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1.  Risk of Fracture with Thiazolidinediones: An Individual Patient Data Meta-Analysis 
Background: The use of thiazolidinediones (TZDs) has been associated with increased fracture risks. Our aim was to estimate the risk of fracture with TZDs in three different healthcare registries, using exactly the same study design, and to perform an individual patient data meta-analysis of these three studies.
Methods: Population-based cohort studies were performed utilizing the British General Practice Research Database (GPRD), the Dutch PHARMO Record Linkage System (RLS), and the Danish National Health Registers. In all three databases, the exposed cohort consisted of all patients (aged 18+) with at least one prescription of antidiabetic (AD) medication. Cox proportional hazards models were used to estimate hazard ratios (HRs) of fracture. The total period of follow-up for each patient was divided into periods of current exposure and past exposure, with patients moving between current and past use.
Results: In all three registries, the risk of fracture was increased for women who were exposed to TZDs: HR 1.48 (1.37–1.60) in GPRD, HR 1.35 (1.15–1.58) in PHARMO, and HR 1.22 (1.03–1.44) in Denmark. Combining the data in an individual patient data meta-analysis resulted, for women, in a 1.4-fold increased risk of any fracture for current TZD users versus other AD drug users [adj. HR 1.44 (1.35–1.53)]. For men, there was no increased fracture risk [adj. HR 1.05 (0.96–1.14)]. Risks were increased for fractures of the radius/ulna, humerus, tibia/fibula, ankle, and foot, but not for hip/femur or vertebral fractures. Current TZD users with more than 25 TZD prescriptions ever before had a 1.6-fold increased risk of fracture compared with other AD drug users [HR 1.59 (1.46–1.74)].
Conclusion: In this study, we consistently found a 1.2- to 1.5-fold increased risk of fractures for women using TZDs, but not for men, across three different healthcare registries. TZD users had an increased risk for fractures of the extremities, and risks further increased for prolonged users of TZDs.
PMCID: PMC3582108  PMID: 23549934
thiazolidinediones; fracture; individual patient data; meta-analysis; epidemiology
2.  The Risk of Fractures Associated with Thiazolidinediones: A Self-controlled Case-Series Study 
PLoS Medicine  2009;6(9):e1000154.
Ian Douglas and colleagues analyze records from the UK General Practice Research Database, and find that among individuals prescribed thiazolidinediones who develop a fracture, fractures are more common during periods of thiazolidinedione exposure than unexposed periods.
The results of clinical trials have suggested that the thiazolidinedione antidiabetic agents rosiglitazone and pioglitazone are associated with an increased risk of fractures, but such studies had limited power. The increased risk in these trials appeared to be limited to women and mainly involved fractures of the arm, wrist, hand, or foot: risk patterns that could not be readily explained. Our objective was to further investigate the risk of fracture associated with thiazolidinedione use.
Methods and Findings
The self-controlled case-series design was used to compare rates of fracture during thiazolidinedione exposed and unexposed periods and thus estimate within-person rate ratios. We used anonymised primary care data from the United Kingdom General Practice Research Database (GPRD). All patients aged 40 y or older with a recorded fracture and at least one prescription for a thiazolidinedione were included (n = 1,819). We found a within-person rate ratio of 1.43 (95% confidence interval [CI] 1.25–1.62) for fracture at any site comparing exposed with unexposed periods among patients prescribed any thiazolidinedione. This association was similar in men and women and in patients treated with either rosiglitazone or pioglitazone. The increased risk was also evident at a range of fracture sites, including hip, spine, arm, foot, wrist, or hand. The risk increased with increasing duration of thiazolidinedione exposure: rate ratio 2.00 (95% CI 1.48–2.70) for 4 y or more of exposure.
Within individuals who experience a fracture, fracture risk is increased during periods of exposure to thiazolidinediones (both rosiglitazone and pioglitazone) compared with unexposed periods. The increased risk is observed in both men and women and at a range of fracture sites. The risk also increases with longer duration of use.
Please see later in the article for the Editors' Summary
Editors' Summary
Worldwide, nearly 250 million people have diabetes and this number is increasing rapidly, particularly in developing countries. Diabetes is a chronic disease characterized by dangerous amounts of sugar (glucose) in the blood. Blood-sugar levels are normally controlled by insulin, a hormone that the pancreas releases when blood-sugar levels rise after eating (the digestion of food produces glucose). Blood-sugar control fails in people with diabetes because they make no insulin (type 1 diabetes) or because the fat cells and muscle cells that usually respond to insulin by removing sugar from the blood have become insulin insensitive (type 2 diabetes). Type 1 diabetes is treated with insulin injections; type 2 diabetes—the most common type of diabetes—is controlled with diet, exercise, and antidiabetic pills, drugs that help the pancreas make more insulin (for example, sulfonylureas) or that make cells more sensitive to insulin (for example, thiazolidinediones). Long-term complications of diabetes include kidney failure, blindness, and nerve damage, and an increased risk of developing cardiovascular problems, including heart disease and strokes.
Why Was This Study Done?
Thiazolidinediones are widely used to treat type 2 diabetes but, worryingly, these drugs seem to increase people's risk of developing cardiovascular problems. In addition, they may increase the risk of bone fractures although the evidence for this particular association is limited. Given the large number of people with diabetes, it is important to understand the benefits and risks of thiazolidinedione treatment of diabetes as fully as possible. In this self-controlled case-series study, therefore, the researchers investigate the risk of fracture associated with the use of rosiglitazone and pioglitazone (two thiazolidinedione antidiabetic agents). A “self-controlled case-series study” compares how often an event (in this case, a fracture) occurs (the event's “rate”) in a population of individuals during a period of time when the individuals are not exposed to a medical intervention (in this case, treatment with thiazolidinediones) to its rate during a period when they are exposed to the intervention. Because each person acts as their own control, this study design helps to eliminate the possibility that unrecognized characteristics that vary between people (“confounders”) are responsible for differences in the event rate rather than the intervention itself.
What Did the Researchers Do and Find?
The researchers identified 1,819 people aged 40 years or older with a recorded fracture and at least one prescription for a thiazolidinedione by searching the UK General Practice Research Database, which contains personal and health data for more than 6 million UK residents. They compared these people's fracture rate during periods when they were taking a thiazolidinedione to their fracture rate when they weren't taking one of these drugs. After adjusting for age (age is a potential confounder because the risk of fractures increases with age and all the patients were older during their exposed period than during their unexposed period), the rate ratio for fracture at any site in patients during thiazolidinedione-exposed periods compared with thiazolidinedione-unexposed periods was 1.43. That is, nearly one and half times as many fractures occurred when people were taking thiazolidinediones than when they were not taking these drugs. The association between taking thiazolidinediones and the risk of fracture was similar in men and women and at several fracture sites but increased with the length of thiazolidinedione exposure.
What Do These Findings Mean?
These findings suggest that taking thiazolidinediones is associated with an increased risk of fracture at a wide range of sites in both men and women. They also suggest that the risk of fracture increases with treatment duration. These findings do not prove that thiazolidinediones cause fractures because, despite the self-controlled case-series design of this study, it remains possible that the people who have fractures share some unknown characteristic that affects their chances of breaking a bone. The accuracy of the findings is also dependent on the quality of the data in the General Practice Research Database. Nonetheless, these results are in keeping with the findings of clinical trials and other observational studies, suggesting they represent a real effect of treatment with thiazolidinediones. Although it is not clear yet how thiazolidinediones weaken bones, these findings need to be included in the ongoing debate about the risks and benefits of the treatment of type 2 diabetes with thiazolidinediones.
Additional Information
Please access these Web sites via the online version of this summary at
The International Diabetes Federation provides information about all aspects of diabetes
The US National Diabetes Information ClearingHouse provides detailed information about diabetes (including information on medicines for diabetes) for patients, health-care professionals, and the general public (in English and Spanish)
The UK National Health Service also provides information for patients and carers about type 2 diabetes (in several languages)
MedlinePlus provides links to further resources and advice about diabetes and diabetes medicines (in English and Spanish)
Information about the UK General Practice Research Database and about the self-controlled case-series method is available
More information is available where the research was done at The London School of Hygiene & Tropical Medicine
PMCID: PMC2741577  PMID: 19787025
3.  Hospitalised hip fracture risk with rosiglitazone and pioglitazone use compared with other glucose-lowering drugs 
Diabetologia  2012;55(11):2929-2937.
Current drug labels for thiazolidinediones (TZDs) warn of increased fractures, predominantly for distal fractures in women. We examined whether exposure to TZDs affects hip fracture in women and men and compared the risk to that found with other drugs used in diabetes.
Using a nationwide database of prescriptions, hospital admissions and deaths in those with type 2 diabetes in Scotland we calculated TZD exposure among 206,672 individuals. Discrete-time failure analysis was used to model the effect of cumulative drug exposure on hip fracture during 1999–2008.
There were 176 hip fractures among 37,479 exposed individuals. Hip fracture risk increased with cumulative exposure to TZD: OR per year of exposure 1.18 (95% CI 1.09, 1.28; p = 3 × 10−5), adjusted for age, sex and calendar month. Hip fracture increased with cumulative exposure in both men (OR 1.20; 95% CI 1.03, 1.41) and women (OR 1.18; 95% CI 1.07, 1.29) and risks were similar for pioglitazone (OR 1.18) and rosiglitazone (OR 1.16). The association was similar when adjusted for exposure to other drugs for diabetes and for other potential confounders. There was no association of hip fracture with cumulative exposure to sulfonylureas, metformin or insulin in this analysis. The 90-day mortality associated with hip fractures was similar in ever-users of TZD (15%) and in never-users (13%).
Hip fracture is a severe adverse effect with TZDs, affecting both sexes; labels should be changed to warn of this. The excess mortality is at least as much as expected from the reported association of pioglitazone with bladder cancer.
PMCID: PMC3464390  PMID: 22945303
Fractures; Hip fracture; Pharmacoepidemiology; Thiazolidinedione; Type 2 diabetes
4.  Thiazolidinediones, Cardiovascular Disease and Cardiovascular Mortality: Translating Research Into Action For Diabetes (TRIAD) 
Studies have associated thiazolidinedione (TZD) treatment with cardiovascular disease (CVD) and questioned whether the two available TZDs, rosiglitazone and pioglitazone, have different CVD risks. We compared CVD incidence, cardiovascular (CV) and all-cause mortality in type 2 diabetic patients treated with rosiglitazone or pioglitazone as their only TZD.
We analyzed survey, medical record, administrative, and National Death Index (NDI) data from 1999 through 2003 from Translating Research Into Action for Diabetes (TRIAD), a prospective observational study of diabetes care in managed care. Medications, CV procedures, and CVD were determined from health plan (HP) administrative data, and mortality was from NDI. Adjusted hazard rates (AHR) were derived from Cox proportional hazard models adjusted for age, sex, race/ethnicity, income, history of diabetic nephropathy, history of CVD, insulin use, and HP.
Across TRIAD’s ten HPs, 1,815 patients (24%) filled prescriptions for a TZD, 773 (10%) for only rosiglitazone, 711 (10%) for only pioglitazone, and 331 (4%) for multiple TZDs. In the seven HPs using both TZDs, 1,159 patients (33%) filled a prescription for a TZD, 564 (16%) for only rosiglitazone, 334 (10%) for only pioglitazone, and 261 (7%) for multiple TZDs. For all CV events, CV and all-cause mortality, we found no significant difference between rosiglitazone and pioglitazone.
In this relatively small, prospective, observational study, we found no statistically significant differences in CV outcomes for rosiglitazone- compared to pioglitazone-treated patients. There does not appear to be a pattern of clinically meaningful differences in CV outcomes for rosiglitazone- versus pioglitazone-treated patients.
PMCID: PMC3548906  PMID: 20583206
Thiazolidinediones; rosiglitazone; pioglitazone; diabetes
5.  Effects of Long-Term Pioglitazone Treatment on Peripheral and Central Markers of Aging 
PLoS ONE  2010;5(4):e10405.
Thiazolidinediones (TZDs) activate peroxisome proliferator-activated receptor gamma (PPARγ) and are used clinically to help restore peripheral insulin sensitivity in Type 2 diabetes (T2DM). Interestingly, long-term treatment of mouse models of Alzheimer's disease (AD) with TZDs also has been shown to reduce several well-established brain biomarkers of AD including inflammation, oxidative stress and Aβ accumulation. While TZD's actions in AD models help to elucidate the mechanisms underlying their potentially beneficial effects in AD patients, little is known about the functional consequences of TZDs in animal models of normal aging. Because aging is a common risk factor for both AD and T2DM, we investigated whether the TZD, pioglitazone could alter brain aging under non-pathological conditions.
Methods and Findings
We used the F344 rat model of aging, and monitored behavioral, electrophysiological, and molecular variables to assess the effects of pioglitazone (PIO-Actos® a TZD) on several peripheral (blood and liver) and central (hippocampal) biomarkers of aging. Starting at 3 months or 17 months of age, male rats were treated for 4–5 months with either a control or a PIO-containing diet (final dose approximately 2.3 mg/kg body weight/day). A significant reduction in the Ca2+-dependent afterhyperpolarization was seen in the aged animals, with no significant change in long-term potentiation maintenance or learning and memory performance. Blood insulin levels were unchanged with age, but significantly reduced by PIO. Finally, a combination of microarray analyses on hippocampal tissue and serum-based multiplex cytokine assays revealed that age-dependent inflammatory increases were not reversed by PIO.
While current research efforts continue to identify the underlying processes responsible for the progressive decline in cognitive function seen during normal aging, available medical treatments are still very limited. Because TZDs have been shown to have benefits in age-related conditions such as T2DM and AD, our study was aimed at elucidating PIO's potentially beneficial actions in normal aging. Using a clinically-relevant dose and delivery method, long-term PIO treatment was able to blunt several indices of aging but apparently affected neither age-related cognitive decline nor peripheral/central age-related increases in inflammatory signaling.
PMCID: PMC2861595  PMID: 20454453
6.  Management of type 2 diabetes mellitus 
Canadian Family Physician  2005;51(5):683-687.
To review evidence supporting use of thiazolidinediones (TZDs) in management of type 2 diabetes mellitus (DM2).
A MEDLINE search found several randomized controlled trials (level I evidence). No systematic reviews of these trials were found in the Cochrane Library.
Thiazolidinediones lower hemoglobin AIc levels by as much as 1.0% to 1.5%. Effects can be seen in as little as 4 weeks, but full lowering takes 6 to 12 weeks. When used in combination with other diabetic agents, such as sulfonylureas and biguanides, TZDs’ hypoglycemic effects appear to be complementary. Thiazolidinediones directly improve insulin sensitivity and recovery of pancreatic beta cell function. Nevertheless, there is no evidence indicating that TZDs are superior to other antidiabetic agents currently available or that TZDs reduce the long-term complications of DM2.
Ongoing trials will further define the role of TZDs in management of diabetic patients. In current practice, cost is often a factor in the decision to prescribe TZDs.
PMCID: PMC1472920  PMID: 15934272
7.  Retrospective Analysis of Long-Term Adherence to and Persistence with DPP-4 Inhibitors in US Adults with Type 2 Diabetes Mellitus 
Advances in Therapy  2014;31:1287-1305.
Patients with type 2 diabetes mellitus (T2DM) must remain adherent and persistent on antidiabetic medications to optimize clinical benefits. This analysis compared adherence and persistence among adults initiating dipeptidyl peptidase-4 inhibitors (DPP-4is), sulfonylureas (SUs), and thiazolidinediones (TZDs) and between patients initiating saxagliptin or sitagliptin, two DPP-4is.
This retrospective cohort study utilized the US MarketScan® (Truven Health Analytics, Ann Arbor, MI, USA) Commercial and Medicare Supplemental health insurance claims databases. Adults aged ≥18 years with T2DM who initiated a DPP-4i, SU, or TZD from January 1, 2009 to January 31, 2012 were included. Patients must have been continuously enrolled for ≥1 year prior to and ≥1 year following initiation. Adherence was measured using proportion of days covered (PDC), with PDC ≥ 0.80 considered adherent. Persistence was measured as time to discontinuation, defined as last day with drug prior to a 60+ days gap in therapy. Multivariable logistic regression and Cox proportional hazards models compared the outcomes between cohorts, controlling for baseline differences.
The sample included 238,372 patients (61,399 DPP-4i, 134,961 SU, 42,012 TZD). During 1-year follow-up, 47.3% of DPP-4i initiators, 41.2% of SU initiators, and 36.7% of TZD initiators were adherent. Adjusted odds of adherence were significantly greater among DPP-4i initiators than SU (adjusted odds ratio [AOR] = 1.678, P < 0.001) and TZD initiators (AOR = 1.605, P < 0.001). During 1-year follow-up, 55.0% of DPP-4i initiators, 47.8% of SU initiators, and 42.9% of TZD initiators did not discontinue therapy. Adjusted hazards of discontinuation were significantly greater for SU (adjusted hazard ratio [AHR] = 1.390, P < 0.001) and TZD initiators (AHR = 1.402, P < 0.001) compared with DPP-4i initiators. Saxagliptin initiators had significantly better adherence (AOR = 1.213, P < 0.001) compared with sitagliptin initiators, and sitagliptin initiators had significantly greater hazard of discontinuation (AHR = 1.159, P < 0.001). Results were similar over a 2-year follow-up.
US adults with T2DM who initiated DPP-4i therapy, particularly saxagliptin, had significantly better adherence and persistence compared with patients who initiated SUs or TZDs.
Electronic supplementary material
The online version of this article (doi:10.1007/s12325-014-0171-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4271133  PMID: 25504156
Adherence; Dipeptidyl peptidase-4 inhibitors; Persistence; Type 2 diabetes mellitus
8.  Bone Loss in Diabetes: Use of Antidiabetic Thiazolidinediones and Secondary Osteoporosis 
Current Osteoporosis Reports  2010;8(4):178-184.
Clinical evidence indicates that bone status is affected in patients with type 2 diabetes mellitus (T2DM). Regardless of normal or even high bone mineral density, T2DM patients have increased risk of fractures. One class of antidiabetic drugs, thiazolidinediones (TZDs), causes bone loss and further increases facture risk, placing TZDs in the category of drugs causing secondary osteoporosis. Risk factors for development of TZD-induced secondary osteoporosis are gender (women), age (elderly), and duration of treatment. TZDs exert their antidiabetic effects by activating peroxisome proliferator-activated receptor-γ (PPAR-γ) nuclear receptor, which controls glucose and fatty acid metabolism. In bone, PPAR-γ controls differentiation of cells of mesenchymal and hematopoietic lineages. PPAR-γ activation with TZDs leads to unbalanced bone remodeling: bone resorption increases and bone formation decreases. Laboratory research evidence points toward a possible separation of unwanted effects of PPAR-γ on bone from its beneficial antidiabetic effects by using selective PPAR-γ modulators. This review also discusses potential pharmacologic means to protect bone from detrimental effects of clinically used TZDs (pioglitazone and rosiglitazone) by using combinational therapy with approved antiosteoporotic drugs, or by using lower doses of TZDs in combination with other antidiabetic therapy. We also suggest a possible orthopedic complication, not yet supported by clinical studies, of delayed fracture healing in T2DM patients on TZD therapy.
PMCID: PMC2947013  PMID: 20809203
Diabetes; Thiazolidinediones; Bone; Osteoporosis; Fracture
9.  Effects of replacing metformin with pioglitazone on glycemic control in japanese patients with poorly controlled type 2 diabetes mellitus: A 12-week, open-label, prospective study 
Background: Insulin resistance is a critical aspect of the pathophysiology of type 2 diabetes mellitus and is also associated with other risk factors for cardiovascular disease (eg, dyslipidemia and hypertension). Accordingly, insulin resistance is a possible target for lowering plasma glucose concentration and preventing diabetic macroangiopathy. Biguanides, such as metformin, and thiazolidinediones (TZDs), such as pioglitazone, improve insulin resistance.
Objectives: The aims of this study were to assess the effects of replacing a biguanide with a TZD on glycemic control in patients with poorly controlled type 2 diabetes mellitus, and also to identify the factors affecting interpatient variation in the effects of treatment change.
Methods: This was a 12-week, open-label, prospective study in which previously prescribed metformin (500 or 750 mg/d) was replaced with pioglitazone (15 or 30 mg/d) in patients with poorly controlled type 2 diabetes mellitus. Patients with a glycosylated hemoglobin (HbA1c) concentration >7% despite treatment with diet, exercise, and hypoglycemic agents other than TZDs were eligible for the study. Patients who never received TZDs were also eligible for inclusion. Vital signs, metabolic parameters, and arterial stiffness were assessed at baseline and after 12 weeks of treatment with pioglitazone. The primary end point was change in HbA1c concentration after replacing metformin with pioglitazone. Tolerability was assessed by medical history, physical examination, and laboratory tests (aspartate aminotransferase, alanine aminotransferase, and γ-glutamyl transpeptidase).
Results: Twenty-one Japanese patients (15 women, 6 men; mean [SD] age, 61.8 [8.4] years; body mass index, 25.5 [3.0] kg/m2) were included in the study. HbA1c concentration was not significantly changed from baseline after 12 weeks of pioglitazone treatment (8.0% [0.7%] vs 8.2% [0.7%]). Fasting plasma glucose (FPG) concentration also was not significantly changed after the replacement of treatment (156 [27] vs 144 [30] mg/dL). In addition, the resistin concentration did not change significantly from baseline after 12 weeks of pioglitazone treatment (6.6 [3.8] vs 6.4 [3.6] ng/mL). In contrast, significant improvement from baseline was observed in triglyceride (TG) concentrations (157 [109] vs 117 [68] mg/dL; P = 0.003), high-density lipoprotein cholesterol (HDL-C) (55 [12] vs 61 [16] mg/dL; P = 0.016), remnant-like particle cholesterol (6.6 [6.0] vs 5.3 [3.5] mg/dL; P = 0.048), and serum adiponectin (8.8 [4.3] vs 23.3 [11.7] μg/mL; P < 0.001). Pulse wave velocity was also significantly improved (1730 [361] vs 1622 [339] m/sec; P = 0.009). Changes in HbA1c were significantly correlated with serum fasting insulin concentration at baseline in the patients not receiving insulin preparations (r = -0.635, P = 0.013). The percentage change in serum adiponectin concentration was correlated with the percentage changes in HbA1c and FPG concentrations (HbA1c, r = -0.518, P = 0.019; FPG, r = -0.594, P = 0.006). Body weight was significantly increased after treatment (62.6 [11.9] vs 65.5 [12.2] kg; P < 0.001). Mild edema was reported in 5 patients. One patient discontinued treatment due to an increase in serum creatine kinase activity to ~6.6 times the upper limit of normal.
Conclusions: Replacement of metformin with pioglitazone did not produce significant differences in HbA1c and FPG concentrations from baseline after 12 weeks of treatment in these patients with poorly controlled type 2 diabetes mellitus. However, the replacement was effective in a subset of patients whose serum insulin concentrations were high or whose serum adiponectin concentrations were sensitive to TZDs. In addition, the replacement was associated with significant improvements in TG, HDL-C, serum adiponectin concentration, pulse wave velocity, and body weight increase from baseline.
PMCID: PMC3969936  PMID: 24692813
insulin resistance; metformin; pioglitazone; Japanese
10.  Insulin Sensitizers and Heart Failure: An Engine Flooded with Fuel 
Current hypertension reports  2010;12(6):399-401.
•Of Importance
In 2007, a meta-analysis of 42 randomized controlled trials involving the thiazolidinedione (TZD) rosiglitazone reported a 1.4 fold increase in the risk of acute myocardial infarction (AMI) compared with non-TZD therapies. Subsequently, another meta-analysis of 19 randomized controlled trials involving the TZD pioglitazone found a significant reduction in the composite outcome of nonfatal AMI, stroke, and all-cause mortality, thereby suggesting a potential difference in cardiovascular risk between the two TZDs.
To determine if the risk of serious cardiovascular harm is increased by rosiglitazone compared with pioglitazone.
The study was designed as a nationwide observational, retrospective, inception cohort of 227,571 Medicare beneficiaries aged 65 years or older (mean age, 74.4 years) who initiated treatment with rosiglitazone or pioglitazone through a Medicare Part D prescription drug plan from July 2006-June 2009 and who underwent follow-up for up to three years after TZD initiation. Individual and composite end points of AMI, stroke, heart failure, and all-cause mortality were assessed using the following: incidence rates by TZD, attributable risk, number needed to harm, Kaplan-Meier plots of time to event, and Cox proportional hazard ratios for time to event. Data were adjusted for potential confounding factors, with pioglitazone as a reference.
A total of 8,667 end points were observed during the study period. The adjusted hazard ratio for rosiglitazone compared with pioglitazone was 1.06 (95% CI, 0.96-1.18) for AMI; 1.27 (95% CI, 1.12-1.45) for stroke; 1.25 (95% CI, 1.16-1.34) for heart failure; 1.14 (95% CI, 1.05-1.24) for death; and 1.18 (95% CI, 1.12-1.23) for the composite of AMI, stroke, heart failure, or death. The attributable risk for this composite end point was 1.68 (95% CI, 1.27-2.08) excess events per 100 person-years of treatment with rosiglitazone compared with pioglitazone. The corresponding number needed to harm was 60 (95% CI, 48-79) treated for one year.
This study contributes to the rising tide of retrospective analyses suggesting post-marketing cardiovascular complications from the insulin sensitizing group of agents known as TZDs, especially rosiglitazone. In this study, rosiglitazone was associated with an increased risk of stroke, heart failure, and death and the composite of AMI, stroke, heart failure, or death. Limitations of the present study include the absence of randomization, a potential for misclassification, and a potential for unmeasured confounding factors. Still, we consider this work important for the following reasons.
PMCID: PMC3612890  PMID: 20963518
11.  Cancer Risk for Patients Using Thiazolidinediones for Type 2 Diabetes: A Meta-Analysis 
The Oncologist  2013;18(2):148-156.
This systematic review and meta-analysis examined the effect of thiazolidinediones on overall cancer risk, as well as bladder and other site-specific tumors, in patients with type 2 diabetes. Overall, there was no association between TZD and cancer risk. A modestly increased risk of bladder cancer was found, particularly with use of pioglitazone.
Learning Objectives
Evaluate the risk of cancer as well as cardiovascular and renal disease in the use of oral antidiabetics.Define and adequately quantify the effect of TZD on the risk of bladder cancer, other selected cancers, and all neoplasms.
To clarify and quantify the effect of thiazolidinediones (TZDs; e.g., pioglitazone, rosiglitazone) on the risk of bladder cancer, other selected cancers, and overall cancer in patients with type 2 diabetes, we performed a systematic review and meta-analysis of observational studies.
A PubMed/MEDLINE search was conducted for studies published in English up to June 30, 2012. Random-effect models were fitted to estimate summary relative risks (RR).
Seventeen studies satisfying inclusion criteria (3 case-control studies and 14 cohort studies) were considered. Use of TZDs was not associated to the risk of cancer overall (summary RR: 0.96; 95% confidence interval [CI]: 0.91–1.01). A modest excess risk of bladder cancer was reported in pioglitazone (RR: 1.20; 95% CI: 1.07–1.34 from six studies) but not in rosiglitazone (RR: 1.08; 95% CI: 0.95–1.23 from three studies) users. The RRs of bladder cancer were higher for longer duration (RR: 1.42 for >2 years) and higher cumulative dose of pioglitazone (RR: 1.64 for >28,000 mg). Inverse relations were observed with colorectal cancer (RR: 0.93; 95% CI: 0.90–0.97 from six cohort studies) and liver cancer (RR: 0.65; 95% CI: 0.48–0.89 from four studies), whereas there was no association with pancreatic, lung, breast, and prostate cancers.
Adequate evidence excludes an overall excess cancer risk in TZD users within a few years after starting treatment. However, there is a modest excess risk of bladder cancer, particularly with reference to pioglitazone. Assuming that this association is real, the potential implications on the risk-benefit analysis of TZD use should be evaluated.
PMCID: PMC3579598  PMID: 23345544
Cancer; Diabetes; Meta-analysis; Oral antidiabetic therapy; Pioglitazone; Thiazolidinedione
12.  Association Between Longer Therapy With Thiazolidinediones and Risk of Bladder Cancer: A Cohort Study 
The use of pioglitazone, a thiazolidinedione (TZD), may increase the risk of bladder cancer in patients with type 2 diabetes. In this study, we assessed the risk of bladder cancer associated with the use of TZDs and between pioglitazone and rosiglitazone, an alternative TZD.
We conducted a retrospective cohort study of patients with type 2 diabetes mellitus who initiated treatment with a TZD (n = 18 459 patients) or a sulfonylurea (SU) (n = 41 396 patients) between July 1, 2000, and August 31, 2010, using The Health Improvement Network database in the United Kingdom. Incident cancers were identified for 196 708 person-years of follow-up. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of bladder cancer in the TZD cohort compared with the SU cohort (referent), adjusted for potential confounders. Risk associated with increasing duration of drug exposure was also examined. All statistical tests were two-sided.
We identified 60 incident bladder cancers in the TZD cohort and 137 cancers in the SU cohort. No difference in bladder cancer risk was found between the two cohorts (TZD vs SU, HR = 0.93, 95% CI = 0.68 to 1.29) in analyses that did not account for duration of exposure. However, the risk of bladder cancer was increased among patients with the longest duration of TZD vs SU therapy (≥5 years of use, HR = 3.25, 95% CI = 1.08 to 9.71) and among those with the longest time since initiation of therapy (≥5 years since first use, HR = 2.53, 95% CI = 1.12 to 5.77). Risk of bladder cancer also increased with increasing time since initiation of pioglitazone (P trend < .001) and rosiglitazone (P trend = .006). Comparison of pioglitazone to rosiglitazone use did not demonstrate difference in cancer risk (P = .49).
Long-term TZD therapy (≥5 years) in patients with type 2 diabetes may be associated with an increased risk of bladder cancer, which may be common to all TZDs.
PMCID: PMC3529598  PMID: 22878886
13.  Anti-proliferative activity of oral anti-hyperglycemic agents on human vascular smooth muscle cells: thiazolidinediones (glitazones) have enhanced activity under high glucose conditions 
Inhibition of vascular smooth muscle cell (vSMC) proliferation by oral anti-hyperglycemic agents may have a role to play in the amelioration of vascular disease in diabetes. Thiazolidinediones (TZDs) inhibit vSMC proliferation but it has been reported that they anomalously stimulate [3H]-thymidine incorporation. We investigated three TZDs, two biguanides and two sulfonylureas for their ability of inhibit vSMC proliferation. People with diabetes obviously have fluctuating blood glucose levels thus we determined the effect of media glucose concentration on the inhibitory activity of TZDs in a vSMC preparation that grew considerably more rapidly under high glucose conditions. We further explored the mechanisms by which TZDs increase [3H]-thymidine incorporation.
VSMC proliferation was investigated by [3H]-thymidine incorporation into DNA and cell counting. Activation and inhibition of thymidine kinase utilized short term [3H]-thymidine uptake. Cell cycle events were analyzed by FACS.
VSMC cells grown for 3 days in DMEM with 5% fetal calf serum under low (5 mM glucose) and high (25 mM glucose) increased in number by 2.5 and 4.7 fold, respectively. Rosiglitazone and pioglitazone showed modest but statistically significantly greater inhibitory activity under high versus low glucose conditions (P < 0.05 and P < 0.001, respectively). We confirmed an earlier report that troglitazone (at low concentrations) causes enhanced incorporation of [3H]-thymidine into DNA but did not increase cell numbers. Troglitazone inhibited serum mediated thymidine kinase induction in a concentration dependent manner. FACS analysis showed that troglitazone and rosiglitazone but not pioglitazone placed a slightly higher percentage of cells in the S phase of a growing culture. Of the biguanides, metformin had no effect on proliferation assessed as [3H]-thymidine incorporation or cell numbers whereas phenformin was inhibitory in both assays albeit at high concentrations. The sulfonylureas chlorpropamide and gliclazide had no inhibitory effect on vSMC proliferation assessed by either [3H]-thymidine incorporation or cell numbers.
TZDs but not sulfonylureas nor biguanides (except phenformin at high concentrations) show favorable vascular actions assessed as inhibition of vSMC proliferation. The activity of rosiglitazone and pioglitazone is enhanced under high glucose conditions. These data provide further in vitro evidence for the potential efficacy of TZDs in preventing multiple cardiovascular diseases. However, the plethora of potentially beneficial actions of TZDs in cell and animal models have not been reflected in the results of major clinical trials and a greater understanding of these complex drugs is required to delineate their ultimate clinical utility in preventing macrovascular disease in diabetes.
PMCID: PMC2211460  PMID: 17963526
14.  Association between cancer prevalence and use of thiazolidinediones: results from the Vermont Diabetes Information System 
BMC Medicine  2007;5:17.
Peroxisome proliferator-activated receptors (PPARs) have emerged as important drug targets for diabetes. Drugs that activate PPARγ, such as the thiazolidinediones (TZDs), are widely used for treatment of Type 2 diabetes mellitus. PPARγ signaling could also play an anti-neoplastic role in several in vitro models, although conflicting results are reported from in vivo models. The effects of TZDs on cancer risk in humans needs to be resolved as these drugs are prescribed for long periods of time in patients with diabetes.
A total of 1003 subjects in community practice settings were interviewed at home at the time of enrolment into the Vermont Diabetes Information System, a clinical decision support program. Patients self-reported their personal and clinical characteristics, including any history of malignancy. Laboratory data were obtained directly from the clinical laboratory and current medications were obtained by direct observation of medication containers. We performed a cross-sectional analysis of the interviewed subjects to assess a possible association between cancer diagnosis and the use of TZDs.
In a multivariate logistic regression model, a diagnosis of cancer was significantly associated with TZD use, even after correcting for potential confounders including other oral anti-diabetic agents (sulfonylureas and biguanides), age, glycosylated hemoglobin A1C, body mass index, cigarette smoking, high comorbidity, and number of prescription medications (odds ratio = 1.59, P = 0.04). This association was particularly strong among patients using rosiglitazone (OR = 1.89, P = 0.02), and among women (OR = 2.07, P = 0.01).
These data suggest an association between TZD use and cancer in patients with diabetes. Further studies are required to determine if this association is causal.
PMCID: PMC1934377  PMID: 17584937
15.  Thiazolidinediones on PPARγ: The Roles in Bone Remodeling 
PPAR Research  2011;2011:867180.
Thiazolidinediones (TZDs) are synthetic PPARγ (peroxisome proliferator-activated receptor gamma) agonists and a class of drugs for diabetes mellitus type 2 that can decrease blood sugar efficiently by enhancing insulin sensitivity. However, increased bone fracture risk in diabetic individuals treated with TZDs is one of the reported side effects. Recent studies show that TZDs such as rosiglitazone simultaneously inhibit osteoblast differentiation and activate osteoclast differentiation, leading to bone loss due to decreased bone formation and increased bone resorption. Furthermore, TZDs may activate PPARγ in tissues other than bone, such as the hypothalamus-pituitary-gonad (HPG) axis to indirectly regulate bone mass. This paper will focus on current new developments that implicate potential mechanisms for how PPARγ modulates skeletal homeostasis and how TZDs exert bone-loss side effects.
PMCID: PMC3205770  PMID: 22135675
16.  Antidiabetic thiazolidinediones induce ductal differentiation but not apoptosis in pancreatic cancer cells 
AIM: Thiazolidinediones (TZD) are a new class of oral antidiabetic drugs that have been shown to inhibit growth of same epithelial cancer cells. Although TZD were found to be ligands for peroxisome proliferator-activated receptor γ (PPARγ), the mechanism by which TZD exert their anticancer effect is presently unclear. In this study, we analyzed the mechanism by which TZD inhibit growth of human pancreatic carcinoma cell lines in order to evaluate the potential therapeutic use of these drugs in pancreatic adenocarcinoma.
METHODS: The effects of TZD in pancreatic cancer cells were assessed in anchorage-independent growth assay. Expression of PPARγ was measured by reverse-transcription polymerase chain reaction and confirmed by Western blot analysis. PPARγ activity was evaluated by transient reporter gene assay. Flow cytometry and DNA fragmentation assay were used to determine the effect of TZD on cell cycle progression and apoptosis respectively. The effect of TZD on ductal differentiation markers was performed by Western blot.
RESULTS: Exposure to TZD inhibited colony formation in a PPARγ-dependent manner. Growth inhibition was linked to G1 phase cell cycle arrest through induction of the ductal differentiation program without any increase of the apoptotic rate.
CONCLUSION: TZD treatment in pancreatic cancer cells has potent inhibitory effects on growth by a PPAR-dependent induction of pacreatic ductal differentiation.
PMCID: PMC4250701  PMID: 15754392
Thiazolidinediones; Pancreatic cancer; PPARγ; Cancer growth; Differentiation
17.  Is thiazolidinediones use a factor in delaying the need for insulin therapy in type 2 patients with diabetes? A population-based cohort study 
BMJ Open  2012;2(6):e001910.
To understand the independent role of thiazolidinediones (TZDs) in delaying progression to parenteral insulin therapy.
Population-based retrospective cohort study.
British Columbia, Canada.
A total of 18 867 type 2 diabetes patients (mean age 58.9) treated with metformin as first-line therapy who then switched or added a TZD or sulphonylurea as a second-line treatment between 1 January 1998 and 31 March 2008.
Outcome measures
Multivariable Poisson regression models were used to estimate the effect of using TZD compared to sulphonylureas on time to the initiation of insulin treatment (third-line).
The adjusted rate difference in women aged <60 showed 2.22 fewer insulin initiation events per 100 person-years (PYs) in the TZD group versus the sulphonylurea group (95% CI −3.46 to −0.99). Men in the same age group had 1.50 fewer insulin initiation events per 100 PYs in the TZD group versus the sulphonylurea group (95% CI −2.44 to −0.56). The average time in days to initiation on insulin in the sulphonylurea, rosiglitazone and pioglitazone group was 343, 252 and 339, respectively. The cumulative hazard for starting insulin for sulphonylurea patients at 12, 24, 36 and 48 months was approximately three times higher compared to TZD patients.
Second-line TZD therapy compared to second-line sulphonylurea therapy was associated with a lower incidence of insulin initiation as third-line treatment in patients with type 2 diabetes, with a mean delay of 90 days. This duration of delay must be weighed against the absence of a proven reduction in morbidity or mortality with TZDs and their known serious cardiovascular harm.
PMCID: PMC3533046  PMID: 23148347
type 2 diabetes; thiazolidinediones; sulfonylurea; insulin; Diabetes & Endocrinology; Epidemiology
18.  The effects of thiazolidinediones (TZD) on human bone marrow stromal cell differentiation in vitro and in TZD-treated patients with type 2 diabetes 
Thiazolidinedione (TZD) therapy has been associated with increased risk of bone fractures. Studies in rodents have led to a model in which decreased bone quality in response to TZDs is due to a competition of lineage commitment between osteoblasts and adipocytes for a common precursor cell resulting in decreased osteoblast numbers. Our goal was to investigate the effects of TZD exposure on osteoblast-adipocyte lineage determination from primary human bone marrow stromal cells (hBMSCs) both in vitro and in vivo from non-diabetic subjects and patients with type 2 diabetics. Our experimental design included two phases. Phase 1: An in vitro study of TZDs effects on hBMSCs differentiation into osteoblasts and adipocytes in non-diabetic subjects. Phase 2: a randomized placebo controlled trial to determine the effects of six month pioglitazone treatment in vivo on hBMSC differentiation using adipocyte/osteoblast colony forming unit assays in patients with type 2 diabetes. In vitro, TZDs (pioglitazone and rosiglitazone) enhanced adipogenesis of hBMSCs while neither altered osteoblast differentiation and/or function as measured by alkaline phosphatase activity, gene expression, and mineralization. The ability of TZDs to enhance adipogenesis occurred at a specific time/stage of the differentiation process and pre-treating with TZDs did not further enhance adipogenesis. In vivo, six month TZD treatment decreased osteoblast precursors, increased adipocyte precursors, and increased total colony number in patients with type 2 diabetes. Our results indicate that TZD exposure in vitro potently stimulates adipogenesis but does not directly alter osteoblast differentiation/mineralization or lineage commitment from hBMSCs. TZD-treatment in type 2 diabetic patients however results in decreased osteoblastogenesis from hBMSCs compared to placebo indicating an indirect negative effect on osteoblasts suggesting an alternative model by which TZDs might negatively regulate bone quality.
PMCID: PMC3546231  PMID: 23022285
osteoblast; adipocyte; human bone marrow; osteoporosis; drug-induced osteopenia
19.  Sequence Variation in PPARG May Underlie Differential Response to Troglitazone 
Diabetes  2005;54(11):3319-3325.
Thiazolidinediones (TZDs) are peroxisome proliferator–activated receptor-γ (PPARG) agonists used to treat type 2 diabetes. TZDs can also be used to reduce rates of type 2 diabetes in at-risk individuals. However, a large fraction of TZD-treated patients (30–40%) do not respond to TZD treatment with an improvement in insulin sensitivity (Si). We hypothesized that variation within the gene encoding PPARG may underlie this differential response to TZD therapy. We screened ~40 kb of PPARG in 93 nondiabetic Hispanic women (63 responders and 30 nonresponders) with previous gestational diabetes who had participated in the Troglitazone In the Prevention Of Diabetes study. TZD nonresponse was defined as the lower tertile in change in Si after 3 months of treatment. Baseline demographic and clinical measures were not different between responders and nonresponders. We identified and genotyped 131 variants including 126 single nucleotide polymorphisms and 5 insertion-deletion polymorphisms. Linkage disequilibrium analysis identified five haplotype blocks. Eight variants were associated with TZD response (P < 0.05). Three variants were also associated with changes in Si as a continuous variable. Our results suggest that PPARG variation may underlie response to TZD therapy in women at risk for type 2 diabetes.
PMCID: PMC2923445  PMID: 16249460
20.  Diffusion patterns of new anti-diabetic drugs into hospitals in Taiwan: the case of Thiazolidinediones for diabetes 
Diffusion of new drugs in the health care market affects patients' access to new treatment options and health care expenditures. We examined how a new drug class for diabetes mellitus, thiazolidinediones (TZDs), diffused in the health care market in Taiwan.
Assuming that monthly hospital prescriptions of TZDs could serve as a micro-market to perform drug penetration studies, we retrieved monthly TZD prescription data for 580 hospitals in Taiwan from Taiwan's National Health Insurance Research Database for the period between March 1, 2001 and December 31, 2005. Three diffusion parameters, time to adoption, speed of penetration (monthly growth on prescriptions), and peak penetration (maximum monthly prescription) were evaluated. Cox proportional hazards model and quantile regressions were estimated for analyses on the diffusion parameters.
Prior hospital-level pharmaceutical prescription concentration significantly deterred the adoption of the new drug class (HR: 0.02, 95%CI = 0.01 to 0.04). Adoption of TZDs was slower in district hospitals (HR = 0.43, 95%CI = 0.24 to 0.75) than medical centers and faster in non-profit hospitals than public hospitals (HR = 1.79, 95%CI = 1.23 to 2.61). Quantile regression showed that penetration speed was associated with a hospital's prior anti-diabetic prescriptions (25%Q: 18.29; 50%Q: 25.57; 75%Q: 30.97). Higher peaks were found in hospitals that had adopted TZD early (25%Q: -40.33; 50%Q: -38.65; 75%Q: -32.29) and in hospitals in which the drugs penetrated more quickly (25%Q: 16.53; 50%Q: 24.91; 75%Q: 31.50).
Medical centers began to prescribe TZDs earlier, and they prescribed more TZDs at a faster pace. The TZD diffusion patterns varied among hospitals depending accreditation level, ownership type, and prescription volume of Anti-diabetic drugs.
PMCID: PMC3042909  PMID: 21281475
21.  Clinical outcomes and health care costs combining metformin with sitagliptin or sulphonylureas or thiazolidinediones in uncontrolled type 2 diabetes patients 
To compare clinical outcomes and health care costs across three cohorts of uncontrolled diabetic patients who initiated treatment with one of the following: sulphonylureas (SU), thiazolidinediones (TZD) or sitagliptin (SITA).
Materials and methods
We performed a retrospective study based on a linkage between administrative and laboratory databases maintained by three Italian local health units. The index period ranged from July 2008–June 2010. Patients were treatment-naïve to either SU, TZD, or SITA, but they were already treated with other oral hypoglycemic agents. Demographics and clinical characteristics were assessed at baseline. Adherence was measured by the medication possession ratio and adherent was defined as a patient with a medication possession ratio of 80% or greater. We used a Poisson regression model to estimate the risk ratios for disease-related hospitalizations that occurred during the 18-month follow-up period. The total annual costs included all the pharmacological treatments and the direct costs due to hospitalizations and outpatient services.
We identified 928 patients treated with SU, 330 patients treated with TZD, and 83 patients treated with SITA. SITA patients were significantly younger and with fewer previous hospital discharges. The baseline mean glycated hemoglobin level was 8.1% for SU, 8.0% for TZD, and 8.3% for SITA patients. SITA-naïve patients were more adherent than the SU- and TZD-naïve patients (79.5% versus 53.2% and 62.8%, respectively; P<0.001). The SU and TZD group showed a significant increased risk of disease-related hospitalizations compared with the SITA group (the unadjusted rate was 10.42 and 7.16 per 100 person-years versus 1.64 per 100 person-years, P=0.003; compared with SU, the adjusted incidence rate ratio for SITA was 0.21, P=0.030). The total annual costs per patient were €972 for SITA, €706 for SU, and €908 for those treated with TZD.
Uncontrolled diabetic patients who initiated – as a second-line therapy in addition to metformin – treatment with SITA, compared to those who initiated treatment with SU or TZD, showed a reduced risk of disease-related hospitalizations. The total annual costs per patient were not significantly different among the three groups.
PMCID: PMC4211865  PMID: 25364266
diabetes; clinical practice; sitagliptin; adherence; health care costs
22.  Comparing the effects of insulin glargine and thiazolidinediones on plasma lipids in type 2 diabetes: a patient-level pooled analysis 
The prevalence of dyslipidaemia and the risk of cardiovascular disease are elevated in patients with type 2 diabetes. This analysis compared the effects of insulin glargine versus thiazolidinediones (TZDs) on lipid profiles.
Patient-level data were pooled from two randomized clinical studies. The population included 552 men and women aged >18 years, diagnosed with type 2 diabetes for at least 6 months, on metformin and/or sulphonylurea, and with A1C ≥7.5% and <12.0% at screening. Lipid outcome measures included change from baseline in lipid levels [low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol, triglycerides, and free fatty acids] and attainment of lipid goals for LDL-C, non-HDL-C, and triglycerides.
Both insulin glargine and TZDs improved lipid profiles from baseline values. Compared with TZDs, treatment with insulin glargine led to 7.9% greater reduction in LDL-C (p < 0.0003), 7.5% greater reduction in non-HDL-C (p < 0.0001), and 7.8% greater reduction in total cholesterol (p < 0.0001), whereas the HDL-C increase with TZD was 7.6% greater than that with insulin glargine (p < 0.0001). The percentage of patients attaining the lipid goals was comparable between insulin glargine and pioglitazone, but lower for rosiglitazone. Insulin glargine improved glycaemic control more than TZDs; however, insulin glargine caused more hypoglycaemia. Treatment with TZDs caused more weight gain and peripheral oedema.
These findings suggest that the favourable effects of insulin glargine on plasma lipid profiles should be considered among the advantages of treatment with insulin glargine as they are for TZDs. Copyright © 2011 John Wiley & Sons, Ltd.
PMCID: PMC3380564  PMID: 22081557
insulin glargine; lipids; thiazolidinediones; type 2 diabetes
23.  Association between diabetes or antidiabetic therapy and lung cancer: A meta‐analysis 
Diabetes can increase the risk of cancers at several sites, but the association between diabetes and lung cancer remains unclear. We aimed to provide the quantitative estimates for the association between diabetes or antidiabetic treatment and lung cancer risk in the present meta‐analysis.
Materials and Methods
Cohort studies were identified by searching the PubMed database (January 1960 through October 2012) and manually assessing the cited references in the retrieved articles. Study‐specific relative risks (RRs) and 95% confidence intervals (CIs) were estimated using a random‐effects model. Study quality was assessed using the Newcastle–Ottawa scale.
A total of 19 cohort studies were included in the present meta‐analysis. Of these, 14 studies focused on the association between diabetes and lung cancer incidence, and seven studies focused on the association between antidiabetic treatment and lung cancer incidence. Compared with non‐diabetic individuals, diabetic patients do not have an increased risk of lung cancer (RR = 1.04, 95% CI 0.87–1.24). The association between diabetes and lung cancer remained not statistically significant in subgroup analysis stratified by study characteristics, study quality, diabetes ascertainment or important confounders. A null association between insulin or biguanides therapy and lung cancer risk was found. However, the diabetic patients receiving thiazolidinedione (TZD) treatment had a 20% reduced risk of lung cancer than those without TZD treatment.
No association between diabetes and lung cancer risk was found. However, TZD treatment might reduce lung cancer risk in diabetic patients.
PMCID: PMC4020263  PMID: 24843722
Diabetes; Lung cancer; Meta‐analysis
24.  Unmasking Differential Effects of Rosiglitazone and Pioglitazone in the Combination Treatment with n-3 Fatty Acids in Mice Fed a High-Fat Diet 
PLoS ONE  2011;6(11):e27126.
Combining pharmacological treatments and life style interventions is necessary for effective therapy of major diseases associated with obesity, which are clustered in the metabolic syndrome. Acting via multiple mechanisms, combination treatments may reduce dose requirements and, therefore, lower the risk of adverse side effects, which are usually associated with long-term pharmacological interventions. Our previous study in mice fed high-fat diet indicated additivity in preservation of insulin sensitivity and in amelioration of major metabolic syndrome phenotypes by the combination treatment using n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFA) and rosiglitazone, i.e. an anti-diabetic drug of the thiazolidinedione (TZD) family. We investigated here whether pioglitazone, a TZD-drug in clinical use, could elicit the additive beneficial effects when combined with n-3 LC-PUFA. Adult male mice (C57BL/6N) were fed an obesogenic corn oil-based high-fat diet (cHF) for 8 weeks, or randomly assigned to various dietary treatments (i) cHF+F, cHF with n-3 LC-PUFA concentrate replacing 15% of dietary lipids; (ii) cHF+ROSI, cHF with 10 mg rosiglitazone/kg diet; (iii) cHF+F+ROSI; (iv) cHF+PIO, cHF with 50 mg pioglitazone/kg diet; and (v) cHF+F+PIO, or chow-fed. Plasma concentrations of 163 metabolites were evaluated using a targeted metabolomics approach. Both TZDs preserved glucose homeostasis and normal plasma lipid levels while inducing adiponectin, with pioglitazone showing better effectiveness. The beneficial effects of TZDs were further augmented by the combination treatments. cHF+F+ROSI but not cHF+F+PIO counteracted development of obesity, in correlation with inducibility of fatty acid β-oxidation, as revealed by the metabolomic analysis. By contrast, only cHF+F+PIO eliminated hepatic steatosis and this treatment also reversed insulin resistance in dietary obese mice. Our results reveal differential effects of rosiglitazone and pioglitazone, unmasked in the combination treatment with n-3 LC-PUFA, and support the notion that n-3 LC-PUFA could be used as add-on treatment to TZDs in order to improve diabetic patient's therapy.
PMCID: PMC3207833  PMID: 22073272
25.  Use of Thiazolidinediones and the Risk of Colorectal Cancer in Patients With Diabetes 
Diabetes Care  2013;36(2):369-375.
Preclinical data suggest that peroxisome proliferator–activated receptor γ (PPARγ) agonists have antineoplastic effects in colorectal cancer. We aimed to assess the association between the use of synthetic PPARγ agonists, represented by thiazolidinediones (TZDs), and the risk of developing colorectal cancer.
We conducted a nationwide, population-based, case-control study using the Taiwan National Health Insurance Research Database. Case subjects were defined as patients who were diagnosed with diabetes at least 365 days prior to a new diagnosis of colorectal cancer between 2000 and 2008. We randomly selected diabetic control subjects for each case subject, which were matched by sex, age, and the duration of diabetes. Among the 24,496 eligible case subjects and control subjects, we used conditional logistic regression to assess the risk of colorectal cancer in association with the use of TZDs. An additional analysis was conducted to assess the effects of concomitant use of TZDs and low-dose aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) on the risk of colorectal cancer.
A decreased risk of colorectal cancer was observed in patients who had used TZDs compared with those who had never used TZDs (adjusted odds ratio 0.86 [95% CI 0.79–0.94]). Furthermore, the benefit of a decreased colorectal cancer risk was also found with concomitant use of TZDs and low-dose aspirin or NSAIDs.
The use of TZDs may be associated with a decreased risk of colorectal cancer in patients with diabetes. Further studies are warranted to confirm our findings.
PMCID: PMC3554275  PMID: 23043163

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