In this review, we aim to update readers about the most recent studies on common pharmaceuticals and their association with pancreatic cancer risk. The use of prophylactic aspirin, metformin, beta-blockers, and statins has been studied in the past but showed inconclusive results in the reduction of pancreatic cancer incidence. However, in recent studies, these medications along with combination therapy of aspirin and metformin were found to have a more significant association with decreasing risk. Given the poor prognosis of pancreatic cancer despite treatment, medication prophylaxis prevention should be considered. In this review, we hope to encourage future case-control or prospective studies on common medications that have shown great potential in delaying pancreatic cancer development.

The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, also known as statins, are administered as first-line therapy for hypercholesterolemia, both as primary and secondary prevention. Besides the lipid-lowering effect, statins have been suggested to inhibit the development of cardiovascular disease through anti-inflammatory, antioxidant, vascular endothelial function-improving, plaque-stabilizing, and platelet aggregation-inhibiting effects. The preventive effect of statins on atherothrombotic stroke has been well established, but statins can influence other cerebrovascular diseases. This suggests that statins have many neuroprotective effects in addition to lowering cholesterol. Furthermore, research suggests that statins cause pro-apoptotic, growth-inhibitory, and pro-differentiation effects in various malignancies. Preclinical and clinical evidence suggests that statins inhibit tumor growth and induce apoptosis in specific cancer cell types. The pleiotropic effects of statins on cardiovascular and cerebrovascular diseases have been well established; however, the effects of statins on cancer patients have not been fully elucidated and are still controversial. This review discusses the recent evidence on the effects of statins on cardiovascular and cerebrovascular diseases and cancer. Additionally, this study describes the pharmacological action of statins, focusing on the aspect of ‘beyond lipid-lowering’.

• Aged
• Diabetes Mellitus/diagnosis
• Diabetes Mellitus/drug therapy
• Disease Progression
• Female
• Glycemic Control
• Humans
• Incidence
• Male
• Middle Aged
• Pancreatic Neoplasms/epidemiology
• Pancreatic Neoplasms/etiology
• Risk Factors
• Sex Factors
• United States/epidemiology
• Veterans

• P01 CA236585 NCI NIH HHS
• R21 CA220073 NCI NIH HHS
• U01 DK108314 NIDDK NIH HHS
• NCI
• NIH
• NIH National Institute Diabetes and Digestive and Kidney Diseases award

• cancer risk factors
• early detection
• exposome
• pancreatic cancer
• systematic review

• Pancreatic neoplasms
• Pancreatitis
• Pharmacoepidemiology

• Aged
• Case-Control Studies
• Databases, Factual
• Drug-Related Side Effects and Adverse Reactions
• Female
• Humans
• Male
• Middle Aged
• Pancreatic Neoplasms/epidemiology
• Pancreatitis/chemically induced
• Risk Assessment
• Scotland/epidemiology

• 25535 Cancer Research UK
• C37316/A25535 Cancer Research UK

• Alcohol intake
• Environmental and synthetic toxins
• Infectious diseases
• Life style factors
• Metabolic syndrome
• Obesity
• Pancreatic cancer
• Red and processed meat
• Tobacco smoking
• Type 2 diabetes

• Alcohol Drinking/adverse effects
• Alcohol Drinking/epidemiology
• Comorbidity
• Diabetes Mellitus/epidemiology
• Environmental Exposure/adverse effects
• Gene-Environment Interaction
• Humans
• Inflammation/epidemiology
• Life Style
• Obesity/epidemiology
• Pancreatic Neoplasms/diagnosis
• Pancreatic Neoplasms/epidemiology
• Pancreatic Neoplasms/genetics
• Red Meat/adverse effects
• Risk Assessment
• Risk Factors
• Smoking/adverse effects
• Smoking/epidemiology
• Stress, Psychological/epidemiology

• Cancer
• Cholesterol
• Endocrine
• HDL
• LDL

Although several studies have suggested that aspirin and statins may help prevent pancreatic ductal adenocarcinoma (PDAC), this concept has been controversial. This study aimed to evaluate the association between use of statin or aspirin and PDAC in a nationwide large cohort.

In this nested case‐control study, we used data from a 12‐year nationwide longitudinal cohort in Korea. Cases with PDAC and controls who were matched to cases by age, sex, income, and index year at a 1:5 ratio were established. We used multivariate logistic regression analyses to identify the independent risk factors of PDAC.

We identified a total of 827 patients with PDAC between 2007 and 2013, and included 4135 matched controls. Diabetes mellitus, chronic and acute pancreatitis, pancreatic cystic lesions, and cholelithiasis were independent risk factors for PDAC. Statin use (odds ratio [OR], 0.92; 95% confidence interval [CI] 0.76‐1.11; P = .344; adjusted OR [aOR], 0.70; 95% CI 0.56‐0.87; P = .001) was associated with a reduced risk of PDAC after correction of the confounding factors, but aspirin use (OR, 0.98; 95% CI 0.84‐1.15; P = .838; aOR 0.84; 95% CI 0.70‐1.01, P = .068) was not associated with PDAC. Among the patients with risk factors, both statin use (OR, 0.50; 95% CI 0.38‐0.66; P < .001; aOR, 0.62; 95% CI 0.45‐0.84; P = .002) and aspirin use (OR, 0.48; 95% CI 0.31‐0.67; P < .001; aOR 0.67; 95% CI 0.50‐0.89, P = .006) were associated with a reduced risk of PDAC.

This study suggests that statin use was associated with a reduced risk of PDAC incidence but aspirin use was not. Both statin use and aspirin use were associated a reduced risk of PDAC incidence for patients with risk factors.

• aspirin
• cohort
• pancreatic cancer
• prevention
• statin

Statins are reported to reduce the risk of cancer, but the results of various published studies have been contradictory. We carried out an umbrella review to provide an overview and understand the strength of evidence, extent of potential biases, and validity of claimed associations between the use of statins and cancer incidence. We comprehensively re-analyzed the data of meta-analyses of randomized controlled trials (RCTs) and observational studies on associations between statin use and cancer incidence. We also assessed the strength of evidence of the re-analyzed outcomes, which were determined from the criteria including statistical significance of the p-value of random-effects, as well as fixed-effects meta-analyses, small study effects, between-study heterogeneity, and a 95% prediction interval. Using a conventional method to assess the significance of meta-analysis (p-value < 0.05), statins had a statistically significant effect on reducing cancer incidence in 10 of 18 types of cancer. When we graded the level of evidence, no cancer type showed convincing evidence, and four cancers (esophageal cancer, hematological cancer, leukemia, and liver cancer) showed suggestive evidence of a preventive effect. There was weak evidence of an association with six cancers, and no significance for the remaining eight cancers. None of the meta-analyses of RCTs on the association of statin and cancer incidence showed a statistical significance. Although there was a preventive effect of statin on cancer incidence in 10 of the 18 cancer types, the evidence supporting the use of statins to reduce cancer incidence was low. Therefore, the associations between statin use and cancer incidence should be carefully considered by clinicians.

• cancer
• meta-analysis
• statin
• umbrella review

• epidemiology
• pancreatic cancer
• pancreatitis
• risk factors
• statins

• Cholangiocarcinoma
• Diabetes
• Hepatobiliary cancer
• Hepatocellular cancer
• Metabolic syndrome
• Obesity

• Aged
• Bile Duct Neoplasms/epidemiology
• Bile Duct Neoplasms/etiology
• Body Mass Index
• Carcinoma, Hepatocellular/epidemiology
• Carcinoma, Hepatocellular/etiology
• Case-Control Studies
• Cholangiocarcinoma/epidemiology
• Cholangiocarcinoma/etiology
• Diabetes Complications
• Female
• Gallbladder Neoplasms/epidemiology
• Gallbladder Neoplasms/etiology
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Hypertension/complications
• Incidence
• Liver Neoplasms/epidemiology
• Liver Neoplasms/etiology
• Male
• Metabolic Syndrome/complications
• Obesity/complications
• Smoking/adverse effects

• Chemoprevention
• Meta-analysis
• Pancreatic cancer
• Statins

• Case-Control Studies
• Chemoprevention
• Cohort Studies
• Female
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
• Male
• Pancreatic Neoplasms/prevention & control
• Randomized Controlled Trials as Topic
• Risk Assessment/statistics & numerical data

• Chemoprevention
• Cohort studies
• Hydroxymethylglutaryl-CoA reductase inhibitors
• Pancreatic neoplasms
• Risk factors

• Epidemiology
• HPFS
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• NHS
• Neoplasm

• Adenocarcinoma/mortality
• Adult
• Aged
• Female
• Follow-Up Studies
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
• Male
• Middle Aged
• Pancreatic Neoplasms/mortality
• Prospective Studies
• Survival Analysis
• Treatment Outcome

• R35 CA197735 NCI NIH HHS
• U01 CA210171 NCI NIH HHS
• P01 CA087969 NCI NIH HHS
• R01 CA124908 NCI NIH HHS
• R01 CA205406 NCI NIH HHS
• UM1 CA186107 NCI NIH HHS
• UM1 CA167552 NCI NIH HHS
• R01 CA049449 NCI NIH HHS
• P50 CA127003 NCI NIH HHS

• Humans
• Pancreatic Neoplasms/prevention & control
• Risk
• Risk Factors

Statin treatment of hypercholesterolemia is accompanied also with depletion of the mevalonate intermediates, including farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) necessary for proper function of small GTPases. These include Ras proteins, prevalently mutated in pancreatic cancer. In our study, we evaluated the effect of three key intermediates of the mevalonate pathway on GFP-K-Ras protein localization and the gene expression profile in pancreatic cancer cells after exposure to individual statins.

These effects were tested on MiaPaCa-2 human pancreatic cancer cells carrying a K-Ras activating mutation (G12C) after exposure to individual statins (20 μM). The effect of statins (atorvastatin, lovastatin, simvastatin, fluvastatin, cerivastatin, rosuvastatin, and pitavastatin) and mevalonate intermediates on GFP-K-Ras protein translocation was analyzed using fluorescence microscopy. The changes in gene expression induced in MiaPaCa-2 cells treated with simvastatin, FPP, GGPP, and their combinations with simvastatin were examined by whole genome DNA microarray analysis.

All tested statins efficiently inhibited K-Ras protein trafficking from cytoplasm to the cell membrane of the MiaPaCa-2 cells. The inhibitory effect of statins on GFP-K-Ras protein trafficking was partially prevented by addition of any of the mevalonate pathway’s intermediates tested. Expressions of genes involved in metabolic and signaling pathways modulated by simvastatin treatment was normalized by the concurrent addition of FPP or GGPP. K-Ras protein trafficking within the pancreatic cancer cells is effectively inhibited by the majority of statins; the inhibition is eliminated by isoprenoid intermediates of the mevalonate pathway.

Our data indicate that the anticancer effects of statins observed in numerous studies to a large extent are mediated through isoprenoid intermediates of the mevalonate pathway, as they influence expression of genes involved in multiple intracellular pathways.

The online version of this article (10.1186/s12944-017-0641-0) contains supplementary material, which is available to authorized users.

• Farnesyl pyrophosphate
• Gene expression
• Geranylgeranyl pyrophosphate
• HMG-CoA reductase inhibitors
• Isoprenoids
• K-Ras oncogene
• Mevalonate
• Pancreatic cancer
• Prenylation
• Statins

• Aged
• Aspirin/adverse effects
• Case-Control Studies
• Drug Therapy, Combination
• Female
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects
• Life Style
• Male
• Pancreatic Neoplasms/chemically induced
• Risk Factors

• liver cancer
• meta-analysis
• prospective cohort studies
• statins

• Dose-Response Relationship, Drug
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage
• Liver Neoplasms/epidemiology
• Liver Neoplasms/prevention & control
• Observational Studies as Topic
• Risk

To conduct an overview of meta-analyses to critically appraise the evidence and present a comprehensive evaluation of the association between statin use and risk of site specific cancers.

MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews and Web of Science databases were searched from inception until 31^st May 2016. The electronic database search was supplemented by a hand search in PROSPERO and relevant journals which are not indexed in above databases. Meta-analyses that examined the association between statin use and risk of site specific cancers were included. Two reviewers independently screened the literature, abstracted data, and assessed study quality using the Assessment of Multiple Systematic Reviews (AMSTAR) tool.

Overall, 38 meta-analyses covered 13 site specific cancers were included. More than half (68%) of the meta-analyses were moderate in quality with an AMSTAR score 4-7 out of a possible 11. Based on current evidence from meta-analyses, use of statin decreases the risk of certain cancers, such as colorectal (8%-12%), gastric (27%-44%), hematological (19%), liver (37%-42%), oesophageal (14%-28%), ovarian (21%) and prostate cancer (7%). On the other side, evidence from meta-analyses also suggests that there is no association between statin use and risk of bladder, breast, endometrial, kidney, lung, pancreatic and skin cancers.

This overview of meta-analyses with variable quality has been shown that the statins may have a potential role in cancer chemoprevention and reduce the risk of some site specific cancers, but not all.

• Statin
• Cancer
• Meta-analysis

Statins, besides being powerful cholesterol-lowering drugs, also exert potent anti-proliferative activities. However, their anti-cancer efficacy differs among the individual statins. Thus, the aim of this study was to identify the biological pathways affected by individual statins in an in vitro model of human pancreatic cancer. The study was performed on a human pancreatic cancer cell line MiaPaCa-2, exposed to all commercially available statins (12 μM, 24 h exposure). DNA microarray analysis was used to determine changes in the gene expression of treated cells. Intracellular concentrations of individual statins were measured by UPLC (ultra performance liquid chromatography)-HRMS (high resolution mass spectrometer). Large differences in the gene transcription profiles of pancreatic cancer cells exposed to various statins were observed; cerivastatin, pitavastatin, and simvastatin being the most efficient modulators of expression of genes involved namely in the mevalonate pathway, cell cycle regulation, DNA replication, apoptosis and cytoskeleton signaling. Marked differences in the intracellular concentrations of individual statins in pancreatic cancer cells were found (>11 times lower concentration of rosuvastatin compared to lovastatin), which may contribute to inter-individual variability in their anti-cancer effects. In conclusion, individual statins exert different gene expression modulating effects in treated pancreatic cancer cells. These effects may be partially caused by large differences in their bioavailability. We report large differences in gene transcription profiles of pancreatic cancer cells exposed to various statins. These data correlate to some extent with the intracellular concentrations of statins, and may explain the inter-individual variability in the anti-cancer effects of statins.

Background: In the era of precision medicine, more attention is paid to the search for predictive markers of treatment efficacy and tolerability. Statins are one of the classes of drugs that could benefit from this approach because of their wide use and their incidence of adverse events. Methods: Literature from PubMed databases and bibliography from retrieved publications have been analyzed according to terms such as statins, pharmacogenetics, epigenetics, toxicity and drug–drug interaction, among others. The search was performed until 1 October 2016 for articles published in English language. Results: Several technical and methodological approaches have been adopted, including candidate gene and next generation sequencing (NGS) analyses, the latter being more robust and reliable. Among genes identified as possible predictive factors associated with statins toxicity, cytochrome P450 isoforms, transmembrane transporters and mitochondrial enzymes are the best characterized. Finally, the solute carrier organic anion transporter family member 1B1 (SLCO1B1) transporter seems to be the best target for future studies. Moreover, drug–drug interactions need to be considered for the best approach to personalized treatment. Conclusions: Pharmacogenetics of statins includes several possible genes and their polymorphisms, but muscular toxicities seem better related to SLCO1B1 variant alleles. Their analysis in the general population of patients taking statins could improve treatment adherence and efficacy; however, the cost–efficacy ratio should be carefully evaluated.

• drug transporters
• epigenetics
• pharmacogenetics
• statins
• toxicity

• Animals
• Cytochrome P-450 Enzyme System/genetics
• Cytochrome P-450 Enzyme System/metabolism
• Epigenomics
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/metabolism
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
• Liver-Specific Organic Anion Transporter 1/genetics
• Liver-Specific Organic Anion Transporter 1/metabolism
• Membrane Transport Proteins/genetics
• Membrane Transport Proteins/metabolism
• Mitochondrial Proteins/genetics
• Mitochondrial Proteins/metabolism
• Pharmacogenetics
• Polymorphism, Genetic
• Precision Medicine

• chemoprevention
• metabolic syndrome
• obesity
• pancreatic cancer
• statins

• Gemcitabine
• Gfi-1
• Pancreatic ductal adenocarcinoma
• Simvastatin
• TGF-β1
• Tumor-associated macrophages

• Aspirin
• COX-2 inhibitor
• NSAIDs
• Pancreatic cancer
• Paracetamol
• Statin

• Environmental factors
• Pancreas
• Pancreatic cancer
• Protective factors
• Risk factors

• Adenocarcinoma/mortality
• Aged
• Anticholesteremic Agents/therapeutic use
• Atorvastatin/therapeutic use
• Dose-Response Relationship, Drug
• Female
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
• Male
• Middle Aged
• Pancreatic Neoplasms/mortality
• Proportional Hazards Models
• Retrospective Studies
• Risk Factors
• Simvastatin/therapeutic use
• Survival Rate
• Time Factors

• Cancer risk
• Pancreatic cancer
• Statins

To determine the effect of different statins on the induction of diabetes mellitus.

Four statins (atorvastatin, pravastatin, rosuvastatin, and pitavastatin) were used. Cytotoxicity, insulin secretion, glucose-stimulated insulin secretion, and G₀/G₁ phase cell cycle arrest were investigated in human pancreas islet β cells, and glucose uptake and signaling were studied in human skeletal muscle cells (HSkMCs).

Human pancreas islet β cells treated with 100 nM atorvastatin, pravastatin, rosuvastatin, and pitavastatin had reduced cell viability (32.12%, 41.09%, 33.96%, and 29.19%, respectively) compared to controls. Such cytotoxic effect was significantly attenuated by decreasing the dose to 10 and 1 nM, ranged from 1.46% to 17.28%. Cells treated with 100 nM atorvastatin, pravastatin, rosuvastatin, and pitavastatin had a reduction in the rate of insulin secretion rate by 34.07%, 30.06%, 26.78%, and 19.22%, respectively. The inhibitory effect was slightly attenuated by decreasing the dose to 10 and 1 nM, ranging from 10.84% to 29.60%. Insulin secretion stimulated by a high concentration of glucose (28 mmol/L) was significantly higher than a physiologic concentration of glucose (5.6 mmol/L) in all treatment groups. The glucose uptake rates at a concentration of 100 nM were as follows: atorvastatin (58.76%) < pravastatin (60.21%) < rosuvastatin (72.54%) < pitavastatin (89.96%). We also found that atorvastatin and pravastatin decreased glucose transporter (GLUT)-2 expression and induced p-p38 MAPK levels in human pancreas islet β cells. Atorvastatin, pravastatin, and rosuvastatin inhibited GLUT-4, p-AKT, p-GSK-3β, and p-p38 MAPK levels in HSkMCs.

Statins similar but different degree of effects on pancreas islet β cells damage and induce insulin resistance in HSkMC.

• glucose
• human pancreas islet β cell
• human skeletal muscle cells
• insulin
• statins

• Aged
• Aged, 80 and over
• Case-Control Studies
• Cohort Studies
• Databases, Factual
• Dose-Response Relationship, Drug
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
• Male
• Middle Aged
• National Health Programs
• Prostatic Neoplasms/diagnosis
• Prostatic Neoplasms/mortality
• Prostatic Neoplasms/therapy
• Survival Analysis
• Taiwan/epidemiology

• chemoprevention
• diabetes mellitus
• pancreatic cancer
• statins

• 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors
• cancer risk
• case-control
• pancreatic adenocarcinoma
• statins

• Pancreas cancer
• meta-analysis
• pooled analysis
• population attributable fraction
• review
• risk factors

• kidney cancer
• meta-analysis
• risk
• statin

• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
• Liver Neoplasms/prevention & control
• Risk Assessment

• Cyclooxygenase-2
• Farnesylation
• Fatty acid synthase
• Hypoxia inducible factor 1α
• Lipid metabolism
• Lipogenic enzymes inhibitors
• Monounsaturated fatty acids
• Oncogenes
• Pancreatic cancer
• Tumor suppressors

• Animals
• Antineoplastic Agents/therapeutic use
• Biomarkers, Tumor/metabolism
• Carcinoma, Pancreatic Ductal/diagnosis
• Carcinoma, Pancreatic Ductal/metabolism
• Carcinoma, Pancreatic Ductal/pathology
• Carcinoma, Pancreatic Ductal/therapy
• Disease Progression
• Energy Metabolism/drug effects
• Fatty Acid Synthase, Type I/metabolism
• Fatty Acids/metabolism
• Humans
• Lipogenesis/drug effects
• Pancreatic Neoplasms/diagnosis
• Pancreatic Neoplasms/drug therapy
• Pancreatic Neoplasms/metabolism
• Pancreatic Neoplasms/pathology
• Predictive Value of Tests
• Treatment Outcome

• cancer
• meta-analysis
• pharmacoepidemiology
• randomized trials
• review

• Antihypertensive Agents/adverse effects
• Antirheumatic Agents/adverse effects
• Bone Density Conservation Agents/adverse effects
• Humans
• Hypoglycemic Agents/adverse effects
• Hypolipidemic Agents/adverse effects
• Meta-Analysis as Topic
• Neoplasms/chemically induced
• Observational Studies as Topic
• Randomized Controlled Trials as Topic
• Risk

• atypical antipsychotics
• bipolar disorder
• cardiovascular disease
• metabolic syndrome
• primary prevention
• schizophrenia
• statins

Clinical studies have shown that statin use may alter the risk of lung cancer. However, these studies yielded different results. To quantify the association between statin use and risk of lung cancer, we performed a detailed meta-analysis. A literature search was carried out using MEDLINE, EMBASE and COCHRANE database between January 1966 and November 2012. Before meta-analysis, between-study heterogeneity and publication bias were assessed using adequate statistical tests. Fixed-effect and random-effect models were used to calculate the pooled relative risks (RR) and corresponding 95% confidence intervals (CIs). Subgroup analyses, sensitivity analysis and cumulative meta-analysis were also performed. A total of 20 (five randomized controlled trials, eight cohorts, and seven case–control) studies contributed to the analysis. Pooled results indicated a non-significant decrease of total lung cancer risk among all statin users (RR = 0.89, 95% CI [0.78, 1.02]). Further, long-term statin use did not significantly decrease the risk of total lung cancer (RR = 0.80, 95% CI [0.39 , 1.64]). In our subgroup analyses, the results were not substantially affected by study design, participant ethnicity, or confounder adjustment. Furthermore, sensitivity analysis confirmed the stability of results. The findings of this meta-analysis suggested that there was no significant association between statin use and risk of lung cancer. More studies, especially randomized controlled trials and high quality cohort studies are warranted to confirm this association.

• Cohort Studies
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects
• Lung Neoplasms/chemically induced
• Prognosis
• Randomized Controlled Trials as Topic
• Risk Factors