HOUSTON, June 29 — Studies examining a possible cancer link to insulin glargine (Lantus) produced mixed conclusions that drew quick, reassuring responses from diabetes authorities.

Published online in Diabetologia, one of the studies showed a statistically significant increased risk of cancer in patients treated with the insulin analog glargine, but only after adjustment for insulin dose. Results of a second study showed a trend toward an increased risk of breast cancer in glargine users but no other types of malignancy.

A third study showed no overall increase in cancer risk associated with insulin glargine. However, a subgroup analysis limited to patients who received insulin glargine exclusively showed an increased risk of all cancers and breast cancer.

A fourth study yielded no evidence of an excess cancer risk attributable to glargine.

• Explain to patients that several studies arrived at conflicting conclusions regarding the risk of cancer associated with use of insulin glargine.
• Note that all of the studies were based on retrospective analyses of large databases, not on a randomized clinical trial.
• Note, too, that diabetes authorities, including authors of the studies, say that the data do not warrant a change in insulin treatment for diabetes.

In an accompanying editorial, two leading European voices in the field of diabetes said the collection of articles “is sufficient to establish that there is a case to answer, but is entirely insufficient to bring in a verdict.”

“There is no evidence that insulin, however formulated, causes cancer,” said Ulf Smith, MD, president of the European Association for the Study of Diabetes (EASD), and Edwin Gale, MD, editor of Diabetologia.

“There is no evidence of an overall increase in the rate of cancer development in patients on insulin glargine, and some suggestion that the risk may actually be reduced. There is no evidence of harm in type 1 diabetes or in premenopausal breast cancer.”

The data reported in Diabetologia are of interest but are not practice changing, said Yale endocrinologist Silvio Inzucchi, MD, who was not involved in any of the studies.

“We’ve been burned in medicine before by epidemiological studies that try to decipher risks and benefits of medications based on outcomes in a general treated population; in other words, outside a randomized clinical trial,” Dr. Inzucchi said in an interview.

“The whole suspicion related to glargine needs to be fleshed out,” he added. “I remain unconvinced.”

Echoing the editorialists and Dr. Inzucchi, the American Diabetes Association, American Association for Clinical Endocrinologists, and EASD all issued statements that characterized the findings as insufficient to warrant changes in a diabetic patient’s current insulin regimen.

Most of the controversy centered on an analysis of insurance data on 127,031 patients in Germany. The patients were cancer free at baseline, when they received first-time diabetes therapy exclusively with human insulin or the insulin anlogs aspart, lispro, or glargine.

The primary outcome was new cancer diagnoses during a mean follow-up of 1.68 years.

The analysis revealed a positive association between cancer incidence and insulin dose for all types of insulin, reported Lars G. Hemkens, of the Institute for Quality and Efficiency in Health Care in Cologne, and colleagues.

Because the analysis excluded combination therapy, the average daily dose was lower for glargine than for human insulin. An unadjusted analysis showed a lower cancer incidence in glargine-treated patients.

However, adjustment for dose revealed a dose-dependent increase in the hazard ratio, ranging from 1.09 for a daily glargine dose of 10 IU to 1.31 for a daily dose of 50 IU (P<0.0001 versus human insulin).

The adjusted analysis showed no increased risk with aspart or lispro compared with human insulin.

“Considering the overall relationship between insulin dose and cancer, and the lower dose with glargine, the cancer incidence with glargine was higher than expected compared with human insulin,” the authors concluded.

“Our results based on observational data support safety concerns surrounding the mitogenic properties of glargine in diabetic patients,” they said.

The suggestion of an increased risk of breast cancer emerged from an analysis of 114,841 Swedish diabetic patients followed for two years during exclusive treatment with insulin monotherapy.

After adjustment for age and sex, use of insulin glargine doubled the risk of breast cancer (RR 1.99, 95% CI 1.31 to 3.03).

The risk of prostate cancer, gastrointestinal cancer, or any type of malignancy was not significantly increased by glargine use, Gunnar Steineck, MD, PhD, of the Sahlgrenska Academy in Gothenburg, and colleagues reported.

“No definitive conclusions regarding a possible causal relationship between insulin glargine use and the occurrence of malignancies can be drawn from the results of this study,” the authors concluded.

Scottish investigators also found no increased cancer risk associated with use of insulin glargine. The study involved almost 50,000 patients treated with insulin from January 2002 through December 2005, reported Helen Colhoun, MD, of the University of Dundee, and colleagues.

The investigators defined a fixed cohort of 36,254 patients on the basis of insulin exposure during a four-month period in 2003. They also identified a cohort of 12,852 new insulin users. A total of 715 cases of cancer occurred in the fixed cohort and 381 in the new users.

Overall, patients using insulin glargine had the same incidence of cancers as patients who did not receive glargine.

A subset of 447 patients who used insulin glargine exclusively did have a significantly higher incidence of all cancers compared with patients with exclusive use of other types of insulin (HR 1.55, 95% CI 1.01 to 2.37, P=0.045).

Exclusive use of glargine also was associated with an increased risk of breast cancer (P=0.042 to P=0.004 in different statistical models).

Patients who used insulin glargine in combination with other insulins had a slightly lower incidence of cancer compared with patients who used other insulins.

The analysis revealed no increased risk of breast cancer in association with insulin glargine.

Moreover, cancer rates did not differ among patients with type 2 diabetes treated with insulin glargine only, other types of insulin, or combination insulin therapy that included glargine.

“Given the overall data, we consider the excess cases of all cancers and breast cancer in the subgroup of insulin glargine-only users to more likely reflect allocation bias rather than an effect of insulin glargine itself,” the authors concluded.

British investigators found an increased risk of solid tumors in patients treated with insulin or insulin secretagogues compared with metformin among 62,809 diabetic patients treated in general practices. However, the addition of metformin to insulin eliminated most of the excess risk, Craig J. Currie, PhD, of the Cardiff University, and colleagues reported.

Analysis of cancer risk by type of insulin used showed no difference in patients treated with human insulin or insulin analogs.

Dr. Hemkens and colleagues reported no competing interests. Dr. Currie and co-author C. D. Poole reported prior financial relationships with Eli Lilly, GlaxoSmithKline , Medtronic, Novo Nordisk, Roche, and sanofi-aventis. Drs. Smith and Gale reported no competing interests. Disclosure information was not listed for the remaining authors.

This article was developed in collaboration with ABC News.

Primary source: Diabetologia

Source reference:
Hemkens LG, et al “Risk of malignancies in patients with diabetes treated with human insulin or insulin analogs: a cohort study” Diabetologia 2009; DOI:10.1007/s00125-009-1418-4.

Additional source: Diabetologia

Source reference:
Jonasson JM, et al “Insulin glargine use and short-term incidence of malignancies — a population-based follow-up study in Sweden” Diabetologia 2009; epub.

Additional source: Diabetologia

Source reference:
Currie CJ, et al “The influence of glucose-lowering therapies on cancer risk in type 2 diabetes” Diabetologia 2009; DOI:10.1007/s00125-009-1440-6.

SAN FRANCISCO, June 29 — Widespread prostate cancer screening substantially increases diagnosis without much evidence for a survival benefit, a review found.

Prostate-specific antigen (PSA) screening reduced prostate cancer-specific mortality risk by a “barely significant” 20% in the best-case-scenario clinical trial evidence, Ian M. Thompson, MD, of the University of Texas Health Science Center in San Antonio, and colleagues reported in the July/Aug. issue of CA: A Cancer Journal for Clinicians.

But this small shift in lifetime risk from 3% to 2.4% came at the expense of an increase in risk of diagnosis from 6% to 9% without screening to at least 17%, and even more than 20% in a heavily screened population.

Unresolved issues with the PSA threshold also argue against the efficacy of screening, the researchers noted.

The cumulative evidence supports a recommendation against mass screening, rather than justifying its current common use in the U.S., said review co-author Otis W. Brawley, MD, of the American Cancer Society in Atlanta.

• Explain to interested patients that the review did not support routine prostate cancer screening.
• Note that the American Cancer Society and other major medical groups do not recommend routine prostate cancer screening for men at average risk.

PSA screening should only be done in a “shared decision-making” setting between individual men and their physician, he recommended in an accompanying editorial with Peter Boyle, PhD, of the International Prevention Research Institute in Lyon, France.

“For nearly two decades, testing has been based on blind faith in early detection as opposed to being based on evidence of a decrease in mortality as observed in well-designed clinical trials,” they wrote.

Although it may be hard to put the PSA-testing genie back in the bottle, they cautioned: “If we are to stem the spiraling costs of healthcare, we must move toward the use of evidence-based rather than the faith-based or profit-based practice of medicine.”

An estimated 55% of all men 50 and older get annual PSA screening, with about 75% tested at some point in their lifetime.

This has had a dramatic impact on incidence rates for prostate cancer in the U.S., as the lifetime risk of diagnosis more than doubled after introduction of screening in the 1980s (7.3% in 1977 to nearly 17% in 2005).

However, simply finding more cancers is a poor goal in prostate cancer, which is “virtually ubiquitous in men as they age,” Dr. Thompson’s group said.

The primary aim from a public health standpoint is to reduce the risk of death from prostate cancer or at least reduce its morbidity or related healthcare costs, they said.

Indeed, since 1993 — just four or five years after screening began — there has been a continual decline in the age-adjusted prostate cancer death rate from 39.3 per 100,000 to 24.6 in 2005.

But attribution bias may be at work, the researchers noted.

“The decrease in prostate cancer mortality, occurring just four to five years after screening began, is difficult to attribute to screening when dealing with a disease of such a long natural history,” Dr. Thompson’s group wrote.

Alternative explanations for some, if not most, of the decline in mortality are the significant improvements in surgery, radiation, and use of hormonal therapies during the same period as screening proliferated, they said.

Computer models suggest that 29% to 50% of screen-detected prostate cancers would not have become clinically significant and were therefore overdiagnosed.

Only about 10% of men with localized prostate cancer opt for active surveillance rather than treatment, which carries a substantial risk of sexual, urinary, and bowel complications.

“The best way to address the issue of whether prostate cancer screening saves lives is through a well-designed, well-conducted, prospective randomized clinical trial,” the investigators said.

Four have been published:

• The Quebec study found a 16% excess of deaths in men randomized to screening compared with a control group not invited to screening.
• A Swedish trial found a 47% higher rate of diagnosis and 4% higher risk of death from prostate cancer in men randomized to screening compared with those not offered screening.
• Interim analysis of the U.S. Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening trial revealed no significant difference in mortality (rate ratio 1.13 for more versus less intensive screening, 95% confidence interval 0.75 to 1.70).
• Interim analysis of the European Randomized Study of Screening for Prostate Cancer (ERSPC) revealed a mortality rate ratio 0.80 favoring screening (P=0.04) but a near doubling in incidence.

Thus in the “best case scenario” as indicated by the ERSPC, the number needed to screen was 1,410 and 48 additional cases of prostate cancer needed to be treated to prevent one prostate cancer death. (See Studies Question Regular PSA Screening)

“This means an average man who gets screened is 48 times more likely to be harmed by screening than he is to be saved by screening at nine years after diagnosis,” Drs. Brawley and Boyle noted.

And in the end, it’s unlikely that the ERSPC study will meet its primary endpoint since interim analyses have eroded its statistical power and made criteria for statistical significance more rigorous, they wrote.

Dr. Thompson reported serving as a consultant to Veridex. Dr. Brawley reported being an editor of the journal in which the review was published.

Primary source: CA: A Cancer Journal for Clinicians

Source reference:
Brawley OW, et al “Screening for prostate cancer” CA Cancer J Clin 2009; 59.

Additional source: CA: A Cancer Journal for Clinicians

Source reference:
Boyle P, Brawley OW “Prostate cancer: Current evidence weighs against population screening” CA Cancer J Clin 2009; 59.

Related Article(s):

• Studies Question Regular PSA Screening

SAN FRANCISCO, June 29 — Widespread prostate cancer screening substantially increases diagnosis without much evidence for a survival benefit, a review found.

Prostate-specific antigen (PSA) screening reduced prostate cancer-specific mortality risk by a “barely significant” 20% in the best-case-scenario clinical trial evidence, Ian M. Thompson, MD, of the University of Texas Health Science Center in San Antonio, and colleagues reported in the July/Aug. issue of CA: A Cancer Journal for Clinicians.

But this small shift in lifetime risk from 3% to 2.4% came at the expense of an increase in risk of diagnosis from 6% to 9% without screening to at least 17%, and even more than 20% in a heavily screened population.

Unresolved issues with the PSA threshold also argue against the efficacy of screening, the researchers noted.

The cumulative evidence supports a recommendation against mass screening, rather than justifying its current common use in the U.S., said review co-author Otis W. Brawley, MD, of the American Cancer Society in Atlanta.

• Explain to interested patients that the review did not support routine prostate cancer screening.
• Note that the American Cancer Society and other major medical groups do not recommend routine prostate cancer screening for men at average risk.

PSA screening should only be done in a “shared decision-making” setting between individual men and their physician, he recommended in an accompanying editorial with Peter Boyle, PhD, of the International Prevention Research Institute in Lyon, France.

“For nearly two decades, testing has been based on blind faith in early detection as opposed to being based on evidence of a decrease in mortality as observed in well-designed clinical trials,” they wrote.

Although it may be hard to put the PSA-testing genie back in the bottle, they cautioned: “If we are to stem the spiraling costs of healthcare, we must move toward the use of evidence-based rather than the faith-based or profit-based practice of medicine.”

An estimated 55% of all men 50 and older get annual PSA screening, with about 75% tested at some point in their lifetime.

This has had a dramatic impact on incidence rates for prostate cancer in the U.S., as the lifetime risk of diagnosis more than doubled after introduction of screening in the 1980s (7.3% in 1977 to nearly 17% in 2005).

However, simply finding more cancers is a poor goal in prostate cancer, which is “virtually ubiquitous in men as they age,” Dr. Thompson’s group said.

The primary aim from a public health standpoint is to reduce the risk of death from prostate cancer or at least reduce its morbidity or related healthcare costs, they said.

Indeed, since 1993 — just four or five years after screening began — there has been a continual decline in the age-adjusted prostate cancer death rate from 39.3 per 100,000 to 24.6 in 2005.

But attribution bias may be at work, the researchers noted.

“The decrease in prostate cancer mortality, occurring just four to five years after screening began, is difficult to attribute to screening when dealing with a disease of such a long natural history,” Dr. Thompson’s group wrote.

Alternative explanations for some, if not most, of the decline in mortality are the significant improvements in surgery, radiation, and use of hormonal therapies during the same period as screening proliferated, they said.

Computer models suggest that 29% to 50% of screen-detected prostate cancers would not have become clinically significant and were therefore overdiagnosed.

Only about 10% of men with localized prostate cancer opt for active surveillance rather than treatment, which carries a substantial risk of sexual, urinary, and bowel complications.

“The best way to address the issue of whether prostate cancer screening saves lives is through a well-designed, well-conducted, prospective randomized clinical trial,” the investigators said.

Four have been published:

• The Quebec study found a 16% excess of deaths in men randomized to screening compared with a control group not invited to screening.
• A Swedish trial found a 47% higher rate of diagnosis and 4% higher risk of death from prostate cancer in men randomized to screening compared with those not offered screening.
• Interim analysis of the U.S. Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening trial revealed no significant difference in mortality (rate ratio 1.13 for more versus less intensive screening, 95% confidence interval 0.75 to 1.70).
• Interim analysis of the European Randomized Study of Screening for Prostate Cancer (ERSPC) revealed a mortality rate ratio 0.80 favoring screening (P=0.04) but a near doubling in incidence.

Thus in the “best case scenario” as indicated by the ERSPC, the number needed to screen was 1,410 and 48 additional cases of prostate cancer needed to be treated to prevent one prostate cancer death. (See Studies Question Regular PSA Screening)

“This means an average man who gets screened is 48 times more likely to be harmed by screening than he is to be saved by screening at nine years after diagnosis,” Drs. Brawley and Boyle noted.

And in the end, it’s unlikely that the ERSPC study will meet its primary endpoint since interim analyses have eroded its statistical power and made criteria for statistical significance more rigorous, they wrote.

Dr. Thompson reported serving as a consultant to Veridex. Dr. Brawley reported being an editor of the journal in which the review was published.

Primary source: CA: A Cancer Journal for Clinicians

Source reference:
Brawley OW, et al “Screening for prostate cancer” CA Cancer J Clin 2009; 59.

Additional source: CA: A Cancer Journal for Clinicians

Source reference:
Boyle P, Brawley OW “Prostate cancer: Current evidence weighs against population screening” CA Cancer J Clin 2009; 59.

Related Article(s):

• Studies Question Regular PSA Screening