1. Type 2 Diabetes and Cancer
Dr. Manel Mata
Family Physician. La Mina Primary Care Centre. Barcelona Family and Community
Medicine Teaching Unit. Catalonian Institute of Health.
DAP_Cat Group. Institut Universitari d’Investigació en Atenció Primaria IDIAP-Jordi Gol.
Barcelona. Spain.
RedGDPS (Spanish Network of Primary Care Groups for the Study of Diabetes).
www.Redgdps.org
2. Type 2 Diabetes and Cancer
Dr. Manel Mata
Conflict of interest disclosure:
Honoraria from ASTRA-ZENECA, BAYER, BOEHRINGER INGELHEIM, BMS,
ESTEVE, GSK, LILLY, MENARINI, MERCK, MSD, NOVARTIS, NOVONORDISK,
SANOFI and SERVIER for the participation in Advisory Boards and lectures
about the treatment of diabetes.
3. • The relationship between diabetes
and cancer
• Does antidiabetic treatment have an
influence on the risk of cancer ?
Type 2 Diabetes and cancer
4. American Diabetes Association
American Cancer Society
Giovanucci E et al. Diabetes Care. 2010;33(7):1674-85.
T2DM is associated with increased risk for some cancers (liver, pancreas,
endometrium, colorectal, breast, bladder) and reduced risk for prostate
5. Garg SK et al. Diabetes, Obesity and Metabolism. 2014; 16: 97-110
Increased risk of cancer in diabetic patients
Summary of cohorts and case control studies meta-analysis
Liver 2.5
Pancreas 2.6
Endometrium 2.2
Breast 1.3
Prostate 0.9
6. Garg SK et al. Diabetes, Obesity and Metabolism. 2014;16:97-110
Men Women
All 1.44 1.35
Liver 5.16 6.37
Pancreas 1.67 2.13
Breast -- 1.65
Prostate 1.30 --
Increased cancer mortality
in diabetic patients
7. There are numerous considerations when assessing cancer
risk between diabetics and non diabetics:
• Some cancers of metabolically active organs, such liver and
pancreas, may induce the onset of type 2 diabetes
•The general pattern of an initial elevated peak in cancer risk
at the time of diabetes onset, which is substantially higher
than subsequent risk, suggests that many cancers are being
diagnosed at or around the time of recognition of diabetes
Johnson JA et al. Diabetologia 2012; 55:1607–18
8. Walker JJ et al. Lancet Diabetes Endocrinol 2013; 1: 132–39
Timing of exposure: reverse causality and detection bias
Reports from two different population databases have shown an initial
spike in the risk of most cancers immediately after the onset of
diabetes, followed by a subsequent normalisation of risk
1. Investigation of early cancer symptoms leads to the diagnosis of
diabetes (reverse causality)
2. Diagnosis of diabetes can lead to additional clinical investigations,
resulting in the identification of cancers (bias in cancer detection)
3. Reverse causality and bias in cancer detection might also be present
in the time of initiation for a new drug.
9. Cancer Incidence
excluding 1st year
aRR
Liver 3.50
Pancreas 2.85
Colon 1.56
Breast 1.56
Bladder 0.53
Prostate 0.76
Kidney 0.25
Tayside (Scotland) DART MEMO database
9,577 newly diagnosed T2DM 1993–2004,
19,154 matched non-diabetic comparators
National Cancer Register.
No significant differences in
Any cancer 1.05 (0.93-1.18)
Ogunleye AA, Ogston SA, Morris AD, Evans JMM
10. Diabetes and Cancer
share common risk factors
• Non-modifiable: Aging, Male sex, Race/Ethnicity
• Modifiable:
Obesity
Diet (high calories, red meat, processed foods...)
Sedentarism
Smoking habit
Excessive alcohol consumption
Giovannucci E, et al. Diabetes Care 2010; 33: 1674-85
The relationship between type 2
diabetes and cancer is consistent
and reasonably strong.
Johnson JA & Pollak M. Diabetologia. 2010;53:2086-8
American Diabetes Association
American Cancer Society
11. Biological links between
Diabetes and Cancer
• Hyperinsulinemia
• Hyperglycaemia
• Chronic inflammation (citokines)
• Insulin receptor/insulin-like growth factor I (IGF-I) Axis
– Promotion of cell proliferation
– Decreased apoptosis
Giovannucci E et al. Diabetes Care 2010; 33: 1674-85
American Diabetes Association
American Cancer Society
12. Garg SK et al. Diabetes, Obes and Metab. 2014; 16: 97-110
The accumulation of experimental
and epidemiological evidence is more
consistent with the hyperinsulinaemia
hypothesis and less so with the
hyperglycaemia hypothesis.
Johnson JA & Pollak M. Diabetologia. 2010;53:2086-8
13. Obesity and Endometrial Cancer
https://tginnovations.wordpress.com/2013/08/10/you-already-know-how-to-defeat-cancer/
14. • The relationship between diabetes and
cancer
• Does antidiabetic treatment have an
influence on the risk of cancer ?
Type 2 Diabetes and cancer
15. Antidiabetic drugs and cancer
- Metformin neutral or protective
Safety signals:
- Sulfonylureas colon
- Insulin pancreas, colon
- Pioglitazone bladder
- Sitagliptin and Exenatide pancreas
- Dapagliflozin bladder
16. Although still limited, early evidence suggests that metformin is
associated with a lower risk of cancer and that exogenous
insulin is associated with an increased cancer risk.
Further research is needed to clarify these issues and evaluate
if insulin glargine is more strongly associated with cancer risk
compared with other insulins.
Giovanucci E et al. Diabetes Care. 2010;33(7):1674-85.
17. Considerations when comparing users vs non users:
• Confounding by indication: the non-random allocation of all
glucose-lowering therapies in observational studies
• Accounting for total, and perhaps cumulative drug exposure
• Immortal time bias: the period between cohort entry and
date of first exposure, during which cancer has not occurred,
is misclassified or excluded (not accounted for in the analysis)
Johnson JA et al. Diabetologia 2012; 55:1607–18
18. Several observational studies indicate that T2D patients treated
with metformin have a lower risk of cancer, but these should be
interpreted with caution because of possible confounders, mostly
notably confounding by indication.
Smith U & Gale EAM. Diabetologia 2010; 53:1541–4
Data from Ranzomized Clinical Trials (meta-analysis)
• Improving blood glucose control confers no benefit in cancer risk.
• UKPDS 34 reported a not statistically significant 29% reduction in
cancer mortality rates with metformin.
Johnson JA & Bowker SL et al Diabetologia 2011; 54:25–31
Metformin and cancer
19. Metformin was associated with reduced risk (OR 0.38), while insulin
(OR 4.99) and insulin secretagogues (OR 2.52) with increased risk
of pancreatic cancer in diabetic patients.
Li D et al. Gastroenterology 2009;137:482–8
Case-control study 2004 to 2008
973 pancreatic cancer (259 DM)
863 controls (109 DM. Texas (US)
20. Insulin (HR 1.26) and sulfonylureas (HR 1.38)
were associated with increased cancer risk in
comparison to metformin, but this differences
disapeared after several adjustments
Kowall B et al. Diabetes Care 2015 ; 38:59-65
SU and insulin vs metformin
German database. N=22,556, 4.8 years
21. Sulfonylureas vs No SU
ADOPT trial 1.17 (ns)
6 Cohort studies 1.19 (ns)
10 Case-control studies 1.05 (ns)
Thakkar B et al. Metabolism 2013; 62:922-34
22. Metformin vs No Metformin
ADOPT trial 1.01 (ns)
9 Cohort studies 0.85 (ns)
13 Case-control studies 0.71 (0.57-0.88)
Thakkar B et al. Metabolism 2013; 62:922-34
23. Our results show that metformin may reduce cancer
incidence and mortality in patients with diabetes.
However, the reduction seems to be of modest
magnitude and not affecting all populations equally.
Gandini S et al. Cancer Prev Res 2014; 7(9); 867–85
47 studies (65,540 cancers)
Metformin vs No Metformin
0.690.90
0.660.45
24. Provinciali N et al. Expert Opin. Drug Saf. 2015; 14(10):1573-1585
Metformin acts as a mitochondrial
poison inhibiting complex 1of the
mitochondrial respiratory chain.
Mitochondrial ATP production is
impaired, creating a state of
energy restriction.
25. Provinciali N et al. Expert Opin. Drug Saf. 2015; 14(10):1573-1585
Epidemiologic data support the conclusion that metformin has beneficial
anticancer effects in diabetics or subjects with high BMI or insulin
resistance.
Thus far, the evidence from clinical trials stems largely from modulation of
biomarkers in a direction consistent with benefit, that is, decreased
proliferation or increased apoptosis, in breast and endometrial cancers.
Multiple trials are ongoing and should inform the field as to whether this
potential anti-cancer agent truly has benefit.
27. Bowker SL et al. Diabetes Care 2006; 29(2):254-8
10.309 T2DM starting sulfonylurea, metformin or insulin monotherapy
Saskatchewan database (Canada) 1991-1996. Mean follow-up: 5,4 years (range 1-9)
Adjusted HR by age, sex and commorbidity (Chronic Disease Score)
Greater cancer mortality with sulfonylureas (1.3)
and insulin (1.9) in comparison to Metformin
28. Currie C et al. J Clin Endocrinol Metab 2013; 98: 668–77
UK General Practice Research
Database, 2000–2010
84,622 T2DM patients
Conclusions:
Exogenous insulin therapy was associated with an increased risk
of diabetes-related complications, cancer (OR 1.81), and all-cause
mortality (OR 2.2).
Differences in baseline characteristics between treatment groups should
be considered when interpreting these results.
29. Men Women
Increased mortality in diabetic patients with cancer
(greater in those treated with insulin)
Conclusions/interpretation:
More intensive diabetes treatment
reflects a larger degree of
comorbidity at the time of cancer
diagnosis and a poorer survival
noDM
DM no Med
DM+OHA
DM+INS
RR 6.5
426,129 patients
with incident cancer,
(42,205 with
diabetes prior to
cancer diagnosis)
DM+INS
RR 5
Ranc K et al. Diabetologia 2014; 57:927-34
30. The link beetween exogenous insulin and cancer:
Insulin has affinity for the IGF-1 receptors expressed by
tumor cells
Increased insulin, IGF-1, and IGF-2 signaling through the insulin receptor and
IGF-1 receptor can induce tumorigenesis by up-regulating the insulin receptor
and IGF-1 receptor signaling pathways
Gallagher EJ et al. Endocr Pract. 2010;16(5):864-873.
32. Diabetologia, 26 june 2009
Five original papers and one
editorial about cancer and glargine
33. ORIGIN Glargine vs. Standard Care
• 1st CV Composite: HR = 1.02 (0.94, 1.11)
• 2nd CV Composite: HR = 1.04 (0.97, 1.11)
• Death: HR = 0.98 (0.90, 1.08)
• Microvascular Composite: HR = 0.97 (0.90, 1.05)
• Cancer: HR = 1.00 (0.88, 1.13)
• Conversion IFG/IGT to DM: HR = 0.72 (0.58, 0.91) P=0.006
N=12,537; 573 sites; 40 countries; Median Follow-up: 6.2 years
The ORIGIN trial Investigators. 10.1056/NEJMoa1203858 en NEJM.org
Outcome Reduction with Initial Glargine INtervention
34. Owens DR. Diabetes Care 2012; 35:2426-8
On the basis of the findings from
epidemiological studies and
the latest pharmacokinetic data
the chapter on whether insulin
glargine per se is an independent
risk factor for cancer should now
be closed.
35. 17.9.10 FDA alert
9.6.11 Withdrawal in France and Germany
15.6.11 FDA Warning
21.7.11 EMA Warning
……….
5.12.14 Observational study of 6 population
databases (5,9 M patients-year): No increase
2010
Pioglitazone and bladder cancer
36. N= 1,491,060, 40-79 year-old T2DM on antidiabetic treatment,
155,535 on Pioglitazone. Follow-up 42 months (2006-2009)
175 bladder cancer cases in Pio users vs 1,841 in nonPio users
49.4 vs 42.8 per 100,000 person-years (aRR 1.22)
HR
Any exposure 1.22
Exposure >24 months 1.36
Cumulative dose >28,000 mg 1.75
EMA 21/07/11
• The benefits outweigh the risks in those patients responding well to pioglitazone
• After three to six months of treatment, discontinue pioglitazone in patients not
having sufficient benefit
• Discontinue treatment with pioglitazone in those patients who have, or have had,
bladder cancer, include those who are awaiting investigation of haematuria.
Neumann A et al. Diabetologia 2012; 55:1953-62
37. Observational study of 6 population
databases (5.9 M patient-years)
3,248 incident bladder cancer cases
RR (95% CI)*
Pioglitazone
Men 1.01 (0.97-1.06)
Women 1.04 (0.97-1.11)
Rosiglitazone
Men 1.01 (0.98-1.03)
Women 1.00 (0.94-1.07)
*adjusted for age, calendar year, diabetes duration,
smoking and any ever use of the drug
There was no evidence for any association between
cumulative exposure to pioglitazone and bladder
cancer in men (HR 1.01) or in women (RR 1.04) after
adjustment for age, calendar year, diabetes duration,
smoking, and any ever use of pioglitazone.
Levin D. Diabetologia. 2015 Mar;58(3):493-504.
Diabet Med. 2015;32(3):305-13.
39. Butler P & Gale E
Nauck M
Diabetes Care Publish Ahead of Print,
published online May 6, 2013
To date, the FDA has not seen a
convincing signal between the use of
GLP-1 or DPP-4 agents and pancretic
cancer, but it continues to monitor new
findings and carefully evaluates them.
JUNE 2013
40. Incretins and Pancreatic Ductal Adenocarcinoma
One study of eight necropsies (7 sitagliptin and 1 exenatide) described
enlargement of the pancreas, chronic inflammation and dysplasia
(premalignant) that might favor the long term appearance of ductal cancer
Butler AE et al. Diabetes 2013; 62: 2595-604
Plausible model:
Stimulation of GLP1 receptors might proliferate exocrine ducts accelerating
dysplasia in patients with a chronic low-grade pancreatic inflammation
Butler A & Gale E, Diabetes Care. published online May 6, 2013
The FDA and the EMA agree that assertions concerning a
causal association between incretin-based drugs and
pancreatitis or pancreatic cancer, as expressed recently in the
scientific literature and in the media, are inconsistent with the
current data.
Egan AG et al. NEJM 2014; 370(9) Pub Online 27 february 2014
41. TECOS (Sitagliptin)3
Placebo
n=7,339
Sitagliptin
n=7,332
p value
Pancreatic cancer 14 (0.2%) 9 (0.1%) 0.32
DPP4 inhibitors in the cardiovascular outcomes trials
Pancreas cancer
SAVOR TIMI53 (Saxagliptin)2 Placebo
(N=8,212)
Saxagliptin
(N=8,280)
p value
Cancer (%) 4.4 4.0 0.15
Pancreatic Cancer, n (%) 12 (0.1) 5 (0.06) 0.095
EXAMINE (Alogliptin)1 No pancreatic cancer cases in both arms
1. White et al. NEJM 2013 2. Scirica et al. NEJM 2013 3. Green et al. NEJM 2015
42. http://professional.diabetes.org/Presentations_Details.aspx?session=4740
ELIXA study lixisenatide vs placebo
Pancreatic neoplasm during the study
n (%)
Placebo
N=3032
Lixisenatide
N=3031
Events adjudicated as malignant by PSAC
Patients with events
Related
Possibly related
Unlikely related
Not related
9 (0.3)
0
2 (<0.1)
3 (<0.1)
4 (0.1)
3 (<0.1)
0
0
2 (<0.1)
1 (<0.1)
Events adjudicated as benign by PSAC
Patients with events 0 1 (<0.1)
Events with insufficient documentation
Patients with events 1 (<0.1) 1 (<0.1)
PSAC, Pancreatic Safety Assessment Committee
44. Malignancy (continued)
*Incidence rate ratio = 1.047 (95% CI: 0.702, 1.579)
DAPA=dapagliflozin
Johnsson K et al. Diabetologia 2012;55(Suppl1)743-P
SGLT2 inhibitors (Dapagliflozin) and risk of cancer
EMA 12/11/12
A causal relationship between dapagliflozin and bladder
cancer is unlikely.
As a precautionary measure, dapagliflozin is not
recommended for use in patients concomitantly treated
with pioglitazone.
RR 5.4
45. Messages to take home
• T2DM is associated with an increased incidence and mortality for some
cancers.
•Epidemiologic data support the conclusion that metformin has beneficial
anticancer effects in diabetics or subjects with high BMI or insulin
resistance. Multiple trials are ongoing and should inform the field as to
whether this potential anti-cancer agent truly has benefit.
• Some safety signals have emerged from clinical trials or observational
studies: Further research is needed to clarify these issues.
• Cancer risk should not be a major factor in choosing between available
diabetes therapies. Only for selected patients at high risk for cancer or
recurrences may require careful consideration.