Metformin associated with lower cancer mortality in type 2 diabetes: ZODIAC-16.

Abstract

Several studies have suggested an association between specific diabetes treatment and cancer mortality. We studied the association between metformin use and cancer mortality in a prospectively followed cohort.
In 1998 and 1999, 1,353 patients with type 2 diabetes were enrolled in the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) study in the Netherlands. Vital status was assessed in January 2009. Cancer mortality rate was evaluated using standardized mortality ratios (SMRs), and the association between metformin use and cancer mortality was evaluated with a Cox proportional hazards model, taking possible confounders into account.
Median follow-up time was 9.6 years, average age at baseline was 68 years, and average A1C was 7.5%. Of the patients, 570 died, of which 122 died of malignancies. The SMR for cancer mortality was 1.47 (95% CI 1.22-1.76). In patients taking metformin compared with patients not taking metformin at baseline, the adjusted hazard ratio (HR) for cancer mortality was 0.43 (95% CI 0.23-0.80), and the HR with every increase of 1 g of metformin was 0.58 (95% CI 0.36-0.93).
In general, patients with type 2 diabetes are at increased risk for cancer mortality. In our group, metformin use was associated with lower cancer mortality compared with nonuse of metformin. Although the design cannot provide a conclusion about causality, our results suggest a protective effect of metformin on cancer mortality.

Full text

Page 1

Metformin Associated With Lower Cancer
Mortality in Type 2 Diabetes
ZODIAC-16
GIJS W.D. LANDMAN, MD1,2
NANNE KLEEFSTRA, MD2,3
KORNELIS J.J. VAN HATEREN, MD2
KLAAS H. GROENIER, PHD4
RIJK O.B. GANS, MD, PHD5
HENK J.G. BILO, MD, PHD, FRCP2,5
OBJECTIVE — Several studies have suggested an association between specific diabetes treat-
ment and cancer mortality. We studied the association between metformin use and cancer
mortality in a prospectively followed cohort.
RESEARCH DESIGN AND METHODS — In 1998 and 1999, 1,353 patients with type
2 diabetes were enrolled in the Zwolle Outpatient Diabetes project Integrating Available Care
(ZODIAC)studyintheNetherlands.VitalstatuswasassessedinJanuary2009.Cancermortality
rate was evaluated using standardized mortality ratios (SMRs), and the association between
metformin use and cancer mortality was evaluated with a Cox proportional hazards model,
taking possible confounders into account.
RESULTS — Median follow-up time was 9.6 years, average age at baseline was 68 years, and
average A1C was 7.5%. Of the patients, 570 died, of which 122 died of malignancies. The SMR
for cancer mortality was 1.47 (95% CI 1.22–1.76). In patients taking metformin compared with
patientsnottakingmetforminatbaseline,theadjustedhazardratio(HR)forcancermortalitywas
0.43(95%CI0.23–0.80),andtheHRwitheveryincreaseof1gofmetforminwas0.58(95%CI
0.36–0.93).
CONCLUSIONS — In general, patients with type 2 diabetes are at increased risk for cancer
mortality. In our group, metformin use was associated with lower cancer mortality compared
withnonuseofmetformin.Althoughthedesigncannotprovideaconclusionaboutcausality,our
results suggest a protective effect of metformin on cancer mortality.
Diabetes Care 33:322–326, 2010
M
might be associated with an increased
cancer risk (1). Soon after this publica-
tion, the European Medicines Agency
issued a statement that changes to the
prescribing advice were not necessary.
This initially disturbing news overshad-
owed positive news regarding the rela-
tion between metformin and cancer risk
(2). If metformin indeed decreases can-
cer mortality risk, it would further
strengthen the position of metformin as
uch debate has arisen recently
after an online publication
stated that insulin glargine
the preferred initial treatment in pa-
tients with type 2 diabetes.
In general, there is evidence that type
2 diabetes alters the risk of developing a
variety of cancers (3–7) and that cancer
mortality is increased (8). Glucose-
lowering therapy itself could also be asso-
ciated with cancer risk. For example, the
risk for colon cancer seemed to be in-
creased in patients using insulin (9).
However, the quality and validity of that
study are questionable.
Insulin is a growth-promoting hor-
mone with mitogenic effects, and it has
been suggested that hyperinsulinemia
promotes carcinogenesis (10). Con-
versely, metformin may have protective
effects on cancer development. Met-
formin targets AMP-activated protein ki-
nase, which induces glucose uptake in
muscles. Activation of AMP-activated
protein kinase requires LKB1, a well-
known tumor suppressor. The relation-
ship between metformin and LKB1 could
therefore be an explanation for the poten-
tialbeneficialeffectsofmetforminoncan-
cer development (11).
Two previous studies showed that
cancer risk was lower in patients exposed
to metformin than in unexposed patients
(12,13). Metformin has also been shown
to be potentially beneficial in patients
with specific types of cancer. For exam-
ple,type2diabeticpatientsreceivingneo-
adjuvant chemotherapy for breast cancer
as well as metformin were more likely to
have a complete remission than patients
not receiving metformin (14). Further-
more, patients receiving metformin seem
to have a lower incidence of prostate and
pancreatic cancer (15,16).
Intheonlystudydesignedtoevaluate
cancer mortality, treatment with a sulfo-
nylurea drug and insulin was associated
with an increased risk of cancer-related
mortality compared with treatment with
metformin (17). These results are some-
whatquestionable,becauseinthisstudya
limitedsetofconfounderswasusedinthe
multivariate analyses. For instance, the
BMI of the patients was not taken into
account. Furthermore, the design of this
trialwasretrospective.Weaimedtostudy
the effect of metformin on cancer mortal-
ity in a prospectively designed cohort of
type 2 diabetic patients in primary care.
RESEARCH DESIGN AND
METHODS— Thepresentstudyispart
of the Zwolle Outpatient Diabetes project
IntegratingAvailableCare(ZODIAC)study
(18), which started in 1998 and is part of
a diabetes shared care project. In this
project, general practitioners are assisted
in their care of type 2 diabetic patients by
hospital-based diabetes specialist nurses.
At baseline, patients with a very short life
● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●
From1Internal Medicine, Isala Clinics, Zwolle, the Netherlands; the2Diabetes Centre, Isala Clinics, Zwolle,
the Netherlands; the3Medical Research Group, Langerhans, Zwolle, the Netherlands;4General Practice,
University Medical Center Groningen, Groningen, the Netherlands; and5Internal Medicine, University
Medical Center Groningen, Groningen, the Netherlands.
Corresponding author: Gijs W.D. Landman, g.w.d.landman@isala.nl.
Received 28 July 2009 and accepted 4 November 2009. Published ahead of print at http://care.
diabetesjournals.org on 16 November 2009. DOI: 10.2337/dc09-1380.
© 2010 by the American Diabetes Association. Readers may use this article as long as the work is properly
cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.
org/licenses/by-nc-nd/3.0/ for details.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby
marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
E p i d e m i o l o g y / H e a l t h S e r v i c e s R e s e a r c h
O R I G I N A L A R T I C L E
322
DIABETES CARE, VOLUME 33, NUMBER 2, FEBRUARY 2010care.diabetesjournals.org

Page 2

expectancy (including patients with active
cancer) or insufficient cognitive abilities
were excluded from this study. Therefore,
general practitioners excluded 5% of pa-
tients treated in primary care from partici-
patinginthestudy.Nearly90%(n?1,357)
of the remaining patients agreed to partici-
pate, but 4 patients were also excluded be-
cause of insufficient baseline data. The
ZODIAC study was approved by the medi-
cal ethics committee of the Isala Clinics in
Zwolle, the Netherlands.
Data collection
Baseline data were collected in 1998 and
1999 and consisted of a medical history,
including macrovascular complications,
diabetes duration, medication use, and
tobacco consumption. Laboratory and
physical assessment data were collected
annually and included the following vari-
ables: A1C, nonfasting lipid profile, se-
rum creatinine, urinary albumin-to-
creatinine ratio, blood pressure, weight,
and height. At the beginning of 2009, life
status and cause of death were retrieved
from records maintained by the hospital
and general practitioners. Thirteen base-
line variables were selected for their
possible confounding effects in the rela-
tionshipbetweenmetforminuseandcan-
cer mortality: smoking (yes or no), age,
sex, diabetes duration, A1C, serum creat-
inine, BMI, blood pressure, total choles-
terol–to–HDL ratio, albuminuria, insulin
use, sulfonylurea use, and macrovascular
complications (yes or no).
Statistical analysis
To study the incidence of cancer mortality,
standardized mortality ratios (SMRs) were
calculatedfortotalmortalityandcardiovas-
cular and cancer mortality using general
mortality reference rates from the Nether-
lands (http://statline.cbs.nl/StatWeb/). SMRs
were also calculated for metformin users
andnonusers.WeusedaCoxproportional
hazardsmodeltoinvestigatetheassociation
between metformin use and cancer mortal-
ity with and without adjustment of the se-
lected confounders. We used two different
models. In model 1, the 13 earlier men-
tionedbaselinevariablesweretakenintoac-
count as possible confounders. This model
thus included factors associated with both
cardiovascularmortalityandcancermortal-
ity.Model2includedfactorsdirectlyrelated
to cancer mortality: age, sex, BMI, insulin
use, and sulfonylurea use.
Toevaluatetherelationshipwithdose
of metformin, we repeated the analyses
and included the dose of metformin per
dayasacontinuousvariable.Adjustments
were made for all covariates.
We also investigated which variable
was an actual confounder in the relation
between metformin and cancer mortal-
ity. Confounding was defined as a 10%
change in the ? coefficient of the hazard
ratio (HR). We created interaction
terms for all variables with metformin.
The proportional hazards assumption
was examined using log (?log) survival
plots. The parallel lines in the plots in-
dicate that the assumption was met. All
tests were two-sided, and analyses were
performed with SPSS (version 15.0.1;
SPSS, Chicago, IL).
RESULTS— The baseline characteris-
tics of the study population are shown in
Table 1. After a median follow-up time of
9.6 years, a total of 570 (42%) patients
had died. There were 122 (21%) cancer
deaths, of which 26 (21%) related to lung
cancer and 21 (17%) to abdominal can-
cer.Atotalof238(41%)patientshaddied
of cardiovascular disease.
The cause of death was known for
541 (94%) patients. Life status of 20 pa-
tients (1.5%) could not be obtained. Data
on medication use were complete for
1,350 patients (?99%).
SMRs
The SMR for total mortality was 2.22
(95% CI 2.03–2.42), for cardiovascular
mortality was 2.45 (2.15–2.79), and for
cancer mortality was 1.47 (1.22–1.76).
The SMR for cancer mortality in the non-
metformin group was 1.62 (1.32–1.96).
The SMR for cancer mortality in the met-
formin group was 0.88 (0.51–1.44).
Cancer mortality
The unadjusted HR of metformin use for
cancer mortality was 0.54 (95% CI 0.32–
0.91). For model 1, taking all 13 possible
variablesintoaccount,theadjustedHRof
metformin use for cancer mortality was
0.43 (0.23–0.80) (Fig. 1). The adjusted
HR for model 2 was 0.46 (0.26–0.83).
There were no significant interaction
terms between metformin and cancer
mortality. Furthermore, only sulfonylurea
use and macrovascular complications were
confounders in the relationship between
metformin use and cancer mortality. With
adjustmentonlyformacrovascularcompli-
cations and sulfonylurea, the outcome did
notchange.Furthermore,afterexclusionof
mortality in the first 3 years after baseline,
theresultsremainedsimilar(HR0.38[95%
CI 0.18–0.81]). Sulfonylurea use was not
significantly associated with cancer mortal-
ity (0.69 [0.36–1.34]) nor was insulin use
(0.70 [0.36–1.34]).
Dose-response analysis
The HR of metformin as a continuous
variable for cancer mortality was 0.58
(95% CI 0.36–0.93). The hazard for can-
cer mortality decreased by 42% for every
1-g increase in the metformin dose.
All-cause and cardiovascular
mortality
After adjustment for all covariates, the
HRsfortotalandcardiovascularmortality
among metformin users were 0.94 (95%
Table 1—Baseline characteristics
CharacteristicsTotalMetformin usersNo metformin use
n
Age (years)
Female sex (%)
Diabetes duration (years)
Smoking (%)
BMI (kg/m2)
Systolic blood pressure (mmHg)
A1C (%)
eGFR (ml/min per 1.73 m2)
Total cholesterol–to–HDL ratio
Albumin-to-creatinine ratio
Macrovascular complications (%)
Insulin use (%)
Sulfonylurea use (%)
Diet only (%)
Dataaremeans?SD,median(interquartilerange)fornonnormallydistributeddata,or%.*P?0.01;†P?
0.05; ‡P ? 0.001, two-sided parametric test (Student t) and nonparametric test (Mann-Whitney U) as
appropriate. eGFR, estimated glomerular filtration rate.
1,353
67.8 ? 11.7
57.6
6.0 (3–11)
18.6
28.9 ? 4.8
153.0 ? 25.2
7.5 ? 1.2
73.9 ? 28.1
5.2 ? 1.6
2.2 (1.0–7.2)
32.7
16.5
55.0
13.0
2891,064
68.0 ? 12.0
56.5
7.1 (4–12)
18.4
28.8 ? 4.6*
153.6 ? 25.3
7.4 ? 1.3*
73.0 ? 27.6†
5.1 ? 1.5
2.1 (1.0–6.8)
32.1
19.3‡
65.8‡
67.3 ? 10.6
61.2
4.9 (3–11)
19.2
29.6 ? 5.1
154.3 ? 24.9
7.7 ? 1.1
76.9 ? 30.0
5.3 ? 1.6
2.6 (1.1–9.4)
35.3
5.9
15.9
Landman and Associates
care.diabetesjournals.orgDIABETES CARE, VOLUME 33, NUMBER 2, FEBRUARY 2010
323

Page 3

CI 0.73–1.22) and 2.27 (1.36–3.78), re-
spectively (Figs. 2 and 3). The HR for all
other causes of death was 0.97 (0.72–
1.30)(Fig.4).Asignificantinteractionbe-
tween metformin and sulfonylurea use
was observed in the cardiovascular mor-
talityanalysisandaninteractiontermwas
added to the model. The proportional
hazard assumptions were met for all
analyses.
CONCLUSIONS — For the first time
in a prospective study, we found (after a
median follow-up time of 9.6 years) that
metformin use at baseline was associated
withlesscancer-relatedmortalityandthat
this association appeared to be dose-
dependent. Patients with type 2 diabetes
who were not taking metformin showed
an increased cancer mortality ratio com-
pared with that for the general popula-
tion. The mortality of patients taking
metformin was comparable with that for
the general population.
A study by Currie et al. (2) suggested
an increased cancer risk for patients tak-
inginsulinandwithmetforminadecrease
in this risk to a level as observed in
the general population. Another study,
in which population-based sampling
was used, showed a reduced cancer risk
for patients taking metformin compared
with patients taking a sulfonylurea drug
(12). The researchers suggested a dose-
response relation: the greater the met-
formin exposure, the stronger the risk
reduction. It is not clear whether the re-
searchersexcludedoradjustedfortheuse
of insulin in this study. A third study, a
large administrative database study,
showed that patients exposed to a sulfo-
nylureadrugandinsulinweremorelikely
to have a cancer-related death than pa-
tients using metformin (17). The re-
searchers of this retrospective study had
no data about cardiovascular mortality
and did not adjust for some essential con-
founders such as BMI and smoking.
Our study has some notable strengths.
First, our study is the first observational
study with a prospective design investi-
gating the relation between metformin
and cancer (mortality). Second, we ad-
justed for more potential confounders
thantheresearchersinthepreviousstudy
(17). Third, we were able to present data
on non–cancer-related mortality and
compared our results with those for the
general population in the Netherlands.
Fourth, the number of deaths in the 10-
year follow-up period was sufficient to
make reliable estimates regarding associ-
ations with mortality. If there is an asso-
ciation between cancer mortality and
metformin use, a long-term follow-up is
needed, because cancer takes a long time
to develop, and it takes time before pa-
tients die of cancer.
Figure 1—Cumulative survival curve for cancer mortality.
Figure 2—Cumulative survival curve for total mortality.
Metformin and cancer mortality in type 2 diabetes
324
DIABETES CARE, VOLUME 33, NUMBER 2, FEBRUARY 2010 care.diabetesjournals.org

Page 4

There are, of course, also limitations
to our study. Cancer mortality depends
on the type and aggressiveness of the can-
cer and the effectiveness of the cancer
treatment. Unfortunately, data concern-
ing nonfatal cancer incidence are lacking
in the ZODIAC study. Diabetes or diabe-
tes treatment may have an effect on the
intensityofthecancertreatmentoronthe
choice of a specific cancer treatment reg-
imen. Furthermore, no adjustment could
be made for a history of cancer in our
analyses because these data were impre-
cise. However, after excluding the first 3
years of follow-up from the analysis, the
relationship remained highly significant.
Excluding the first 3 years of follow-up
could correct for undiagnosed cancer at
the start of the study, which could influ-
ence outcome. Furthermore, we were not
able to perform analyses for site-specific
cancers, because our analyses were based
on only 122 cancer deaths. Finally, the
study started in 1998. At that time, met-
formin was not a first-choice treatment, a
factthatisalsoconfirmedbytherelatively
small group of patients using metformin
at baseline.
Patients who were taking metformin
at the beginning of this study (in 1998)
might also be different from patients tak-
ingmetforminatthistime.Patientstaking
metformin had an increased risk for car-
diovascular mortality after 10 years. A
possible explanation is that their cardio-
vascular disease risk was higher at base-
line. For example, metformin users had a
higher BMI compared with nonusers.
Our study confirms that the cancer
mortality risk for metformin users is
lower compared with that of nonusers. In
ouropinion,thisfindingfurtherstrength-
ensthepositionofmetforminasthetreat-
mentoffirstchoiceinpatientswithtype2
diabetes.Furtherresearchisneededtoes-
tablish whether metformin is a definite
beneficial causal factor in lowering the
risk of cancer mortality.
Acknowledgments— No potential conflicts
of interest relevant to this article were
reported.
References
1. HemkensLG,GrouvenU,BenderR,Gu ¨n-
ster C, Gutschmidt S, Selke GW, Sawicki
PT. Risk of malignancies in patients with
diabetestreatedwithhumaninsulinorin-
sulin analogues: a cohort study. Diabeto-
logia 2009;52:1732–1744
2. Currie CJ, Poole CD, Gale EA. The influ-
ence of glucose-lowering therapies on
cancer risk in type 2 diabetes. Diabetolo-
gia 2009;52:1766–1777
3. CalleEE,MurphyTK,RodriguezC,Thun
MJ, Heath CW Jr. Diabetes mellitus and
pancreatic cancer mortality in a prospec-
tivecohortofUnitedStatesadults.Cancer
Figure 3—Cumulative survival for cardiovascular mortality.
Figure4—Cumulativesurvivalfornon-cancerandnon-cardiovascular(CV)(allothercauses)mortality.
Landman and Associates
care.diabetesjournals.orgDIABETES CARE, VOLUME 33, NUMBER 2, FEBRUARY 2010
325

Page 5

Causes Control 1998;9:403–410
4. Will JC, Vinicor F, Calle EE. Is diabetes
mellitus associated with prostate cancer
incidence and survival? Epidemiology
1999;10:313–318
5. Chow WH, Gridley G, Nyre ´n O, Linet
MS, Ekbom A, Fraumeni JF Jr, Adami
HO. Risk of pancreatic cancer following
diabetes mellitus: a nationwide cohort
studyinSweden.JNatlCancerInst1995;
87:930–931
6. HuFB,MansonJE,LiuS,HunterD,Cold-
itz GA, Michels KB, Speizer FE, Giovan-
nucci E. Prospective study of adult onset
diabetesmellitus(type2)andriskofcolo-
rectalcancerinwomen.JNatlCancerInst
1999;91:542–547
7. Adami HO, Chow WH, Nyre ´n O, Berne
C, Linet MS, Ekbom A, Wolk A,
McLaughlin JK, Fraumeni JF Jr. Excess
risk of primary liver cancer in patients
with diabetes mellitus. J Natl Cancer Inst
1996;88:1472–1477
8. CoughlinSS,CalleEE,TerasLR,PetrelliJ,
Thun MJ. Diabetes mellitus as a predictor
of cancer mortality in a large cohort of US
adults. Am J Epidemiol 2004;159:1160–
1167
9. Yang YX, Hennessy S, Lewis JD. Insulin
therapy and colorectal cancer risk among
type 2 diabetes mellitus patients. Gastro-
enterology 2004;127:1044–1050
10. van der Burg B, Rutteman GR, Blanken-
stein MA, de Laat SW, van Zoelen EJ. Mi-
togenic stimulation of human breast
cancer cells in a growth factor–defined
medium: synergistic action of insulin
and estrogen. J Cell Physiol 1988;134:
101–108
11. Ben Sahra I, Laurent K, Loubat A, Gior-
getti-Peraldi S, Colosetti P, Auberger P,
Tanti JF, Le Marchand-Brustel Y, Bost F.
The antidiabetic drug metformin exerts
an antitumoral effect in vitro and in vivo
throughadecreaseofcyclinD1level.On-
cogene 2008;27:3576–3586
12. Evans JM, Donnelly LA, Emslie-Smith
AM, Alessi DR, Morris AD. Metformin
and reduced risk of cancer in diabetic pa-
tients. BMJ 2005;330:1304–1305
13. Libby G, Donnelly LA, Donnan PT, Alessi
DR, Morris AD, Evans JM. New users of
metformin are at low risk of incident can-
cer: a cohort study among people with
type 2 diabetes. Diabetes Care 2009;32:
1620–1625
14. Jiralerspong S, Palla SL, Giordano SH,
Meric-Bernstam F, Liedtke C, Barnett
CM, Hsu L, Hung MC, Hortobagyi GN,
Gonzalez-Angulo AM. Metformin and
pathologic complete responses to neoad-
juvant chemotherapy in diabetic patients
with breast cancer. J Clin Oncol 2009;27:
3297–3302
15. Wright JL, Stanford JL. Metformin use
andprostatecancerinCaucasianmen:re-
sults from a population-based case-con-
trol study. Cancer Causes Control 2009;
20:1617–1622
16. Li D, Yeung SC, Hassan MM, Konopleva
M, Abbruzzese JL. Antidiabetic therapies
affect risk of pancreatic cancer. Gastroen-
terology 2009;137:482–488
17. Bowker SL, Majumdar SR, Veugelers P,
Johnson JA. Increased cancer-related
mortality for patients with type 2 diabetes
who use sulfonylureas or insulin. Diabe-
tes Care 2006;29:254–258
18. Ubink-VeltmaatLJ,BiloHJ,GroenierKH,
Rischen RO, Meyboom-de Jong B. Shared
care with task delegation to nurses for
type2diabetes:prospectiveobservational
study. Neth J Med 2005;63:103–110
Metformin and cancer mortality in type 2 diabetes
326
DIABETES CARE, VOLUME 33, NUMBER 2, FEBRUARY 2010care.diabetesjournals.org