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Possible link between insulin glargine and cancer
Experts recommend continued use of insulin glargine until further, conclusive data are available.
Data from four studies published in Diabetologia suggest a possible link between insulin glargine and increased risk for cancer.
Concern about the possible link was raised by a German study of 127,031 patients with diabetes in an insurance database. The research identified a statistically significant, dose-dependent link between patients who had used insulin glargine (Lantus, Sanofi Aventis) and those who had been diagnosed with cancer (adjusted HR=1.09). Patients who were given a daily dose of 10 IU insulin glargine had an increased risk for cancer (HR=1.19) compared with patients given human insulin. When the dose was increased to 50 IU, the risk for cancer escalated to 31% (HR=1.31). The link was not reported with insulin aspart or lispro.
Results prompted the editors of Diabetologia and the European Association for the Study of Diabetes to convene and commission three additional observational analyses that examined the safety of insulin glargine before publishing the German database study findings. Further research was carried out using databases from Scotland, Sweden and the United Kingdom.
Until further research becomes available, experts have encouraged the continued use of insulin glargine. However, patients with diabetes and health care professionals can consider alternatives, such as long-acting human insulin or a mixture of long- and short-acting human insulin twice a day.
“With respect to insulin glargine, it is in no one’s interest to mount a witch-hunt against this popular and widely used insulin — many will reflect upon the fate of rosiglitazone — but it is in everyone’s interest for the truth to be known,” Edwin A. M. Gale, MD, editor of Diabetologia, and Ulf Smith, MD, PhD, president of EASD, wrote in an accompanying editorial.
“One point has become abundantly clear, and this is that cancer must now be numbered among the complications of diabetes,” the two wrote.
Replicated findings
A population-based follow-up study conducted in Sweden followed nearly 115,000 adults who were issued a prescription for insulin in 2005. The records were linked to data from the cancer registry for 2006 and 2007.
During 2006 and 2007, patients using insulin glargine alone had an increased incidence rate of breast cancer compared with those who used insulin other than glargine (RR=1.99), after adjustment for BMI, age at diabetes onset, cardiovascular disease and a variety of other factors. Monotherapy with insulin glargine was not associated with an increased risk for gastrointestinal cancer (RR=0.93), prostate cancer (RR=1.27) or overall rate of malignancy (RR=1.07) after adjustment for age and sex.
The researchers and editorialists stressed a need for caution when interpreting these findings. For example, “the number of breast cancers was relatively low: 25 cases on insulin glargine vs. 183 on insulins other than insulin glargine,” Gale and Smith wrote.
Another study evaluated 36,254 insulin users included in a large clinical database of people with diagnosed diabetes in Scotland. At the time of the study, relatively few were on insulin glargine: 447 on glargine alone and 3,512 on glargine plus other insulins.
During four years of follow-up, the incidence of all cancers were the same among the 3,959 patients using insulin glargine and patients who used other types of insulin (HR=1.02). However, the 447 patients who used insulin glargine alone had a significantly higher incidence of all cancers than the 32,295 using other insulins (HR=1.55); those using insulin glargine with other insulins had a slightly lower incidence (HR=0.81). Insulin glargine was not associated with an increased rate for breast cancer in this study (HR=1.49).
The researchers noted several important differences in baseline characteristics between the treatment groups. The insulin glargine group was older (68 vs. 41 years), more overweight and hypertensive and more likely to be on oral antidiabetic therapies and have a diagnosis of type 2 diabetes (97% vs. 37%) compared with the insulin glargine plus other insulins group. Of note, differences in cancer risk may be attributed to the different between-group baseline characteristics rather than the treatment itself, according to Gale and Smith.
Taken together, the number of breast cancer cases in the Scottish and Swedish studies was very small, meaning the findings could have occurred due to chance, according to the editorialists.
The fourth study, conducted in the United Kingdom, was a retrospective cohort study of 62,809 people treated in U.K. general practices. All were aged 40 years and older and started treatment with oral agents or insulin after 2000. They were divided into four treatment groups: metformin monotherapy, sulfonylurea monotherapy, combination therapy with metformin and sulfonylurea or insulin. Insulin users were subdivided into glargine, long-acting human insulin, biphasic analogue or human biphasic insulin.
Results suggest a protective effect of metformin — metformin alone was associated with the lowest risk for cancer. Metformin plus insulin was associated with a reduced progression to cancer (HR=0.54). Compared with metformin monotherapy, the hazard ratio for cancer was 1.42 for the insulin group, 1.36 with sulfonylurea monotherapy and 1.08 with metformin plus sulfonylurea.
The risk for cancer for patients using basal human insulin alone vs. insulin glargine alone was 1.24. Insulin therapy was associated with an increased risk for colorectal (HR=1.69) or pancreatic cancer (HR=4.63) but not breast or prostate cancer when compared with metformin. Patients on insulin or secretagogues were “more likely to develop solid cancers than those on metformin, and combination with metformin abolished most of this excess risk,” the researchers concluded.
The editorialists added that “metformin may come to play a major role in cancer prevention in diabetes.”
Interpreting the risk
Gale and Smith acknowledged “that we have entered an area of considerable complexity.” While further research is warranted to determine whether these concerns are real or can be set aside, several organizations have released statements advising health care professionals and patients.
“Findings from these research papers are conflicting and inconclusive, and the American Diabetes Association cautions against overreaction until more information is available. Until more information is available, the ADA advises patients using insulin not to stop taking it,” according to a statement.
In another, “EASD emphasizes that the studies reported are far from conclusive, but they do indicate the need for further investigation of this issue.”
An official Sanofi-Aventis statement said “these data clearly show that no definitive conclusions can be drawn regarding a possible causal relationship between insulin glargine use and the occurrence of malignancies, as the authors of the study point out.” Further, Sanofi-Aventis said it would continue to vigorously monitor the safety of insulin glargine in close collaboration with regulatory agencies and scientific experts.
Both the researchers and editorialists stated that insulin glargine and other insulins do not cause cancer, but the four studies expose the possibility that glargine could cause existing cancer cells to grow and divide more rapidly — which might explain why more cancers came to be diagnosed over one to three years of observation.
“We believe people are entitled to know that use of insulin glargine might be associated with greater risk, but this must also be balanced against the possibility that we might be causing unnecessary harm by raising these concerns,” Gale and Smith wrote.
For more information on these studies and the editorial, visit Diabetologia. – by Katie Kalvaitis
The studies involve convoluted statistical manipulation of epidemiologic data. Of the four studies, there is fundamental internal disagreement and inconsistencies. The risk, if any, seems small and one has to remember that insulin is essential if not life-saving therapy for millions of patients with diabetes. Decisions with regard to continuation or alteration of therapies require more data than is presently available. Further data may prompt a reevaluation in the future.
– Alan J. Garber, MD
Professor, Departments of Medicine, Biochemistry and
Molecular Biology,
and Cellular & Molecular Biology Baylor College of
Medicine Houston, Texas