Winner's curse: The sad aftermath of the discovery of insulin.

Every young researcher dreams of making a great discovery, but few achieve it. If they do, success does not guarantee happiness. There is little satisfaction in discovering something if others get the credit, and those who achieve fame must face the 'winner's curse' of living up to their reputation. Few discoveries have been more dramatic than the isolation of insulin which, as Michael Bliss said, resembled a secular miracle. And yet, as he also pointed out, this great discovery brought little happiness to those who made it. Some were sidelined, and Banting and Best were saddled with the winner's curse. Here, we look at the ways in which a great discovery can haunt its discoverers.

Productivity of authors in the field of diabetes: bibliographic analysis of trial publications.

OBJECTIVE: To determine whether trial publications of glucose lowering drugs are dominated by a small group of highly prolific authors ("supertrialists") and to identify some of their characteristics. DESIGN: Bibliographic analysis of trial publications. DATA SOURCES AND REVIEW METHODS: We searched PubMed for all randomised controlled trials (RCTs) relating to glucose lowering drugs published between 1 January 1993 and 31 December 2013. From these publications we identified the 110 most prolific authors using PubReMiner. The 991 RCTs they published were examined for various characteristics such as author number, commercial sponsorship, company authorship, conflicts of interest, etc. The track record of the top 11 authors was studied in more detail. MAIN OUTCOME MEASURE: Proportion of articles published by the top 110 and the top 11 authors. RESULTS: 3782 articles from 13,592 authors were identified. The top 110 authors were named in 1227 (32.4%) of all articles, and the top 11 authors in 397 (10.5%) of all articles. The top 110 authors published 991 RCTs for a median of 20 (range 4-77) RCTs per author; the top 11 published 354 RCTs for a median of 42 (36-77) RCTs per author. Of the 110 top authors, 48 were employed by a pharmaceutical company. Of the 991 RCTs, 906 were commercially sponsored. Of 704 articles that could be assessed for conflicts of interest, only 42 (6%) were considered fully independent. Medical writing assistance was acknowledged in 439 (44.3%) of 991 RCTs. CONCLUSION: The past two decades have seen an explosive increase in the number of published clinical trials regarding glucose lowering treatment. Some authors have made a disproportionate contribution to the therapeutic evidence base; one third of the RCT evidence base on glucose lowering drug treatment for diabetes was generated by <: 1% of authors. Of these, 44% were company employees and 56% were academics who work closely with the pharmaceutical companies.

Smoke or fire? Acute pancreatitis and the liraglutide trials.

Over the past few years, substantial clinical data have been presented showing that incretin-based therapies are effective glucose-lowering agents. Specifically, glucagon-like peptide 1 receptor agonists demonstrate an efficacy comparable to insulin treatment with minimal hypoglycemia and have favorable effects on body weight. Thus, many of the unmet clinical needs noted from prior therapies are addressed by these agents. However, even after many years of use, many continue to raise concerns about the long-term safety of these agents and, in particular, the concern with pancreatitis. This clearly remains a complicated topic. Thus, in this issue of Diabetes Care, we continue to update our readers on this very important issue by presenting two studies evaluating incretin-based medications and risk of pancreatitis. Both have undergone significant revisions based on peer review that provided significant clarification of the data. We applaud both author groups for being extremely responsive in providing the additional data and revisions requested by the editorial team. As such, because of the critical peer review, we feel both articles achieve the high level we require for Diabetes Care and are pleased to now present them to our readers. In keeping with our aim to comprehensively evaluate this topic, we asked for additional commentaries to be prepared. In the narrative outlined below, Prof. Edwin A.M. Gale provides a commentary on the report that focuses on clinical trials of liraglutide in the treatment of diabetes. In the narrative that follows Prof. Gale's contribution, Dr. Laurent Azoulay provides a commentary about the remaining uncertainty in this area and also discusses the results from a nationwide population-based case-control study. From the journal's perspective, both of the articles on pancreatitis and incretin-based therapies reported in this issue have been well vetted, and we feel both of the commentaries are insightful.

A critical analysis of the clinical use of incretin-based therapies: Are the GLP-1 therapies safe?

There is no question that incretin-based glucose-lowering medications have proven to be effective glucose-lowering agents. Glucagon-like peptide 1 (GLP-1) receptor agonists demonstrate an efficacy comparable to insulin treatment and appear to do so with significant effects to promote weight loss with minimal hypoglycemia. In addition, there are significant data with dipeptidyl peptidase 4 (DPP-4) inhibitors showing efficacy comparable to sulfonylureas but with weight neutral effects and reduced risk for hypoglycemia. However, over the recent past there have been concerns reported regarding the long-term consequences of using such therapies, and the issues raised are in regard to the potential of both classes to promote acute pancreatitis, to initiate histological changes suggesting chronic pancreatitis including associated preneoplastic lesions, and potentially, in the long run, pancreatic cancer. Other issues relate to a potential risk for the increase in thyroid cancer. There are clearly conflicting data that have been presented in preclinical studies and in epidemiologic studies. To provide an understanding of both sides of the argument, we provide a discussion of this topic as part of this two-part point-counterpoint narrative. In the point narrative below, Dr. Butler and colleagues provide their opinion and review of the data to date and that we need to reconsider the use of incretin-based therapies because of the growing concern of potential risk and based on a clearer understanding of the mechanism of action. In the counterpoint narrative following the contribution by Dr. Butler and colleagues, Dr. Nauck provides a defense of incretin-based therapies and that the benefits clearly outweigh any concern of risk.

Mortality after incident cancer in people with and without type 2 diabetes: impact of metformin on survival.

OBJECTIVE: Type 2 diabetes is associated with an increased risk of several types of cancer and with reduced survival after cancer diagnosis. We examined the hypotheses that survival after a diagnosis of solid-tumor cancer is reduced in those with diabetes when compared with those without diabetes, and that treatment with metformin influences survival after cancer diagnosis. RESEARCH DESIGN AND METHODS: Data were obtained from >350 U.K. primary care practices in a retrospective cohort study. All individuals with or without diabetes who developed a first tumor after January 1990 were identified and records were followed to December 2009. Diabetes was further stratified by treatment regimen. Cox proportional hazards models were used to compare all-cause mortality from all cancers and from specific cancers. RESULTS: Of 112,408 eligible individuals, 8,392 (7.5%) had type 2 diabetes. Cancer mortality was increased in those with diabetes, compared with those without (hazard ratio 1.09 [95% CI 1.06-1.13]). Mortality was increased in those with breast (1.32 [1.17-1.49]) and prostate cancer (1.19 [1.08-1.31]) but decreased in lung cancer (0.84 [0.77-0.92]). When analyzed by diabetes therapy, mortality was increased relative to nondiabetes in those on monotherapy with sulfonylureas (1.13 [1.05-1.21]) or insulin (1.13 [1.01-1.27]) but reduced in those on metformin monotherapy (0.85 [0.78-0.93]). CONCLUSIONS: This study confirmed that type 2 diabetes was associated with poorer prognosis after incident cancer, but that the association varied according to diabetes therapy and cancer site. Metformin was associated with survival benefit both in comparison with other treatments for diabetes and in comparison with a nondiabetic population.

Therapy: The second time as farce: rosiglitazone and the regulators.

Rosiglitazone is the second of the marketed thiazolidinediones to fall from grace, and its demise bears an uncanny resemblance to the earlier downfall of troglitazone. Both narratives demonstrate the inadequacy of a regulatory system that is mandated to place a higher value on commercial secrecy than on patient safety.