Use Of Thiazolidinediones Research Articles

Effect of Hexadecyl Azelaoyl Phosphatidylcholine on Cardiomyocyte Apoptosis in Myocardial Ischemia-Reperfusion Injury: A Hypothesis.

Reperfusion after myocardial ischemia can induce cardiomyocyte death, known as myocardial reperfusion injury. The pathophysiology of the process of reperfusion suggests the confluence multiple pathways. Recent studies have focused on the inflammatory response, which is considered to be the main mechanism during the process of myocardial ischemia-reperfusion injury and can cause cardiomyocyte apoptosis. Peroxisome proliferator-activated receptors gamma activated by endogenous ligands and exogenous ligand can decrease the inflammatory response in cardiomyocytes. Thiazolidinediones are synthetic, high-affinity, selective ligands for peroxisome proliferator-activated receptors gamma, and can inhibit the inflammatory response, decrease myocardial infarct size, and protect cardiac function. However, thiazolidinediones, including rosiglitazone and pioglitazone, can also contribute to adverse cardiovascular events such as congestive heart failure. Therefore, there are some limitations to the use of thiazolidinediones. Most endogenous ligands were of low affinity until hexadecyl azelaoyl phosphatidylcholine was identified as a high-affinity ligand and agonist for peroxisome proliferator-activated receptors gamma. Hexadecyl azelaoyl phosphatidylcholine binds recombinant peroxisome proliferator-activated receptors with an affinity (Kd(app) ≈40 nM) which is equivalent to rosiglitazone. Therefore, hexadecyl azelaoyl phosphatidylcholine is a specific peroxisome proliferator-activated receptors gamma agonist. Given these findings, we hypothesized that the use of hexadecyl azelaoyl phosphatidylcholine can activate the peroxisome proliferator-activated receptors gamma signal pathways and prevent the inflammatory response process of myocardial ischemia-reperfusion injury, with reduced cardiomyocyte apoptosis and death.

A Pharmacogenetic Approach to the Treatment of Patients With PPARG Mutations.

Loss-of-function mutations in PPARG cause familial partial lipodystrophy type 3 (FPLD3) and severe metabolic disease in many patients. Missense mutations in PPARG are present in ∼1 in 500 people. Although mutations are often binarily classified as benign or deleterious, prospective functional classification of all missense PPARG variants suggests that their impact is graded. Furthermore, in testing novel mutations with both prototypic endogenous (e.g., prostaglandin J2 [PGJ2]) and synthetic ligands (thiazolidinediones, tyrosine agonists), we observed that synthetic agonists selectively rescue function of some peroxisome proliferator-activated receptor-γ (PPARγ) mutants. We report on patients with FPLD3 who harbor two such PPARγ mutations (R308P and A261E). Both PPARγ mutants exhibit negligible constitutive or PGJ2-induced transcriptional activity but respond readily to synthetic agonists in vitro, with structural modeling providing a basis for such differential ligand-dependent responsiveness. Concordant with this finding, dramatic clinical improvement was seen after pioglitazone treatment of a patient with R308P mutant PPARγ. A patient with A261E mutant PPARγ also responded beneficially to rosiglitazone, although cardiomyopathy precluded prolonged thiazolidinedione use. These observations indicate that detailed structural and functional classification can be used to inform therapeutic decisions in patients with PPARG mutations.

Thiazolidinediones and Risk of Atrial Fibrillation Among Patients with Diabetes and Coronary Disease

BackgroundWe sought to determine whether insulin-sensitizing therapy (thiazolidinediones or metformin) decreased the risk of developing atrial fibrillation compared with insulin-providing therapy (insulin, sulfonylurea, or a meglitinide). Thiazolidinediones are insulin sensitizers that also decrease the inflammatory response. Because inflammation is a risk factor for atrial fibrillation, we hypothesized that treating diabetes with thiazolidinediones might decrease the risk of developing atrial fibrillation. MethodsThe Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial enrolled patients with type 2 diabetes and documented coronary artery disease. All patients were randomized to insulin-sensitizing therapy or insulin-providing therapy. ResultsA total of 2319 patients entered the study, with 1160 assigned to the insulin-sensitization strategy and 1159 assigned to the insulin-provision strategy. Over a median follow-up of 4.2 years, 90 patients (3.9%) developed new-onset atrial fibrillation. In the intention-to-treat analysis, the incidence of atrial fibrillation was 8.7 per 1000 person-years in patients assigned to insulin sensitization compared with 9.5 in patients assigned to insulin provision with a hazard ratio (HR) of 0.91 (95% confidence interval [CI], 0.60-1.38, P = .66). In a time-varying exposure analysis, the incidence rate per 1000 person-years was 7.2 while exposed to thiazolidinediones and 9.7 while not exposed to thiazolidinediones with an adjusted HR of 0.80 (95% CI, 0.33-1.94, P = .62). In a subset of patients matched on propensity to receive a thiazolidinediones, the HR was 0.75 (95% CI, 0.43-1.30, P = .30). ConclusionsWe did not find a significant reduction of atrial fibrillation incidence with use of thiazolidinediones.

Trends in Diabetes Treatment and Monitoring among Medicare Beneficiaries.

Diabetes is a costly and common condition, but little is known about recent trends in diabetes management among Medicare beneficiaries. To evaluate the use of diabetes medications and testing supplies among Medicare beneficiaries. Retrospective cohort analysis of Medicare claims from 2007 to 2014. Traditional Medicare beneficiaries with a diagnosis of diabetes in the current or any prior year. We analyzed choices of first diabetes medication for those new to medication and patterns of adding medications. We also examined the use of testing supplies, use of statins and ACE inhibitors/angiotensin receptor blockers, and spending. Diagnosed diabetes increased from 28.7% to 30.2% of beneficiaries from 2007 to 2014. The use of metformin as the most commonly prescribed first medication increased from 50.2% in 2007 to 70.2% in 2014, whereas long-acting sulfonylureas decreased from 16.6% to 8.2%. The use of thiazolidinediones fell considerably, while the use of new diabetes medication classes increased. Among patients prescribed insulin, long-acting insulin as the first choice increased substantially, from 38.9% to 56.8%, but short-acting or combination regimens remained common, particularly among older or sicker beneficiaries. Prescriptions of testing supplies for more than once-daily testing were also common. The mean total cost of diabetes medications per patient increased over the period due to the increasing use of high-cost drugs, particularly by those patients with costs above the 90th percentile of spending, although the median costs decreased for both medications and testing supplies. The use of metformin and long-acting insulin have increased substantially among elderly Medicare patients with diabetes, but a substantial subgroup continues to receive costly and complex treatment regimens.

Thiazolidinediones and risk of colorectal cancer in patients with diabetes mellitus: A meta-analysis.

Background/Aims:A growing body of evidence has suggested that thiazolidinediones (TZDs) potentially reduce the risk of colorectal cancer (CRC). This study aimed to evaluate the effect of TZDs on CRC risk in patients with diabetes mellitus (DM).Patients and Methods:A systematic search of electronic databases was performed for studies evaluating the exposure to TZDs and reporting CRC risk in diabetic patients. Pooled estimates with 95% confidence intervals (CIs) were estimated using fixed or random effects models.Results:A total of 10 observational studies reporting more than 18,972 CRC cases in 2,470,768 DM patients were included. Meta-analysis showed a 9% reduction in CRC risk associated with TZDs use in all studies [relative risk (RR) =0.91, 95% CI = 0.84–0.99, P = 0.03] and cohort studies (RR = 0.89, 95% CI = 0.80–0.99, P = 0.04), respectively. However, such effect was not shown in case–control studies. In subgroup analyses, lower CRC risk was found in Asian population (RR = 0.40, 95% CI = 0.29–0.53, P = 0.00), and a trend toward lower CRC risk was observed in US population (RR = 0.94, 95% CI = 0.88–1.01, P = 0.08). CRC risk was significantly modified with non-pioglitazone TZD use (RR = 0.88, 95% CI = 0.82–0.95, P = 0.00), but not with pioglitazone use (RR = 0.95, 95% CI = 0.89–1.01, P = 0.11). No significant difference was observed with cancer site (colon or rectum). There was considerable inherent heterogeneity across studies, partly explained by study location.Conclusions:This meta-analysis supports a protective association between TZDs use and CRC risk in patients with DM. Future well-designed prospective studies with larger cohorts would be needed to understand this association better.

Lack of Longitudinal Association Between Thiazolidinediones and Incidence and Progression of Diabetic Eye Disease: The ACCORD Eye Study

To report the longitudinal association between use of thiazolidinediones (TZDs), visual acuity (VA) change, and diabetic eye disease incidence and progression. Cohort study ancillary to a randomized clinical trial. We analyzed baseline and 4-year follow-up data of 2856 ACCORD trial participants with no history of proliferative diabetic retinopathy. Based on stereoscopic fundus photographs, we evaluated diabetic macular edema (DME) progression and DR progression. We also evaluated 10- and 15-letter change on the ETDRS visual acuity chart. Main outcome measures were incidence or progression of DME or DR and change in visual acuity. TZD use was not associated with DME incidence in either the analysis of any use (adjusted odds ratio [aOR] [95% CI]: 1.22 [0.72-2.05]) or duration of use (aOR: 1.02 [0.99-1.04]). Diabetic retinopathy (DR) incidence/progression was more common in patients with no or mild DR at baseline who were ever treated with TZDs (aOR: 1.68 [1.11-2.55]), but this association disappeared when adjusting for the time on TZD (aOR: 1.02 [1.00-1.04]). DR progression among those with moderate or worse DR at baseline was no different between TZD users and non-users. TZD usage had no effect on the ultimate visual acuity outcome. In this longitudinal study of patients with type 2 diabetes, we found no association between TZD use and visual acuity outcomes or DME progression, and no consistent evidence of increased DR progression in patients ever treated with TZDs vs those never treated with TZDs.

Thiazolidinedione therapy and breast cancer risk in diabetic women: A systematic review and meta-analysis.

Rising experimental evidence suggests that thiazolidinediones (TZDs) exert a protective effect on breast cancer. However, studies concerning this issue were inconsistent and limited. Hence, we performed a meta-analysis with data from currently available studies to evaluate the effect of TZDs on breast cancer risk among diabetic women. We comprehensively searched for all pertinent studies addressing TZDs use and breast cancer risk published before January 1, 2016, in PubMed, Clinical Trials, and Cochrane Library. Data synthesis was performed in a random-effects model using Stata version 12.0 (Stata Corp, College Station, Texas). Fourteen independent studies were eventually selected in this meta-analysis, including 5 randomized controlled clinical trials (RCTs), 7 cohort studies, and 2 case-control studies. No significant associations of TZD use and risk of breast cancer were observed in the RCTs (pooled risk ratio [RR]: 0.77, 95% confidence interval (CI), 0.39-1.53, I2 =26%) or case-control studies (pooled odds ratio, 0.99, 95% CI, 0.76-1.28, I2 =31%). A 19% reduction in breast cancer risk (pooled RR: 0.81, 95% CI, 0.66-0.99, I2 =72%) was found in the cohort studies. However, after removing the study with the smallest event number and the greatest effect size, the association became nonsignificant with greatly decreased heterogeneity (pooled RR: 0.94, 95% CI, 0.86-1.03, I2 =16%). This meta-analysis did not find any significant association between TZDs use and risk of breast cancer among diabetic women.

Factors Associated with Type 2 Diabetes Mellitus Treatment Choice Across Four European Countries

PurposeThe aim of this analysis was to identify factors associated with the choice of type 2 diabetes mellitus (T2DM) therapy at the time of intensification of antidiabetic treatment across 4 European countries. MethodsAntidiabetic drug prescription/dispensing records and patients' characteristics were obtained from the electronic health care records of patients with T2DM from the Netherlands (NL), Italy, and Spain (ES) (all, 2007–2011); and the United Kingdom (UK; 2008–2012). Oral monotherapy was defined as first-line; oral dual therapy, as second-line; >2 oral treatments or oral combined with an injectable, as third-line; and injectables only, as fourth-line treatment. Treatment intensification was defined as the start of a higher line of treatment. Comedication, comorbidities, clinical parameters, and other factors associated with treatment choice were identified using multivariate relative risk estimation by Poisson regression with robust error variance. FindingsIn the 5-year study period, 485,120 patients (79% of the treated T2DM population) underwent treatment intensification. Changes in treatment choice were clearly visible over the study period, such as a decline in the use of thiazolidinediones (NL, ES, UK) and increases in the use of dipeptidyl peptidase-4 inhibitors (DPP4i) (NL, ES, UK) and glucagon-like peptide-1 receptor agonists (UK). With first-line treatment, advanced age and renal comorbidity were associated with the use of sulfonylureas (SUs; all countries), whereas high body mass index (BMI) was inversely associated with SU use in the United Kingdom and Spain. With second-line treatment, advanced age was associated with metformin + SU use (all countries); and renal comorbidity with SU + DPP4i use in the United Kingdom and the Netherlands. High BMI was associated with metformin + thiazolidinedione (TZD) use in the United Kingdom and Spain, and with metformin + DPP4i in the United Kingdom. With third-line treatment, advanced age and renal comorbidity were associated with the use of SU + insulin (NL, ES, UK). Hemoglobin A1c >8.5% was positively associated, and high BMI was inversely associated, with the use of any third-line combination containing insulin. Across treatment lines TZD and metformin were negatively associated with renal and cardiac morbidity. Second and third line treatment choices strongly depended on prior treatments. With fourth-line treatment, women were more likely to receive glucagon-like peptide-1 receptor agonists than were men in the United Kingdom and Spain. ImplicationsThe results suggest that the main factors driving treatment choice at any stage of intensification were age, hemoglobin A1c, BMI, renal and cardiac morbidity, and treatment history. These drivers were consistent with guidelines on, and contraindications of, specific medications. Differences between countries were generally consistent with, but not solely attributable to, differences in local guidelines and reimbursement policies.

Effects of thiazolidinedione in patients with active bladder cancer.

To examine the influence of perioperative thiazolidinedione (TZD) on cancer-specific outcomes in patients with diabetes mellitus (DM) undergoing radical cystectomy (RC) for urothelial carcinoma (UC). A retrospective cohort of 173 patients with DM undergoing RC from 2005 to 2010 was identified. Of those, 53 were on TZD treatment at the time of RC, with 33 patients taking pioglitazone. Baseline clinicopathological characteristics, as well as cancer-specific survival (CSS), recurrence-free survival (RFS), and overall survival (OS) were compared between the patients on and off TZD therapy at the time of RC. In subgroup analysis, outcomes in patients specifically taking pioglitazone at the time of RC were compared to those not on a TZD. Baseline clinicopathological characteristics were similar between patients on and off TZD therapy at the time of RC. Overall, the median CSS rate was not reached in either group (P = 0.7). The estimated 5-year CSS was 67.8% in the non-TZD group and 66.3% in the TZD group. On multivariate analysis incorporating patient age, pathological T-staging, and adjuvant chemotherapy, TZD use was found not to be a significant predictor for CSS (hazard ratio 1.20, 95% confidence interval 0.66-2.17; P = 0.5). Additionally, RFS (P= 0.3) and OS (P = 0.2) were also similar between the two groups without adjusting for other variables. Comparison between patients taking pioglitazone vs patients not taking TZD yielded similar CSS (P = 0.2), RFS (P = 0.5), and OS (P= 0.2). CSS, as well as RFS and OS after RC were not compromised in patients on TZD therapy at the time of RC. Additional investigation is warranted in patients with non-muscle-invasive bladder cancer and muscle-invasive bladder cancer undergoing bladder-sparing procedures to assess the safety of using TZD in the setting of active UC.

Use of thiazolidinediones and risk of hip fracture in old people in a case-control study in Taiwan.

Little research is available on the association between use of thiazolidinediones and hip fracture in old people in Taiwan. We conducted a population-based case–control study to examine this issue.Using the database of the Taiwan National Health Insurance Program, we identified 603 type 2 diabetic subjects 65 years or older in age with newly diagnosed hip fracture in 2000 to 2013 as cases. We randomly selected 603 type 2 diabetic subjects 65 years or older without hip fracture as the controls. Both cases and controls were matched with sex, age, comorbidities, and index year of diagnosing hip fracture. Current use of thiazolidinediones was defined as subjects whose last remaining one tablet of thiazolidinediones was noted ≤30 days before the date of diagnosing hip fracture. Never use of thiazolidinediones was defined as subjects who never had a prescription of thiazolidinediones. The odds ratio (OR) and 95% confidence interval (CI) for hip fracture associated with thiazolidinediones use was estimated by the multivariable unconditional logistic regression analysis.After adjustment for covariables, the multivariable logistic regression analysis revealed that the adjusted OR of hip fracture was 1.64 for subjects with current use of thiazolidinediones (95% CI 1.01, 2.67), when compared with subjects with never use of thiazolidinediones.Our findings suggest that current use of thiazolidinediones is associated with a 64% higher risk of hip fracture in type 2 diabetic old people in Taiwan. Clinicians should consider the possibility of thiazolidinediones-associated hip fracture among type 2 diabetic old people currently using thiazolidinediones.

Efekt antidiabetickej liečby na kosť

It is well established that osteoporosis and diabetes are prevalent diseases with significant associated morbidity and mortality. Patients with diabetes mellitus are at an increased risk of bone fractures. Today we have several groups of effective and save antidiabetic drugs, which are very given often in combination. Although diabetes-related complications are important in the etiology, the effects of medications on bone metabolism and fracture risk should not be neglected, because the diabetes medication may affect also bone health and fracture risk. Increased risk of fracture has been identified with use of thiazolidinediones, most definitively in women. Also treatment with sulfonylureas can have negative adverse effect on bone. One consequence of these findings has been greater attention to fracture outcomes in trails of new diabetes medication (incretins and SGLT2 inhibitors). The aim of the review is to summarize effects of antidiabetic treatment on bone - bone mineral density, fractures and bone turnover markers. The authors also try to recommend a strategy how to treat a diabetic patient regarding the risk of osteoporotic fractures.Key words: antidiabetic drugs - diabetes mellitus - fracture risk - osteoporosis.

Does Weight Gain Associated with Thiazolidinedione Use Negatively Affect Cardiometabolic Health?

Thiazolidinediones (TZDs) are oral anti-diabetic drugs that are peroxisome proliferator-activated receptor gamma (PPARγ) agonists and act as insulin sensitizers. The clinical efficacy and durability of the currently available TZDs in improving glycemic control are well established. However, TZDs cause weight gain, which has been thought to be a class effect of TZDs. TZD-associated weight gain may result mainly from increased fat mass and fluid retention and may be in part congruent to the mechanism of action of TZD. Increases in fat mass are almost exclusively limited to subcutaneous fat, while there are no effects or even decreases in visceral fat. Insulin resistance and cardiovascular risk associated with fat accumulation (obesity) depend on body fat distribution, with visceral fat associated with insulin resistance and a greater degree of risk than subcutaneous fat. Therefore, despite TZD-associated weight gain, TZDs are less likely to confer an increased risk of insulin resistance and cardiovascular complications. As patients with diabetes are younger and/or more obese in Korea, TZDs may be a cost-effective treatment option, offering a unique insulin-sensitizing action and good durability for the long-term management of type 2 diabetes.

Use of oral antidiabetic agents and risk of community-acquired pneumonia: a nested case-control study.

To evaluate the association between use of different oral antidiabetic agents (OAD) and the risk of community-acquired pneumonia (CAP) in patients with type-2 diabetes (T2DM). Case-control study nested in a cohort of patients with T2DM and use of OAD between 2002 and 2013, based in a Spanish general practice research database. Cases were people diagnosed with T2DM, aged >18 years and with a validated diagnosis of CAP between 2002 and 2013. Ten controls were matched on age, sex and calendar year. Odds ratio (OR) of CAP was estimated comparing patients treated with: (1) metformin vs. other monotherapies or no antidiabetic treatment; (2) metformin + sulfonylureas vs. other antidiabetic combinations. OR of CAP was also assessed according to antidiabetic treatment duration. From a cohort of 76 009 T2DM patients, we identified 1803 cases of CAP. No difference in the incidence of CAP was observed when comparing any OAD in monotherapy with metformin. Compared with current use of metformin + sulfonylurea, thiazolidinediones + metformin was associated with an increased risk of CAP (adjusted OR = 2.48, 95% CI 1.40-4.38). The use of any combination with thiazolidinediones was also associated with higher risk of CAP (adjusted OR = 2.00, 95% CI 1.22-3.28). Current use of DPP-4 inhibitors was not associated with an increased risk of CAP. No differences in the incidence of CAP were observed between the use of OAD in monotherapy vs. metformin. Thiazolidinedione use in combination was associated with an increase in the risk of CAP when compared to metformin + sulfonylureas. The use of DPP-4 inhibitors was not associated with an increased risk of CAP.

Thiazolidinedione use and atrial fibrillation in diabetic patients: a meta-analysis

BackgroundAccumulating evidence suggests that thiazolidinediones (TZDs) may exert protective effects in atrial fibrillation (AF). The present meta-analysis investigated the association between TZD use and the incidence of AF in diabetic patients.MethodsElectronic databases were searched until December 2016. Of the 346 initially identified records, 3 randomized clinical trials (RCTs) and 4 observational studies with 130,854 diabetic patients were included in the final analysis.ResultsPooled analysis of the included studies demonstrated that patients treated with TZDs had approximately 30% lower risk of developing AF compared to controls [odds ratio (OR): 0.73, 95% confidence interval (CI): 0.62 to 0.87, p = 0.0003]. This association was consistently observed for both new onset AF (OR =0.77, p = 0.002) and recurrent AF (OR =0.41, p = 0.002), pioglitazone use (OR =0.56, p = 0.04) but not rosiglitazone use (OR =0.78, p = 0.12). The association between TZD use and AF incidence was not significant in the pooled analysis of three RCTs (OR =0.77, 95% CI = 0.53–1.12, p = 0.17), but was significantly in the pooled analysis of the four observational studies (OR =0.71, p = 0.0003).ConclusionsThis meta-analysis suggests that TZDs may confer protection against AF in the setting of diabetes mellitus (DM). This class of drugs can be used as upstream therapy for DM patients to prevent the development of AF. Further large-scale RCTs are needed to determine whether TZDs use could prevent AF in the setting of DM.

Abstract 013: Using the Diabetes Collaborative Registry (DCR) to Estimate the Potential Real-world Impact of the Iris Trial on Improving Outcomes in Patients With Cerebrovascular Disease

Background: Thiazolidinediones use has markedly decreased since concerns arose regarding the CV safety of rosiglitazone. Recently, however, the IRIS trial demonstrated that pioglitazone reduced the risk of MI and stroke in patients with recent stroke or TIA and insulin resistance but without overt type 2 diabetes (T2D). We estimated the current use and potential impact of pioglitazone in patients enrolled in the Diabetes Collaborative Registry (DCR). Methods: DCR is a US-based outpatient registry of patients with diabetes or prediabetes seen in cardiology, endocrinology, and primary care practices and currently encompasses 374 practices and 5114 providers. Patients ≥40 years with HbA1c <7% on no diabetes medications (other than pioglitazone), prior stroke or TIA, and no history of heart failure were considered potentially eligible for IRIS. Although IRIS determined insulin resistance based on HOMA-IR levels, these were not available in DCR, and thus HbA1c levels were used as surrogates. Results: Among 242,590 patients in DCR with HbA1c data, 58,466 had prediabetes or diet-controlled T2D. Of these, 6,772 (12%) were deemed potentially IRIS-eligible. Mean age was 70 y, 52% were men, and mean HbA1c was 6.0%. Pioglitazone was used in 146 of these patients (2.2%); rates were slightly higher among patients seen by cardiologists vs. endocrinologists vs. primary care (2.6% vs. 1.4% vs. 0.0%, p<0.001). Patients treated (vs. not) with pioglitazone were more likely to be older (73 vs. 70 y), have higher body mass indices (32 vs. 30 kg/m 2 ), higher HbA1c (6.1 vs. 5.9%), and concomitant coronary artery disease (69% vs. 56%) (all p<0.02). If all potentially eligible patients in DCR were treated with pioglitazone for 4.8 years, 93 strokes and 86 myocardial infarctions may have been prevented, assuming similar risk reductions in this “real-world” patient population as observed in IRIS. Conclusion: In a large US-based outpatient registry, we found that 12% of outpatients with prediabetes or diet-controlled T2D met the main eligibility criteria for IRIS, partly due to the narrow inclusion criteria of the trial but also likely reflective of a general paucity of screening for prediabetes and insulin resistance in this cohort. Pioglitazone was rarely used in these patients but could have a substantial impact on CV outcomes in these eligible patients. The population impact could be even greater if the CV benefit of pioglitazone can be demonstrated in patients with cerebrovascular disease and overt T2D or even the broader population of patients with insulin resistance and cardiovascular disease. The effect of pioglitazone in these patients, who are also at high CV risk, should be the focus of future work.

Protective Effects of Vildagliptin against Pioglitazone-Induced Bone Loss in Type 2 Diabetic Rats.

Long-term use of thiazolidinediones (TZDs) is associated with bone loss and an increased risk of fracture in patients with type 2 diabetes (T2DM). Incretin-based drugs (glucagon-like peptide-1 (GLP-1) agonists and dipeptidylpeptidase-4 (DPP-4) inhibitors) have several benefits in many systems in addition to glycemic control. In a previous study, we reported that exendin-4 might increase bone mineral density (BMD) by decreasing the expression of SOST/sclerostin in osteocytes in a T2DM animal model. In this study, we investigated the effects of a DPP-4 inhibitor on TZD-induced bone loss in a T2DM animal model. We randomly divided 12-week-old male Zucker Diabetic Fatty (ZDF) rats into four groups; control, vildagliptin, pioglitazone, and vildagliptin and pioglitazone combination. Animals in each group received the respective treatments for 5 weeks. We performed an intraperitoneal glucose tolerance test (IPGTT) before and after treatment. BMD and the trabecular micro-architecture were measured by DEXA and micro CT, respectively, at the end of the treatment. The circulating levels of active GLP-1, bone turnover markers, and sclerostin were assayed. Vildagliptin treatment significantly increased BMD and trabecular bone volume. The combination therapy restored BMD, trabecular bone volume, and trabecular bone thickness that were decreased by pioglitazone. The levels of the bone formation marker, osteocalcin, decreased and that of the bone resorption marker, tartrate-resistant acid phosphatase (TRAP) 5b increased in the pioglitazone group. These biomarkers were ameliorated and the pioglitazone-induced increase in sclerostin level was lowered to control values by the addition of vildagliptin. In conclusion, our results indicate that orally administered vildagliptin demonstrated a protective effect on pioglitazone-induced bone loss in a type 2 diabetic rat model.

Effect of statin on hepatocellular carcinoma in patients with type 2 diabetes: A nationwide nested case-control study.

Relationship on new statin use and the risk of hepatocellular carcinoma (HCC) in patients with incident type 2 diabetes mellitus (T2DM), who might be at the risk of developing HCC, is uncertained. A nationwide population-based nested case-control study was conducted within the National Health Insurance Service National Sample Cohort 2002-2013 in Korea. Newly prescribed statin after newly diagnosed T2DM was defined as statin use. Controls were matched to case patients on age, sex, follow-up time, and the date of diabetes diagnosis at a five-to-one ratio. Odds ratios (ORs) for associations of statin use with HCC were calculated using conditional logistic regression. After at least a 5-year HCC-free period, there were 229 incident HCC cases and 1,145 matched controls from 47,738 patients with incident diabetes. Of these 229 incident HCC cases, 27 (11.8%) were statin users, whereas 378 (33.0%) were statin users among 1,145 controls. Statin use was associated with a reduced risk of HCC development (adjusted OR [AOR]= 0.36, 95% confidence interval [CI] 0.22-0.60) after adjustment for chronic viral hepatitis, liver cirrhosis, alcoholic liver disease, previous cancer, aspirin use, insulin use, sulfonylurea use, metformin use, thiazolidinedione use, history of chronic obstructive pulmonary disease, Charlson comorbidity score, household income level, and residential area. Risk reduction was accentuated with an increase of cumulative defined daily doses (cDDD) compared with non-users (AORs 0.53, 0.36, 0.32, and 0.26 in ≤60, 60-180, 181-365, and >365cDDD, respectively; P for trend <0.0001). The risk reduction was apparent in the presence of liver disease (AOR = 0.27, 95% CI 0.14-0.50), including heterogeneous groups of clinical diagnosis of liver disease, but not significant in the absence of liver disease (AOR = 0.64, 95% CI 0.32-1.29). Among patients with new onset T2DM, statin use before HCC diagnosis may have a beneficial inhibitory effect on HCC development in a dose-dependent manner, especially in individuals with liver disease.

Patient Education: Preventing Progression of Type 2 Diabetes: The Reflex to Use Pharmacological Therapy

Primary care providers are often neglectful of lifestyle interventions in the management of the progression of glucose intolerance to type 2 diabetes. Several studies have examined the benefits of pharmacologic therapy in conjunction with lifestyle modification to delay or retard this progression. This article focuses on 3 of these studies: the DREAM trial, the ADOPT trial, and the Finnish Diabetes Study. All reinforce the use and effectiveness of thiazolidinediones in the prevention of progression, yet active lifestyle intervention complements and maintains a lower diabetes risk over time.

Characterization of alendronic- and undecylenic acid coated magnetic nanoparticles for the targeted delivery of rosiglitazone to subcutaneous adipose tissue

Obesity is a state of positive energy balance where excess white adipose tissue accumulates to the detriment of metabolic health. Improving adipocyte function with systemic administration of thiazolidinediones (TZDs) improves metabolic outcomes in obesity, however TZD use is limited clinically due to undesirable side effects. Here we evaluate magnetic nanoparticles (MNPs) as a tool to target rosiglitazone (Rosi) specifically to adipose tissue. Results show Rosi can be adsorbed to MNPs (Rosi-MNPs) with hydrophobic coatings for which we present binding and release kinetics. Rosi adsorbed to MNPs retained the ability to induce PPARγ target gene expression in cells. Biodistribution analysis of radiolabeled Rosi-MNPs revealed a fat-implanted magnet significantly enhanced localization of Rosi to the targeted adipose tissue when administered by subcutaneous injection to obese mice. We propose MNPs for targeted delivery of anti-diabetic agents to superficially located subcutaneous adipose tissue.

Anti-Hyperglycemic Agents and New-Onset Acute Myocardial Infarction in Diabetic Patients with End-Stage Renal Disease Undergoing Dialysis.

BackgroundDiabetes and chronic kidney disease (CKD) are a high-stakes combination for cardiovascular disease. Patients with decreased kidney function and end-stage renal disease (ESRD) have increased risk of hypoglycemia when attaining better glycemic control, leading to higher risk of myocardial infarction (MI). For these patients, which kinds of anti-hyperglycemic agents would be associated with higher risk of MI is not clear.MethodsWe identified patients from a nation-wide database called Registry for Catastrophic Illness, which encompassed almost 100% of the patients receiving dialysis therapy in Taiwan from 1995 to 2008. Patients with diabetes and ESRD were selected as the study cohort. Propensity score adjustment and Cox's proportional hazards regression model were used to estimate the hazard ratios (HRs) for new-onset MI.ResultsAmong 15,161 patients, 39% received insulin, 40% received sulfonylureas, 18% received meglitinides and 3% received thiazolidinedione (TZD). After a median follow-up of 1,357 days, the incidence of MI was significant increase in patients taking sulfonylureas (HR = 1.523, 95% confidence interval [CI] = 1.331–1.744), meglitinides (HR = 1.251, 95% CI = 1.048–1.494) and TZD (HR = 1.515, 95% CI = 1.071–2.145) by using patients receiving insulin therapy as the reference group. The risk of MI remains higher in other three groups in subgroup analyses.ConclusionsIn conclusion, among diabetic patients with ESRD undergoing dialysis, the use of sulfonylureas, meglitinides and TZD are associated with higher risk of new-onset MI as compared with insulin.