Li-Chiu Wu

Association of thiazolidinediones with liver cancer and colorectal cancer in type 2 diabetes mellitus

The objective of this nationwide case‐control study was to evaluate the risk of specific malignancy in diabetic patients who received thiazolidinediones (TZDs). A total of 606,583 type 2 diabetic patients, age 30 years and above, without a history of cancer were identified from the Taiwan National Health Insurance claims database during the period between January 1 2000 and December 31 2000. As of December 31 2007, patients with incident cancer of liver, colorectal, lung, and urinary bladder were included as cases and up to four age‐ and sex‐matched controls were selected by risk‐set sampling. Logistic regression models were applied to estimate the odds ratio (OR) and 95% confidence interval (CI) between TZDs and cancer incidence. A total of 10,741 liver cancer cases, 7,200 colorectal cancer cases, and 70,559 diabetic controls were included. A significantly lower risk of liver cancer incidence was found for any use of rosiglitazone (OR: 0.73, 95% CI: 0.65‐0.81) or pioglitazone (OR: 0.83, 95% CI: 0.72‐0.95), respectively. The protective effects were stronger for higher cumulative dosage and longer duration. For colorectal cancer, rosiglitazone, but not pioglitazone, was associated with a significantly reduced risk (OR: 0.86; 95% CI: 0.76‐0.96). TZDs were not associated with lung and bladder cancer incidence, although a potential increased risk for bladder cancer with pioglitazone use ≥3 years could not be excluded (OR: 1.56; 95% CI: 0.51‐4.74). Conclusion: The use of pioglitazone and rosiglitazone is associated with a decreased liver cancer incidence in diabetic patients. The effects on occurrence of specific cancer types may be different for pioglitazone and rosiglitazone. (HEPATOLOGY 2012;)

Oral Insulin Secretagogues, Insulin, and Cancer Risk in Type 2 Diabetes Mellitus

BACKGROUND Hyperinsulinemia might be the mechanism leading to an increased cancer risk in patients with type 2 diabetes. The objective was to evaluate the association between oral insulin secretagogues, insulins, and cancer incidence. METHODS A total of 108,920 patients with newly diagnosed type 2 diabetes were identified from the Taiwan National Health Insurance claims database during the period from 1 January 2000 to 31 December 2000. As of 31 December 2007, patients with incident cancer were included as cases, and up to four age- and sex-matched controls were selected by risk-set sampling. Logistic regression models were applied to estimate the odds ratio (OR) and 95% confidence interval (CI) between antidiabetic medication and cancer incidence. RESULTS A total of 8,194 incident cancer cases and 32,776 diabetic controls were included. A significantly increased risk for overall cancer incidence was found for any use of insulin (OR, 1.97; 95% CI, 1.85-2.09) and glinides (OR, 1.16; 95% CI, 1.06-1.28). Significantly increased risks were found for first- and second-generation sulfonylureas (OR, 1.08; 95% CI, 1.01-1.15), but not for third-generation drug, glimepiride (OR, 1.00; 95% CI, 0.93-1.08). Use of insulin and glinides was associated with higher risks for liver, colorectal, lung, stomach, and pancreas cancer, whereas sulfonylurea was mainly associated with an increased risk of liver cancer. CONCLUSIONS The results showed that sulfonylureas and glinides increased the risk for overall cancer, but to a lesser extent than insulin. Therapies that are associated with cancer risks certainly require further investigation.

Angiotensin Receptor Blockade and Risk of Cancer in Type 2 Diabetes Mellitus: A Nationwide Case-Control Study

PURPOSE The objective of this case-control study was to evaluate the risk of malignancy in diabetic patients who received angiotensin receptor blockers (ARBs). PATIENTS AND METHODS A total of 21,750 new diabetic patients who started antihypertensive treatment were identified from the Taiwan National Health Insurance claims database during the period from July 1, 2000, to December 31, 2000. As of December 31, 2007, patients with incident cancer were included as cases and up to four age- and sex-matched controls were selected by risk-set sampling. Logistic regression models were applied to estimate the odds ratios (ORs) and 95% CIs between ARB use and cancer incidence, adjusted for other types of antihypertensive drugs, insulin, oral hypoglycemic agents, statins, and underlying diseases. RESULTS Among the 1,281 patients with incident cancer and 5,104 controls, 333 (26.0%) and 1,341 (26.3%), respectively, received ARBs (OR, 0.98; 95% CI, 0.85 to 1.14). There was no statistically significant association between the effect of ARBs as a class and cancer incidence after adjustment for covariates (OR, 0.94; 95% CI, 0.80 to 1.10). Among the individual ARBs, losartan decreased the risk (OR, 0.78; 95% CI, 0.63 to 0.97) and candesartan (OR, 1.79; 95% CI, 1.05 to 3.06) and telmisartan (OR, 1.54; 95% CI, 0.97 to 2.43) possibly increased the risk of occurrence of malignancy. CONCLUSION The results did not show an effect of ARBs as a class on increasing cancer incidence in patients with diabetes. However, there was a negative association of losartan but a positive one of candesartan and telmisartan with the overall occurrence of cancer. The underlying mechanism certainly requires further investigation.

Effect of radiofrequency catheter ablation for atrial fibrillation on morbidity and mortality: a nationwide cohort study and propensity score analysis.

Background—This study examined the effect of radiofrequency catheter ablation (RFA) on reducing morbidity and mortality among patients with atrial fibrillation (AF). Methods and Results—A retrospective cohort of patients with AF without prior stroke or heart failure (HF) who underwent RFA between 2003 and 2009 was identified using Taiwan’s National Health Insurance claims database. Outpatients with AF who met the same enrollment criteria but did not receive RFA were matched (⩽1:20) by hospitals and dates to serve as controls. Outcomes of interest were death, stroke, or hospitalization for HF. A proportional hazard Cox regression model adjusted by propensity scores (based on age, sex, hypertension, diabetes mellitus, comorbidities, medications, and medical resource utilization) was applied to estimate the hazard ratio and 95% confidence interval. A total of 846 patients with AF who received RFA and 11 324 matched AF controls were included, with a mean follow-up of 3.74 and 3.96 years, respectively. RFA was associated with a lower hazard for stroke (hazard ratio, 0.57; 95% confidence interval, 0.35–0.94; P=0.026). The reduction in the hazard for death and HF did not reach statistical significance (hazard ratio, 0.88; 95% confidence interval, 0.62–1.23; P=0.451 and hazard ratio, 0.78; 95% confidence interval, 0.55–1.12; P=0.185, respectively). Additional analysis using death as a competing risk showed similar results for stroke and HF. Conclusions—RFA did not reduce mortality or hospitalization for HF during the immediate 3.5-year follow-up. Although a beneficial effect on stroke prevention associated with RFA was suggested, residual confounding attributable to unmeasured factors remains a concern.

Infection, antibiotic therapy and risk of colorectal cancer: a nationwide nested case-control study in patients with Type 2 diabetes mellitus.

Patients with Type 2 diabetes mellitus are at a higher risk of colorectal cancer (CRC). The objective of our study was to examine the inter‐relationship among infection sites, systemic antibiotic use and risk of CRC among patients with Type 2 diabetes mellitus. From a diabetic cohort from the Taiwans National Health Insurance claims database, we identified 3,593 incident colon cancer cases, 1,979 rectal cancer cases and 22,288 controls and conducted a nested case–control study to examine the association between antibiotic use and CRC incidence. Logistic regression models were applied to estimate the odds ratio (OR) and the 95% confidence interval (95% CI) between infection sites, antibiotic use and CRC incidence. Patients with intra‐abdominal infection were significantly associated with increased risk for colon cancer (OR = 2.01, 95% CI = 1.73–2.35) and rectal cancer (OR = 1.59, 95% CI = 1.26–2.00). Any antianaerobic antibiotic use was associated with a higher risk of colon cancer (OR = 2.31, 95% CI = 2.12–2.52) and rectal cancer (OR = 1.69, 95% CI = 1.50–1.90) but without an obvious dose–response relationship for cumulative use. Antianaerobic antibiotics also increased the risks for those with nonintra‐abdominal infection. No association was found between antiaerobic agent use and the CRC risk. The results suggest intra‐abdominal infections and antianaerobic antibiotic use may be a marker for precancerous lesions or early CRC, although the possibility of antianaerobic antibiotics playing an additional role cannot be excluded. Further research examining the relationship between intra‐abdominal infection, antianaerobic antibiotics use and possible change of microbiota leading to colorectal carcinogenesis is warranted.

No increased risk of hospitalization for heart failure for patients treated with dipeptidyl peptidase-4 inhibitors in Taiwan.

BACKGROUND Saxagliptin has been reported to be associated with an increased risk of hospitalization for heart failure (HF). The objective of this study was to test whether the increased risk is drug specific or a class effect for dipeptidyl peptidase-4 (DPP-4) inhibitors. METHODS Diabetic patients prescribed sitagliptin, saxagliptin, and vildagliptin between 2011 and 2013 were identified from Taiwans National Health Insurance (NHI) claims database. The outcome of interest was the first hospitalization for HF. The patients were followed for one year from drug initiation to outcome occurrence, death, or study termination (December 31, 2013). A Cox proportional hazards regression model was used to calculate the hazard ratios (HR) and their 95% confidence intervals, using sitagliptin as the reference group. RESULTS A total of 239,669 patients, including 159,330 sitagliptin, 38,561 saxagliptin, and 41,778 vildagliptin initiators, were included in the analysis. With a follow-up period ranging from 269days (vildagliptin) to 313days (sitagliptin), the crude incidence rate of HF was 2.77, 2.63, and 1.91 per 100 person-years for sitagliptin, saxagliptin, and vildagliptin, respectively. Saxagliptin had a similar risk (HR: 0.98, 95% CI: 0.91-1.06) to sitagliptin, while vildagliptin was associated with a lower risk of HF (HR: 0.85, 95% CI: 0.78-0.93). Auxiliary analyses using acarbose (n=130,800) as a reference group consistently showed no increased risk of HF associated with DDP-4 inhibitors. CONCLUSION Three DPP-4 inhibitors studied seem to be safe regarding the risk of HF, while the reduced risk of vildagliptin might be a spurious association or a chance finding.

National antiviral treatment program and the incidence of hepatocellular carcinoma and associated mortality in Taiwan: a preliminary report.

Background:Taiwan’s Bureau of National Health Insurance launched the National Antiviral Treatment Program (NATP) in 2003 to reimburse patients for antiviral drugs and interferons for chronic hepatitis B and C. The objective was to examine the impact of the NATP on the incidence and mortality due to hepatocellular carcinoma (HCC). Methods:The cumulative numbers of NATP participants were retrieved from the National Health Insurance claims database. The national incidence and mortality rates of HCC were obtained from the Taiwan Cancer Registry in each quarter from 1979 to 2009. An interrupted time-series analysis was applied to test the temporal trend change before and after NATP. Results:From 1979 to 1995, the HCC incidence increased in men and women of all age groups. From 2003 to 2009, 31,155 men and 10,769 women received anti–hepatitis B virus therapy, whereas 13,939 men and 10,721 women received anti–hepatitis C virus therapy. The incidence of HCC reached a plateau and then started to decline in men aged 30–39 (slope change P=0.003), 50–59 (P=0.051), and 60–69 years (P<0.001). A similar trend was noted in women aged 50–59 (P=0.035), 60–69 (P=0.006), and 70–79 years (P=0.052). The HCC mortality rate had been decreasing since 1996 and a further decline was observed after 2004 in men aged 60–69 years and women aged 60–79 years. Conclusions:There is a strong temporal relationship between NATP and the stabilization of the HCC incidence and related mortality. The cost-effectiveness of the NATP needs further evaluation.

Different angiotensin receptor blockers and incidence of diabetes: a nationwide population-based cohort study

BackgroundAngiotensin receptor blockers (ARBs) have been shown to exert various peroxisome proliferator-activated receptor gamma (PPARγ) binding activities and insulin-sensitizing effects. The objective of this study was to investigate the association of different ARBs with new-onset diabetes mellitus.MethodsIn the respective cohort, a total of 492,530 subjects who initiated ARB treatment between January 2004 and December 2009 were identified from Taiwan National Health Insurance Database. The primary outcome was newly diagnosed diabetes, defined as at least one hospital admission or two or more outpatient visits within a year with an ICD-9-CM code 250. Cox proportional regression was used to estimate the risk of diabetes associated with each ARB, using losartan as the reference.ResultsA total of 65,358 incident diabetes cases were identified out of 1,771,173 person-years. Olmesartan initiators had a small but significantly increased risk of developing diabetes after adjusting for baseline characteristics and mean daily dose (hazard ratio [HR], 1.07; 95% confidence interval [CI], 1.03-1.12). After excluding those followed for less than one year, the increase in diabetes risk are more pronounced (HR, 1.09; 95% CI, 1.05-1.14). This association was consistent across all subgroup analyses. Similar results were observed when a more strict definition of diabetes combining both diabetes diagnosis and anti-diabetic treatment was used. On the other hand, there was no difference in diabetes risk between telmisartan and losartan.ConclusionsAmong all ARBs, olmesartan might be associated with a slightly increased risk of diabetes mellitus. Our data suggest differential diabetes risks associated with ARBs beyond a class effect.

Different Angiotensin-Converting Enzyme Inhibitors and the Associations With Overall and Cause-Specific Mortalities in Patients With Hypertension

BACKGROUND Angiotensin-converting enzyme (ACE) inhibitors have been widely used in the treatment of hypertension, but the comparative effectiveness in reducing mortality among different drugs is seldom reported. METHODS We identified hypertensive patients who started captopril, enalapril, lisinopril, fosinopril, perindopril, ramipril, or imidapril therapy from Taiwans National Health Insurance database between 1 January 2004 and 31 December 2009. Overall and cause-specific mortalities were ascertained through a linkage to Taiwans National Death Registry. Patients were followed from the initiation of ACE inhibitors to death, disenrollment, or study termination (31 December 2010). A Cox proportional hazard regression model was used to calculate the hazard ratio (HR) and 95% confidence interval (CI), using ramipril as the reference group. RESULTS A total of 989,489 hypertensive patients were included, with a mean follow-up ranging from 3.5 years for imidapril to 4.5 years for enalapril. Captopril initiators had the highest overall mortality rate (117.8 per 1,000,000 person-days) as compared to other ACE inhibitors (54.3-79.4 per 1,000,000 person-days). Patients who started captopril therapy had a significantly increased risk of overall mortality (HR: 1.28, 95% CI: 1.24-1.31) when compared with ramipril. Enalapril (HR: 1.08, 95% CI: 1.05-1.11) and fosinopril (HR: 1.08, 95% CI: 1.05-1.12) were also associated with a modestly increased risk. No difference in mortality was found for lisinopril, perindopril, and imidapril, as compared with ramipril. CONCLUSIONS There are differences in the mortality risk associated with different ACE inhibitors. However, potential residual confounding effects might still exist.

Examining the Association of Olmesartan and Other Angiotensin Receptor Blockers With Overall and Cause-Specific Mortality

Concerns about an increased cardiovascular risk with the angiotensin receptor blocker, olmesartan, prompted the current study to examine associations between olmesartan and other angiotensin receptor blockers with overall and cause-specific mortalities. We collected patients who started to use losartan, valsartan, irbesartan, candesartan, telmisartan, and olmesartan between January 1, 2004, and December 31, 2009, from Taiwan’s National Health Insurance claims database. Prescribed drug types, dosage, and other clinical information were collected. Overall mortality and cause-specific mortality were ascertained through linkages with Taiwan’s National Death Registry. Two follow-up analyses, labeled intention-to-treat and as-treated, were conducted. A Cox proportional hazard regression model was used to calculate the hazard ratio (HR) and 95% confidence interval (CI) using losartan as the reference group. A total of 690 463 subjects were included, with a mean follow-up ranging from a low of 2.8 years for olmesartan to a high of 4.1 years for irbesartan. Subjects who began with valsartan had a modest but significantly increased risk of overall mortality (HR, 1.04; 95% CI, 1.02–1.06) compared with losartan. Irbesartan (HR, 0.96; 95% CI, 0.94–0.99), candesartan (HR, 0.95; 95% CI, 0.92–0.99), telmisartan (HR, 0.93; 95% CI, 0.90–0.96), and olmesartan (HR, 0.93; 95% CI, 0.88–0.97) were associated with a slightly lower overall mortality risk than losartan. The analysis indicates that the differences in mortality risk among individual angiotensin receptor blockers were only marginal and thus less likely to be clinically important. Although uncontrolled confounding might still exist, olmesartan does not seem to increase cardiovascular risk compared with losartan.