Previous meta-analyses have shown that the anti-diabetic agent metformin is associated with reduced cancer incidence and mortality. However, this effect has not been consistently demonstrated in animal models and recent epidemiological studies. We performed a meta-analysis with a focus on confounders and biases, including BMI, study type, and time related biases. We identified 71 articles published between January 1, 1966 to May 31, 2013 through Pubmed, ISI Web of Science (Science Citation Index Expanded), Embase, and the Cochrane library that were related to metformin and cancer incidence or mortality. Study characteristics and outcomes were abstracted for each study that met inclusion criteria. We included estimates from 47 independent studies and 65,540 cancer cases in diabetic patients. Overall cancer incidence was reduced by 31% (SRR=0.69, 95%CI: 0.52–0.90), although between-study heterogeneity was considerable (I2=88%). Cancer mortality was reduced by 34% (SRR=0.66, 95%CI: 0.54–0.81; I2=21%). BMI-adjusted studies and studies without time-related biases also showed significant reduction in cancer incidence (SRR=0.82, 95%CI: 0.70–0.96 with I2=76% and SRR=0.90; 95%CI: 0.89–0.91 with I2=56%, respectively), albeit with lesser magnitude (18% and 10% reduction, respectively). However, studies of cancer mortality and individual organ sites did not consistently show significant reductions across all types of analyses. Although these associations may not be causal, our results show that metformin may reduce cancer incidence and mortality in diabetic patients. However the reduction seems to be of modest magnitude and not affecting all populations equally. Clinical trials are needed to determine if these observations apply to non-diabetic populations and to specific organ sites.
Multiple epidemiological studies have documented an association between metformin, used for treatment of type 2 diabetes, and reduced cancer incidence and mortality. Cell line models may not accurately reflect the effects of metformin in the clinical setting. Moreover, findings from animal model studies have been inconsistent, whilst those from more recent epidemiological studies have tempered the overall effect size. The purpose of this review is to examine metformin's chemopreventive potential by outlining relevant mechanisms of action, the most recent epidemiologic evidence, and recently completed and ongoing clinical trials. Although repurposing drugs with excellent safety profiles is an appealing strategy for cancer prevention and treatment in the adjuvant setting, there is no substitute for well-executed, large randomised clinical trials to define efficacy and determine the populations that are most likely to benefit from an intervention. Thus, enthusiasm remains for understanding the role of metformin in cancer through ongoing clinical research.
Background. Policymakers need estimates of the impact of tobacco control (TC) policies to set priorities and targets for reducing tobacco use. We systematically reviewed the independent effects of TC policies on smoking behavior. Methods. We searched MEDLINE (through January 2012) and EMBASE and other databases through February 2009, looking for studies published after 1989 in any language that assessed the effects of each TC intervention on smoking prevalence, initiation, cessation, or price participation elasticity. Paired reviewers extracted data from studies that isolated the impact of a single TC intervention. Findings. We included 84 studies. The strength of evidence quantifying the independent effect on smoking prevalence was high for increasing tobacco prices and moderate for smoking bans in public places and antitobacco mass media campaigns. Limited direct evidence was available to quantify the effects of health warning labels and bans on advertising and sponsorship. Studies were too heterogeneous to pool effect estimates. Interpretations. We found evidence of an independent effect for several TC policies on smoking prevalence. However, we could not derive precise estimates of the effects across different settings because of variability in the characteristics of the intervention, level of policy enforcement, and underlying tobacco control environment.
The largest and longest clinical trial of metformin for the prevention of diabetes is the Diabetes Prevention Program/Diabetes Prevention Program Outcomes Study (DPP/DPPOS). In this review, we summarise data from the DPP/DPPOS, focusing on metformin for diabetes prevention, as well as its long-term glycaemic and cardiometabolic effects and safety in people at high-risk of developing diabetes. The DPP (1996–2001) was a RCT of 3234 adults who, at baseline, were at high-risk of developing diabetes. Participants were assigned to masked placebo (n = 1082) or metformin (n = 1073) 850 mg twice daily, or intensive lifestyle intervention (n = 1079). The masked metformin/placebo intervention phase lasted 3.2 years, with primary outcome of diabetes incidence reported early, at 2.8 years, because of demonstrated efficacy. At the end of the DPP, all participants were offered lifestyle education and 88 % (n = 2776) of the surviving DPP cohort continued follow-up in the DPPOS. Participants originally assigned to metformin continued to receive metformin, unmasked. The DPP/DPPOS cohort has now been followed for over 15 years with prospective assessment of glycaemic, cardiometabolic, health economic, and safety outcomes. After an average follow-up of 2.8 years, metformin reduced the incidence of diabetes by 31 % compared with placebo, with a greater effect in those who were more obese, had a higher fasting glucose or a history of gestational diabetes. The DPPOS addressed the longer-term effects of metformin, showing a risk reduction of 18 % over 10 and 15 years post-randomisation. Metformin treatment for diabetes prevention was estimated to be cost-saving. At 15 years, lack of progression to diabetes was associated with a 28 % lower risk of microvascular complications across treatment arms, a reduction that was no different among treatment groups. Recent findings suggest metformin may reduce atherosclerosis development in men. Originally used for the treatment of type 2 diabetes, metformin, now proven to prevent or delay diabetes, may serve as an important tool in battling the growing diabetes epidemic. Long-term follow-up, currently underway in the DPP/DPPOS, is now evaluating metformin’s potential role, when started early in the spectrum of dysglycaemia, on later-stage comorbidities, including cardiovascular disease and cancer.
Purpose Local transdermal therapy to the breast may achieve effective target-organ drug delivery, while diminishing systemic effects. We conducted a randomized, double-blind, placebo-controlled phase II trial comparing transdermal 4-hydroxytamoxifen gel (4-OHT) to oral tamoxifen (oral-T) in women with ductal carcinoma in-situ (DCIS). Methods 27pre and postmenopausal women were randomized to 4-OHT (4mg/day) or oral-T (20mg/day) for 6-10 weeks before surgery. Plasma, nipple aspirate fluid, and breast adipose tissue concentrations of tamoxifen and its major metabolites were determined by liquid chromatography-tandem mass spectrometry. The primary endpoint was Ki67 labeling in DCIS lesions, measured by immunohistochemistry. In plasma, insulin-like growth factor-1 (IGF-1), sex hormone-binding globulin (SHBG), and coagulation protein concentrations were determined. Results Post-therapy Ki-67 decreased by 3.4% in the 4-OHT and 5.1% in the oral-T group (p < 0.03 in both, between-group p=0. 99). Mean plasma 4-OHT was 0.2 and 1.1 ng/mL in 4-OHT and oral groups, respectively (p=0.0003), while mean breast adipose tissue concentrations of 4-OHT were 5.8 ng/g in the 4-OHT group and 5.4 ng/g in the oral group (p=0.88). There were significant increases in plasma SHBG, Factor VIII and von Willebrand factor and a significant decrease in plasma IGF-1 with oral-T, but not with 4-OHT. The incidence of hot flashes was similar in both groups. Conclusions The anti-proliferative effect of 4-OHT gel applied to breast skin was similar to that of oral-T, but effects on endocrine and coagulation parameters were reduced. These findings support the further evaluation of local transdermal therapy for DCIS and breast cancer prevention.
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