recommendation, the choice of drug did not vary significantly by older age, weight, or presence of cardiovascular disease. Patients with low HbA1c, or HbA1c <6%, and age ≥65 years were less likely to receive hypoglycemia-inducing medications, while older patients with comorbidities were more likely. Insurance, but not income, was associated with the use of higher-cost medications.Conclusions: Following ADA recommendations, the use of metformin increased, but physicians generally did not individualize treatment according to patients' characteristics. Substantial opportunities exist to improve pharmacologic management of diabetes. [ABSTRACT FROM AUTHOR]

Background: Third-line antidiabetic drug (ADD) intensification patterns and glycemic control post intensification in type 2 diabetes mellitus (T2DM) have not been thoroughly explored in a real-world setting. Objective: This study explored the patterns and risks of third-line ADD intensification post second-line ADDs and the probability of desirable glucose control over 12 months by third-line ADD classes at the population level. Methods: We used the electronic medical records of 255,236 patients with T2DM in the USA initiating a second-line ADD post metformin from January 2013 to evaluate the rates and risks of third-line intensification and the probability of desirable glycemic control with different ADDs after addressing inherent heterogeneity using appropriate methodologies. Results: Patients had a mean age of 60 years and glycated hemoglobin (HbA1c) of 8.5% at second-line ADD. Over 209,136 person-years (PY) of follow-up, 40% had initiated a third-line ADD at HbA1c of 8.8%. Patients receiving dipeptidyl peptidase-4 inhibitors (DPP-4i) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) as the second-line ADD had a 7% (95% hazard ratio [HR] confidence interval [CI] 1.05–1.10) and 28% (95% HR CI 1.24–1.33) higher adjusted risk of intensifying with a third-line ADD than did those receiving sulfonylureas as the second-line ADD. Those receiving sodium-glucose cotransporter-2 inhibitors (SGLT-2i) as second-line ADD had a 17% (95% HR CI 0.80–0.87) lower risk. The adjusted probability of reducing HbA1c by ≥ 1% was similar in those receiving third-line sulfonylureas, thiazolidinediones, GLP-1 RAs, SGLT-2i, and insulin (minimum, maximum 95% CI of probability 0.61, 0.68), whereas those receiving DPP-4i had a significantly lower probability (0.58; 95% CI 0.56–0.59). Similarly, the probability of reducing HbA1c < 7.5% was similar in the sulfonylurea, GLP-1 RA, and SGLT-2i groups (minimum, maximum of 95% CI of probability 0.41, 0.49), whereas those receiving DPP-4i had a significantly lower probability of achieving an HbA1c < 7.5% (0.37; 95% CI 0.36–0.38). Conclusion: This study, based on a large representative cohort of patients with T2DM from the USA, suggests the need for revisiting real-world practices in choosing therapeutic intensification pathways and a more proactive strategy to tackle the persistent risk factor burden in patients with T2DM. [ABSTRACT FROM AUTHOR]

Aim: To examine the risks of all‐cause mortality and cardiovascular events associated with adding vs switching to second‐line therapies in a comparative safety study of people with Type 2 diabetes mellitus. Methods: We conducted a retrospective cohort study using an as‐treated analysis of people served by the Veterans Health Administration who were on metformin and subsequently augmented this treatment or switched to other oral glucose‐lowering treatments between 1998 and 2012. This study included 145 250 people with long follow‐up. Confounding was addressed through several strategies, involving weighted propensity score models with rich confounder adjustment and strict inclusion criteria, coupled with an incident‐user design. Results: Second‐line use of sulfonylureas was related to higher mortality (hazard ratio 1.39, 95% CI 1.14, 1.70) and cardiovascular risks (hazard ratio 1.19, 95% CI 1.09, 1.30) compared with thiazolidinedione therapy. Differential hazards were associated with discontinuing or not discontinuing metformin; switching to sulfonylurea therapy was associated with a higher risk of all‐cause mortality and cardiovascular events compared with all other therapies. Furthermore, add‐on sulfonylurea therapy was associated with an elevated risk for both outcomes when compared with thiazolidinedione add‐on therapy. Conclusions: The results of the present study may inform decisions on whether to augment or discontinue metformin; when considering the long‐term risks, switching to a sulfonylurea appears unfavourable compared with other therapies. Instead, adding a thiazolidinedione to existing metformin therapy appears to be superior to adding or switching to a sulfonylurea. What's new?: Observational cohort evidence links long‐term risks to sulfonylurea therapy, but little is known about how changes to existing metformin therapy modify this effect.Switching to sulfonylurea therapy led to a greater risk of all‐cause mortality and greater cardiovascular risk compared with all the other therapies studied. Add‐on sulfonylurea therapy was associated with elevated risk relative to add‐on thiazolidinedione therapy.Discontinuing metformin and switching to a sulfonylurea appears to have unfavourable effects compared with other therapies. Instead, adding a thiazolidinedione to existing metformin therapy may be superior to adding or switching to sulfonylurea therapy. [ABSTRACT FROM AUTHOR]

Aims: In people with metformin‐treated diabetes, to evaluate the risk of acute pancreatitis, pancreatic cancer and other diseases of the pancreas post second‐line anti‐hyperglycaemic agent initiation. Methods: People with Type 2 diabetes diagnosed after 2004 who received metformin plus a dipeptidyl peptidase‐4 inhibitor (DPP‐4i, n = 50 095), glucagon‐like peptide‐1 receptor agonist (GLP‐1RA, n = 12 654), sulfonylurea (n = 110 747), thiazolidinedione (n = 17 597) or insulin (n = 34 805) for at least 3 months were identified in the US Centricity Electronic Medical Records. Time to developing acute pancreatitis, other diseases of the pancreas and pancreatic cancer was estimated, balancing and adjusting anti‐hyperglycaemic drug groups for appropriate confounders. Results: In the DPP‐4i group, the adjusted mean time to acute pancreatitis was 2.63 [95% confidence intervals (CI) 2.38, 2.88] years; time to pancreatic cancer was 2.70 (2.19, 3.21) years; and time to other diseases of the pancreas was 2.73 (2.33, 3.12) years. Compared with DPP‐4i, the insulin group developed acute pancreatitis 0.48 years (P < 0.01) earlier and the GLP‐1RA group developed pancreatic cancer 3 years later (P < 0.01). However, with the constraint of no event within 6 months of insulin initiation, the risk of acute pancreatitis in the insulin group was insignificant. No other significant differences were observed between groups. Conclusions: No significant differences in the risk of developing pancreatic diseases in those treated with various anti‐hyperglycaemic drug classes were found. What's new?: Association of treatment with incretin‐based therapies and the risk of pancreatic diseases remains controversial. However, no study explored the comparative safety of different anti‐hyperglycaemic drugs in this context.This study provides a holistic population‐level comparative outcome evaluation of the risk of pancreatic diseases from the time of receiving different second‐line anti‐hyperglycaemic drugs post metformin.Although treatment with incretin‐based therapies was not found be to be associated with an increased risk of pancreatic diseases, people treated with insulin experienced higher risk of such diseases. [ABSTRACT FROM AUTHOR]

Objective: To examine whether dipeptidyl peptidase 4 inhibitors (DPP-4I) increase acute pancreatitis risk in older patients and whether the association varies by age, sex, and history of cardiovascular disease (CVD).Research Design and Methods: We conducted a cohort study of DPP-4I initiators versus thiazolidinedione (TZD) or sulfonylurea initiators using U.S. Medicare beneficiaries, 2007-2014. Eligible initiators were aged 66 years or older without history of pancreatic disease or alcohol-related diseases. Patients were followed up for hospitalization due to acute pancreatitis and censored at 90 days after treatment changes. Weighted Cox models were used to estimate the hazard ratio (HR) for acute pancreatitis. Analyses were performed overall as well as within subgroups defined by age, sex, and CVD history.Results: We found no increased risk of acute pancreatitis comparing 49,374 DPP-4I initiators to 132,223 sulfonylurea initiators (weighted HR 1.01; 95% CI 0.83-1.24) and comparing 57,301 DPP-4I initiators to 32,612 TZD initiators (weighted HR 1.11; 95% CI 0.76-1.62). Age and sex did not modify the association. Among patients with CVD, acute pancreatitis incidence was elevated in initiators of DPP-4I and sulfonylurea (2.3 and 2.4 per 1,000 person-years, respectively) but not in TZD initiators (1.5). Among patients with CVD, higher risk of acute pancreatitis was observed with DPP-4I compared with TZD (weighted HR 1.84; 95% CI 1.02-3.35) but not compared with sulfonylurea.Conclusions: Our study provides evidence that DPP-4I is not associated with an increased risk of acute pancreatitis in older adults overall. The positive association observed in patients with CVD could be due to chance or bias but merits further investigation. [ABSTRACT FROM AUTHOR]

Objective: The cardiovascular safety of saxagliptin, a dipeptidyl-peptidase 4 inhibitor, compared with other antihyperglycemic treatments is not well understood. We prospectively examined the association between saxagliptin use and acute myocardial infarction (AMI).Research Design and Methods: We identified patients aged ≥18 years, starting from the approval date of saxagliptin in 2009 and continuing through August 2014, using data from 18 Mini-Sentinel data partners. We conducted seven sequential assessments comparing saxagliptin separately with sitagliptin, pioglitazone, second-generation sulfonylureas, and long-acting insulin, using disease risk score (DRS) stratification and propensity score (PS) matching to adjust for potential confounders. Sequential testing kept the overall chance of a false-positive signal below 0.05 (one-sided) for each pairwise comparison.Results: We identified 82,264 saxagliptin users and more than 1.5 times as many users of each comparator. At the end of surveillance, the DRS-stratified hazard ratios (HRs) (95% CI) were 1.08 (0.90-1.28) in the comparison with sitagliptin, 1.11 (0.87-1.42) with pioglitazone, 0.79 (0.64-0.98) with sulfonylureas, and 0.57 (0.46-0.70) with long-acting insulin. The corresponding PS-matched HRs were similar. Only one interim analysis of 168 analyses met criteria for a safety signal: the PS-matched saxagliptin-pioglitazone comparison from the fifth sequential analysis, which yielded an HR of 1.63 (1.12-2.37). This association diminished in subsequent analyses.Conclusions: We did not find a higher AMI risk in saxagliptin users compared with users of other selected antihyperglycemic agents during the first 5 years after U.S. Food and Drug Administration approval of the drug. [ABSTRACT FROM AUTHOR]

The U.S. Food and Drug Administration (FDA) issued guidance on requirements to assess cardiovascular disease (CVD) risk with drugs being developed for approval for clinical use. The guidance was triggered by a meta-analysis published by Nissen and Wolski that suggested an increased risk for myocardial infarction with the use of rosiglitazone. This article discusses controversies around CVD trials in diabetes beginning with the University Group Diabetes Program. This is followed by a brief description of the FDA guidance for evaluating CVD risk with glucose-lowering medications. Limitations of meta-analyses of data from phase 2 and 3 (phase 2/3) trials to inform CVD risk are highlighted. These include the differences between patient characteristics in phase 2/3 trials and those in cardiovascular outcome trials (CVOTs) and the relatively short exposure time in phase 2/3 trials. The differences may partly explain the observed disparity between phase 2/3 meta-analyses and the results of completed CVOTs. Approaches to understanding CVD risk with a new medication should get to the answer about risk as efficiently as possible to minimize any potential harm to patients. In that context, we discuss options for clinical trial design and an alternative approach for statistical analyses. [ABSTRACT FROM AUTHOR]

Aims: Incretin-based antihyperglycemic therapies increase intestinal mucosal expansion and polyp growth in mouse models. We aimed to evaluate the effect of dipeptidyl peptidase-4 inhibitors (DPP-4i) or glucagon-like peptide-1 receptor agonists (GLP-1ra) initiation on colorectal cancer incidence. Methods: We conducted a cohort study on US Medicare beneficiaries over age 66 from 2007 to 2013 without prevalent cancer. We identified three active-comparator and new-user cohorts: DPP-4i versus thiazolidinediones (TZD), DPP-4i versus sulphonylureas (SU), and GLP-1ra versus long acting insulin (LAI). Follow-up started from 6 months post-second prescription and ended 6 months after stopping (primary as-treated analysis). We estimated hazard ratios (HR) and 95 % confidence intervals (CI) for incident colorectal cancer adjusting for measured confounders using propensity score weighting. Results: The median duration of treatment ranged 0.7-0.9 years among DPP-4i cohorts. Based on 104 events among 39,334 DPP-4i and 63 events among 25,786 TZD initiators, there was no association between DPP-4i initiation and colorectal cancer (adjusted HR = 1.17 (CI 0.88, 1.71)). There were 73 events among 27,047 DPP-4i and 266 events among 76,012 SU initiators with the adjusted HR 0.98 (CI 0.74, 1.30). We identified 5600 GLP-1ra and 54,767 LAI initiators and the median duration of treatment was 0.8 and 1.2 years, respectively. The adjusted HR was 0.82 (CI 0.42, 1.58) based on <11 events among GLP-1ra versus 276 events among LAI initiators. Conclusion: Although limited by the short duration of treatment, our analyses based on real-world drug utilization patterns provide evidence of no short-term effect of incretin-based agents on colorectal cancer. [ABSTRACT FROM AUTHOR]

Boxed warnings-also known as "black box" warnings-can be a powerful tool in communicating drug risks to physicians and patients. The overall number of boxed warnings has grown in recent years as the US Food and Drug Administration (FDA) has approved more drugs on the basis of limited pre-marketing information and as new safety issues for marketed drugs have been identified. Two recent manufacturers' petitions to remove boxed warnings on the drugs rosiglitazone (Avandia) and varenicline (Chantix) have led to divergent FDA decisions and revealed different considerations involved in boxed warning imposition and removal. For ethical and practical reasons, the FDA is justified in applying a higher standard for boxed warning removal than for imposition, as removal of a boxed warning may have unintended effects on physician and patient behavior. However, no guidelines on boxed warning removal currently exist. To promote safe use of approved prescription drugs, the FDA should adopt a uniform and transparent process governing decisions to impose or remove boxed warnings. [ABSTRACT FROM AUTHOR]

Objective: Dipeptidyl peptidase-4 (DPP4), also known as CD26, is a transmembrane glycoprotein that has a costimulatory function in the immune response. DPP4 inhibitors (DPP4i) are oral glucose-lowering drugs for type 2 diabetes mellitus (T2DM). This study evaluated the risk of incident rheumatoid arthritis (RA) and other autoimmune diseases (AD) such as systemic lupus erythematosus, psoriasis, multiple sclerosis and inflammatory bowel disease, associated with DPP4i in patients with T2DM.Methods: Using US insurance claims data (2005-2012), we conducted a population-based cohort study that included initiators of combination therapy with DPP4i (DPP4i plus metformin) and non-DPP4i (non-DPP4i plus metformin). RA and other AD were identified with ≥2 diagnoses and ≥1 dispensing for AD-specific immunomodulating drugs or steroids. Composite AD includes RA or other AD. Propensity score (PS)-stratified Cox proportional hazards models compared the risk of AD in DPP4i initiators versus non-DPP4i, controlling for potential confounders.Results: After asymmetric trimming on the PS, 73 928 patients with T2DM starting DPP4i combination therapy and 163 062 starting non-DPP4i combination therapy were selected. Risks of incident RA and composite AD were lower in the DPP4i group versus non-DPP4i with the PS-stratified HR of 0.66 (95% CI 0.44 to 0.99) for RA, 0.73 (0.51 to 1.03) for other AD and 0.68 (95% CI 0.52 to 0.89) for composite AD.Conclusions: In this large cohort of diabetic patients, those initiating DPP4i combination therapy appear to have a decreased risk of incident AD including RA compared with those initiating non-DPP4i combination therapy. These results may suggest possible pharmacological pathways for prevention or treatment of AD. [ABSTRACT FROM AUTHOR]

Background: Published guidelines for treatment of type 2 diabetes mellitus (T2DM) agree on initial pharmacotherapy. However, few specific recommendations on second-line agents are provided. Objective: The objective of this study was to describe antidiabetic treatment patterns in Medicare Advantage patients with T2DM within 6 months of measurement of the glycosylated hemoglobin (HbA) level. Research Design: This retrospective cross-sectional study utilized medical, pharmacy, and laboratory claims from a large Medicare Advantage with Prescription Drug (MAPD) coverage payer. MAPD members between 65 and 89 years old identified as having T2DM between 2009 and 2011 were eligible for inclusion. A 12-month baseline period before the first HbA value (index date) was evaluated for demographic and clinical differences. Antidiabetic therapy was evaluated for 6 months post-index. The study population was stratified into three cohorts based on index HbA value: controlled (<8 %, 64 mmoL/mol), uncontrolled (≥8 %, 64 mmoL/mol and <10 %, 86 mmoL/mol), and severely uncontrolled (≥10 %, 86 mmoL/mol). Results: Despite elevated HbA values (≥8 %, 64 mmoL/mol), 7-8 % of patients did not receive antidiabetic therapy during the post-index period. Metformin and sulfonylureas were the oral antidiabetics (OADs) most frequently used as monotherapy. The majority of patients on combination therapy were on two or more OADs and higher injectable use was observed in the severely uncontrolled cohort. Metformin was included in >60 % of the combination regimens with metformin + sulfonylurea being the most common. Conclusion: This study suggests suboptimal treatment of those not in glycemic control (HbA ≥8 %, 64 mmoL/mol). Many patients classified as severely uncontrolled based on HbA received only monotherapy. Opportunities exist for treatment modification within this population to achieve tighter glycemic control. [ABSTRACT FROM AUTHOR]

Background Weight gain and hypoglycaemia are common adverse effects associated with anti-diabetic treatments. Aim Our aim was to evaluate the long-term effects of adjunctive exenatide therapy on weight loss and glycaemic control in patients with type 2 diabetes. Methods A review of medical records in a specialist diabetes clinic over 5 years identified 446 patients who were prescribed exenatide therapy. We examined change in glycosylated haemoglobin ( HbA1c), weight, albumin-creatinine ratio and hypoglycaemic medication during 24 months follow up. Results Subjects were aged 59 ± 10 years (49% women) and received exenatide in combination with oral agents and insulin (47%). During an average of 17 ± 14 months follow up, 51% (more women than men; odds ratio 1.69, 95% confidence interval 1.14-2.49) remained on treatment. Lack of efficacy (33%) and/or gastrointestinal (27%) side-effects were the main reasons for treatment cessation. At 24 months, there was a reduction in HbA1c of 0.7 ± 1.2% and weight loss of 4.3 ± 5.2 kg. Change in HbA1c was similar regardless of concurrent insulin therapy, yet insulin was associated with greater weight reduction (4.8 ± 5.3 vs 3.8 ± 5.1 kg, P = 0.016). Independent predictors of HbA1c response were higher baseline HbA1c, longer duration of diabetes and use of insulin or sulfonylureas at study end. Predictors of weight response were baseline use of insulin or thiazolidinediones, increased age, female sex and sulfonylurea or thiazolidinediones at study end. Longer exenatide treatment duration was favourable for reducing HbA1c and weight. Conclusions Exenatide is effective in reducing HbA1c and weight, regardless of concurrent insulin, and in a specialist diabetes outpatient clinic, is recommended for use in clinical practice. [ABSTRACT FROM AUTHOR]

The American Diabetes Association emphasizes the importance of individualized patient care in the management of diabetes. One of the important considerations in choosing an antihyperglycemic agent is its side-effect and safety profile. This article reviews the common and clinically significant side effects of each class of agents, including ways to prevent and overcome their occurrence. [ABSTRACT FROM AUTHOR]

Type II diabetes mellitus (T2DM) is a fast-growing epidemic affecting people globally. Furthermore, multiple complications and comorbidities are associated with T2DM. Lifestyle modifications along with pharmacotherapy and patient education are the mainstay of therapy for patients afflicted with T2DM. Western medications are frequently associated with severe adverse drug reactions and high costs of treatment. Herbal medications have long been used in the treatment and prevention of T2DM in both traditional Chinese medicine (TCM) and traditional Indian medicine (TIM). This review examines in vivo, in vitro, and clinical evidence supporting the use of various herbs used in TCM and TIM. The problems, challenges, and opportunities for the incorporation of herbal frequently used in TCM and TIM into Western therapy are presented and discussed. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 67-year-old man who was presented with a medical history of type 2 diabetes, along with hypertension, heart failure, and atrial fibrillation. He was given glipizide but required a second agent to achieve his HbA1c goal; for HbA1c various options such as Metformin, Thiazolidinediones and Dipeptidyl peptidase-4 (DPP-4) inhibitors are available. After checking patients history DPP4 was added to the treatment; the patient was responsive to it.

Objectives: Pioglitazone hydrochloride (Actos) and rosiglitazone maleate (Avandia) are members of the thiazolidinedione (TZD) class of oral anti-diabetic drugs (OADs) and are used to treat type 2 diabetes mellitus (T2DM). Greater beneficial effects on lipids have been demonstrated with pioglitazone, however. Study objectives were to evaluate the long-term cost-effectiveness of pioglitazone compared to rosiglitazone in treating patients with T2DM and dyslipidemia, and determine the extent to which reported beneficial lipid effects of pioglitazone would improve clinical and economic outcomes through reduced macrovascular complications. Research design and methods: The validated CORE Diabetes Model (CDM) was used to simulate changes in glycosylated hemoglobin (HbA1c), complications, and direct medical costs. Baseline parameters came from a multicenter, double-blind trial comparing lipid and glycemic effects of pioglitazone (n=400) and rosiglitazone (n=402) among individuals with T2DM and untreated dyslipidemia. Sensitivity analyses examined the impact of cohort, clinical, and cost inputs on incremental cost effectiveness ratios (ICERs). Results: In the base case, pioglitazone was associated with mean (standard deviation [SD]) quality-adjusted life years (QALYs) of 7.476 (0.123) vs. 7.326 (0.128) for rosiglitazone. Pioglitazone had $3038 higher total direct costs, but $580 lower complication costs. Risks of four cardiovascular complications were reduced with pioglitazone (relative risks 0.860-0.942), while risks of 17 other complications were slightly higher (relative risks 1.001-1.056). The ICER for pioglitazone treatment was $20 171/QALY. Results were most sensitive to the effects of HbA1c, high-density lipoprotein-cholesterol, overall lipid effects, and pioglitazone acquisition costs. Conclusions: Study limitations include issues of generalizability of the trial patient population, as well as inability to capture non-adherence and variation in 'real-world' treatment patterns. Nevertheless, pioglitazone (when compared to rosiglitazone) was found to have long-term value as a treatment option for T2DM patients with dyslipidemia treated within the US payer setting. [ABSTRACT FROM AUTHOR]

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Type 2 diabetes affects millions of people in the United States, and its incidence is increasing at an alarming rate. A key underlying feature of type 2 diabetes is insulin resistance, which is associated with characteristic clinical features and increased cardiovascular risk. Currently, there are several classes of drugs that are used to manage type 2 diabetes. However, only the thiazo-lidinediones (TZDs) have been shown to consistently improve estimates of 3-cell function. By improving insulin sensitivity and potentially preserving p-cell function, the TZDs are able to provide durable glycemic control. The TZDs also have been found to reduce inflammatory markers, improve vascular function and lipid profiles, and decrease blood pressure in patients with type 2 diabetes, which may improve long-term cardiovascular outcomes. Studies are being conducted to determine the role of TZDs in the prevention of cardiovascular complications in patients with type 2 diabetes. The effectiveness of these agents in improving multiple cardiovascular surrogate markers make the TZDs particularly appealing as a pivotal treatment option and suggests that they be considered a cornerstone of therapy in the management of type 2 diabetes. [ABSTRACT FROM AUTHOR]

An epidemic of type 2 diabetes mellitus is occurring in the United States, with the largest increases in prevalence being reported in people younger than 40 years. The most current estimates from 2002 indicate that 18 million Americans have diabetes. Of these, nearly 95% have type 2 diabetes, and 5.2 million individuals are currently undiagnosed. This increase in diabetes is closely tied to the epidemic of obesity also taking place in this country. Recent advances have led to an unraveling of the complex mechanisms that contribute to the development of type 2 diabetes, including the role of free fatty acids. Insulin resistance often appears years before diabetes develops and frequently is accompanied by other metabolic abnormalities, such as dyslipidemia and hypertension. The dual defects of insulin resistance and β-cell failure must be present for type 2 diabetes mellitus to develop. The complications of diabetes are classified as microvascular (eg. retinopathy, nephropathy, neuropathy) and macrovascular (eg, myocardial infarction, stroke). In patients with type 2 diabetes, better glycemic control, as measured by glycosylated hemoglobin (HbA1c levels, reduces the risk of complications. Current guidelines from the American Diabetes Association recommend an HbA1c below 7%. Target values for cholesterol levels and blood pressure also have become increasingly stringent. However, despite these goals and the growing body of evidence that reduction of long-term complications can be achieved with improved glycemic control, many patients fall short of glycemic targets. Indeed, recent data indicate that fewer than 40% of patients with diabetes achieve an HbA1c, lower than 7%. Even more startling is the finding that only 7% of patients with diabetes evaluated in the National Health and Nutrition Examination Survey achieved HbA1c below 7%. blood pressure below 130/80 mm Hg. and total cholesterol under 200 mg/dL. Options for... [ABSTRACT FROM AUTHOR]

Heart failure (HF) is a significant health problem in the United States, with a prevalence of 5 million patients and 500000 new diagnoses each year. ¹Heart failure is also a significant health care-dollar expenditure, with 5.4% of the health care budget contributing to its treatment.¹Furthermore, it is a disease of the elderly, affecting 6% to 10% of those older than 65 years. ²Since the elderly with concomitant disease states are highly affected, polypharmacy may be more problematic in this subpopulation [ABSTRACT FROM AUTHOR]

: BackgroundTroglitazone was removed from the U.S. market because its use was associated with an increased risk of liver failure. We evaluated the clinical features of all cases reported to the Food and Drug Administration and estimated the duration and magnitude of the risk of liver failure associated with continued use of the drug.: MethodsData from cases of liver failure associated with troglitazone use were abstracted and analyzed. The extent of troglitazone use was determined from national marketing data, and the duration of use was estimated with data from a large, multistate, health care company. Survival analysis was performed to estimate monthly incidence rates and the cumulative risk of liver failure.: ResultsNinety-four cases of liver failure (89 acute, 5 chronic) were reported. Of the acute cases, 58 (67%) were women and only 11 (13%) recovered without liver transplantation. Progression from normal hepatic functioning to irreversible liver injury occurred within 1 month in 19 patients who were indistinguishable clinically from the 70 patients who had an unknown time course to irreversibility, except for the post hoc observation that prior cholecystectomy was less common in those with rapid onset. The incidence of liver failure was elevated from the first through at least the 26th month of troglitazone use. Accounting for case underreporting, the number needed to harm from troglitazone use was between 600 to 1500 patients at 26 months.: ConclusionThe progression to irreversible liver injury probably occurred within a 1-month interval in most patients, casting doubt on the value of monthly monitoring of serum aminotransferase levels as a means of preventing troglitazone-induced acute liver failure. The cumulative risk of hepatic failure increased with continued use. [Copyright &y& Elsevier]

Reports on topics discussed at the annual American Cancer Society's (ACS) Science Writers Seminar held March 28 to 30, 1999 in Miami, Florida. Details of an ACS Behavioral Research Group study that will follow cancer survivors for ten years; Early detection of cancer; Improving specificity of prostate-specific antigen; First differentiation agent for liposarcoma.

Abstract: Hepatocellular carcinoma (HCC), a disease with poor survival rates unless recognized and treated early, ranks as the fifth most common cancer worldwide and has a rising incidence in the United States. Recent data indicate that the growing epidemic of type 2 diabetes mellitus may contribute to this alarming trend. In this issue, Lai et al. utilize a large Taiwanese insurance claims database to demonstrate that diabetes is associated with an increased risk of HCC. Moreover, this risk escalates if diabetes coincides with chronic hepatitis C and cirrhosis. Lai et al. also show that treatment with metformin or thiazolidinediones may reduce the risk of HCC. The findings may prompt risk stratification for HCC surveillance and improved disease control in diabetes as measures of cancer prevention. [ABSTRACT FROM AUTHOR]

Aims: Type 2 diabetes (T2D) accelerates progression of chronic liver disease to cirrhosis, yet the effects of most glucose-lowering drugs (GLDs) on cirrhosis risk in T2D are unknown. To address this gap, we compared cirrhosis risk following initiation of newer second-line GLDs vs. thiazolidinediones (TZDs), which improve histology in non-alcoholic fatty liver disease., Materials and Methods: Using the US Medicare Fee-for-Service database (2007-2015) and an active comparator, new-user design, we estimated crude incidence rates (IRs) and propensity-score adjusted hazard ratios (aHR) for incident cirrhosis, comparing newer GLDs (dipeptidyl peptidase-4 inhibitors (DPP4i), glucagon-like peptide-1 receptor agonists (GLP1RA), and sodium-glucose co-transporter 2 inhibitors (SGLT2i)) vs. TZDs., Results: Among 239,549 total initiators, we observed 318, 151, and < 30 cirrhosis events when comparing DPP4i vs. TZD, GLP1RA vs. TZD, and SGLT2i vs. TZD, respectively. IRs ranged from 1.7 [95% CI, 0.8-3.6] to 3.6 [2.5-5.2] events per 1000 person-years. Point aHR estimates for cirrhosis were elevated among newer GLD initiators vs. TZD (DPP4i: 1.15 [0.89-1.50]; GLP1RA: 1.34 [0.82-2.20]; SGLT2i: 1.16, [0.44-3.08]), although estimates were imprecise due to short durations of drug exposure., Conclusions: We observed mildly elevated cirrhosis risk with newer GLDs vs. TZD; however, uncertainty remains due to imprecise and statistically non-significant effect estimates., Competing Interests: Declaration of competing interest Yang JY: No conflicts to disclose. Alexopoulos AS: No conflicts to disclose. Moon A: No conflicts to disclose. Kim H: No conflicts to disclose. Pate V: VP receives salary support from R01 AG056479 (National Institute on Aging), R01 HL118255 (National Institutes of Health, NIH), and the National Center for Advancing Translational Sciences (NCATS, UL1TR002489), NIH. Barritt AS: Dr. Barritt reports consulting fees from Target Pharmasolutions, Intercept, and Genfit, Inc. Crowley MJ: Dr. Crowley receives support from the Durham Center of Innovation to Accelerate Discovery and Practice Transformation (ADAPT) (Health Services Research and Development grant CIN 13-410) at the Durham Veterans Affairs Health Care System. Buse JB: Outside of the submitted work, Dr. Buse reports contracted consulting fees and associated travel support paid to his employer from Adocia, AstraZeneca, Dance Biopharm, Dexcom, Eli Lilly, Fractyl, GI Dynamics, Intarcia Therapeutics, Lexicon, MannKind, Metavention, NovaTarg, Novo Nordisk, Orexigen, PhaseBio, Sanofi, Senseonics, vTv Therapeutics, and Zafgen; grants and related travel support from AstraZeneca, Eli Lilly, Intarcia Therapeutics, Johnson & Johnson, Lexicon, Medtronic, Novo Nordisk, Sanofi, Theracos and vTv Therapeutics; personal fees from Cirius Therapeutics Inc., CSL Behring; stock or stock options from Mellitus Health, PhaseBio, Stability Health, and Pendulum Health; grants from the US National Institutes of Health (UL1TR002489, U01DK098246, UC4DK108612, U54DK118612, P30DK124723), PCORI and American Diabetes Association. Stürmer T: TS receives investigator-initiated research funding and support as Principal Investigator (R01 AG056479) from the National Institute on Aging (NIA), and as Co-Investigator (R01 CA174453; R01 HL118255, R21-HD080214), National Institutes of Health (NIH). He also receives salary support as Director of Comparative Effectiveness Research (CER), NC TraCS Institute, UNC Clinical and Translational Science Award (UL1TR002489), the Center for Pharmacoepidemiology (current members: GlaxoSmithKline, UCB BioSciences, Merck, Takeda), from pharmaceutical companies (Amgen, AstraZeneca, Novo Nordisk), and from a generous contribution from Dr. Nancy A. Dreyer to the Department of Epidemiology, University of North Carolina at Chapel Hill. Dr. Stürmer does not accept personal compensation of any kind from any pharmaceutical company. He owns stock in Novartis, Roche, BASF, AstraZeneca, and Novo Nordisk. The database infrastructure used for this project was funded by the Department of Epidemiology, UNC Gillings School of Global Public Health; the Cecil G. Sheps Center for Health Services Research, UNC; the CER Strategic Initiative of UNC's Clinical Translational Science Award (UL1TR002489); and the UNC School of Medicine., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The low cost of thiazolidinediones makes them a potentially valuable therapeutic option for the > 300 million economically disadvantaged persons worldwide with type 2 diabetes mellitus. Differential selectivity of thiazolidinediones for peroxisome proliferator-activated receptors in the myocardium may lead to disparate arrhythmogenic effects. We examined real-world effects of thiazolidinediones on outpatient-originating sudden cardiac arrest (SCA) and ventricular arrhythmia (VA)., Methods: We conducted population-based high-dimensional propensity score-matched cohort studies in five Medicaid programs (California, Florida, New York, Ohio, Pennsylvania | 1999-2012) and a commercial health insurance plan (Optum Clinformatics | 2000-2016). We defined exposure based on incident rosiglitazone or pioglitazone dispensings; the latter served as an active comparator. We controlled for confounding by matching exposure groups on propensity score, informed by baseline covariates identified via a data adaptive approach. We ascertained SCA/VA outcomes precipitating hospital presentation using a validated, diagnosis-based algorithm. We generated marginal hazard ratios (HRs) via Cox proportional hazards regression that accounted for clustering within matched pairs. We prespecified Medicaid and Optum findings as primary and secondary, respectively; the latter served as a conceptual replication dataset., Results: The adjusted HR for SCA/VA among rosiglitazone (vs. pioglitazone) users was 0.91 (0.75-1.10) in Medicaid and 0.88 (0.61-1.28) in Optum. Among Medicaid but not Optum enrollees, we found treatment effect heterogeneity by sex (adjusted HRs = 0.71 [0.54-0.93] and 1.16 [0.89-1.52] in men and women respectively, interaction term p-value = 0.01)., Conclusions: Rosiglitazone and pioglitazone appear to be associated with similar risks of SCA/VA.

Aim: The aim of the study was to empirically demonstrate the effect of varying study designs when evaluating the safety of pioglitazone in treating bladder cancer., Methods: We identified Medicare beneficiaries above 65 years of age with diabetes between 2008 and 2015 and with classified exposure (at least two claims within 180 days) to glucose-lowering drugs (GLD), pioglitazone or another drug. The effects of varying the following study design parameters on bladder cancer risk were assessed: use of a new vs existing drug, choice of referent (all non-users and users of GLDs, non-insulin GLDs and DPP-4s) and whether or not censoring accounted for treatment change. We used the Cox proportional hazards model to obtain adjusted HRs and 95% CIs., Results: We included 1,510,212 patients classified as pioglitazone users (N = 135,188) or non-users (N = 1,375,024). Users had more diabetic complications than non-users, but fewer than insulin users. The HR ranged from 1.10 (1.01-1.20) to 1.13 (0.99-1.29) when censoring ignored treatment change, suggesting a weak association or none between pioglitazone and bladder cancer, probably under-estimating risk. However, the HR was 1.20 (1.01-1.42) when cohorts were restricted to new users, censored upon treatment change, and when DPP-4 was used as the referent, suggesting an increased risk of bladder cancer associated with pioglitazone., Conclusions: The continued demand for new GLDs indicates the need for more robust observational methods to improve the value of generating real-world evidence in equipping clinicians to make informed prescribing decisions. Although there is no one-size-fits-all approach, we recommend active comparator new user study designs that compare therapeutically equivalent drugs and account for treatment changes during follow-up to present the least biased comparative safety estimates., (© 2019 John Wiley & Sons Ltd.)

Aims To compare bladder cancer incidence between patients initiating pioglitazone treatment and patients initiating treatment with dipeptidyl-peptidase-4 inhibitors [DPP-4s] or sulfonylureas. Methods We identified Medicare beneficiaries aged >65 years who initiated treatment with pioglitazone ( N = 38 700), DPP-4s ( N = 82 552) or sulfonylureas ( N = 126 104) between 2007 and 2014 after at least 6 months without prescriptions for these drug classes. Patients were followed from second prescription until bladder cancer outcome (2 claims within 60 days) using a 6-month induction/latency period, censoring for treatment change, death or end of 2014. We used propensity score-weighted Cox proportional-hazards models to obtain adjusted hazard ratios (a HR) and their 95% confidence intervals. Results Overall mean age of participants was 75 years and 41% were men. Over a median of 1.2 treatment years, 727 beneficiaries developed bladder cancer. Pioglitazone initiators had an increased incidence of bladder cancer (308 vs 204 [DPP-4s] or 231 [sulfonylureas] per 100 000 person-years; aHR, 1.57 [1.23-2.00] vs DPP-4s and 1.32 [1.02-1.70] vs sulfonylureas). The increased risk emerged within the first 2 years of treatment (aHR, 1.63 [1.22-2.17] vs DPP-4s and 1.32 [0.98-1.78] vs sulfonylureas). If treatment was discontinued within the first 2 years, the risk after 2 years post initiation was attenuated (aHR, 0.89 [0.61-1.28]) compared with patients treated for more than 2 years (aHR, 1.45 [0.93-2.26]) both vs DPP-4s. Findings were consistent across secondary and sensitivity analyses. Conclusions Pioglitazone was associated with an elevated risk of bladder cancer compared with DPP-4s and sulfonylureas. The elevated risk emerged within the first 2 years of treatment and was attenuated after discontinuing. Pioglitazone's relative effectiveness should be weighed against a small absolute increase in risk of bladder cancer. [ABSTRACT FROM AUTHOR]

In this article the author discusses an advisory from the American Heart Association/American College of Cardiology Foundation Science on the relationship between thiazolidinedione drugs used to control blood glucose levels and cardiovascular risk. He cites the difficulty of detecting cardiovascular risk in patients taking these drugs since cardiovascular diseases are common. In the light of inconclusive evidence linking rosiglitazone to increased cardiovascular risk, it suggests avoiding the drugs until reassuring evidence for the drug is available.

Insulin resistance and progressive beta-cell failure are fundamental defects in type 2 diabetes. Treatments that improve insulin sensitivity and beta-cell function can improve these defects and improve glycemic control. The thiazolidinediones (TZDs) improve insulin sensitivity, fasting and postprandial plasma glucose levels, and glycosylated hemoglobin (HbA1c) levels. These agents can be used as monotherapy, and they have been successfully combined with other antidiabetic therapies. The TZDs have also been associated with improvements in various cardiovascular risk factors, including hypertension, the dyslipidemic profile often observed in patients with diabetes or insulin resistance, aspects of endothelial dysfunction, abnormal hemostasis, and levels of several inflammatory markers. Studies are currently under way to evaluate the effects of TZDs on cardiovascular event rates. Accumulating evidence suggests that TZDs may enhance or preserve beta-cell function and thus may have a more durable therapeutic effect than some of the other oral antidiabetic agents. Using TZDs as monotherapy or as a component of combination therapy will contribute to improved glycemic control and should reduce the risk of diabetic complications. A number of studies have shown that a strategy of aggressive use of pharmacologic agents to achieve glycemic control is associated with cost benefits.

Objective: To determine the efficacy and safety of rosiglitazone (RSG) when added to insulin in the treatment of type 2 diabetic patients who are inadequately controlled on insulin monotherapy., Research Design and Methods: After 8 weeks of insulin standardization and placebo (PBO) run-in, 319 type 2 diabetic patients with mean baseline HbA(1c) > or = 7.5% (8.9 +/- 1.1 to 9.1 +/- 1.3) on twice-daily insulin therapy (total daily dose > or = 30 U) were randomized to 26 weeks of additional treatment with RSG (4 or 8 mg daily) or PBO. Insulin dose could be down- titrated only for safety reasons. The primary end point was reduction of HbA(1c) from baseline., Results: RSG 4 and 8 mg daily significantly improved glycemic control, which was unchanged on PBO. By intent-to-treat analysis, treatment with RSG 8 mg plus insulin resulted in a mean reduction from baseline in HbA(1c) of 1.2% (P < 0.0001), despite a 12% mean reduction of insulin dosage. Over 50% of subjects treated daily with RSG 8 mg plus insulin had a reduction of HbA(1c) > or = 1.0%. Neither total:HDL cholesterol nor LDL:HDL cholesterol ratios significantly changed with RSG treatment. Serious adverse events did not differ among groups., Conclusions: The addition of RSG to insulin treatment results in significant improvement in glycemic control and is generally well tolerated.

Objective: To evaluate the efficacy and safety of four doses of pioglitazone monotherapy in the treatment of patients with type 2 diabetes., Research Design and Methods: There were 408 patients randomized in this multicenter double-blind placebo-controlled clinical trial. Patients who had HbA1c > or = 7.0%, fasting plasma glucose (FPG) > or = 140 mg/dl, and C-peptide > 1 ng/ml were randomized to receive placebo or 7.5, 15, 30, or 45 mg pioglitazone administered once a day for 26 weeks., Results: Patients treated with 15, 30, or 45 mg pioglitazone had significant mean decreases in HbA1c (range -1.00 to -1.60% difference from placebo) and FPG (-39.1 to -65.3 mg/dl difference from placebo). The decreases in FPG were observed as early as the second week of therapy; maximal decreases occurred after 10-14 weeks and were maintained until the end of therapy (week 26). In the 15-, 30-, or 45-mg pioglitazone groups, there were significant mean percent decreases in triglycerides, significant mean percent increases in HDL cholesterol, and only small percent changes in total cholesterol and LDL. The subset of patients naive to therapy had greater improvements in HbA1c and FPG (difference from placebo of -2.55% and -79.9 mg/dl for the 45-mg group) compared with previously treated patients. The overall adverse event profile of pioglitazone was similar to that of placebo. There was no evidence of drug-induced hepatotoxicity or drug-induced elevations of alanine aminotransferase levels in this study, Conclusions: Pioglitazone monotherapy significantly improves HbA1c and FPG while producing beneficial effects on serum lipids in patients with type 2 diabetes with no evidence of drug-induced hepatotoxicity.