title: Additive effects of blood glucose lowering drugs, statins and renin-angiotensin system blockers on all-site cancer risk in patients with type 2 diabetes.
abstract: BACKGROUND
  Hyperglycemia is associated with increased risk of all-site cancer that may be mediated through activation of the renin-angiotensin-system (RAS) and 3-hydroxy-3-methyl-glutaryl-coenzyme-A-reductase (HMGCR) pathways. We examined the joint associations of optimal glycemic control (HbA1c <7%), RAS inhibitors and HMGCR inhibitors on cancer incidence in patients with type 2 diabetes.
  
  
  METHODS
  Patients with type 2 diabetes, with or without a history of cancer or prior exposure to RAS or HMGCR inhibitors at baseline were observed between 1996 and 2005. All patients underwent a comprehensive assessment at baseline and were followed until the censored date at 2005 or their death.
  
  
  RESULTS
  After a median follow-up period of 4.91 years (interquartile range, 2.81 to 6.98), 271 out of 6,103 patients developed all-site cancer. At baseline, patients with incident cancers were older, had longer disease duration of diabetes, higher alcohol and tobacco use, and higher systolic blood pressure and albuminuria, but lower triglyceride levels and estimated glomerular filtration rate (P <0.05). Patients who developed cancers during follow-up were less likely to have started using statins (22.5% versus 38.6%, P <0.001), fibrates (5.9% versus 10.2%, P = 0.02), metformin (63.8% versus 74.5%, P <0.001) or thiazolidinedione (0.7% versus 6.8%, P <0.001) than those who remained cancer-free. After adjusting for co-variables, new treatment with metformin (hazard ratio: 0.39; 95% confidence interval: 0.25, 0.61; P <0.001), thiazolidinedione (0.18; 0.04, 0.72; P = 0.015), sulphonylurea (0.44; 0.27, 0.73; P = 0.014), insulin (0.58; 0.38, 0.89; P = 0.01), statins (0.47; 0.31, 0.70; P <0.001) and RAS inhibitors (0.55; 0.39, 0.78; P <0.001) were associated with reduced cancer risk. Patients with all three risk factors of HbA1c ≥7%, non-use of RAS inhibitors and non-use of statins had four-fold adjusted higher risk of cancer than those without any risk factors (incidence per 1,000-person-years for no risk factors: 3.40 (0.07, 6.72); one risk factor: 6.34 (4.19, 8.50); two risk factors: 8.40 (6.60, 10.20); three risk factors: 13.08 (9.82, 16.34); P <0.001).
  
  
  CONCLUSIONS
  Hyperglycemia may promote cancer growth that can be attenuated by optimal glycemic control and inhibition of the RAS and HMGCR pathways.
authors.forename: Alice P S
authors.initials: AP
authors.lastname: Kong
authors.forename: Xilin
authors.initials: X
authors.lastname: Yang
authors.forename: Wing-Yee
authors.initials: WY
authors.lastname: So
authors.forename: Andrea
authors.initials: A
authors.lastname: Luk
authors.forename: Ronald C W
authors.initials: RC
authors.lastname: Ma
authors.forename: Risa
authors.initials: R
authors.lastname: Ozaki
authors.forename: Kitty K T
authors.initials: KK
authors.lastname: Cheung
authors.forename: Heung-Man
authors.initials: HM
authors.lastname: Lee
authors.forename: Linda
authors.initials: L
authors.lastname: Yu
authors.forename: Gang
authors.initials: G
authors.lastname: Xu
authors.forename: Chun-Chung
authors.initials: CC
authors.lastname: Chow
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, SAR, China. jchan@cuhk.edu.hk.
authors.forename: Juliana C N
authors.initials: JC
authors.lastname: Chan
mesh_terms: D001786:Blood Glucose; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D005260:Female; D005947:Glucose / Q000494:pharmacology; D006441:Hemoglobin A; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006943:Hyperglycemia / Q000150:complications* / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008297:Male; D008687:Metformin / Q000627:therapeutic use; D009369:Neoplasms / Q000453:epidemiology / Q000209:etiology / Q000517:prevention & control*; D012084:Renin-Angiotensin System / Q000187:drug effects*; D012306:Risk; D012307:Risk Factors; D013453:Sulfonylurea Compounds / Q000627:therapeutic use; D045162:Thiazolidinediones / Q000627:therapeutic use
chemical_list: D001786:Blood Glucose; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; D045162:Thiazolidinediones; D006441:Hemoglobin A; D008687:Metformin; C089946:2,4-thiazolidinedione; D005947:Glucose