Introduction
The question of a possible increased risk of cancer, especially breast cancer, in users of the insulin analogue, glargine (A21Gly, B31Arg, B32Arg human insulin), was raised following the publication of experimental data showing a higher affinity of insulin glargine for IGF1 receptors and signalling pathways, and a pro-angiogenic effect [
1‐
5], with possible promoting and anti-apoptotic effects on human breast cancer cells [
6]. Epidemiological studies also found an increased dose-dependent relative risk of cancer in exclusive users of insulin glargine [
7,
8]. This excess risk of cancer was not confirmed in meta-analyses of short-term clinical trials [
9] or in a long-term open trial [
10] or in other epidemiological studies [
11,
12]. A re-analysis of the database that provided one of the initial signals confirmed the initial signal, but was unable to reproduce it in later years [
13]. There has been much discussion of the real meaning of these findings [
14,
15], the relative role of insulin itself or its analogues in the increased risk of cancer [
16‐
18], the role of diabetes and hyperglycaemia as such [
19,
20], or even of the reality of an increased risk of cancer in insulin users [
21‐
23].
Because of these uncertainties, and notwithstanding an on-going risk management programme [
24], we explored the Echantillon Généraliste de Bénéficiaires: random 1/97 permanent sample of the French national healthcare insurance system database (EGB) [
25] to test for a possible association between the dispensing of insulin glargine and the occurrence of cancer. Since increased mortality rates might hide an increased risk of cancer, the combined outcome of death or cancer was also studied. We also tested a possible effect of increasing exposure to insulin, sulfonylureas and metformin on the event rates for cancer.
Results
Patient group selection and the analysis cohorts are shown in Fig.
1. Of 8,485 patients with a first dispensing of insulin, 6,649 were initially included. Because in incident type 1 diabetic patients there was no case of cancer in those exposed to insulin glargine and only one in those exposed to human insulin, further analyses were restricted to type 2 diabetic patients. Of these type 2 diabetic patients, 1,199 were incident exclusive users (most restrictive population) and 1,843 were all predominant users (largest group). Baseline insulin glargine and human insulin patient characteristics were very similar from the most restrictive to the more extensive populations (Tables
1 and
2), even though the population size, which did not change much with insulin glargine (from 927 to 1,140 patients), almost tripled with human insulin (from 272 to 703 subjects). Patients on insulin glargine or human insulin had the same age within a year or two. More men were on insulin glargine (50%) than on human insulin (40%). Patients on insulin glargine had more concomitant diseases and medications (Table
1). More than 70% of patients on human insulin were exposed only to NPH insulin, with 30% exposed to premix insulins combining intermediate and fast-acting insulins.
Table 1
Baseline characteristics of incident type 2 diabetic patients exposed to insulin glargine or human insulin as indicated
n
| 927 | 272 | 1,140 | 703 |
Male sex, n (%) | 467 (50.4) | 108 (39.7) | 575 (50.4) | 291 (41.4) |
Age at first dispensing of insulin, mean (SD) | 68.1 (13.3) | 69.7 (15.2) | 67.8 (13.2) | 69.9 (13.6) |
Long-term disease inscription for diabetes, n (%) |
Before 1995 | 156 (16.8) | 74 (27.2) | 216 (18.9) | 284 (40.4) |
1995–1999 | 194 (20.9) | 41 (15.1) | 245 (21.5) | 136 (19.3) |
2000–2004 | 441 (47.6) | 123 (45.2) | 513 (45.0) | 243 (34.6) |
2005–2009 | 136 (14.7) | 34 (12.5) | 166 (14.6) | 40 (5.7) |
At least one diagnosis of long-term disease, n (%) |
Severe hypertension | 148 (16.0) | 32 (11.8) | 171 (15.0) | 66 (9.4) |
Cardiovascular diseases | 139 (15.0) | 45 (16.5) | 173 (15.2) | 93 (13.2) |
Psychiatric disorders | 59 (6.4) | 14 (5.1) | 62 (5.4) | 27 (3.8) |
Other diseases | 202 (21.8) | 63 (23.2) | 247 (21.7) | 125 (17.8) |
Systemic drug dispensing, mean (SD) |
A10, oral glucose-lowering | 9.5 (5.8) | 4.5 (4.9) | 9.4 (5.9) | 4.5 (5.2) |
Other A, gastrointestinal tract/metabolism | 3.4 (4.5) | 2.8 (4.0) | 3.3 (4.5) | 2.9 (4.2) |
B, blood and blood forming organs | 2.8 (3.6) | 2.2 (3.1) | 2.9 (3.6) | 2.7 (3.5) |
C10, lipid-modifying agents | 2.8 (3.0) | 1.5 (2.4) | 2.9 (3.0) | 2.0 (2.8) |
Other C, cardiovascular system | 11.7 (10.1) | 9.0 (8.8) | 11.7 (10.0) | 11.8 (10.0) |
G, genito-urinary system | 0.8 (2.0) | 0.4 (1.3) | 0.7 (2.0) | 0.5 (1.7) |
H, endocrine system | 0.9 (2.1) | 0.8 (1.8) | 0.9 (2.1) | 0.6 (1.7) |
J07, vaccines | 0.4 (0.5) | 0.2 (0.5) | 0.3 (0.5) | 0.2 (0.4) |
Other J, anti-infectives for systemic use | 0.8 (1.3) | 0.8 (1.4) | 0.8 (1.3) | 0.7 (1.3) |
L, anti-neoplastic and immunomodulating agents | 0.1 (0.5) | 0.1 (0.5) | 0.1 (0.6) | 0.1 (0.5) |
M, muscles, bones and joints | 1.4 (2.7) | 1.0 (2.1) | 1.4 (2.7) | 1.1 (2.3) |
N01–N02, analgesics–anaesthetics | 2.7 (3.3) | 2.1 (2.4) | 2.7 (3.3) | 2.5 (2.9) |
Other N, brain and nervous system | 4.2 (6.7) | 3.3 (5.6) | 4.0 (6.4) | 4.0 (6.1) |
P, anti-parasitic products | 0.0 (0.2) | 0.0 (0.1) | 0.0 (0.2) | 0.0 (0.1) |
R, respiratory system | 1.7 (4.1) | 1.3 (3.3) | 1.6 (3.9) | 1.5 (3.7) |
S, sensory organs | 1.0 (2.7) | 0.7 (2.3) | 1.1 (2.8) | 1.1 (3.3) |
PRb, mean (SD) |
Insulin | 57.9 (23.4) | 65.0 (24.8) | 58.4 (22.9) | 65.1 (23.2) |
Biguanide | 41.8 (41.2) | 17.1 (32.6) | 41.8 (40.8) | 20.9 (35.3) |
Sulfonylurea | 36.8 (40.8) | 15.3 (30.9) | 35.7 (40.2) | 17.4 (32.1) |
Other oral glucose-lowering agents | 26.8 (37.3) | 8.4 (24.3) | 26.9 (36.9) | 10.7 (26.3) |
Table 2
Hazard ratios from multivariate Cox proportional hazards models for diagnosis of cancer in patients with type 2 diabetes exposed to insulin glargine or human insulin, stratified by propensity score quartiles users as indicated
Number of patient-years exposure |
Human insulin | 614.2 | 820.5 | 1,705.4 | 2,341.0 |
Insulin glargine | 2,272.8 | 2,800.3 | 2,342.1 | 3,125.1 |
Number of cases of cancer |
Human insulin (n) | 14 | 17 | 54 | 57 |
Insulin glargine (n) | 41 | 44 | 42 | 46 |
Cancer incidence per 1,000 person-years, HR (95% CI) |
Human insulin | 22.8 (10.9, 34.7) | 20.7 (10.9, 30.6) | 31.7 (23.2, 40.1) | 24.3 (18.0, 30.7) |
Insulin glargine | 18.0 (12.5, 23.6) | 15.7 (11.1, 20.4) | 17.9 (12.5, 23.4) | 14.7 (10.5, 19.0) |
Crude HR (95% CI) |
Human insulin | 1.0 | 1.0 | 1.0 | 1.0 |
Insulin glargine | 0.80 (0.44, 1.47) | 0.76 (0.43, 1.33) | 0.53 (0.35, 0.80) | 0.57 (0.39, 0.84) |
Adjusted HR (95% CI) |
Human insulin | 1.0 | 1.0 | 1.0 | 1.0 |
Insulin glargine | 0.59 (0.28, 1.25) | 0.60 (0.31, 1.18) | 0.61 (0.32, 1.18) | 0.58 (0.34, 1.01) |
New long-term disease after initiation of insulin | 1.08 (0.50, 2.33) | 1.03 (0.50, 2.12) | 0.66 (0.35, 1.25) | 0.78 (0.43, 1.40) |
IPR |
0–39% | 1.0 | 1.0 | 1.0 | 1.0 |
40–59% | 1.12 (0.51, 2.48) | 1.14 (0.53, 2.45) | 1.03 (0.53, 2.00) | 1.10 (0.58, 2.07) |
60–79% | 1.75 (0.82, 3.73) | 1.63 (0.78, 3.38) | 1.51 (0.82, 2.80) | 1.47 (0.81, 2.68) |
80–100% | 2.14 (0.97, 4.72) | 2.05 (0.95, 4.45) | 2.33 (1.28, 4.22) | 2.26 (1.26, 4.06) |
Sulfonylureas PR |
0–19% | 1.0 | 1.0 | 1.0 | 1.0 |
20–79% | 1.15 (0.52, 2.55) | 1.03 (0.47, 2.24) | 1.25 (0.71, 2.20) | 1.25 (0.71, 2.20) |
80–100% | 2.30 (1.17, 4.54) | 2.69 (1.42, 5.09) | 1.98 (1.17, 3.35) | 2.28 (1.38, 3.76) |
Biguanides PR |
0–19% | 1.0 | 1.0 | 1.0 | 1.0 |
20–79% | 0.51 (0.21, 1.21) | 0.52 (0.23, 1.16) | 0.48 (0.23, 1.00) | 0.49 (0.24, 0.98) |
80–100% | 0.82 (0.43, 1.57) | 0.74 (0.40, 1.38) | 0.98 (0.60, 1.59) | 0.92 (0.57, 1.48) |
Other oral glucose-lowering agent PR |
0–19% | 1.0 | 1.0 | 1.0 | 1.0 |
20–79% | 0.65 (0.26, 1.59) | 0.82 (0.37, 1.81) | 0.71 (0.35, 1.45) | 0.77 (0.40, 1.47) |
80–100% | 1.04 (0.46, 2.34) | 1.04 (0.46, 2.33) | 1.08 (0.59, 1.98) | 1.05 (0.57, 1.92) |
Exposures varied from 2,273 to 3,125 patient-years for insulin glargine and from 614 to 2,340 patient-years for human insulin. Cancer was reported in 18.0 (95% CI 12.5, 23.6) and 22.8 (95% CI 10.9, 34.7) per 1,000 patient-years in exclusive users of insulin glargine and human insulin, respectively (Table
2), and in 14.7 (95% CI 10.5, 19.0) and 24.3 (95% CI 18.0, 30.7) per 1,000 patient-years in all predominant insulin glargine and human insulin patients.
The main study endpoint, the HR for diagnoses of cancer with insulin glargine compared with human insulin in incident exclusive users, was 0.59 (95% CI 0.28, 1.25). This value for all predominant users was 0.58 (95% CI 0.34, 1.01; Table
2). The results were the same, regardless of whether the propensity score was used as a continuous adjustment variable or as a stratifying variable. Kaplan–Meier all-cause cancer-free crude survival curves were very similar, parallel or superimposed (not shown).
There was no significant difference in the event rates for the more common types of cancer. More specifically, in all population groups there were numerically more cases and higher event rates for breast cancers in users of human insulin than in users of insulin glargine (Table
3).
Table 3
Event rates per thousand patient-years of follow-up for the more common cancer types in incident exclusive users and in all predominant users of insulin glargine or human insulin
All cancers | 41 | 18.0 (12.5, 23.6) | 14 | 22.8 (10.9, 34.7) | 46 | 14.7 (10.5, 19.0) | 57 | 24.3 (18.0, 30.7) |
Prostatee
| 8 | 7.1 (3.1, 14.0) | 2 | 6.4 (1.0, 30.3) | 9 | 5.8 (2.7, 11.0) | 11 | 11.7 (4.8, 18.7) |
Lung | 6 | 2.6 (1.0, 5.7) | 1 | 1.6 (0.0, 0.1) | 6 | 1.9 (0.7, 4.2) | 5 | 2.1 (0.7, 5.0) |
Pancreas | 4 | 1.8 (0.5, 4.5) | 3 | 4.9 (1.0, 14.3) | 4 | 1.3 (0.3, 3.3) | 5 | 2.1 (0.7, 5.0) |
Breastf
| 2 | 1.7 (0.2, 6.3) | 3 | 8.0 (1.7, 23.4) | 2 | 1.3 (0.2, 4.6) | 8 | 5.7 (2.5, 11.2) |
Colorectal | 3 | 1.3 (0.3, 3.9) | 1 | 1.6 (0.0, 9.1) | 5 | 1.6 (0.5, 3.7) | 6 | 2.6 (0.9, 5.6) |
Bladder | 2 | 0.9 (0.1, 3.2) | 1 | 1.6 (0.0, 9.1) | 3 | 1.0 (0.2, 2.8) | 1 | 0.4 (0.0, 2.4) |
Liver, biliary duct | 2 | 0.9 (0.1, 3.2) | 1 | 1.6 (0.0, 9.1) | 2 | 0.6 (0.1, 2.3) | 2 | 0.9 (0.1, 3.1) |
For the secondary endpoints, the occurrence of cancer diagnoses was associated with increasing insulin exposure as assessed by the PR, ranging for insulin possession rate (IPR) 80% to 100% vs 0% to 20% from 2.14 (95% CI 0.97, 4.72) in the incident exclusive population to 2.26 (95% CI 1.26, 4.06) in all predominant users (Table
2). Cancer diagnoses were also associated with exposure to sulfonylureas for all populations, ranging for PR 80% to 100% vs 0% to 20% from 2.30 (95% CI 1.17, 4.54) for incident exclusive patients to 2.28 (95% CI 1.38, 3.76) for all predominant patients (Table
2 ). Although exposure to biguanide was generally associated with an HR below 1, this never reached significance and did not show clear exposure-dependence (Table
2).
Death or cancer was reported in 22.4 (95% CI 16.3, 28.6) per thousand patient-years for incident exclusive users of insulin glargine and in 45.6 (95% CI 28.7, 62.5) per thousand patient-years for users of human insulin. The HR for all-cause death or cancer with insulin glargine compared with human insulin, stratified by the propensity score and adjusted for drug possession ratios, varied from 0.58 (95% CI 0.32, 1.06) in incident exclusive users to 0.56 (95% CI 0.36, 0.87) in all predominant patients. The hypothesis of a concurrent risk of death masking the risk of cancer in insulin glargine patients was thus not verified. Risk of cancer or death was also increased in the higher stratum of the IPR (80% to 100% vs 0% to 20%), ranging from adjusted HR 2.94 (95% CI 1.52, 5.68) in incident exclusive users to 2.82 (95% CI 1.75, 4.55) in all predominant users. A moderately increased risk of cancer or death in the higher stratum of sulfonylurea exposure was also found; it ranged from HR 1.62 (95% CI 0.89, 2.94) in exclusive incident users to 1.87 (95% CI 1.22, 2.87) in all predominant users.
Discussion
In this random sample of the national healthcare insurance reimbursement database, we found that the dispensing of insulin glargine alone was not associated with an increased risk of subsequent cancer diagnoses compared with human insulin alone. Our analysis used multivariate Cox analysis stratified for propensity scores and exposure to glucose-lowering drugs. The upper limit of the 95% CI of this HR was lower than the HR reported in previous studies [
7,
8], allowing us to confidently rule out the possibility that results of those previous studies were reproduced in this representative sample of the French population.
We detected an association of increasing mean PR for any insulin and for sulfonylureas with the risk of cancer, adding weight to the hypothesis that increased risk of cancer is associated with increased insulin exposure, whether exogenous or stimulated.
Various sensitivity analyses, including patients with at least 80% of exposure time on the same insulin, or including only incident (previously untreated with insulin for at least 6 months) or all patients treated with insulin, reached the same conclusion with little variation in the point estimates for the HRs. There was little difference between crude and adjusted risk ratios.
The main hypothesis for this study was based on the studies that appeared in 2009 in
Diabetologia [
7,
8,
11,
29] and were the source of much controversy [
30]. These studies found that the incidence of cancer seemed greater in patients dispensed only insulin glargine than in patients dispensed only human insulin. They also found no overall difference between different insulin types, but post-hoc analyses found an increased risk of cancer, especially of the breast, in diabetic patients who were exposed only to insulin glargine [
7,
8,
11] compared with those exposed only to human insulin. Our findings did not reproduce these results. On the contrary, we can confidently rule out the possibility that the increased risk reported in those studies applied in our population. In all population groups studied, the point estimate of the HR for the risk of cancer with insulin glargine was below one. Our results are consistent with some of the experimental data [
31]. Other studies have also found a similar point estimate around 0.80 for the risk of cancer with insulin glargine compared with human insulin [
9,
29]. Similarly, we found no excess risk of breast cancer with insulin glargine.
Among the previously published studies, Hemkens et al. [
7] reported an excess incidence of cancer only after adjusting for dose of insulin glargine. We were not able to adjust for dose, but did adjust for dispensing (PR) as a proxy for exposure. In doing so, we found that there was an increased risk of cancer with increased relative dispensing of insulin and that this was common to all insulins tested by us, with no interaction with the type of insulin. What might be thought unusual is that Hemkens et al. did not find a dose-dependent risk for insulins other than insulin glargine [
7]. Jonasson et al. [
8] reported an excess incidence of breast cancer only, but not of all cancers or any other cancer. Further analyses of the same population over different time periods were unable to reproduce the increased risk found initially [
13]. The findings of the SDRN Epidemiology Group were inconsistent across the different study designs, with some (but not all) study designs suggesting an excess of all cancer incidence and breast cancer [
11]. We found no such increase in any of our study populations. In fact, we found a numerically lower rate of breast cancer in insulin glargine users than in human insulin users.
The explanation of why our findings do not confirm those of these previous studies might reside in possible biases, either in previous studies, or in the present study.
We can probably exclude most biases concerning case ascertainment or selection. In this reimbursement database, randomly selected patients from the national healthcare insurance databases are prospectively registered, and data are collected prospectively and independently of patients, prescribers or any pre-specified hypothesis. Our population is by design representative of the French population [
25]. Registration for long-term diseases is mandatory for patients to receive full cover for healthcare expenditures related to the disease. Thus it is very unlikely that patients treated for cancer would not be registered to obtain full cover for this expensive disease. There is no reason for diagnoses of cancer to have been registered differently for patients treated with insulin glargine compared with those on human insulin.
It also seems unlikely that human insulin was channelled to higher cancer risk patients or insulin glargine to lower-risk patients. The very small effect of the propensity score stratification on the results indicates that there were very small differences between the insulin user populations. Most of our patients were included in the database before the alerts on insulin glargine and cancer risk in 2009, which was, in fact, the end of the inclusion period. Following the notorious putative cancer risk alert for insulin glargine, any change in indication or reduction in the use of insulin glargine in patients suspected to be at higher risk of cancer would have appeared only in 2009, and would therefore have affected only a very small proportion of the patients. Increased awareness of a possible risk of cancer with insulin glargine might have increased detection of cancer in insulin glargine users, but again this would only have happened at the very end of the follow-up period. This potential detection bias might have explained a higher apparent risk of cancer in insulin glargine users, but this is not what we found. We adjusted for common confounders, such as age, duration of exposure and concomitant diseases. The latter include markers of increased risk of cancer, such as coronary heart disease or peripheral arterial disease, but these, too, were not less frequent in insulin glargine users than in human insulin users. We were unable to adjust for BMI or smoking, but there is no indication that these would be confounders modifying prescription patterns and resulting in a distorted apparent risk. BMI is associated with cancer and with type 2 diabetes [
32‐
36], although it is unclear whether this association is independent or related to insulin resistance [
37]. In other studies, there was no difference in mean BMI between different insulin groups in type 2 diabetic patients, and there is no medical reason to prefer one insulin over the other on the basis of BMI. We did not account for smoking, but any confounding would result from a preferential use of one or the other type of insulin in smokers or non-smokers, which seems unlikely. In addition, there was no indication of a different rate of lung cancer, or of diagnoses involving chronic lung disease or other proxies such as coronary heart disease. On the other hand, we confirmed the increased risk of cancer diagnoses with increasing use of insulin (any type) or increasing use of sulfonylureas in all population groups, a finding that supports the notion that insulin as such plays a cancer-promoting role, be it exogenously added or endogenously secreted upon stimulation [
38]. We did not confirm the protective effect of biguanides [
16], although the risk of cancer with biguanides was indeed lower than in sulfonylurea users.
The first conclusion of our study is therefore that we found no confirmation of the hypothesis that patients exposed only to insulin glargine have a higher risk of cancer (including breast cancer) than those exposed only to human insulin. On the contrary, we found fewer cancer diagnoses in insulin glargine than in human insulin users.
One explanation of our finding could be concurrent risk bias. Thus if patients treated with insulin glargine died sooner than patients on human insulin, they might be at less apparent risk of developing cancer. However, we found the opposite, namely that patients on insulin glargine tended to die less soon than patients on human insulin, a finding that in some cohorts reached significance. Again, the risk of ascertainment bias would be low, since registration of death comes from the census bureau and the pension funds, and is independent of treatment or use of healthcare resources. We have no indication as to whether the increased death rate is due to the insulin chosen, or to patient selection or channelling of human insulin to more severely ill patients than those on insulin glargine. Different death rates between insulin glargine and human insulin users have not been reported in clinical trials of insulin glargine, but patients randomised to insulin glargine had fewer episodes of hypoglycaemia, a condition that might predispose to earlier death [
39]. The follow-up was short in the above trials. In actual practice, human insulin might have been chosen for tighter control of diabetes [
40‐
42], which has also been associated with higher mortality rates [
43]. Higher all-cause death rates might reduce the apparent risk of cancer in users of human insulin and could perhaps help explain findings in other epidemiological studies showing higher rates of cancer with insulin glargine or lower rates with comparators. None of the above studies reported on all-cause death or other competing risks. One retrospective study comparing use of bolus insulin analogues with bolus human insulin in hospital also found that the death rate in patients treated with human insulin was double that of patients given insulin analogues, results that are quantitatively not very different from ours, albeit in a very different setting [
44].
Because our analysis of deaths was exploratory without any pre-formulated hypothesis, the exact role of the patient status or the choice of insulin remains to be determined. It would, therefore, be desirable to re-analyse clinical trials comparing analogues with human insulin for all-cause death rates and to verify our findings in other settings and other databases.
In conclusion, we did not confirm previous findings of an increased risk of cancer with insulin glargine compared with human insulin. We did, however, confirm the increased risk of cancer with higher insulin or sulfonylurea exposure. We also found an increased risk of all-cause death with human insulin compared with insulin glargine, a finding that certainly warrants further exploration.