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EndocrinologyUpdate Endocrinology News from Mayo Clinic Vol. 6, No. 4, 2011 The Knowledge Synthesis Program INSIDE THIS ISSUE The Knowledge Synthesis Program, part of the incidentalomas, growth hormone deficiency, Knowledge and Evaluation Research (KER) Unit hyperaldosteronism, pediatric obesity, hirsutism, of the Division of Endocrinology at Mayo Clinic Cushing syndrome, hyperprolactinemia, and 2 Type 2 Diabetes in Rochester, Minnesota, is an active research transgender care.” and Cardiovascular program providing methodologic support to the The KER Unit team is led by M. Hassan Disease: Managing Endocrine Society Clinical Practice Guidelines Murad, MD, MPH, of the Division of Preventive One to Prevent the Other Subcommittee. Victor M. Montori, MD, MSc, of Medicine at Mayo Clinic in Rochester, and Dr the Division of Endocrinology, Diabetes, Metabo- Montori. The team includes experienced refer- lism, and Nutrition at Mayo Clinic in Rochester, ence librarians, endocrinology staff, clinical and 4 Multifactorial Basis says: “The Knowledge Synthesis Program has sup- research fellows, research assistants, and col- for Age-Associated ported numerous clinical practice guidelines over laborators who provide additional expertise in Hypoandrogenemia the past 5 years, assisting task force members with research or guideline methods or in endocrinol- in Men formulating evidence-based recommendations ogy. Dr Murad explains: “The program follows for the care of patients with diabetes mellitus, rigorous procedures that start with developing congenital adrenal hyperplasia, male hypogonad- protocols for the systematic reviews needed to 6 Clinical Guidelines ism, osteoporosis, vitamin D deficiency, pituitary support guideline panels. Systematic reviews seek for Hyperthyroidism The KER Unit team. Standing, left to right: Juan Pablo Domecq Garces, MD, Gabriela J. Prutsky Lopez, MD, Victor M. Montori, MD, MSc, Kasey R. Boehmer, Tarig A. Elraiyah, MBBS, and Rim R. Hasan, MD. Seated, left to right: Mohammed Nabhan, MD, M. Hassan A. Murad, MD, MPH, and Belal M. Firwana, MD. to provide summaries of the existing research premed students to experienced faculty—have evidence, identifying best estimates of association, gained the insights and knowledge that can help diagnostic test performance, or treatment effect, them form a better understanding of evidence- and explanations for between-study differences in based endocrinology. Over the years, several results. Extensive discussion leads to the definition Mayo Clinic residents, fellows, and consultants of the population target of the recommendations have participated in the program and fulfilled this and the interventions and outcomes that need educational goal.” to undergo formal synthesis. Librarians conduct He continues: “The knowledge synthesis exer- comprehensive literature searches that span cises also expose our investigators to the compli- multiple databases. The team of investigators cated situation of intellectual interest and financial selects the relevant studies on the basis of strict relations that cloud the objectivity of our field’s criteria and extracts data from the individual stud- experts. For example, our group reported that ies, which are often reanalyzed as a whole body many of the expressed expert opinions regarding of evidence, in a process called meta-analysis. The the safety of rosiglitazone were strongly associ- team evaluates the quality of the evidence follow- ated with their financial relations with the relevant ing a state-of-the-art framework—the Grades of drug company. Whether this association resulted Recommendation, Assessment, Development, and from or led to the opinion of the expert can only Evaluation (GRADE) approach—and presents be speculated. We have also uncovered chal- the results to the guidelines panel. The system- lenges with the credibility of research assessing atic reviews are usually published alongside the the effect of treatments on biochemical measures guidelines.” that, while objective, bear unclear relation with The Knowledge Synthesis Program supports the effect of these treatments on outcomes that several other professional societies and organiza- matter to patients, such as living longer, feeling tions (all not-for-profit; the KER Unit does not better, or being able to pursue one’s goals without receive funding from for-profit pharmaceutical or hindrance from health or health care.” device corporations). The program has secured Dr Murad concludes: “Much more work lies multiple grants to maintain its operations, ahead. With many reviews identifying that the infrastructure, and goals since 2005. Dr Murad evidence base to answer many common endocri- highlights: “Our fundamental goal is to provide an nology questions remains at high risk of bias and unbiased summary of the best available evidence very sparse, the KER Unit reviews offer a virtual to decision makers (clinicians and guideline list of important research questions that must developers) and assist them in incorporating this be answered to better the value of care for our evidence into recommendations that are useful patients. Also, much education work remains to and clear.” promote practices that reflect not only the state Dr Montori explains: “The Knowledge Syn- of the evidence, but also the context, values, and thesis Program has an important secondary goal: preferences of the informed patient. Indeed, many education. The tasks of developing reviews and practices appear to reflect physician training or assisting in the formulation of useful and clear the effects of product marketing. Finally, endocri- recommendations offer opportunities for highly nologists must come to terms with the resource motivated individuals. Through a formal men- implications of their recommendations.” torship program, many such individuals—from Type 2 Diabetes and Cardiovascular Disease: Managing One to Prevent the Other The prevalence of type 2 diabetes mellitus (T2DM) cemia was the mediator of all of the complications is increasing inexorably in Western countries of diabetes, many studies undertaken over the past and developing nations. Epidemiological studies half century have cast doubt on this notion. This indicate that one-half to three-quarters of people research indicates that many factors, including with T2DM are destined to die of cardiovascular hypertension, dyslipidemia, and a prothrombotic events and their sequelae. However, considerable state, contribute to the increased cardiovascular controversy exists concerning the mediators of this risk of type 2 diabetes.” increased risk and whether treatment can reduce The nonischemic cardiomyopathy that occurs the risk. John M. Miles, MD, of the Division of in T2DM is an area of increasing interest to Endocrinology, Diabetes, Metabolism, and Nutri- investigators. Ananda Basu, MD, of the Division of tion at Mayo Clinic in Rochester, Minnesota, says: Endocrinology, Diabetes, Metabolism, and Nutri- “Although early scientists assumed that hypergly- tion at Mayo Clinic in Rochester, explains: “The 2 MAYO CLINIC | EndocrinologyUpdate notion that fatty heart (the accumulation of lipid in regulator of renal tubu- the heart muscle, analogous to fatty liver) is a com- lar sodium metabolism, mon occurrence in obesity and type 2 diabetes and promoting sodium mediates diastolic dysfunction leading, in some retention. These cases, to overt heart failure has gained credence observations explain, in in recent years on the basis of results from animal part, why the American and human studies. There is virtually no informa- Diabetes Association tion on the effect of diabetes pharmacotherapy on recommends metfor- this phenomenon.” min as first-line therapy Before 1995, pharmacological treatment of for type 2 diabetes.” T2DM in the United States was limited to insulin Dr Basu says: and sulfonylurea agents. Dr Miles notes: “Since “Other classes of that time, numerous new agents with unique and diabetes agents, disparate mechanisms of action have become such as thiazolidine- available. It is now clear that there are marked diones (TZDs) and differences among agents in their nonglycemic -glucosidase inhibi- Ananda Basu, MD, and John M. Miles, MD effects, with potential implications regarding car- tors, have been shown diovascular risk reduction.” The differences among to have favorable effects on cardiovascular out- these agents are summarized in the Table. comes in some clinical trials, although results are The UK Prospective Diabetes Study dem- inconsistent. TZDs (specifically, pioglitazone) lower onstrated that insulin provision therapy in the blood pressure and decrease PAI-1, improve dys- form of either insulin or sulfonylureas produced lipidemia and endothelial function, and induce a a statistically significant (P=.01), but somewhat favorable redistribution of body fat. -Glucosidase disappointing (~15%), reduction in the incidence inhibitors lower blood pressure and decrease low- of myocardial infarction, durable over 20 years density lipoprotein cholesterol (and in some stud- of follow-up. Dr Miles explains: “The same study ies also lower triglyceride levels), improve endo- showed a one-third reduction in myocardial thelial function, and promote modest weight loss. infarction with metformin over 20 years. The Although improvements in forearm endothelial differences between the modest benefit of insulin function have been shown with acute administra- provision and the more robust effect of metformin tion of glucagonlike peptide 1 (GLP-1) and GLP-1 could not be explained