The Relationship between Metformin and Cancer in Patients with Type 2 Diabetes

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1 Originl Article Epidemiology pissn eissn D I A B E T E S & M E T A B O L I S M J O U R N A L The Reltionship between Metformin nd Cncer in Ptients with Type 2 Dibetes Hyun Hee Chung*, Jun Sung Moon*, Ji Sung Yoon, Hyoung Woo Lee, Kyu Chng Won Deprtment of Internl Medicine, Yeungnm University College of Medicine, Degu, Kore Bckground: Recently, severl studies reported tht the cncer incidence in type 2 dibetes ptients is higher thn in the generl popultion. Although number of risks re shred between cncer nd dibetes ptients, there hve been few studies of its correltion. We evluted the influences of severl fctors including low density lipoprotein cholesterol (LDL-C), lbuminuri nd use of metformin on the risk of cncer in ptients with type 2 dibetes. Methods: We enrolled 1,320 ptients with t lest 5 yers of follow-up nd 73 ptients were dignosed with cncer during this period. The ssocitions of the risk fctors with cncer incidence were evluted by multiple regression nlysis. The subjects were plced into two subgroups bsed on metformin dosge (<1,000 mg/dy, 1,000 mg/dy) nd we compred cncer incidence using nlysis of covrince. Results: LDL-C nd lbuminuri were not significntly correlted with cncer risk. In contrst, metformin showed reverse correltion with cncer risk (P=0.006; reltive risk, 0.574). In the metformin nondministrtion group, smoking, mle gender, nd high triglyceride levels tended to be contributing fctors without sttisticl significnce. Cncer occurence ws lower in the low dose metformin group (less thn 1,000 mg/dy) (P=0.00). Conclusion: These results suggest tht the dministrtion of low dose metformin in ptients with type 2 dibetes my be ssocited with reduced risk of cncer. Keywords: Dibetes mellitus, type 2; Metformin; Neoplsms INTRODUCTION The prevlence of dibetes mellitus nd cncer re on the rise throughout the world. According to World Cncer Report [1], the estimted number of cncer dignoses ws 124 million in 2008 with highest rtes in lung, brest, colon nd rectl cncer nd the highest mortlity in lung, stomch nd liver cncer. The prevlence of cncer is estimted to be pproximtely 6.6% nd, the morbidity of dibetes ws 10.7% in 2007, of which type 2 dibetes ccounted for bout 95% in the United Sttes [2]. Cncer is the second lrgest cuse of deth in the world nd dibetes is the twelfth [3]. In Kore, cncer is the leding cuse of deth nd dibetes is the fifth lrgest cuse of deth [4]. According to number of epidemiologic studies, the risk of cncer is significntly higher in ptients with dibetes [5,6]. Joslin et l. [7] stted, Studies of the ssocition of dibetes nd cncer hve been conducted over period of yers, but evidence of positive reltion remins inconclusive. However, study in Switzerlnd on type 1 dibetes reported tht cncer incidence in ptients with dibetes ws more thn 20% higher thn in ptients without dibetes [8]. Also, Prk et l. [9] reported tht the mortlity of cncer rose from 4.7% to 21.9% over the pst 10 yers in ptients with dibetes in Kore. Cncer nd dibetes shre number of risk fctors such s hyperglycemi, hyperinsulinemi, nd dyslipidemi, but they cnnot wholly elucidte the correltion between these two diseses [10]. There re lso numerous reports of studies on the s- Corresponding uthor: Kyu Chng Won Deprtment of Internl Medicine, Yeungnm University College of Medicine, 170 Hyeonchung-ro, Nm-gu, Degu , Kore E-mil: kcwon@med.yu.c.kr *Hyun Hee Chung nd Jun Sung Moon contributed eqully to this study s first uthors. Received: Sep. 10, 2012; Accepted: Dec. 6, 2012 This is n Open Access rticle distributed under the terms of the Cretive Commons Attribution Non-Commercil License ( which permits unrestricted non-commercil use, distribution, nd reproduction in ny medium, provided the originl work is properly cited. Copyright 2013 Koren Dibetes Assocition

2 Chung HH, et l. socition between cncer risk nd hypoglycemic gents [6, 11,12], which is still under debte. Metformin, in prticulr, ws found to hve reduced cncer risk in controlled study of Scottish ptients [13]. Jirlerspong et l. [14] reported tht dibetic ptients with brest cncer receiving metformin nd neodjuvnt chemotherpy hve higher pthologic complete response rte thn dibetic ptients not receiving metformin. Another study reported tht the ssocition between low density lipoprotein cholesterol (LDL-C) nd cncer ws V-shped mong ptients with type 2 dibetes [15]. In the present study, we investigted the influences of LDL-C, lbuminuri nd the use of metformin on the cncer risk in ptients with type 2 dibetes. METHODS Subjects Dibetes ptients t the Division of Endocrinology nd Metbolism of Yeungnm University Medicl Center from Jnury 2003 to December 2009 were included in this study. Among 1,320 ptients with dibetes history of 5 yers or more, 1,217 ptients were finlly included in this retrospective observtionl study, excluding 103 ptients who hd type 1 dibetes, or hd lredy been dignosed with cncer before the commencement of this study, or whose dt were insufficient. The study protocol ws pproved by the Institutionl Review Bord of Yeungnm University Medicl Center. Methods Blood pressure (BP) ws mesured with stndrdized sphygmomnometer fter t lest 10 minutes of rest. Mesurements of LDL-C were tken nd body mss index (BMI) ws clculted by dividing the weight (kg) with the height squred (m 2 ). The microlbuminuri test nd liver function test were performed t bseline. History of smoking, drinking, nd mediction (metformin, insulin, ngiotensin-converting-enzyme inhibitors, nd sttin) were tken from the medicl records t the hospitl. Mesurements of fsting blood glucose, bilirubin, sprtte minotrnsferse (AST), lnine minotrnsferse (ALT), gmm glutmyl trnsferse (GGT), blood ure nitrogen, nd cretinine were tken using the hexokinse method (AU 5400 Autonlyser; Olympus, Tokyo, Jpn). Totl cholesterol ws mesured using enzyme colorimetry (Kyow Medex Co., Ltd., Tokyo, Jpn) nd triglyceride ws mesured using the glycerol elimintion method. High density lipoprotein cholesterol (HDL-C) nd LDL-C were mesured using the direct enzymtic ssy (Kyow Medex Co., Ltd.). Glycted hemoglobin (HbA1c) nd microlbuminuri were performed using HLC-723G7 (Tosoh, Tokyo, Jpn) with high performnce liquid chromtogrphy. Sttisticl nlysis Sttisticl nlyses were performed using the sttisticl progrm IBM PASW version 18.0 for Windows (IBM, Armonk, NY, USA) nd vlues were expressed s men±stndrd devition. Cusl nlysis ws performed to exmine the confounding, inhibiting, nd interctive fctors mong the risk fctors for cncer occurrence. Multiple regression nlysis ws performed to identify significnt predicting fctors for cncer occurrence mong the fctors with Kiser-Meyer-Olkin mesure of 0.6 or higher. Also, the Student s t-test nd chi-squre test were used to compre the significnce in the metformin dministrtion group nd nondministrtion group nd nlysis of covrince ws performed to compre the difference of cncer occurrences between the two groups for different doses of metformin. In ll sttisticl nlysis, P<0.05 with 95% confidence intervl ws pplied in determining the significnce. RESULTS Clinicl chrcteristics nd prevlence of cncer in subjects There were 1,217 subjects in this study consisting of 586 mles (48.6%) nd their men ge ws 62.9±11.4 yers. The men BMI ws 23.5±3.2 kg/m 2 nd the men period of dibetes history 12.1±5.3 yers. The 44.9% of ll subjects hd history of smoking nd the men HbA1c ws 8.4%±1.9%. A lipid ssy showed tht men LDL-C of 104.2±36.7 mg/dl, HDL-C of 52.2±15.9 mg/dl, nd triglyceride of 157.3±136.5 mg/dl. Microlbuminuri ws detected in 47.7% of ll subjects nd the glomerulr filtrtion rte (GFR) ws 77.1±26.7 ml/min/1.73 m 2. Smoking history nd LDL-C were higher in mles, while triglyceride levels were higher in femles. The 656 ptients (53.9%) were on metformin, 521 (42.5%) on insulin, nd 672 (55.2%) on sttin (Tble 1). Of ll 1,217 ptients, cncer ws dignosed in 71 ptients (5.6%) consisting of gstric cncer (n=15), thyroid cncer (n=11), prostte cncer (n=8), heptocellulr crcinom (n=8), pncretic cncer (n=3), nd colon cncer (n=3). Among 15 ptients with stomch cncer, 11 ptients hd Helicobcter pylori infection. There were three ptients with heptitis B virus infection of the heptocellulr cr- 126

3 Metformin reduces the risk of cncer in type 2 dibetes cinom (n=5), but no ptients with positive ntiheptitis C virus ntibody. Tble 1. Bseline chrcteristics Chrcteristic Totl (n=1,217) Mle (n=586) Femle (n=631) Age, yr 62.9± ± ±11.5 BMI, kg/m² 23.5± ± ±3.3 DM durtion, yr 12.1± ± ±5.4 SBP, mm Hg 129.6± ± ±16.4 Smoking, % HbA1c, % 8.4± ± ±2.0 FPG, mg/dl 194.9± ± ±91.5 AST, IU/L 26.9± ± ±16.1 ALT, IU/L 27.1± ± ±17.2 GGT, IU/L 41.4± ± ±62.4 TC, mg/dl 178.6± ± ±46.5 LDL-C, mg/dl 104.2± ± ±4.0 HDL-C, mg/dl 52.2± ± ±15.9 TG, mg/dl 157.3± ± ±116.1 GFR, ml/min/1.73 m ± ± ±26.7 Microlbuminuri 580 (47.7) 301 (51.4) 279 (44.2) Metformin 656 (53.9) 334 (57.1) 322 (51.0) Insulin 517 (42.5) 225 (38.5) 292 (46.3) Sttin 672 (55.2) 268 (45.7) 404 (64.0) Vlues re presented s men±stndrd devition or number (%). BMI, body mss index; DM, dibetes mellitus; SBP, systolic blood pressure; HbA1c, glycted hemoglobin; FPG, fsting plsm glucose; AST, sprtte minotrnsferse; ALT, lnine minotrnsferse; GGT, gmm glutmyl trnsferse; TC, totl cholesterol; LDL-C, low density lipoprotein cholesterol; HDL-C, high density lipoprotein cholesterol; TG, triglyceride; GFR, glomerulr filtrtion rte. P<0.05. Tble 2. The risk of cncer mong ptients with type 2 dibetes Fctor B T-score P vlue Exp (B) (95% CI) LDL-C ( ) Microlbuminuri ( ) Metformin ( ) Multivrite liner regression nlysis. CI, confidence intervl; LDL-C, low density lipoprotein cholesterol. P<0.05. Correltions between cncer risk nd severl other fctors Cusl nlysis ws performed to investigte the fctors in type 2 dibetes ptients tht cn ffect the occurrence of cncer. Regression nlysis on fctors of LDL-C, microlbuminuri, nd metformin, which were selected bsed on Kiser- Meyer-Olkin mesure of 0.6, showed tht only metformin hd Tble 3. Bseline chrcteristics grouped by metformin use Chrcteristic Nonmetformin (n=551) Metformin (n=656) Mle 252 (45.7) 334 (50.91) Age, yr 63.3± ±10.9 BMI, kg/m² 23.2± ±3.1 DM durtion, yr 12.1± ±5.3 SBP, mm Hg 130.4± ±15.3 DBP, mm Hg 77.1± ±26.6 Smoking 229 (41.5) 312 (47.56) Alcohol 222 (40.2) 315 (48.01) HbA1c, % 8.4± ±1.8 FBS, mg/dl 190.9± ±93.8 WBC, K/µL 7.4± ±2.5 AST, IU/L 28.2± ±26.1 ALT, IU/L 28.5± ±18.8 GGT, IU/L 42.4± ±54.9 ALP, IU/L 207.1± ±113.3 TC, mg/dl 176.1± ±42.2 LDL-C, mg/dl 109.9± ±29.6 HDL-C, mg/dl 51.8± ±15.8 TG, mg/dl 147.9± ±154.2 hs-crp, mg/dl 0.9± ±1.6 ESR, mm/h 28.2± ±24.0 BUN, mg/dl 20.7± ±10.1 Cretinine, mg/dl 25.0± ±63.3 GFR, ml/min/1.73 m ± ±23.3 Microlbuminuri, mg/l 36.9± ±58.5 Insulin 291 (52.8) 248 (37.8) ACEI 248 (45.0) 273 (41.6) ARB 277 (50.3) 356 (54.3) Sttin 291 (52.8) 248 (37.8) Vlues re presented s men±stndrd devition or number (%). BMI, body mss index; DM, dibetes mellitus; SBP, systolic blood pressure; HbA1c, glycted hemoglobin FBS, fsting blood sugr; WBC, white blood cell; AST, sprtte minotrnsferse; ALT, lnine minotrnsferse; GGT, gmm glutmyl trnsferse; TC, totl cholesterol; LDL-C, low density lipoprotein cholesterol; HDL-C, high density lipoprotein cholesterol; TG, triglyceride; hs-crp, high sensitivity C-rective protein; BUN, blood ure nitrogen; GFR, glomerulr filtrtion rte; ACEI, ngiotensin-converting enzyme inhibitors; ARB, ngiotensin II receptor blockers. P<

4 Chung HH, et l. Tble 4. The risk of cncer mong ptients with type 2 dibetes mellitus who did not use metformin Fctor B T-score P vlue Exp (B) (95% CI) DM durtion ( ) SBP ( ) Smoking ( ) Alcohol ( ) LDL-C ( ) TC ( ) TG ( ) Gender ( ) Cncer men occurrences Multivrite liner regression nlysis. CI, confidence intervl; DM, dibetes mellitus; SBP, systolic blood pressure; LDL-C, low density lipoprotein cholesterol; TC, totl cholesterol; TG, triglyceride. significnt correltion with cncer occurrence (P=0.006; reltive risk [RR], 0.574) (Tble 2). Clinicl chrcteristics of subjects with or without metformin dministrtion In order to exmine other fctors besides metformin tht my ffect the occurrence of cncer, cusl nlysis ws performed by dividing the subjects into metformin dministrtion group (n=551) nd nondministrtion group (n=656) (Tble 3). In cross-sectionl nlysis, there ws no difference in BMI, durtion of dibetes, systolic nd distolic BP, HbA1c, nd fsting blood glucose, but history of smoking nd drinking showed higher levels in the metformin dministrtion group. The levels of ALP, LDL-C, high sensitivity C-rective protein, nd microlbuminuri were significntly higher in the nondministrtion group, while triglyceride nd cretinine levels were higher in the dministrtion group. Regression nlysis ws then performed on smoking history, totl cholesterol, triglyceride, LDL-C, length of dibetes history, systolic pressure, which were selected bsed on Kiser-Meyer-Olkin mesure of 0.6, nd results reveled no fctor of significnce (Tble 4). 0 Fig. 1. The reltionship between metformin dose nd cncer. The cncer occurrence rte men ws significntly lower in the low dose metformin group (<1,000 mg/dy) compred to the high dose group ( 1,000 mg/dy). P< Cncer occurence by metformin dose A Student s t-test showed no significnt difference between the groups with different doses of metformin dministrtion (<1,000 mg/dy, 1,000 mg/dy) in dibetes mellitus durtion, systolic BP, fsting blood glucose, AST, ALT, GGT, GFR, totl cholesterol, triglyceride, LDL-C, HDL-C, nd mediction history including insulin. However, there ws significnt difference in HbA1c (8.3±1.7% vs. 8.2±0.2%, P=0.05). The low dose metformin group (<1,000 mg/dy) showed significntly lower cncer occurrence thn the high dose group ( 1,000 mg/dy, P<0.0001) (Fig. 1). DISCUSSION <1,000 mg (n=368) 1,000 mg (n=256) According to recent studies on dibetes nd cncer risk, ptients with dibetes re known to hve higher risk of liver, pncretic, colorectl, brest nd endometril cncer, while prostte cncer hs been reported to hve reduced incidence in ptients with dibetes [10]. Hyperinsulinemi is suggested s possible mechnism tht increses the occurrences of liver nd pncretic cncer becuse the liver nd pncres re exposed to higher endogenous insulin concentrtion vi portl circultion [6]. Dibetes-relted fctors such s diposity, nonlcoholic ftty liver, nd liver cirrhosis were lso reported to hve the potentil to increse the occurrence of liver cncer. On the contrry, the RR of prostte cncer in dibetes is known to be lower nd this is most likely ttributed to the decresed testosterone levels in dibetic ptients [16]. In our study, the cncer incidence ws 5.6% in order of gstric, thyroid, prostte, heptocellulr, pncretic, nd colon cncer. Compred with the Sttistics Kore [4], our results showed higher incidences in pncretic cncer (3.7% vs. 2.5%) nd heptocellulr crcinom (11.2% vs. 7.7%), while no reduced risk of prostte 128

5 Metformin reduces the risk of cncer in type 2 dibetes cncer (11.2% vs. 2.9%) ws observed, which my be ttributble to the higher men ge of the subjects in our study. The common potentil risk fctors for cncer nd dibetes include incresed ge, gender, obesity, physicl ctivity, diet, drinking, nd smoking. Individuls tht re overweight (25 BMI<30 kg/m 2 ) or obese (BMI 30 kg/m 2 ) re reported to hve higher cncer risk thn those with norml BMI [5,17]. In prticulr, obesity ws consistently ssocited with brest (mong women in menopuse), colorectl, endometril, pncretic, esophgel, renl, nd gllbldder cncer nd incresed the mortlity of some cncers including prostte cncer [10,17]. Among these risk fctors, we performed cusl nlysis using BMI, smoking nd drinking fctors but the results did not show ny significnt reltionship. In order to eliminte the influence of metformin, we divided the subjects into metformin dministrtion group nd nondministrtion group nd performed regression nlysis on the nondministrtion group, but the results were still not significnt. The risk ssocition between LDL-C nd cncer remins controversil [15,18]. Although its mechnism is not known, the pthwy of L-mevlonic cid synthesis, which produces isoprenoid intermedites of the cholesterol biosynthetic pthwy such s frnesylpyrophosphte nd gernylgernylpyrophosphte, hs been suggested. These intermedites re importnt for posttrnsltionl modifiction of proteins, such s Rs nd Rho GTPses, which ply importnt roles in cellulr pthwys tht re criticl for cncer formtion nd progression [19]. In ddition, it hs been suggested tht HMG-CoA reductse inhibitors (sttins) hve ntitumor effects [19]. In our study, no significnt correltion ws observed between LDL-C nd cncer incidence, which is ssumed to be relted to the low LDL-C levels mong the subjects nd ntitumor effects of sttins in prt becuse 55.2% of subjects were on sttin mediction. It hs been suggested tht the use of insulin nd sulfonylure increses cncer risk [10,20], wheres metformin reduces it [13]. However in our study, the use of insulin or sulfonylure did not show significnt correltion with cncer occurrence, which coincided with recent cohort study conducted in Frnce in which the use of insulin glrgine did not increse the risk of cncer in ptients with type 2 dibetes [21]. On the other hnd, metformin ws lso observed to hve significntly reduced the cncer risk by 43% in our study. Metformin is the most frequently used orl hypoglycemic gent nd the glucose lowering effect is medited by decresing heptic gluconeogenesis [22]. Metformin is known to inhibit cellulr prolifertion, reduce colony formtion, nd cuse prtil cell cycle rrest of cncer cells [11]. Dowling et l. [23] suggested tht metformin-medited AMP-ctivted protein kinse (AMPK) ctivtion leds to inhibition of mmmlin trget of rpmycin (mtor) nd reduction in trnsltion initition, thus providing possible mechnism of ction of metformin in the inhibition of cncer cell growth. Metformin ttenuted the incresed insulin receptor ctivtion ssocited with high-energy diet nd lso led to incresed phosphoryltion of AMP kinse, leding to decrese neoplstic prolifertion [24]. These results, therefore, contribute to the rtionle for evlution of ntineoplstic ctivity of metformin in hyperinsulinemic cncer ptients. The ssocition between metformin doses nd cncer risk is the subject of much debte. Libby et l. [25] reported tht high mximum doses of metformin were relted with lrge reduction in the risk of cncer. However, metformin dose usully increses with incresing durtion of use nd this could produce survivl bis, with higher doses spuriously ssocited with reduced cncer becuse ptients hve survived to receive higher dose. In contrst, it ws observed in our study tht cncer incidence ws significntly lower in the low dose group ( 1,000 mg/dy). We consider this finding new result for severl resons. First, there ws significnt difference in glycosylted hemoglobin between the two groups (P=0.05) nd no significnt intergroup differences were observed for other fctors such s the durtion of dibetes nd BMI. These results imply tht the stte of blood glucose control cn ffect the incidence of mlignncy. Second, the incidence of mlignncy my be more closely relted with the totl exposure mount of metformin rther thn dily dose, so the dys with using metformin will be needed to clrify the dose-response reltionship. However, prcticlly we cnnot evlute the ccurte durtion nd mount of metformin in this study nd thus, further studies re needed. Finlly s stted bove, survivl bis cn be included in this result. This study hd severl limittions. First, being retrospective observtion study, we could not clerly determine the correltion between dibetes nd cncer risk. Second, investigtion of morbidity nd mortlity ws limited becuse of the short follow-up durtion of 6 yers. The lck of correltion of the interction between drugs nd the smll number of subjects ws lso limittion of our study. Bsed on our results, it is suggested tht metformin dministrtion in ptients with type 2 dibetes reduces the risk of 129

6 Chung HH, et l. cncer nd low dose metformin my be ssocited with reduced risk of cncer s well s blood glucose control. Lrgescle prospective long-term studies will be needed for further clrifiction of the correltion between dibetes nd the occurrence of cncer. CONFLICTS OF INTEREST No potentil conflict of interest relevnt to this rticle ws reported. REFERENCES 1. Interntionl Agency for Reserch on Cncer: World cncer report Avilble from: (cited 2010 Apr 1). 2. Centers for Disese Control nd Prevention: Generl informtion nd ntionl estimtes on dibetes in the United Sttes, Avilble from: / ndfs_2007.pdf (cited 2010 Apr 1). 3. Lopez AD, Mthers CD, Ezzti M, Jmison DT, Murry CJ. Globl nd regionl burden of disese nd risk fctors, 2001: systemtic nlysis of popultion helth dt. Lncet 2006;367: Sttistics Kore: Sttistics of cuse of deth. Avilble from: (updted 2010 Sep 9). 5. Clle EE, Rodriguez C, Wlker-Thurmond K, Thun MJ. Overweight, obesity, nd mortlity from cncer in prospectively studied cohort of U.S. dults. N Engl J Med 2003;348: Chri ST, Leibson CL, Rbe KG, Timmons LJ, Rnsom J, de Andrde M, Petersen GM. Pncretic cncer-ssocited dibetes mellitus: prevlence nd temporl ssocition with dignosis of cncer. Gstroenterology 2008;134: Joslin EP, Lombrd HL, Burrows RE, Mnning MD. Dibetes nd cncer. N Engl J Med 1959;260: Zendehdel K, Nyren O, Ostenson CG, Admi HO, Ekbom A, Ye W. Cncer incidence in ptients with type 1 dibetes mellitus: popultion-bsed cohort study in Sweden. J Ntl Cncer Inst 2003;95: Prk SK, Prk MK, Suk JH, Kim MK, Kim YK, Kim IJ, Kng YH, Lee KJ, Lee HS, Lee CW, Kim BH, Lee KI, Kim MK, Kim DK. Cuse-of-deth trends for dibetes mellitus over 10 yers. Koren Dibetes J 2009;33: Vigneri P, Frsc F, Scicc L, Pndini G, Vigneri R. Dibetes nd cncer. Endocr Relt Cncer 2009;16: Alimov IN, Liu B, Fn Z, Edgerton SM, Dillon T, Lind SE, Thor AD. Metformin inhibits brest cncer cell growth, colony formtion nd induces cell cycle rrest in vitro. Cell Cycle 2009; 8: Currie CJ, Poole CD, Gle EA. The influence of glucose-lowering therpies on cncer risk in type 2 dibetes. Dibetologi 2009;52: Evns JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin nd reduced risk of cncer in dibetic ptients. BMJ 2005;330: Jirlerspong S, Pll SL, Giordno SH, Meric-Bernstm F, Liedtke C, Brnett CM, Hsu L, Hung MC, Hortobgyi GN, Gonzlez-Angulo AM. Metformin nd pthologic complete responses to neodjuvnt chemotherpy in dibetic ptients with brest cncer. J Clin Oncol 2009;27: Yng X, So W, Ko GT, M RC, Kong AP, Chow CC, Tong PC, Chn JC. Independent ssocitions between low-density lipoprotein cholesterol nd cncer mong ptients with type 2 dibetes mellitus. CMAJ 2008;179: Ksper JS, Giovnnucci E. A met-nlysis of dibetes mellitus nd the risk of prostte cncer. Cncer Epidemiol Biomrkers Prev 2006;15: World Cncer Reserch Fund, Americn Institute for Cncer Reserch: Food, nutrition, physicl ctivity, nd the prevention of cncer: globl perspective. Avilble from: (updted 2007 Nov 1). 18. Schuit AJ, Vn Dijk CE, Dekker JM, Schouten EG, Kok FJ. Inverse ssocition between serum totl cholesterol nd cncer mortlity in Dutch civil servnts. Am J Epidemiol 1993;137: Lio JK. Clinicl implictions for sttin pleiotropy. Curr Opin Lipidol 2005;16: Yng X, So WY, M RC, Yu LW, Ko GT, Kong AP, Ng VW, Luk AO, Ozki R, Tong PC, Chow CC, Chn JC. Use of sulphonylure nd cncer in type 2 dibetes: the Hong Kong Dibetes Registry. Dibetes Res Clin Prct 2010;90: Blin P, Lsslle R, Dureu-Pournin C, Ambrosino B, Bernrd MA, Abouelfth A, Gin H, Le Jeunne C, Priente A, Droz C, Moore N. Insulin glrgine nd risk of cncer: cohort study in the French Ntionl Helthcre Insurnce Dtbse. Dibetologi 2012;55: Shw RJ, Lmi KA, Vsquez D, Koo SH, Brdeesy N, Depinho RA, Montminy M, Cntley LC. The kinse LKB1 medites glucose homeostsis in liver nd therpeutic effects of metformin. Science 2005;310:

7 Metformin reduces the risk of cncer in type 2 dibetes 23. Dowling RJ, Zkikhni M, Fntus IG, Pollk M, Sonenberg N. Metformin inhibits mmmlin trget of rpmycin-dependent trnsltion initition in brest cncer cells. Cncer Res 2007;67: Algire C, Zkikhni M, Blouin MJ, Shui JH, Pollk M. Metformin ttenutes the stimultory effect of high-energy diet on in vivo LLC1 crcinom growth. Endocr Relt Cncer 2008; 15: Libby G, Donnelly LA, Donnn PT, Alessi DR, Morris AD, Evns JM. New users of metformin re t low risk of incident cncer: cohort study mong people with type 2 dibetes. Dibetes Cre 2009;32: