Davide Soranna

Cancer Risk Associated with Use of Metformin and Sulfonylurea in Type 2 Diabetes: A Meta-Analysis

OBJECTIVE Oral antidiabetic drugs (including metformin and sulfonylurea) may play a role in the relationship between type 2 diabetes and cancer. To quantify the association between metformin and sulfonylurea and the risk of cancer, we performed a meta-analysis of available studies on the issue. MATERIALS AND METHODS We performed a MEDLINE search for observational studies that investigated the risk of all cancers and specific cancer sites in relation to use of metformin and/or sulfonylurea among patients with type 2 diabetes mellitus. Fixed- and random-effect models were fitted to estimate the summary relative risk (RR). Between-study heterogeneity was tested using χ(2) statistics and measured with the I(2) statistic. Publication bias was evaluated using funnel plot and Eggers regression asymmetry test. RESULTS Seventeen studies satisfying inclusion criteria and including 37,632 cancers were evaluated after reviewing 401 citations. Use of metformin was associated with significantly decreased RR of all cancers (summary RR 0.61, 95% confidence interval [CI] 0.54-0.70), colorectal cancer (0.64, 95% CI 0.54-0.76), and pancreatic cancer (0.38, 95% CI 0.14-0.91). With the exception of colorectal cancer, significant between-study heterogeneity was observed. Evidence of publication bias for metformin-cancer association was also observed. There was no evidence that metformin affects the risk of breast and prostate cancers, nor that sulfonylurea affects the risk of cancer at any site. CONCLUSIONS Metformin, but not sulfonylurea, appears to reduce subsequent cancer risk. This has relevant implications in light of the exploding global epidemic of diabetes.

Long-term effect of high dose omega-3 fatty acid supplementation for secondary prevention of cardiovascular outcomes: A meta-analysis of randomized, double blind, placebo controlled trials

BACKGROUND Although omega-3 fatty acids have well documented properties which would reduce the cardiovascular (CV) disease risk, the evidence from randomized controlled trials (RCTs) remains inconclusive. We performed a meta-analysis of the available RCTs for investigating the CV preventive effect of administrating at least 1 gram/day, and for at least 1 year, omega-3 fatty acid supplements to patients with existing CV disease. METHODS RCTs published up to March 2013 were searched from PubMed, EMBASE, and the Cochrane Library. Two of us independently reviewed and selected eligible trials. RESULTS Of 360 articles retrieved, 11 randomized, double-blind, placebo controlled trials fulfilling inclusion criteria, overall involving 15,348 patients with a history of CV disease, were considered in the final analyses. No statistically significant association was observed for all-cause mortality (RR, 0.89; 95% CI, 0.78 to 1.02) and stroke (RR, 1.31; 95% CI, 0.90 to 1.90). Conversely, statistically significant protective effects were observed for cardiac death (RR, 0.68; 95% CI, 0.56 to 0.83), sudden death (RR, 0.67; 95% CI, 0.52 to 0.87), and myocardial infarction (RR, 0.75; 95% CI, 0.63 to 0.88). CONCLUSION Overall, our results supply evidence that long-term effect of high dose omega-3 fatty acid supplementation may be beneficial for the onset of cardiac death, sudden death and myocardial infarction among patients with a history of cardiovascular disease.

Statins and the Risk of Diabetes: Evidence From a Large Population-Based Cohort Study

OBJECTIVE To investigate the relationship between adherence with statin therapy and the risk of developing diabetes. RESEARCH DESIGN AND METHODS The cohort comprised 115,709 residents of the Italian Lombardy region who were newly treated with statins during 2003 and 2004. Patients were followed from the index prescription until 2010. During this period, patients who began therapy with an antidiabetic agent or were hospitalized for a main diagnosis of type 2 diabetes were identified (outcome). Adherence was measured by the proportion of days covered (PDC) with statins (exposure). A proportional hazards model was fitted to estimate hazard ratios (HRs) and 95% CIs for the exposure-outcome association, after adjusting for several covariates. A set of sensitivity analyses was performed to account for sources of systematic uncertainty. RESULTS During follow-up, 11,154 cohort members experienced the outcome. Compared with patients with very-low adherence (PDC <25%), those with low (26–50%), intermediate (51–75%), and high (≥75%) adherence to statin therapy had HRs (95% CIs) of 1.12 (1.06–1.18), 1.22 (1.14–1.27), and 1.32 (1.26–1.39), respectively. CONCLUSIONS In a real-world setting, the risk of new-onset diabetes rises as adherence with statin therapy increases. Benefits of statins in reducing cardiovascular events clearly overwhelm the diabetes risk.

Statins and primary liver cancer : a meta-analysis of observational studies

Statins are among the most commonly prescribed drugs used to manage dyslipidemia. Hepatocellular carcinoma is the third leading cause of cancer mortality and its rates have recently been increasing in central and northern Europe and USA. To quantify the association between statin use and risk for HCC, we performed a meta-analysis of published studies. We conducted a MEDLINE search for observational studies reporting the association between exposure to statins and risk for incident liver cancer until March 2012. Fixed-effect and random-effect models were used to estimate summary relative risks (RR) and the corresponding 95% confidence intervals (CIs). Moreover, between-study heterogeneity and publication bias were assessed using adequate statistical tests. Five observational studies (two case–control and three cohort studies) based on 2574 cases of HCC were included. Statin treatment, compared with no treatment, was inversely related to HCC (summary RR=0.58; 95% CI 0.46–0.74). Between-study heterogeneity was significant (P<0.001) and numerically relevant (I2=65%). When only longest statin use was considered, the RR was 0.66 (95% CI 0.55–0.80). Influence analysis on the overall estimate showed that heterogeneity was largely because of one study; when omitting it, the I2 dropped to 27% (P=0.240), whereas the summary RR was only marginally modified (RR=0.52; 95% CI 0.44–0.62). There was no evidence of publication bias. This meta-analysis suggests a favorable effect of statins on HCC, in the absence, however, of a duration–risk relationship.

Factors involved in the discontinuation of antihypertensive drug therapy: An analysis from real life data

Objectives: We have previously shown that in Italian region of Lombardy (about 10 million citizens), adherence to antihypertensive treatment is low, and that this is associated with a greater risk of hospitalization for cardiovascular events. In this study, we used a healthcare database to study the factors involved in discontinuation of antihypertensive drug prescriptions in real life. Methods and results: The analysis was restricted to 493 623 new users of antihypertensive drugs (no prescriptions in the previous 3 years) recruited in 2003, 2006 and 2009. Discontinuation was defined as lack of prescription renewal for at least 3 months. Each patient was followed at most for 1 year. The adjusted risk of treatment discontinuation depended on the type of initial antihypertensive treatment (diuretic monotherapy associated with higher risk) and it was lower in men (−17%) and older (−21 to −29%) patients, in patients with co-treatment with antidiabetic drugs, or hospitalization for cardiovascular or renal disease (−12 to −27%), but greater in patients under co-treatment with antidepressant drugs or hospitalization for concomitant pulmonary, rheumatic, neoplastic or neurological diseases (+9 to +32%). An unexpected relationship between discontinuation of treatment and density of the population of patients residence, with a much greater discontinuation in metropolitan areas, was observed. Conclusions: In a real life setting, discontinuation of antihypertensive treatment is affected in an opposite direction by a large number of factors: type of antihypertensive treatment, co-treatments, clinical conditions and even demographic characteristics of the geographical area where the patient lives. Knowledge of these factors may help the effort to reduce this phenomenon.

Impact of aortic or mitral valve sclerosis and calcification on cardiovascular events and mortality: a meta-analysis.

a Department of Statistics and Quantitative Methods, Section of Biostatistics, Epidemiology and Public Health, University of Milano-Bicocca, Milan, Italy b Cardiology Division, Spedali Civili di Brescia and University of Brescia, Italy c Department of Cardiovascular Diseases, S. Giovanni-Addolorata Hospital, Roma, Italy d Department of Medicine, Section of Cardiology, University of Verona, Italy e Echocardiography Laboratory, Villa Bianca Hospital, Trento, Italy f Cardiology Unit, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy

Adherence With Antihypertensive Drug Therapy and the Risk of Heart Failure in Clinical Practice

Randomized clinical trials have shown that antihypertensive treatment reduces the risk of heart failure (HF). Limited evidence exists, however, on whether and to what extent this benefit is translated into real-life practice. A nested case–control study was carried out by including the cohort of 76 017 patients from Lombardy (Italy), aged 40 to 80 years, who were newly treated with antihypertensive drugs during 2005. Cases were the 622 patients who experienced hospitalization for HF from initial prescription until 2012. Up to 5 controls were randomly selected for each case. Logistic regression was used to model the HF risk associated with adherence to antihypertensive drugs, which was measured by the proportion of days covered by treatment (PDC). Data were adjusted for several covariates. Sensitivity analyses were performed to account for possible sources of systematic uncertainty. Compared with patients with very low adherence (PDC, ⩽25%), low, intermediate, and high adherences were associated with progressively lower risk of HF, reduction in the high-adherence group (>75%) being 34% (95% confidence interval, 17%–48%). Similar effects were observed in younger (40–70 years) and older (71–80 years) patients and between patients treated with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and diuretics. There was no evidence that adherence with calcium-channel blockers reduced the HF risk. Antihypertensive treatment lowers the HF risk in real-life practice, but adherence to treatment is necessary for a substantial benefit to take place. This is the case with a variety of antihypertensive drugs.

Medication persistence and the use of generic and brand-name blood pressure-lowering agents.

Background: Because of their lower cost, healthcare systems recommend physicians to prefer generic products, rather than brand-name medicaments. There is then considerable interest and debate concerning safety and effectiveness of generic products. Few studies have compared patients treated with brand-name and generic drugs for adherence to treatment, with somewhat inconsistent results. The primary objective of this study was to compare the risk of discontinuing antihypertensive drug therapy in patients treated with generic or brand-name agents. Methods: The 101 618 beneficiaries of the Healthcare system of Lombardy, Italy, aged 18 years or older who were newly treated on monotherapy with antihypertensive generic or brand-name drugs during 2008, were followed until the earliest date among those of the occurrence of treatment discontinuation to whatever antihypertensive drug therapy (outcome), or censoring (death, emigration, 12 months after treatment initiation). Hazard ratios of discontinuation associated with starting on generic or brand-name products (intention-to-treat analysis), and incidence rate ratio of discontinuation during periods on generic and brand-name products (as-treated analysis) were respectively estimated from a cohort and self-controlled case series analyses. Results: Patients who started on generics did not experience a different risk of discontinuation compared with those starting on brand-name agents (hazard ratio: 1.00; 95% confidence interval 0.98–1.02). Discontinuation did not occur with different rates during periods covered by generics or brand-name agents (incidence rate ratio: 1.01; 95% confidence interval 0.96–1.11) within the same individuals. A number of sensitivity and subgroup analyses confirmed the robustness of these findings. Conclusion: Generic products are not responsible for the high rate of discontinuation from antihypertensive drug therapy. Assuming therapeutic equivalence, clinical implication is of prescribing generic drug therapies.

Are generic and brand-name statins clinically equivalent? Evidence from a real data-base

BACKGROUND Use of generic drugs can help contain drug spending. However, there is concern among patients and physicians that generic drugs may be clinically inferior to brand-name ones. This study aimed to compare patients treated with generic and brand-name statins in terms of therapeutic interruption and cardiovascular (CV) outcomes. METHODS 13,799 beneficiaries of the health care system of Lombardy, Italy, aged 40 years or older who were newly treated with generic or brand-name simvastatin during 2008, were followed until 2011 for the occurrence of two outcomes: 1) therapeutic discontinuation and 2) hospitalization for CV events. Hazard ratios (HR) associated with use of generic or brand-name at starting therapy (intention-to-treat analysis) and during follow-up (as-treated analysis) were estimated by fitting proportional hazard Cox models. A Monte-Carlo sensitivity analysis was performed to account for unmeasured confounders. RESULTS Patients who started on generic did not experience a different risk of discontinuation (HR: 0.98; 95% CI 0.94 to 1.02) nor of CV outcomes (HR: 0.98; 95% CI 0.79 to 1.22) from those starting on brand-name. Patients who spent >75% of time of follow-up with statin available on generics did not experience a different risk of discontinuation (HR: 0.94; 95% CI 0.87 to 1.01), nor of CV outcomes (HR: 1.06; 95% CI 0.83 to 1.34), compared with those who mainly or only used brand-name statin. CONCLUSIONS Our findings do not support the notion that in the real world clinical practice brand-name statins are superior to generics for keeping therapy and preventing CV outcomes.

Similarity between generic and brand-name antihypertensive drugs for primary prevention of cardiovascular disease: evidence from a large population-based study

Although generic and earlier brand‐name counterparts are bioequivalent, their equivalence in preventing relevant clinical outcomes is of concern.