In the past 3 decades, metabolic-associated fatty liver disease (MAFLD) has emerged as a widespread liver condition, with its global prevalence on the rise. It ranks as a leading contributor to hepatocellular carcinoma (HCC) and necessitates liver transplantation. Under the multiple parallel hits model, the pathogenesis of MAFLD stems from various liver stressors, notably nutrient overload and sedentary lifestyles. While medical management for MAFLD is well-established, encompassing non-pharmaceutical and pharmaceutical interventions, determining the most effective pharmaceutical therapy has remained elusive. This review discusses diabetic medications for MAFLD treatment, emphasizing recent studies and emerging drugs while reviewing other nondiabetic agents. Emerging evidence suggests that combination therapies hold promise for resolving MAFLD and metabolic steatohepatitis (MASH) while managing side effects. Ongoing trials play a pivotal role in elucidating the effects of mono, dual, and triple receptor agonists in individuals with MASH. With the rising burden of MAFLD/MASH and its severe consequences, the need for effective treatments is more pressing than ever. This review provides a comprehensive overview of the current landscape of pharmaceutical interventions for MAFLD and MASH, shedding light on the potential of newer drugs especially diabetic medications and the importance of ongoing research in this field.

Non-alcoholic steatohepatitis (NASH) is a subset of non-alcoholic fatty liver disease (NAFLD), which, apart from excess fat in the liver, may be characterised by some level of inflammatory infiltration and fibrogenesis, occasionally progressing to liver cirrhosis or hepatocellular carcinoma (HCC). The objective of the current review is to elucidate the rising prevalence, the role of microbiome and genetics in pathogenesis, diagnostic challenges, and novel treatment alternatives for NASH. Newer diagnostic techniques are being developed since using liver biopsy in a larger population is not a reasonable option and is primarily restricted to clinical research, at least in developing countries. Besides these technical challenges, another important factor leading to deviation from guideline practice is the lack of health insurance coverage in countries like India. It leads to reluctance on the part of physicians and patients to delay required tests to curb out-of-pocket expenditure. There is no cure for NASH, with liver transplantation remaining the last option for those who progress to end-stage liver disease (ESLD) or are detected with early-stage HCC. Thus, lifestyle modification remains the only viable option for many, but compliance and long-term adherence remain major challenges. In obese individuals, bariatric surgery and weight reduction have shown favourable results. In patients with less severe obesity, endoscopic bariatric metabolic therapies (EBMT) are rapidly emerging as less invasive therapies. However, access and acceptability remain poor for these weight reduction methods. Therefore, intense research is being conducted for potential newer drug classes with several agents currently in phase II or III of clinical development. Some of these have demonstrated promising results, such as a reduction in hepatic fat content, and attenuation of fibrosis with an acceptable tolerability profile in phase II studies. The developments in the management of NASH have been fairly encouraging. Further well-designed long-term prospective studies should be undertaken to generate evidence with definitive results.

In 2019, the Italian Society of Diabetology and the Italian Association of Clinical Diabetologists nominated an expert panel to develop guidelines for drug treatment of type 2 diabetes. After identifying the effects of glucose-lowering agents on major adverse cardiovascular events (MACEs), all-cause mortality, and hospitalization for heart failure (HHF) as critical outcomes, the experts decided to perform a systematic review and meta-analysis on the effect of pioglitazone with this respect.

A MEDLINE database search was performed to identify RCTs, up to June 1st, 2021, with duration≥52 weeks, in which pioglitazone was compared with either placebo or active comparators. The principal endpoints were MACE and HHF (restricted for RCT reporting MACEs within their outcomes), all-cause mortality (irrespective of the inclusion of MACEs among the pre-specified outcomes). Mantel-Haenszel odds ratio (MH-OR) with 95% Confidence Interval (95% CI) was calculated for all the endpoints considered. Eight RCTs were included in the analysis for MACEs and HF (5048 and 5117 patients in the pioglitazone and control group, respectively), and 24 in that for all-cause mortality (10,682 and 9674 patients). Pioglitazone neither significantly increased nor reduced the risk of MACE, all-cause mortality, and HHF in comparison with placebo/active comparators (MH-OR: 0.90, 95% CI 0.78-1.03, 0.91, 95% CI 0.77, 1.09, and 1.16, 95% CI 0.73, 1.83, respectively). Pioglitazone was associated with a significant reduction of MACE in patients with prior cardiovascular events (MH-OR 0.84, 95% CI 0.72-0.99).

This meta-analysis showed no significant effects of pioglitazone on incident MACE, all-cause mortality, and HHF.

To compare the cardiovascular, renal and safety outcomes of second-line glucose-lowering agents used in the management of people with type 2 diabetes.

MEDLINE, EMBASE and CENTRAL were searched from inception to 13 July 2021 for randomised controlled trials comparing second-line glucose lowering therapies with placebo, standard care or one another. Primary outcomes included cardiovascular and renal outcomes. Secondary outcomes were non-cardiovascular adverse events. Risk ratios (RRs) and corresponding confidence intervals (CI) or credible intervals (CrI) were reported within pairwise and network meta-analysis. The quality of evidence was evaluated using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) criteria. Number needed to treat (NNT) and number needed (NNH) to harm were calculated at 5 years using incidence rates and RRs. PROSPERO (CRD42020168322).

We included 38 trials from seven classes of glucose-lowering therapies. Both sodium-glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP1RA) showed moderate to high certainty in reducing risk of 3-point major adverse cardiovascular events, 3P-MACE (network estimates: SGLT2i [RR 0.90; 95% CrI 0.84-0.96; NNT, 59], GLP1RA [RR 0.88; 95% CrI 0.83-0.93; NNT, 50]), cardiovascular death, all-cause mortality, renal composite outcome and macroalbuminuria. SGLT2i also showed high certainty in reducing risk of hospitalization for heart failure (hHF), ESRD, acute kidney injury, doubling in serum creatinine and decline in eGFR. GLP1RA were associated with lower risk of stroke (high certainty) while glitazone use was associated with an increased risk of hHF (very low certainty). The risk of developing ESRD was lower with the use of sulphonylureas (low certainty). For adverse events, sulphonylureas and insulin were associated with increased hypoglycaemic events (very low to low certainty), while GLP1RA increased the risk of gastrointestinal side effects leading to treatment discontinuation (low certainty). DPP-4i increased risk of acute pancreatitis (low certainty). SGLT2i were associated with increased risk of genital infection, volume depletion (high certainty), amputation and ketoacidosis (moderate certainty). Risk of fracture was increased with the use of glitazones (moderate certainty).

SGLT2i and GLP1RA were associated with lower risk for different cardiorenal end points, when used as an adjunct to metformin in people with type 2 diabetes. Additionally, SGLT2i demonstrated benefits in reducing risk for surrogate end points in kidney disease progression. Safety outcomes differ among the available pharmacotherapies.

Cryptococcosis affects more than 220,000 patients/year, with high mortality even when the standard treatment [amphotericin B (AMB), 5-flucytosin (5-FC) and fluconazole] is used. AMB presents high toxicity and 5-FC is not currently available in Brazil. In a pre-clinical study, pioglitazone (PIO - an antidiabetic drug) decreased AMB toxicity and lead to an increased mice survival, reduced morbidity and fungal burden in brain and lungs. The aim of this trial is to evaluate the efficacy and safety of PIO combined with standard antifungal treatment for human cryptococcosis.

A phase 1/2, randomized, double blind, placebo-controlled trial will be performed with patients from Belo Horizonte, Brazil. They will be divided into three groups (placebo, PIO 15 mg/day or PIO 45 mg/day) and will receive an additional pill during the induction phase of cryptococcosis' treatment. Our hypothesis is that treated patients will have increased survival, so the primary outcome will be the mortality rate. Patients will be monitored for survival, side effects, fungal burden and inflammatory mediators in blood and cerebrospinal fluid. The follow up will occur for up 60 days.

We expect that PIO will be an adequate adjuvant to the standard cryptococcosis' treatment.

ICTRP/WHO (and International Clinical Trial Registry Plataform (ICTRP/WHO) (http://apps.who.int/trialsearch/Trial2.aspx?TrialID=RBR-9fv3f4), RBR-9fv3f4 (http://www.ensaiosclinicos.gov.br/rg/RBR-9fv3f4). UTN Number: U1111-1226-1535. Ethical approvement number: CAAE 17377019.0.0000.5149.

Metabolic associated fatty liver disease (MAFLD) is the principal worldwide cause of liver disease and affects nearly a quarter of the global population. The objective of this work was to present the clinical practice guidelines of the Asian Pacific Association for the Study of the Liver (APASL) on MAFLD. The guidelines cover various aspects of MAFLD including its epidemiology, diagnosis, screening, assessment, and treatment. The document is intended for practical use and for setting the stage for advancing clinical practice, knowledge, and research of MAFLD in adults, with specific reference to special groups as necessary. The guidelines also seek to improve patient care and awareness of the disease and assist stakeholders in the decision-making process by providing evidence-based data. The guidelines take into consideration the burden of clinical management for the healthcare sector.

The prevention of cardiovascular morbidity and mortality has always been a primary concern in patients with type 2 diabetes. Modern trials of glucose-lowering therapies now assess major adverse cardiac events as an endpoint in addition to the effects on glycaemic control. Whilst the data on the efficacy of intensive glucose lowering on reducing cardiovascular risk are limited, there are now increasing numbers of glucose-lowering therapies that have proven cardiovascular benefit independent of glucose lowering. This review will summarise the available literature on cardiovascular outcomes in relation to metformin, sulphonylureas, di-peptidyl peptidase-4 inhibitors, glucagon-like peptide receptor agonists, sodium-glucose co-transporter 2 inhibitors, thiazolidinediones, acarbose and insulin. In addition, new paradigms in diabetes management and the importance of treatment selection based on considerations including but not limited to glycaemic control will be discussed.

Our goal is to discuss how to personalize the management of patients with type 2 diabetes by adjusting glycemic targets and tailoring medical therapy to account for unique patient characteristics.

We review the pharmacotherapeutic options for the management of type 2 diabetes, focusing on potential advantages and disadvantages of each class of agents. We also discuss how to approach specific patient subpopulations and propose a conceptual framework for incorporating these factors into clinical practice. As the diabetes treatment landscape rapidly expands, physicians have the exciting opportunity to offer patients increasingly individualized care.

The number of people with type 2 diabetes mellitus (T2DM) is increasing worldwide. The combination of metformin and sulphonylurea (M+S) is a widely used treatment. Whether M+S shows better or worse effects in comparison with other antidiabetic medications for people with T2DM is still controversial.

To assess the effects of metformin and sulphonylurea (second- or third-generation) combination therapy for adults with type 2 diabetes mellitus.

We updated the search of a recent systematic review from the Agency for Healthcare Research and Quality (AHRQ). The updated search included CENTRAL, MEDLINE, Embase, ClinicalTrials.gov and WHO ICTRP. The date of the last search was March 2018. We searched manufacturers' websites and reference lists of included trials, systematic reviews, meta-analyses and health technology assessment reports. We asked investigators of the included trials for information about additional trials.

We included randomised controlled trials (RCTs) randomising participants 18 years old or more with T2DM to M+S compared with metformin plus another glucose-lowering intervention or metformin monotherapy with a treatment duration of 52 weeks or more.

Two review authors read all abstracts and full-text articles and records, assessed risk of bias and extracted outcome data independently. We used a random-effects model to perform meta-analysis, and calculated risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We assessed the certainty of the evidence using the GRADE instrument.

We included 32 RCTs randomising 28,746 people. Treatment duration ranged between one to four years. We judged none of these trials as low risk of bias for all 'Risk of bias' domains. Most important events per person were all-cause and cardiovascular mortality, serious adverse events (SAE), non-fatal stroke (NFS), non-fatal myocardial infarction (MI) and microvascular complications. Most important comparisons were as follows:Five trials compared M+S (N = 1194) with metformin plus a glucagon-like peptide 1 analogue (N = 1675): all-cause mortality was 11/1057 (1%) versus 11/1537 (0.7%), risk ratio (RR) 1.15 (95% confidence interval (CI) 0.49 to 2.67); 3 trials; 2594 participants; low-certainty evidence; cardiovascular mortality 1/307 (0.3%) versus 1/302 (0.3%), low-certainty evidence; serious adverse events (SAE) 128/1057 (12.1%) versus 194/1537 (12.6%), RR 0.90 (95% CI 0.73 to 1.11); 3 trials; 2594 participants; very low-certainty evidence; non-fatal myocardial infarction (MI) 2/549 (0.4%) versus 6/1026 (0.6%), RR 0.57 (95% CI 0.12 to 2.82); 2 trials; 1575 participants; very low-certainty evidence.Nine trials compared M+S (N = 5414) with metformin plus a dipeptidyl-peptidase 4 inhibitor (N = 6346): all-cause mortality was 33/5387 (0.6%) versus 26/6307 (0.4%), RR 1.32 (95% CI 0.76 to 2.28); 9 trials; 11,694 participants; low-certainty evidence; cardiovascular mortality 11/2989 (0.4%) versus 9/3885 (0.2%), RR 1.54 (95% CI 0.63 to 3.79); 6 trials; 6874 participants; low-certainty evidence; SAE 735/5387 (13.6%) versus 779/6307 (12.4%), RR 1.07 (95% CI 0.97 to 1.18); 9 trials; 11,694 participants; very low-certainty evidence; NFS 14/2098 (0.7%) versus 8/2995 (0.3%), RR 2.21 (95% CI 0.74 to 6.58); 4 trials; 5093 participants; very low-certainty evidence; non-fatal MI 15/2989 (0.5%) versus 13/3885 (0.3%), RR 1.45 (95% CI 0.69 to 3.07); 6 trials; 6874 participants; very low-certainty evidence; one trial in 64 participants reported no microvascular complications were observed (very low-certainty evidence).Eleven trials compared M+S (N = 3626) with metformin plus a thiazolidinedione (N = 3685): all-cause mortality was 123/3300 (3.7%) versus 114/3354 (3.4%), RR 1.09 (95% CI 0.85 to 1.40); 6 trials; 6654 participants; low-certainty evidence; cardiovascular mortality 37/2946 (1.3%) versus 41/2994 (1.4%), RR 0.78 (95% CI 0.36 to 1.67); 4 trials; 5940 participants; low-certainty evidence; SAE 666/3300 (20.2%) versus 671/3354 (20%), RR 1.01 (95% CI 0.93 to 1.11); 6 trials; 6654 participants; very low-certainty evidence; NFS 20/1540 (1.3%) versus 16/1583 (1%), RR 1.29 (95% CI 0.67 to 2.47); P = 0.45; 2 trials; 3123 participants; very low-certainty evidence; non-fatal MI 25/1841 (1.4%) versus 21/1877 (1.1%), RR 1.21 (95% CI 0.68 to 2.14); P = 0.51; 3 trials; 3718 participants; very low-certainty evidence; three trials (3123 participants) reported no microvascular complications (very low-certainty evidence).Three trials compared M+S (N = 462) with metformin plus a glinide (N = 476): one person died in each intervention group (3 trials; 874 participants; low-certainty evidence); no cardiovascular mortality (2 trials; 446 participants; low-certainty evidence); SAE 34/424 (8%) versus 27/450 (6%), RR 1.68 (95% CI 0.54 to 5.21); P = 0.37; 3 trials; 874 participants; low-certainty evidence; no NFS (1 trial; 233 participants; very low-certainty evidence); non-fatal MI 2/215 (0.9%) participants in the M+S group; 2 trials; 446 participants; low-certainty evidence; no microvascular complications (1 trial; 233 participants; low-certainty evidence).Four trials compared M+S (N = 2109) with metformin plus a sodium-glucose co-transporter 2 inhibitor (N = 3032): all-cause mortality was 13/2107 (0.6%) versus 19/3027 (0.6%), RR 0.96 (95% CI 0.44 to 2.09); 4 trials; 5134 participants; very low-certainty evidence; cardiovascular mortality 4/1327 (0.3%) versus 6/2262 (0.3%), RR 1.22 (95% CI 0.33 to 4.41); 3 trials; 3589 participants; very low-certainty evidence; SAE 315/2107 (15.5%) versus 375/3027 (12.4%), RR 1.02 (95% CI 0.76 to 1.37); 4 trials; 5134 participants; very low-certainty evidence; NFS 3/919 (0.3%) versus 7/1856 (0.4%), RR 0.87 (95% CI 0.22 to 3.34); 2 trials; 2775 participants; very low-certainty evidence; non-fatal MI 7/890 (0.8%) versus 8/1374 (0.6%), RR 1.43 (95% CI 0.49 to 4.18; 2 trials); 2264 participants; very low-certainty evidence; amputation of lower extremity 1/437 (0.2%) versus 1/888 (0.1%); very low-certainty evidence.Trials reported more hypoglycaemic episodes with M+S combination compared to all other metformin-antidiabetic agent combinations. Results for M+S versus metformin monotherapy were inconclusive. There were no RCTs comparing M+S with metformin plus insulin. We identified nine ongoing trials and two trials are awaiting assessment. Together these trials will include approximately 16,631 participants.

There is inconclusive evidence whether M+S combination therapy compared with metformin plus another glucose-lowering intervention results in benefit or harm for most patient-important outcomes (mortality, SAEs, macrovascular and microvascular complications) with the exception of hypoglycaemia (more harm for M+S combination). No RCT reported on health-related quality of life.

The effects of pioglitazone on bone metabolism are unclear. This study evaluated the long-term effects of pioglitazone on bone mineral density (BMD) and bone metabolism in patients with prediabetes or type 2 diabetes mellitus (T2DM) and non-alcoholic steatohepatitis (NASH).

Ninety-two patients with prediabetes or T2DM and biopsy-proven NASH with BMD and baseline biochemical bone measurements were included. Patients (mean [±SEM] age 51 ± 1 years, 71% male, mean body mass index 34.5 ± 0.5 kg/m² ) were randomly assigned to pioglitazone (45 mg/day) or placebo for 18 months, followed by an 18-month open-label pioglitazone treatment phase. Baseline, 18- and 36-month evaluations included plasma vitamin D and bone turnover biomarker levels, and BMD measurements at the spine, femoral neck, total hip, and one-third radius.

After 18 months of pioglitazone treatment, there were no differences in BMD versus placebo at either the femoral neck (P =0.87), total hip (P =0.78), or one-third radius (P =0.44); however, bone density decreased at the level of the spine with pioglitazone (-3.5%; P =0.002). During the extension phase (18-36 months), patients had no further decreases in BMD or plasma biomarkers of bone turnover during pioglitazone treatment. No patient experienced a low-energy bone fracture.

Treatment of patients with prediabetes or T2DM with pioglitazone for up to 3 years was associated with decreased BMD at the level of the lumbar spine. This reduction in BMD at the lumbar spine at 18 months versus placebo suggests an early deleterious effect of pioglitazone on bone metabolism.

Both diabetes mellitus (DM) and cancer are multifarious, dissimilar, and long-lasting, fatal diseases with a remarkable influence on health worldwide. DM is not only related to cardiovascular diseases, neuropathy, nephropathy, and retinopathy, but also related to a number of liver diseases such as nonalcoholic fatty liver disease, steatohepatitis, and liver cirrhosis. Recently, it is hypothesized that DM has a greater risk for many forms of cancer, such as breast, colorectal, endometrial, pancreatic, gallbladder, renal, and liver cancer including hepatocellular carcinoma (HCC). Both DM and cancer have many common risk factors, but the association between these two is poorly stated. Several epidemiologic studies have revealed the association between pathogenic and prognostic characteristics of DM and a higher incidence of HCC, thus representing DM as an independent risk factor for HCC development. The etiological and pathophysiological relationship between DM and HCC has been presented in this review by linking hyperglycemia, hyperinsulinemia, insulin resistance, and activation of insulin-like growth factor signaling pathways and pharmacological management of HCC associated with DM.

Thiazolidinedione (TZD) drugs used in the treatment of type 2 diabetes mellitus (T2DM) have proven effective in improving insulin sensitivity, hyperglycemia, and lipid metabolism. Though well tolerated by some patients, their mechanism of action as ligands of peroxisome proliferator-activated receptors (PPARs) results in the activation of several pathways in addition to those responsible for glycemic control and lipid homeostasis. These pathways, which include those related to inflammation, bone formation, and cell proliferation, may lead to adverse health outcomes. As treatment with TZDs has been associated with adverse hepatic, cardiovascular, osteological, and carcinogenic events in some studies, the role of TZDs in the treatment of T2DM continues to be debated. At the same time, new therapeutic roles for TZDs are being investigated, with new forms and isoforms currently in the pre-clinical phase for use in the prevention and treatment of some cancers, inflammatory diseases, and other conditions. The aims of this review are to provide an overview of the mechanism(s) of action of TZDs, a review of their safety for use in the treatment of T2DM, and a perspective on their current and future therapeutic roles.

There is a relative lack of long-term data for individual glucose-lowering therapies for the treatment of type 2 diabetes mellitus. A systematic search of published literature reporting data of approximately ≥3 years of follow-up from randomized controlled trials and their extensions was conducted. Trials to evaluate the efficacy and/or safety of glucose-lowering drugs currently approved for the treatment of adults with type 2 diabetes were included. Search results included long-term published data for traditional oral glucose-lowering drugs, insulin, α-glucosidase inhibitors, and incretin-based therapies. In general, results indicated that the short-term risk/benefit profile of these therapies is in line with longer-term evaluations. Individual results from these trials are reviewed in this report. These findings support the use of approved drug classes for longer-term treatment of type 2 diabetes.

Sulfonylureas are ATP-sensitive potassium (KATP) channel blockers commonly used in the treatment of type 2 diabetes mellitus (T2DM). Activation of KATP channels plays a neuroprotective role in ischemia; thus, whether sulfonylureas affect the outcomes of stroke in patients with T2DM needs to be further studied. In our study, streptozotocin (STZ)-induced diabetic mice subjected to transient middle cerebral artery occlusion (MCAO) showed larger areas of brain damage and poorer behavioral outcomes. Blocking the KATP channel by tolbutamide increased neuronal injury induced by oxygen-glucose deprivation (OGD) in vitro and permanent MCAO (pMCAO) in vivo. Activating the KATP channel by diazoxide reduced the effects of both the OGD and pMCAO. Western blot analysis in STZ mouse brains indicated an early increase in protein levels of N-methyl-d-aspartate receptor 2B and postsynaptic density protein-95, followed by a decrease in phosphorylation of glycogen synthase kinase 3β. Our systematic meta-analysis indicated that patients with T2DM treated with sulfonylureas had a higher odds ratio for stroke morbidity than those who received comparator drugs. Taken together, these results suggest that sulfonylurea treatment in patients with T2DM may inhibit the neuroprotective effects of KATP channels and increase the risk of stroke.

Sulfonylureas are an effective and inexpensive treatment for type 2 diabetes. There is conflicting data about the safety of these drugs regarding mortality and cardiovascular outcomes. The objective of the present study was to evaluate the safety of the sulfonylureas most frequently used and to use trial sequential analysis (TSA) to analyze whether the available sample was powered enough to support the results.

Electronic databases were reviewed from 1946 (Embase) or 1966 (MEDLINE) up to 31 December 2014. Randomized clinical trials (RCTs) of at least 52 wk in duration evaluating second- or third-generation sulfonylureas in the treatment of adults with type 2 diabetes and reporting outcomes of interest were included. Primary outcomes were all-cause and cardiovascular mortality. Additionally, myocardial infarction and stroke events were evaluated. Data were summarized with Peto odds ratios (ORs), and the reliability of the results was evaluated with TSA. Forty-seven RCTs with 37,650 patients and 890 deaths in total were included. Sulfonylureas were not associated with all-cause (OR 1.12 [95% CI 0.96 to 1.30]) or cardiovascular mortality (OR 1.12 [95% CI 0.87 to 1.42]). Sulfonylureas were also not associated with increased risk of myocardial infarction (OR 0.92 [95% CI 0.76 to 1.12]) or stroke (OR 1.16 [95% CI 0.81 to 1.66]). TSA could discard an absolute difference of 0.5% between the treatments, which was considered the minimal clinically significant difference. The major limitation of this review was the inclusion of studies not designed to evaluate safety outcomes.

Sulfonylureas are not associated with increased risk for all-cause mortality, cardiovascular mortality, myocardial infarction, or stroke. Current evidence supports the safety of sulfonylureas; an absolute risk of 0.5% could be firmly discarded.

PROSPERO CRD42014004330.

The use of thiazolidinediones (TZDs) has been associated with increased fracture risk. We performed a comprehensive literature review and meta-analysis to estimate the risk of fractures with TZDs

We searched MEDLINE, Embase and the Cochrane Database, from inception to May 2014. We included all randomized trials that described the risk of fractures or changes in bone mineral density (BMD) with TZDs. We pooled data with odds ratios (ORs) for fractures and the weighted mean difference in BMD. To assess heterogeneity in results of individual studies, we used Cochran's Q statistic and the I(2) statistic.

We included 24,544 participants with 896 fracture cases from 22 randomized controlled trials. Meta-analysis showed that the significantly increased incidence of fracture was found in women (OR=1.94; 95%CI: 1.60-2.35; P<0.001), but not in men (OR=1.02; 95%CI: 0.83-1.27; P=0.83). For women, the fracture risk was similar in rosiglitazone (OR=2.01; 95%CI: 1.61-2.51; P<0.001) and pioglitazone (OR=1.73; 95%CI: 1.18-2.55; P=0.005) treatment and appeared to be similar for participants aged <60years old (OR=1.89; 95%CI: 1.51-2.36; P<0.001) and aged ≥60years old (OR=2.07; 95%CI: 1.51-2.36; P<0.001). There was a non-significant trend towards increased risk of fractures in different cumulative durations of TZD exposure. TZD treatment was also associated with significant changes in BMD among women at the lumbar spine(weighted mean difference: -0.49%, 95%CI: -0.66% to -0.32%; P<0.001), the femoral neck (weighted mean difference: -0.34%, 95%CI: -0.51% to -0.16%; P<0.001) and the hip(weighted mean difference: -0.33%, 95%CI: -0.52% to -0.14%; P<0.001).

Our results suggest that TZD treatment is associated with an increased risk of fractures in women, effects of rosiglitazone and pioglitazone are similar, fracture risk is independent of age and fracture risk has no clear association with duration of TZD exposure.

To determine whether thiazolidinedione use is associated with a risk of bladder cancer.

We searched MEDLINE and EMBASE in June 2012 (with PubMed update to July 2013) and conducted meta-analysis on the overall risks of bladder cancer with pioglitazone or rosiglitazone and the risk with different categories of cumulative dose or duration of drug use.

We screened 230 citations and included 18 studies, comprising five randomized controlled trials (RCTs) and 13 observational studies. Meta-analysis showed a significantly higher overall risk of bladder cancer with pioglitazone in RCTs [7878 participants; odds ratio (OR) 2.51, 95% confidence interval (CI) 1.09-5.80] and observational studies (>2.6 million patients; OR for 'ever' users vs. non-users 1.21, 95% CI 1.09-1.35). Subgroup analysis of observational studies by cumulative dose showed the risk of bladder cancer to be greatest with >28.0 g of pioglitazone (OR 1.64, 95% CI 1.28-2.12). A significantly increased risk was found with both 12-24 months (OR 1.41, 95% CI 1.16-1.71) and >24 months (OR 1.51, 95% CI 1.26-1.81) cumulative durations of pioglitazone exposure. No significant risk was seen with rosiglitazone in RCTs (OR 0.84, 95% CI 0.35-2.04) or 'ever' users vs. non-users in observational studies (OR 1.03, 95% CI 0.94-1.12); the evidence for any relationship between bladder cancer risk and rosiglitazone cumulative duration is limited and inconsistent. Direct comparison of pioglitazone to rosiglitazone 'ever' users yielded an OR of 1.25 (95% CI 0.91-1.72).

A modest but clinically significant increase in the risk of bladder cancer with pioglitazone was found, which appears to be related to cumulative dose and duration of exposure. We recommend that prescribers limit pioglitazone use to shorter durations.

By stimulating lipofibroblast maturation, parenterally administered peroxisome proliferator-activated receptor γ (PPARγ) agonists promote lung homeostasis and injury repair in the neonatal lung. In this study, we determined whether PPARγ agonists could be delivered effectively via nebulization to neonates, and whether this approach would also protect against hyperoxia-induced lung injury.

One-day old Sprague-Dawley rat pups were administered PPARγ agonists rosiglitazone (RGZ, 3 mg/kg), pioglitazone (PGZ, 3 mg/kg), or the diluent, via nebulization every 24 h; animals were exposed to 21% or 95% O2 for up to 72 h. Twenty-four and 72 h following initial nebulization, the pups were sacrificed for lung tissue and blood collection to determine markers of lung maturation, injury repair, and RGZ and PGZ plasma levels.

Nebulized RGZ and PGZ enhanced lung maturation in both males and females, as evidenced by the increased expression of markers of alveolar epithelial and mesenchymal maturation. This approach also protected against hyperoxia-induced lung injury, since hyperoxia-induced changes in bronchoalveolar lavage cell and protein contents and lung injury markers were all blocked by nebulized PGZ.

Nebulized PPARγ agonist administration promotes lung maturation and prevents neonatal hyperoxia-induced lung injury in both males and females.

Patients with type 2 diabetes have an increased risk of chronic liver disease (CLD) such as non-alcoholic fatty liver disease and steatohepatitis and about one-third of cirrhotic patients have diabetes. However, the use of several antidiabetic agents may be a cause for concern in the case of hepatic impairment (HI).

An extensive literature search was performed to analyze the influence of HI on the pharmacokinetics (PK) of glucose-lowering agents and the potential consequences for clinical practice as far as the efficacy/safety balance of their use in diabetic patients with CLD is concerned.

Almost no PK studies have been published regarding metformin, sulfonylureas, thiazolidinediones and α-glucosidase inhibitors in patients with HI. Only mild changes in PK of glinides, dipeptidyl peptidase-4 inhibitors and sodium glucose cotransporters type 2 inhibitors were observed in dedicated PK studies in patients with various degrees of HI, presumably without major clinical relevance although large clinical experience is lacking. Glucagon-like peptide-1 receptor agonists have a renal excretion rather than liver metabolism. Rare anecdotal case reports of hepatotoxicity have been described with various glucose-lowering agents contrasting with numerous reassuring data. Nevertheless, caution should be recommended, especially in patients with advanced cirrhosis, including with the use of metformin.

Recent epidemiological data have contributed to the formulation of the hypothesis about the long-term safety of pioglitazone, a thiazolidinedione (TZD), with respect to malignancies, in particular bladder cancer. The primary aim of this meta-analysis of randomized clinical trials, not designed a priori to test this hypothesis, was to explore whether TZDs affect the risk of cancer. A meta-analysis was performed including published and unpublished randomized trials with a duration of at least 52 weeks, enrolling patients with or without diabetes, comparing TZDs with either placebo or other drug therapies on various different outcomes. We found 22 trials reporting at least one cancer and enrolling 13,197 patients to TZD (pioglitazone: n = 3,710 and rosiglitazone: n = 9,487) and 12,359 to placebo or active comparator groups. The mean follow-up was 26.1 months. Overall, those assigned at random to TZDs had a significant reduction (MH-OR 0.85 [0.73-0.98]; p = 0.027) in the incidence of malignancies, with no significant difference in effect between pioglitazone and rosiglitazone. Specifically, subgroup analyses showed a significant reduction for rosiglitazone (MH-OR 0.82 [0.69-0.98]; p = 0.029), but not for pioglitazone (MH-OR 0.66 [0.34-1.28]; p = 0.22). In further subgroup analyses of site-specific malignancies based on the data from four trials, the risk of bladder cancer with pioglitazone (MH-OR) was 2.05 [0.84-5.02]; p = 0.12. Further, rosiglitazone, but not pioglitazone, was associated with a significantly reduced risk of bowel cancer. In contrast, pioglitazone, but not rosiglitazone, was associated with a significant reduction in breast cancer. The present meta-analysis of trials, not designed a priori to test the hypothesis, provides reassuring evidence that TZDs are not associated with risk of overall malignancies. In fact, they are compatible with the possibility of a decreased risk of cancer. In site-specific subgroup analyses, for rosiglitazone, there was a significant decreased risk of bowel cancer. Subgroup analyses for pioglitazone did not allow to exclude an increased risk of bladder cancer, while the risk of breast cancer was significantly decreased. While these data are also useful to formulate not test hypotheses, they provide somewhat more cogent evidence than the previously published epidemiological data.

Cardiovascular safety of sulfonylurea has been questioned by some authors. This article aims at collecting all available data on this issue from randomized trials.

A meta-analysis was performed including all trials with a duration of at least 6 months, comparing a sulfonylurea with a non-sulfonylurea agent in type 2 diabetes. Major cardiovascular events (MACE) and mortality were retrieved and combined to calculate Mantel-Haenzel odds ratio (MH-OR).

Of the 115 selected trials, 62 reported information on MACE, and 30 reported at least one event. MH-OR for sulfonylurea was 1.08 [0.86-1.36], p = 0.52 (1.85 [1.20-2.87], p = 0.005, in the five trials vs. DPP4 inhibitors, no significant differences vs. other comparators). The MH-OR for myocardial infarction and stroke was 0.88 [0.75-1.04], p = 0.13 and 1.28 [1.03-1.60], p = 0.026, respectively. Mortality was significantly increased with sulfonylureas (MH-OR: 1.22 [1.01-1.49], p = 0.047).

In type 2 diabetes, the use of sulfonylureas is associated with increased mortality and a higher risk of stroke, whereas the overall incidence of MACE appears to be unaffected. Significant differences in cardiovascular risk could be present in direct comparisons with specific classes of glucose-lowering agents, such as DPP4 inhibitors, but this hypothesis needs to be confirmed in long-term cardiovascular outcomes trials. The results of this meta-analysis need to be interpreted with caution, mainly because of limitations in trial quality and under-reporting of information on cardiovascular events and mortality. However, the cardiovascular safety of sulfonylureas cannot be considered established unless it is evaluated in long-term cardiovascular outcomes trials.

To compare and study the dipeptidy1 peptidase-4 (DPP-4) inhibitors in combination with metformin against established combination therapies.

This 16-week study was designed to compare sitagliptin versus pioglitazone as add-on therapy in patients of type 2 diabetes mellitus inadequately controlled with metformin alone. Fifty-two patients were randomized into two groups to receive either sitagliptin 100 mg (group 1) or pioglitazone 30 mg (group 2) in addition to metformin. The primary efficacy end point was change in HbA1c. Secondary end points included change in fasting plasma glucose (FPG), body weight and lipid profile. Treatment satisfaction was assessed using the Diabetes Treatment Satisfaction Questionnaire. Both the groups had a significant decrease in HbA1c.

There was no significant difference between mean reductions in FPG in both the groups. There was a significant decrease in the mean body weight and body mass index in group 1 in contrast to the significant increase in the same in group 2. Both the treatment groups reported a significant decrease in High-density lipoprotein (HDL-C) and Triglyceride.

Sitagliptin was well tolerated without any incidence of hypoglycemia. It was concluded that sitagliptin as an add-on to metformin is as effective and well tolerated as pioglitazone.

Type 2 diabetes mellitus (T2DM) is a growing health problem worldwide. Whether sulphonylureas show better, equal or worse therapeutic effects in comparison with other antidiabetic interventions for patients with T2DM remains controversial.

To assess the effects of sulphonylurea monotherapy versus placebo, no intervention or other antidiabetic interventions for patients with T2DM.

We searched publications in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS and CINAHL (all until August 2011) to obtain trials fulfilling the inclusion criteria for our review.

We included clinical trials that randomised patients 18 years old or more with T2DM to sulphonylurea monotherapy with a duration of 24 weeks or more.

Two authors independently assessed the risk of bias. The primary outcomes were all-cause and cardiovascular mortality. Secondary outcomes were other patient-important outcomes and metabolic variables. Where possible, we used risk ratios (RR) with 95% confidence intervals (95% CI) to analyse the treatment effect of dichotomous outcomes. We used mean differences with 95% CI to analyse the treatment effect of continuous outcomes. We evaluated the risk of bias. We conducted trial sequential analyses to assess whether firm evidence could be established for a 10% relative risk reduction (RRR) between intervention groups.

We included 72 randomised controlled trials (RCTs) with 22,589 participants; 9707 participants randomised to sulphonylureas versus 12,805 participants randomised to control interventions. The duration of the interventions varied from 24 weeks to 10.7 years. We judged none of the included trials as low risk of bias for all bias domains. Patient-important outcomes were seldom reported.First-generation sulphonylureas (FGS) versus placebo or insulin did not show statistical significance for all-cause mortality (versus placebo: RR 1.46, 95% CI 0.87 to 2.45; P = 0.15; 2 trials; 553 participants; high risk of bias (HRB); versus insulin: RR 1.18, 95% CI 0.88 to 1.59; P = 0.26; 2 trials; 1944 participants; HRB). FGS versus placebo showed statistical significance for cardiovascular mortality in favour of placebo (RR 2.63, 95% CI 1.32 to 5.22; P = 0.006; 2 trials; 553 participants; HRB). FGS versus insulin did not show statistical significance for cardiovascular mortality (RR 1.36, 95% CI 0.68 to 2.71; P = 0.39; 2 trials; 1944 participants; HRB). FGS versus alpha-glucosidase inhibitors showed statistical significance in favour of FGS for adverse events (RR 0.63, 95% CI 0.52 to 0.76; P = 0.01; 2 trials; 246 participants; HRB) and for drop-outs due to adverse events (RR 0.28, 95% CI 0.12 to 0.67; P = 0.004; 2 trials; 246 participants; HRB).Second-generation sulphonylureas (SGS) versus metformin (RR 0.98, 95% CI 0.61 to 1.58; P = 0.68; 6 trials; 3528 participants; HRB), thiazolidinediones (RR 0.92, 95% CI 0.60 to 1.41; P = 0.70; 7 trials; 4955 participants; HRB), insulin (RR 0.96, 95% CI 0.79 to 1.18; P = 0.72; 4 trials; 1642 participants; HRB), meglitinides (RR 1.44, 95% CI 0.47 to 4.42; P = 0.52; 7 trials; 2038 participants; HRB), or incretin-based interventions (RR 1.39, 95% CI 0.52 to 3.68; P = 0.51; 2 trials; 1503 participants; HRB) showed no statistically significant effects regarding all-cause mortality in a random-effects model. SGS versus metformin (RR 1.47; 95% CI 0.54 to 4.01; P = 0.45; 6 trials; 3528 participants; HRB), thiazolidinediones (RR 1.30, 95% CI 0.55 to 3.07; P = 0.55; 7 trials; 4955 participants; HRB), insulin (RR 0.96, 95% CI 0.73 to 1.28; P = 0.80; 4 trials; 1642 participants; HRB) or meglitinide (RR 0.97, 95% CI 0.27 to 3.53; P = 0.97; 7 trials, 2038 participants, HRB) showed no statistically significant effects regarding cardiovascular mortality. Mortality data for the SGS versus placebo were sparse. SGS versus thiazolidinediones and meglitinides did not show statistically significant differences for a composite of non-fatal macrovascular outcomes. SGS versus metformin showed statistical significance in favour of SGS for a composite of non-fatal macrovascular outcomes (RR 0.67, 95% CI 0.48 to 0.93; P = 0.02; 3018 participants; 3 trials; HRB). The definition of non-fatal macrovascular outcomes varied among the trials. SGS versus metformin, thiazolidinediones and meglitinides showed no statistical significance for non-fatal myocardial infarction. No meta-analyses could be performed for microvascular outcomes. SGS versus placebo, metformin, thiazolidinediones, alpha-glucosidase inhibitors or meglitinides showed no statistical significance for adverse events. SGS versus alpha-glucosidase inhibitors showed statistical significance in favour of SGS for drop-outs due to adverse events (RR 0.48, 95% CI 0.24 to 0.96; P = 0.04; 9 trials; 870 participants; HRB). SGS versus meglitinides showed no statistical significance for the risk of severe hypoglycaemia. SGS versus metformin and thiazolidinediones showed statistical significance in favour of metformin (RR 5.64, 95% CI 1.22 to 26.00; P = 0.03; 4 trials; 3637 participants; HRB) and thiazolidinediones (RR 6.11, 95% CI 1.57 to 23.79; P = 0.009; 6 trials; 5660 participants; HRB) for severe hypoglycaemia.Third-generation sulphonylureas (TGS) could not be included in any meta-analysis of all-cause mortality, cardiovascular mortality or non-fatal macro- or microvascular outcomes. TGS versus thiazolidinediones showed statistical significance regarding adverse events in favour of TGS (RR 0.88, 95% CI 0.78 to 0.99; P = 0.03; 3 trials; 510 participants; HRB). TGS versus thiazolidinediones did not show any statistical significance for drop-outs due to adverse events. TGS versus other comparators could not be performed due to lack of data.For the comparison of SGS versus FGS no meta-analyses of all-cause mortality, cardiovascular mortality, non-fatal macro- or microvascular outcomes, or adverse events could be performed.Health-related quality of life and costs of intervention could not be meta-analysed due to lack of data.In trial sequential analysis, none of the analyses of mortality outcomes, vascular outcomes or severe hypoglycaemia met the criteria for firm evidence of a RRR of 10% between interventions.

There is insufficient evidence from RCTs to support the decision as to whether to initiate sulphonylurea monotherapy. Data on patient-important outcomes are lacking. Therefore, large-scale and long-term randomised clinical trials with low risk of bias, focusing on patient-important outcomes are required.

Higher levels of lipid peroxidation and hypomagnesaemia are frequently associated with Type 2 Diabetes mellitus (T2DM). Addressing these issues would definitely help us in preventing or prolonging the onset of pathogenesis of micro and macrovascular complications. Pioglitazone is used as a trusted insulin sensitizer and an adjuvant to the conventional oral hypoglycemic agents. This study was planned to explore the effects of pioglitazone on oxidative stress, serum magnesium, blood pressure, hepato-biliary and renal systems in addition to its effects on glycemic control.

Sixty-three T2DM cases, who were started on pioglitazone were included in this study. All the physiological and biochemical parameters were estimated prior to and following three months of therapy with pioglitazone.

There was significant improvement in the glycemic control, serum magnesium and MDA levels with p values of 0.000, 0.023 and 0.000 respectively. Pioglitazone did not have any significant effects on the serum lipids and blood pressure in T2DM cases following three months of treatment. We did not observe any pronounced changes in hepato-biliary enzymes, serum urea and creatinine levels reaffirming safety of pioglitazone in T2DM.

Three-month duration of treatment with Pioglitazone in T2DM cases helps in alleviating the levels of lipid peroxides, besides being associated with improved serum magnesium status and glycemic control.

Thiazolidinediones (TZDs) initially showed great promise as unique receptor-mediated oral therapy for type 2 diabetes, but a host of serious side effects, primarily cardiovascular, have limited their utility. It is crucial at this point to perform a risk-benefit analysis to determine what role TZDs should play in our current treatment of type 2 diabetes and where the future of this class of drugs is headed.

This review provides a comprehensive overview of the literature from 2000 onward reporting the known side effects of rosiglitazone and pioglitazone, with commentary on the quality of the data available, putative mechanism of each side effect and clinical significance. Finally, a perspective on the future of the TZDs as a class is provided.

The current TZDs are first-generation, non-specific activators of peroxisome proliferator-activated receptor (PPAR) gamma, resulting in a wide array of deleterious side effects that currently limit their use. However, the development of highly targeted selective PPAR gamma modulators (SPPARγMs) and dual PPAR gamma/alpha agonists is on the horizon.

Endoplasmic reticulum (ER) stress has been implicated in the pathology of type 2 diabetes mellitus (T2DM). Although SIRT1 has a therapeutic effect on T2DM, the mechanisms by which SIRT1 ameliorates insulin resistance (IR) remain unclear. In this study, we investigated the impact of SIRT1 on palmitate-induced ER stress in HepG2 cells and its underlying signal pathway. Treatment with resveratrol, a SIRT1 activator significantly inhibited palmitate-induced ER stress, leading to the protection against palmitate-induced ER stress and insulin resistance. Resveratrol and SIRT1 overexpression induced the expression of oxygen-regulated protein (ORP) 150 in HepG2 cells. Forkhead box O1 (FOXO1) was involved in the regulation of ORP150 expression because suppression of FOXO1 inhibited the induction of ORP150 by SIRT1. Our results indicate a novel mechanism by which SIRT1 regulates ER stress by overexpression of ORP150, and suggest that SIRT1 ameliorates palmitate-induced insulin resistance in HepG2 cells via regulation of ER stress.

Hepatic glucose metabolism is a key player in diseases such as obesity and diabetes as well as in antihyperglycemic drugs screening. Hepatocytes culture in two-dimensional configurations is limited in vitro model for hepatocytes to function properly, while truly practical platforms to perform three-dimensional (3D) culture are unavailable. In this work, we present a practical organoid culture method of hepatocytes for elucidation of glucose metabolism under nominal and stress conditions. Employing this new method of culturing cells within a hollow fiber reactor, hepatocytes were observed to self-assemble into 3D spherical organoids with preservation of tight junctions and display increased liver-specific functions. Compared to both monolayer culture and sandwich culture, the hepatocyte organoids displayed higher intracellular glycogen content, glucose consumption, and gluconeogenesis and approached the in vivo values, as also confirmed by gene expression of key enzymes. Moreover, hepatocyte organoids demonstrated more realistic sensitivity to hormonal challenges with insulin, glucagon, and dexamethasone. Finally, the exposure to high glucose demonstrated toxicities including alteration of mitochondrial membrane potential, lipid accumulation, and reactive oxygen species formation, similar to the in vivo responses, which was not captured by monolayer cultures. Collectively, hepatocyte organoids mimicked the in vivo functions better than hepatocyte monolayer and sandwich cultures, suggesting suitability for applications such as antihyperglycemic drugs screening.

Given the increase in medications for type 2 diabetes mellitus, clinicians and patients need information about their effectiveness and safety to make informed choices.

To summarize the benefits and harms of metformin, second-generation sulfonylureas, thiazolidinediones, meglitinides, dipeptidyl peptidase-4 (DPP-4) inhibitors, and glucagon-like peptide-1 receptor agonists, as monotherapy and in combination, to treat adults with type 2 diabetes.

MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from inception through April 2010 for English-language observational studies and trials. The MEDLINE search was updated to December 2010 for long-term clinical outcomes.

Two reviewers independently screened reports and identified 140 trials and 26 observational studies of head-to-head comparisons of monotherapy or combination therapy that reported intermediate or long-term clinical outcomes or harms.

Two reviewers following standardized protocols serially extracted data, assessed applicability, and independently evaluated study quality.

Evidence on long-term clinical outcomes (all-cause mortality, cardiovascular disease, nephropathy, and neuropathy) was of low strength or insufficient. Most medications decreased the hemoglobin A(1c) level by about 1 percentage point and most 2-drug combinations produced similar reductions. Metformin was more efficacious than the DPP-4 inhibitors, and compared with thiazolidinediones or sulfonylureas, the mean differences in body weight were about -2.5 kg. Metformin decreased low-density lipoprotein cholesterol levels compared with pioglitazone, sulfonylureas, and DPP-4 inhibitors. Sulfonylureas had a 4-fold higher risk for mild or moderate hypoglycemia than metformin alone and, in combination with metformin, had more than a 5-fold increased risk compared with metformin plus thiazolidinediones. Thiazolidinediones increased risk for congestive heart failure compared with sulfonylureas and increased risk for bone fractures compared with metformin. Diarrhea occurred more often with metformin than with thiazolidinediones.

Only English-language publications were reviewed. Some studies may have selectively reported outcomes. Many studies were small, were of short duration, and had limited ability to assess clinically important harms and benefits.

Evidence supports metformin as a first-line agent to treat type 2 diabetes. Most 2-drug combinations similarly reduce hemoglobin A(1c) levels, but some increased risk for hypoglycemia and other adverse events.

Agency for Healthcare Research and Quality.

Thiazolidinediones (TZDs) are useful glucose-lowering agents for patients with Type 2 diabetes. Through PPAR-gamma-mediated effects, these drugs not only improve insulin sensitivity and glycemia, they also have beneficial effects on lipid metabolism and the vascular endothelium, with potential to improve cardiovascular risk. However, this promise has not been entirely fulfilled. The first TZD, troglitazone, was withdrawn after reports of severe liver damage. The second TZD, rosiglitazone, has been reported in meta-analyses to be associated with possible increased risk of cardiovascular disease (CVD) events. The third TZD approved for clinical use in the US, pioglitazone, appears to be associated with decreased CVD events in most studies/meta-analyses.

We undertook a literature search in Pubmed from the year 2000 onwards to review the side effect/safety profile of pioglitazone.

A comprehensive summary of the currently available data on the side effect/safety profile of pioglitazone.

The main adverse effects reported with pioglitazone are those common to the TZD class: weight gain, pedal edema, bone loss and precipitation of congestive heart failure in at-risk individuals, without any increase in CVD/all-cause mortality. Overall, the safety profile of pioglitazone is favorable and remains a useful option for the treatment of insulin-resistant patients with Type 2 diabetes. Further studies are needed to confirm/clarify its cardiovascular benefits.