Background/Objectives Routine use of vitamin D supplements has increased substantially in the United States. However, the safety and tolerability of long-term use of high-dose vitamin D are not known. We assessed the safety and tolerability of high-dose, daily vitamin D 3 in the vitamin D and type 2 diabetes (D2d) study. Subjects/Methods In total, 2423 overweight/obese persons with prediabetes were randomized in a double-blind manner to either 4000 IU of vitamin D 3 (the tolerable upper intake level for adults by the National Academy of Medicine) taken daily or matching placebo. All participants were included in this analysis. Incident adverse events (AE) were ascertained 4 times a year at in-person visits (twice a year) and interim remote encounters (twice a year) and were defined as untoward or unfavorable medical occurrences. Serious adverse events (SAE) included death, life-threatening events, and hospitalizations. Results A total of 8304 AEs occurred during 3 years of follow-up and were less frequent in the vitamin D group compared to placebo (Incidence Rate Ratio [IRR] = 0.94; 95% Confidence Interval (CI) 0.90, 0.98). The overall frequency of protocol-specified AEs of interest, which included nephrolithiasis, hypercalcemia, hypercalciuria, or low estimated glomerular filtration rate, was low and did not differ by group. There were no significant between-group differences in total SAEs (IRR = 0.96 (0.81, 1.14)). Conclusion Vitamin D 3 supplementation at 4000 IU per day was safe and well tolerated among overweight/obese participants at high risk for diabetes who were appropriately monitored for safety. In this population, this dose of vitamin D 3 did not increase risk of AEs or SAEs, including those previously associated with vitamin D such as hypercalcemia, hypercalciuria, or nephrolithiasis. Clinical Trial Registration ClinicalTrials.gov NCT01942694, prospectively registered September 16, 2013

The routine use of vitamin D supplements has increased substantially in the United States. However, the safety and tolerability of long-term use of high-dose vitamin D are unknown. We assessed the safety and tolerability of vitamin D3 at a dose of 4000 IU daily in the vitamin D and type 2 diabetes (D2d) trial. Persons with overweight/obesity and prediabetes without a recent history of nephrolithiasis, hypercalcemia, hypercalciuria, or other conditions potentially associated with vitamin D use, were randomized to either daily 4000 IU of vitamin D3 or placebo. Participants were allowed to take vitamin D up to 1000 IU/day and calcium up to 600 mg/day, in addition to study medication. Incident adverse events (AE), defined as any untoward or unfavorable medical occurrence, were ascertained in both groups at in-person visits and interim phone or email encounters four times a year. Serious AEs (SAE) were defined as those AEs that resulted in death, new or prolonged hospitalization, persistent or significant disability, or congenital anomaly or birth defect, or were life threatening or represented another significant hazard. A total of 8,304 AEs occurred during three years of follow-up. AEs were less frequent in the vitamin D group compared to placebo [4039 (116.1 events per 100 person-years) vs. 4265 (123.8 events per 100 person-years) (Incidence Rate Ratio [IRR] = 0.94; 95% Confidence Interval (CI) 0.90, 0.98)]. The overall frequency of protocol-specified AEs of interest was low, including nephrolithiasis, hypercalcemia, hypercalciuria, and low estimated glomerular filtration rate (eGFR) with no significant between-group differences. There were also no significant differences between the vitamin D and placebo groups in SAEs (IRR = 0.95; 95% CI 0.81, 1.13). Vitamin D3 supplementation at 4,000 IU per day was safe and well-tolerated and did not increase risk of AEs or SAEs, including those typically associated with vitamin D excess such as hypercalciuria or nephrolithiasis. National Institute of Diabetes and Digestive and Kidney Diseases, Office of Dietary Supplements of the National Institutes of Health, the American Diabetes Association.

The benefit/risk ratio of GH use presented by Brown and Bauer (1) in their review encompass more than three decades. The information for GH us is solid but there is no data for recommending IGF-I use in CKD. Its main reference (2) is from the founder and chief technical officer the company that commercialized IGF-I, lacking any human data to support the use of IGF-I in this population questioning the validity of this endorsement. In 2005 IGF-I was approved in the US for the long-term treatment of growth failure in children with severe primary IGF-1 deficiency or with GH gene deletion who have developed neutralizing antibodies to GH. Sixteen years have elapsed since and during this time four additional studies have been reported in clincilatrials.gov (3) and launched to explore the effects of IGF-I alone or in combination with GH in children with short stature of different etiologies. None of these studies included patients with CKD. The largest study, Treatment of Children and Adolescents with Growth Failure Associated with Primary IGF-1 Deficiency, was terminated by the sponsor “due to an unacceptably high incidence of hypoglycemia observed in approximately 50% of the subjects receiving 200 μg/kg rhIGF-1 or greater QD.” (3) Although the rationale for the dose escalation that almost doubled the original selection in successive amendments, is unknow to me, one can speculate that this was triggered by the desire to induce a more potent growth response given the well-known limited ability of IGF-I to stimulate growth acceleration-the end point of the study-, when compared with GH. It is worth highlighting that CKD associated short stature has received an orphan drug designation by the US FDA. As a result, the incentives for commercialization, given the high price of this drug, are extremely enticing. Additionally, FDA approval for rare conditions for a drug that is commercially available may have a lower hurdle. Moreover, an IGF-I indication for CKD has an enormous potential for profit given that CKD is much more prevalent (~10,000 patients in the US alone) than the only current limited indication (in the hundreds worldwide). In this context, I will argue that given the lack of any data showing benefit in children using IGF-I for CKD and the paucity of reliable scientific information in this area, it may be more appropriate not to advocate for the use of IGF-I for this purpose until data from human studies are generated

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Aims: Determine the prevalence of glucocorticoid use in U.S. adults with diabetes and whether prevalence is associated with reduced skeletal health, as measured by fracture history and bisphosphonate use.Methods: Participants were age 2 20 years from the cross-sectional National Health and Nutrition Examination Survey (1999-2010; N = 15,661). Diabetes was determined by self-report, fasting plasma glucose 2126 mg/dL (26.99 mmol/L), or Alc 26.5% (247.5 mmol/mol) (n = 4539). Prevalences of fractures and bisphosphonate use were determined by diabetes status and glucocorticoid use. Logistic regression was stratified by sex and assessed the effect of glucocorticoid use and diabetes associated with fractures and bisphosphonates.Results: The age-standardized prevalence of glucocorticoid use was higher among persons with diabetes (3.2% vs. 2.0% without diabetes, p = 0.001). Among adults with diabetes, the prevalence of fractures was significantly higher among those taking glucocorticoids vs. those not (38.3% vs. 26.1%, p = 0.048). The prevalences of fractures and bisphosphonate use were generally similar in those with and without diabetes when stratified by glucocorticoid use. In logistic regression analysis among men, the combination of diabetes and glucocorticoid use (compared to those with neither) was highly associated with bisphosphonate use, while adjusting for demographic factors. Among women, having diabetes and glucocorticoid use increased the odds of fractures, while adjusting for demographic factors and menopause.Conclusions: The prevalence of fractures was greater for those with diabetes taking glucocorticoids versus those not taking glucocorticoids. This study provides a national framework for further research on elucidating these associations. (C) 2017 Elsevier Inc. All rights reserved.

Although randomized controlled studies are considered the “gold standard” to assess efficacy and safety, this approach is not always practical to ascertain long-term safety. To better define emerging safety signals, particularly for products already on the market, we mostly rely on observational studies. However, we are cognizant that all observational studies suffer from a critical deficiency: the design is not an experimental one. Because each patient's treatment is deliberately chosen rather than randomly assigned, the risk of selection bias is unavoidable. As a result, systematic differences in outcomes may not be due to the treatment itself. Although methods to adjust for identifiable differences are available, it is impossible to be certain that such adjustments are sufficient or whether they address all patients' relevant characteristics. Estimates of the magnitude of the treatment effect and on the generalizability of the findings are therefore imprecise. All these caveats apply to any observational study. Observational studies do not definitively answer a question, but rather generate hypotheses that need to be further explored with additional studies. Questions regarding the short- and long-term safety of GH have been gaining attention due to the expansion of GH indications and the use of increased dosages. In this issue of the JCEM, Carel et al. (1) report the results of a longitudinal follow-up study of subjects receiving GH where they ascertained its long-term effects on mortality. By 2009, after a mean follow-up of 17.3 yr, they were able to determine the vital status of about 95% of approximately 7000 subjects who received GH in France. Indications for GH varied, but 75% were labeled as idiopathic GH deficient (IGHD), 11.5% as idiopathic short stature, 8% as having a GH neurosecretory disorder, and 5.5% as small for gestational age. Ninety-three subjects died. Eighty-six deaths occurred after GH discontinuation, but six occurred while on active treatment. All-cause mortality was 33% higher than expected when compared with the general population. This increase was attributed to a higher than expected number of bone tumors, as well as subarachnoid and intracerebral hemorrhages. The increases were not associated with any other types of cancer. Doses in excess of 50 μg/kg·d were strongly associated with the increase in mortality. Significance was seen only after 15 yr of follow-up. Analyses at 5 and 10 yr did not show a significant increase in mortality compared with the general population. Shorter children at baseline and males were at increased risk, as well as those with more robust responses to provocative tests. The strengths of this study (1) include the balanced review and fair presentation of the information; the extent of the data, including diagnoses, dosages, time of exposure, and long-term follow-up; the attempts to ascertain in depth causes of death; and the use of internal and external controls. A major weakness of this study (1) is the lack of efficacy data. We do not know how these subjects responded to the treatment. Other limitations are related to the inability to identify and secure an appropriate short stature comparator, the lack of data on growth velocity before GH was administered, the absence of IGF-I levels before and during GH, the small number of events, and the significant amount of missing data, particularly in the ascertainment of cause of death in 22% of cases. The mean age at the time of censoring was less than 30 yr, and it is unknown whether the encountered trend will continue or disappear with passage of time. The number of females may be too small to detect any effect in this group. Many of these shortcomings were recognized by the authors, and attempts to address them were made. Each of these deficiencies, however, opens the door to alternative explanations. It is important to stress that the difficulties facing these authors are common in the field, and that investigators undertaking this sort of project are likely to encounter similar barriers.

Hypoglycemia is a common complication of diabetes treatment. This paper describes symptoms, predecessors, consequences and medications associated with the first episode of severe hypoglycemia among ACCORD participants with type 2 diabetes, and compares these between intensive (Int: goal A1C <6.0%) and standard (Std, goal A1C 7–7.9%) glycemia intervention groups.

Although common themes permeate the environment across continents and particular divergences as to how to proceed exist between different regulatory agencies, it seems that policies are still in flux. Not all policies will suffice to fit all dissimilar biologics, and these in place or being developed may, in turn, change to accommodate new or unexpected developments. Consideration for accelerated approval for those compounds that do not present complex questions should be considered.The regulatory agencies should be more forthcoming, the industry sector exercise social responsibility, and the public should have realistic expectations.

OBJECTIVE Randomized treatment comparing an intensive glycemic treatment strategy with a standard strategy in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial was ended early because of an unexpected excess of mortality in the intensive arm. As part of ongoing post hoc analyses of potential mechanisms for this finding, we explored whether on-treatment A1C itself had an independent relationship with mortality. RESEARCH DESIGN AND METHODS Participants with type 2 diabetes (n = 10,251 with mean age 62 years, median duration of diabetes 10 years, and median A1C 8.1%) were randomly assigned to treatment strategies targeting either A1C <6.0% (intensive) or A1C 7.0–7.9% (standard). Data obtained during 3.4 (median) years of follow-up before cessation of intensive treatment were analyzed using several multivariable models. RESULTS Various characteristics of the participants and the study sites at baseline had significant associations with the risk of mortality. Before and after adjustment for these covariates, a higher average on-treatment A1C was a stronger predictor of mortality than the A1C for the last interval of follow-up or the decrease of A1C in the first year. Higher average A1C was associated with greater risk of death. The risk of death with the intensive strategy increased approximately linearly from 6–9% A1C and appeared to be greater with the intensive than with the standard strategy only when average A1C was >7%. CONCLUSIONS These analyses implicate factors associated with persisting higher A1C levels, rather than low A1C per se, as likely contributors to the increased mortality risk associated with the intensive glycemic treatment strategy in ACCORD.

Addressing the dissimilar toxicities of the two most commonly used antithyroid medications, propylthiouracil (PTU) and methimazole (MMI), and focusing particularly on hepatotoxicity and death in children, Rivkees and Szarfman bring to the forefront an issue that time and time again has fallen off our radar screen: the use of PTU can result in tragic consequences and should never be used in children (1). The same statement could be made for adults, with the exception of use during early pregnancy when PTU use may avoid the potential for fetal malformations that may occur with MMI (2). However, the MMI teratogenic link seems tenuous. Rivkees and Szarfman (1) provide an in-depth history of these drugs and recount their well-known similar and distinct mechanisms of action. More importantly, using an elegant methodological approach focused on data mining, they underscore the following central issues. PTU is identified as being the third most frequent cause of drug-induced liver transplant in the United States (3), and administration can lead to severe liver injury and death. This seems clearer in children, and the rate is 17 times higher than the expected rate of liver failure in those not exposed. In the 40-yr period reviewed in Ref. 1, 14 of 23 (33%) cases of death from liver disease after PTU administration were in pediatric patients. In addition to causing fatal liver disease, PTU is also linked to a greater risk of vasculitis; glomerulonephritis and associated positive titers of antineutrophil cytoplasmatic antibody are 50 times higher than expected. However, these complications are generally clinically mild. MMI can also induce liver toxicity, but these effects are milder, confined to cholestasis, not associated with liver failure, and more frequent in people older than 61 yr of age. In children, in addition to the risk of liver failure, mild liver injury associated with PTU is four times higher than with MMI. As in most drug-induced hepatotoxicity, there are no effective tests or means to predict or prevent serious complications. With PTU, complications can occur at any time during treatment and are not dose related. Because many other therapeutic modalities are available that do not result in these complications, the recommendation that PTU should not be used in children seems crystal clear. The information provided in the article by Rivkees and Szarfman (1) complements the report by Emiliano et al. (4) on PTU and MMI, which appeared in the April issue of JCEM and describing prescription practices for MMI and PTU in the United States between 1998 and 2008, showing substantial increases in the use of these drugs. A shift from PTU to MMI as the most common antithyroid drug occurred in 1996 and has led to MMI dominance of the market; the authors speculate that this may have been fueled by the availability of a generic version of MMI. Women were prescribed PTU more frequently than were men. The only group where MMI use was lower was in females of childbearing age. The authors suggest that this tendency may be due to the previously described potential for fetal malformations associated with MMI during pregnancy. Data from this article also suggest that the use of other modalities for the initial treatment of hyperthyroidism—radioactive iodine and/or surgery—have been displaced by the use of these medications. Of concern is that these data indicate that in 22% of patients receiving antithyroid medication PTU continues to be used as the drug of first choice and that this rate has remained unchanged in the period studied, keeping the unease about hepatic toxicity unabated. These articles allow us to debunk the characterization that PTU liver damage is rare. In the absence of adequate data to properly assess drug use, the term “rare” properly suggests to the prescribing physician that complications may never occur. This mistaken message may, in turn, be conveyed to the patient. Data from the first article (1) indicate that the risk of severe liver damage in pediatric patients receiving PTU is quite alarming. Of concern is that a drug that is prescribed to a very limited number of patients is listed as the third cause of drug-induced liver transplantation, secondary to any medications in the United States. This puts this the term “rare complications” in a completely different light. The hope of Rivkees and Szarfman, Emiliano, and their co-workers is that the knowledge gained from these important studies will lead to a more restrictive use of PTU. It is important to note that, as stated by the authors, PTU-induced liver toxicity was recognized soon after this medication was introduced in 1947, and cases of liver injury have occurred year after year (5). How then it is possible that it took more than 60 yr to incorporate a black box into its label? Although it is impossible to properly answer this question, and we can only speculate, many factors contributed to the “hidden” hepatotoxicity signal. The process by which drugs were reviewed when these medications were introduced to the market more than six decades ago had different and less stringent requirements. Even if studies for approval were performed under current standards, it is very difficult to address rare events like severe hepatotoxicity, given that the conditions they treat are rare. One example of these rare conditions is hyperthyroidism in children. Because of the availability of different treatment modalities for hyperthyroidism, large series addressing a single pharmacological agent to treat it, both in children and adults, are usually retrospective analyses and seldom include more than 100 subjects. For complications that may occur in 1 of 2000 exposed individuals, the universe for a case to emerge would be approximately 6000 patients (6). Even if it were feasible to power a study to detect this problem, executing the study at the present time would be unethical. We believe that the most experienced pediatric thyroidologists and even the busiest centers in the world may never see in excess of hundreds of children that may need antithyroid drugs. Given that cases of liver damage are infrequent and that there is not a sophisticated database for patients over age 40, it would have been difficult to compile and analyze emerging information that may have resulted in labeling changes. In addition, the well-known level of underreporting of adverse events (7), particularly in children (8), further increased our inability to put all of the events filed throughout the years into the proper perspective and trigger a regulatory action. Given all of these variables, it is easy to understand how the PTU liver toxicities were never addressed before. Dr. Ana Szarfman has been working for years on mining the adverse event report system using algorithms that allow for ascertainment of rare and common events in an unbiased manner for many drugs undergoing preapproval evaluations as well as those already on the market (9,10). The partnership with Scott Rivkees was triggered by his suspicions that the liver complications were more common than initially thought and should be characterized as “common” rather than “rare.” Nevertheless, many barriers needed to be overcome. Because the system relies on spontaneous reports, mostly provided by health care professionals, these reports are compiled under numerous and distinct labels, although they may reporting an identical event. The first step was to assess which events fit where and whether they all met the same definitions. Once this was done, the number of events was compared to what is expected in the general population. This comparison ability is built into the mining process. The results that are conveyed in the Rivkees and Szarfman report (1) were previously reviewed by many stakeholders from numerous private and government institutions including, among others, representatives of numerous Food and Drug Administration (FDA) offices, the National Institute for Child Health and Human Development, the National Institute for Diabetes and Digestive and Kidney Diseases, and the United Network for Organ Sharing, as well as the Lawson Wilkins Pediatric Endocrine Society, The Endocrine Society, and the American Thyroid Association (ATA) at a special workshop that was held under the sponsorship of the Best Pharmaceuticals for Children Act (BPCA) on October 28, 2008 and at a meeting jointly sponsored by the FDA and the ATA on April 18, 2009 (11). These discussions underscored the presence of these severe events and in turn led to a thoughtful reassessment by the FDA and the addition of a black box into the label (12). Approximately 2 yr of hard work were needed to bring the safety alert related to PTU-induced hepatotoxic to generalized attention. Hopefully, this information will put an end to the continued prescribing of PTU other than as needed in pregnancy. In turn, this information should encourage the selection of alternative therapies for the treatment of hyperthyroidism, particularly in children. Equally as important as the uncovering of the PTU hepatotoxicity problem are the lessons learned in the process. The role of individual clinicians reporting drug-induced adverse events and reporting them to manufacturers and the FDA should be reemphasized. Without this information, the regulatory agencies cannot update their knowledge and in turn enhance our ability to safely prescribe medications. These experiences also teach us that close relationships among prescribers, academic organizations, and federal agencies can promote drug safety. Finally, the value of investing in the application of modern new computer-based methodology that can monitor and link prescribing and adverse event data is clearly apparent.

Background: Fifteen percent of small for gestational age (SGA) children remain short and undergo thyroid axis evaluations. Methods: We analyzed data on thyroid assessment of 58 SGA children. Five had primary autoimmune hypothyroidism. In the remaining 53 patients, TSH, free T4 (FT4), antithyroid antibodies and 90-min TRH test results were analyzed. Patients were grouped into G1 (n = 27; normal) and G2 (n = 26; abnormal) according to their response to the TRH test compared with 30 normal children. Results: No differences were found in chronological age, gestational age, or birth weight standard deviation score (SDS) between groups. G2 showed higher SDS BMI at consultation (p < 0.05). FT4 (ng/dl) levels were similar in all groups, while basal TSH levels were statistically different in G2 compared with G1 and controls. In 21 G2 patients treated with thyroxine, FT4 levels did not change, TSH normalized, BMI SDS and height remained unchanged. Conclusion: These data suggest that in SGA short children thyroid abnormalities may occur. Some of them may be due to a different setting of the hypothalamic-hypophyseal-thyroid axis during intrauterine life. Intrauterine growth retardation may permanently influence endocrine systems by affecting their programming during development. Further follow-up is needed to confirm these findings and to assess their natural history and potential clinical impact.

In the past decade, the number of medications to treat osteoporosis has markedly increased (1). These drugs have distinct mechanisms of action. However, information on the efficacy of these compounds relative to one another remains limited, which frustrates physicians who want to practice according to the evidence. Some may attribute this gap to the U.S. Food and Drug Administration's regulatory mandate requiring well-controlled studies to assess both efficacy and safety for registration trials (2). Although the use of placebo is not a mandate, studies largely rely on placebo as a comparator. There is no doubt that the application of this regulation since 1962 dramatically and positively changed the way medicines are developed and led to the approval of many new drugs. We are all aware that a particular study design will be able to answer a set of questions, and that no single study can answer all of the questions. An extensive literature discusses different approaches for designing clinical trials and the use of placebos and active controls (3, 4). I believe that placebo-controlled trials are an invaluable tool for defining a drug's efficacy during the drug development process. Nonetheless, some question the ethics and utility of using efficacy relative to placebo as the only hurdle to clear before bringing a drug to the market (5, 6). They ask why we deny a patient a known effective treatmentin the form of an active comparatorwhile missing a golden opportunity to assess relative efficacy. A pharmaceutical company takes a substantial risk when it compares a new product with an established drug. Failure to demonstrate superiority over a less expensive agent could be financially ruinous. Providers and patients may not embrace a new therapy when it proves to be inferior to an established product in efficacy, safety, or affordability. In contrast, manufacturers run no such risk when seeking approval based on a comparison with placebo and can then promote their product to physicians who apparently do not question the limitations of this form of evidence. Under the current incentives for drug development, we have more medicines and more choices, but we often lack the scientific evidence to make choices among them. The use of placebo-only practice reduces risk for the pharmaceutical industry, but clearly it does not translate into good medicine or good public policy. In allowing market entry based on a comparison only with placeborather than requiring a comparison with established agentswe lose an opportunity to serve the best interest of our patients. In this issue, Cadarette and colleagues (7) provide information from an observational study conducted to address the knowledge gap created by the lack of head-to-head randomized trials of drugs to prevent and treat osteoporosis. They analyzed a cohort of 43135 Medicare beneficiaries who were enrolled in 1 of 2 statewide pharmaceutical benefits programs and had received a new prescription for bisphosphonates (alendronate or risedronate), calcitonin, or raloxifene. The study outcome was a fracture of the hip, humerus, radius, or ulna within 12 months of the first dose of drug, as detected by a claim for Medicare reimbursement for services rendered for these diagnoses. By using multivariate statistics to adjust for differences in the frequency of several potential confounders in the populations receiving the 4 drugs, the authors explored the relative efficacy of these drugs. They found that individuals receiving alendronate, risedronate, and raloxifene had similar fracture risk, which was considerably lower than with calcitonin. The authors provide a balanced discussion of the strengths and weaknesses of their methodological approach. Their tables contained more than 3600 discrete data points, which underscore the complexity of the analysis. This complexity and the tools the authors used may be foreign to many readers who lack the sophisticated statistical training to fully understand the impact of these analyses. I personally belong in this group and have taken the authors' conclusions at face value. As with many cohort studies, this report has several limitations (810). First, patients were not randomly assigned. Physicians, and therefore clinical circumstances, determined who received which drug. Second, the authors had no access to the factors that led physicians to choose one drug and not another. Third, 1 groupthose who received calcitoninwere more ill, based on the number of comorbid conditions, medications listed, and recent hospitalizations. Fourth, fewer patients receiving calcitonin or raloxifene had an osteoporosis diagnosis. All these factors could influence fracture rates independent of the effectiveness of the drug these patients received, and even the most sophisticated multivariate analysis cannot overcome these limitations. To the authors' credit, they acknowledge several situations in which they cannot exclude confounding by indicationwhereby a clinical finding that determines whether a person receives a drug is causally related to the study outcomeas a possible explanation for some results. Randomly assigned treatment would negate most of these concerns, which is why we have come to rely on randomized trials for evidence about drug treatments. Three points illustrate some of the issues with observational studies based on large data sets. The first is about the clinical importance of a small but statistically significant difference. What is the clinical meaning of a statistically significant difference in mean patient age in the raloxifene group (76.9 years) and the bisphosphonate group (78.7 years)? A 2-year difference could be critical between neonates and 2-year-old children and between 13-year-old prepubertal children and children who are sexually mature at age 15. However, in the older cohort studied by Cadarette and colleagues (7), this difference is probably meaningless physiologically. A second issue is multiple comparisons, which raise concern that some of the observed differences are due to chance, even though the authors raised the bar for interpreting a result as statistically significant. Finally, data obtained for administrative purposes, which are the core source for this study, are often suspect because it is difficult to assess the accuracy of the information and what information may be missing. The authors allude to some of these issues without fully explaining how they could affect their conclusions. In the end, the fracture rates were similar for the 2 bisphosphonates and raloxifene. Will this information be useful to select one drug over another? Will it help physicians decide which of these drugs to use in specific patients? I do not think so. Even if the authors had found a clear, undisputed gradient in efficacy among these drugs, I believe that we would need a prospective randomized study before we could use the findings as the basis for practice guidelines. These results underscore, once more, the lack of good comparative data for choosing drug therapy. Cadarette and colleagues (7) conclude, in accord with many previous articles and reviews, that more randomized, controlled studies are needed, implicitly acknowledging that their approach has important shortcomings. However, the dearth of head-to-head trials suggests that our system for evaluating health technology has not created the incentives to do these trials. Without incentives, the needed studies may never materialize, and we will continue to cope with uncertainty when choosing a drug. A good example of a creative incentive is the pediatric initiative that allowed manufacturers 6 additional months of exclusivity under patent if they made a commitment to study drug effects in pediatric patients (11). Many manufacturers took advantage of this proposal, and I believe that our knowledge about drug effects in children improved. I submit that we have potential opportunities to explore the relative efficacy of drugs for the treatment of most conditions. As Cadarette and colleagues (7) show, government agencies now pay for drugs for millions of Americans. Under these programs, the U.S. government has already paid for antiosteoporosis drugs for thousands of patients, despite weak evidence about which are the most effective. I propose that we devise an ethical way to prospectively randomly assign patients to different (and apparently equivalent) drug regimens and measure the outcomes of treatment, potential adverse events, drug interactions, and costs. I assert that if the government pays for tests or treatments, it has an obligation to evaluate them relative to one another. Although this approach alone will not answer every question, it should narrow the gap between what we know and what we need to know, allow us to make better treatment decisions, and help us to better allocate scarce resources.

In the past decade, many new medications have improved our ability to treat patients with type 2 diabetes (1). The pharmaceutical industry has played a key role in this process. Among these novel medications are newly designed insulins, thiazolidinediones (TZDs), meglitinides, orally active inhibitors of the incretin-degrading enzyme dipeptidyl peptidase-IV, and glucagon-like peptide (GLP) mimetics. Combinations of these drugs, each drug with its distinct pharmacologic mechanism of action, have increased our capacity to manage patients with diabetes. The latter 2 drug classes mentioned enhance or mimic the effects of endogenous incretins, such as GLP hormones secreted by the gut (24). As with most gut peptides, GLP biological activity is exercised locally by inhibiting gastric emptying but also in the pancreas by stimulating glucose-dependent insulin secretion, promoting insulin biosynthesis, and inhibiting glucagon secretion. At the central nervous system level, GLP inhibits food and water intake, promotes satiety and weight loss, and induces nausea and vomiting. These diverse sites of action make GLPs attractive molecules for treating diabetes. In a randomized trial in this issue (5), we learn about use of a GLP mimeticexenatidein combination with a TZD. The study was designed, conducted, and analyzed by employees of the manufacturer in collaboration with academicians from several institutions and [all] authors participated in interpreting the data and drafting or critically reviewing the manuscript (5). Zinman and colleagues report on a relatively small study of patients with type 2 diabetes (n= 233) from 49 centers where exenatide, 10 g twice daily (n= 121), or placebo (n= 122) was added to rosiglitazone (4 mg/d) or pioglitazone (30 mg/d) alone or in combination with metformin (79%) for 16 weeks to assess both efficacy and safety. The study results were the basis for the U.S. Food and Drug Administration (FDA) approval of the combination with a TZD as a new indication for exenatide (3). The FDA had previously approved exenatide in combination with metformin or sulfonylureas. The regulatory barriers for approving a new indication for a drug that is already in the market are usually less severe than for a first-time approval of a new molecular entity, perhaps because the safety information for a drug that is already in the market provides regulators with a sense of security. A recent editorial has contested this rationale and the less stringent requirements for study size and duration, singling out type 2 diabetes as a case in point (1). Zinman and colleagues' presentation, which is very objective and balanced, shows that adding exenatide to a TZD reduced the mean hemoglobin A1c level by almost 1.0 percentage point. Patients receiving exenatide lost a mean of 1.5 kg of body weight, while those in the placebo group maintained their baseline weight. Lipid profile and blood pressure did not change. Hence, the addition of exenatide for up to 16 weeks improved glucose control and moderately reduced weight in patients inadequately managed with submaximal dosages of TZDs alone or with metformin, with no additional metabolic benefit observed. Several aspects of the study design raise concerns about whether these results apply to most patients with type 2 diabetes whose physicians are considering starting an injectable drug because of poor control with TZDs and metformin. While the study patients were inadequately controlled, many were not receiving maximal therapy when the study began. In contrast to standards of recommended care for patients with type 2 diabetes, Zinman and colleagues did not use lifestyle interventions to maximize diabetes control at baseline, and they do not comment about diabetes education or dietary control (69). Without these cointerventions, metabolic control would be suboptimal, which could enhance the effect of any medication. Inadequate conventional drug therapy is another reason for concern that the study patients weren't typical, poorly controlled diabetics. Twenty-one percent of patients were not receiving metformin, which is first-line therapy for type 2 diabetes because of its proven efficacy, safety record, and cost-effectiveness (69). Moreover, the patients taking metformin were not always taking maximal dosages, which is customary before adding a drug like exenatide. The authors do not describe their rationale for not using the maximal tolerated therapeutic dosage of metformin in all suboptimally controlled patients. In addition, some patients were receiving submaximal dosages of TZDs. The authors do not state how many patients received maximal dosages of metformin or TZDs. The authors' failure to provide lifestyle and diet advice and their use of submaximal dosages of the oral medications detracts from their study because, in clinical practice, a physician would optimize current therapy before adding a new medication. We simply don't know whether patients optimally treated with diabetes education, diet, TZDs, and metformin will receive as much benefit from exenatide as the paper reports. Adverse effects, as noted in previous studies, were common. Of the 121 patients who were initially randomly assigned to receive exenatide, only 86 (71%) completed the 16 weeks of the trial, compared with 96 of 122 (79%) of patients receiving placebo. Nausea and vomiting were statistically significantly higher in patients receiving exenatide and were the most common reasons for leaving the study (17 of 31 patients). A 26% dropout rate is rarely observed in short-term clinical studies of antidiabetic drugs. The authors state that many patients dropped out during the initial dose escalation of exenatide and, with time, fewer patients left the study. The reduction of these adverse drug reactions with time could be due to better tolerance. Alternatively, it could be due to a form of survivor bias, wherein patients who were less prone to nausea and vomiting stayed in the study. Because dose increments are necessary to produce the reported results, high rates of desertion are likely when exenatide is used in the general diabetic population. The authors did not provide information about subgroups that were more prone to develop adverse drug reactions. Adverse effects are clearly a substantial problem with exenatide, and physicians considering prescribing exenatide will need help in managing them. The authors collected this information. They should publish it. Drug administration will be a barrier to using exenatide. Like past formulations of regular insulin, exenatide must be given 15 minutes before meals, which contrasts with newer rapidly active insulins that may be injected during and even after meals, which is far more convenient and reduces the burden of meal planning and timing, as well as the risk for hypoglycemia. Moreover, the manufacturer has formulated exenatide for fixed-dose administration. Fixed dosing vitiates a potential advantage of an injectable drug: the ability to fine-tune the dosage to enhance glucose control or to manage adverse drug reactions by using an injector pen that allows administration of doses in multiples of only 5 g or 10 g. The study was much too small and much too short. The estimated number of patients with type 2 diabetes worldwide in 2007 is 246 million (10). Zinman and colleagues' study exposed only 121 patients from 49 different centers to exenatide and TZDs. Because of its short duration, small size, and lack of power, the study fails to clarify many questions. Among the most important questions are: Will glucose control last more than 16 weeks? Who is at greatest risk for adverse drug reactions? Will dose adjustment improve glucose control and decrease adverse drug reactions? Subgroup analyses would answer some of these important questions. A small study precludes meaningful subgroup analyses. More important, small and short studies provide a false sense of safety, because common severe adverse drug reactions may not occur in the condensed timeline and in the limited number of patients. The design and reporting of Zinman and colleagues' study reminds us that the manufacturer controls the flow of information about its product. By virtue of FDA approval for the combination of exenatide and TZDs, the data obtained in the study can lead to enormous financial benefits to the sponsor. Millions of patients receive TZDs and metforminnow physicians may consider adding exenatide. Great power requires greater responsibility. Physicians and patients need answers to the many questions raised by this small study.

OBJECTIVE:The objective is to provide guidelines for the evaluation and treatment of adults with GH deficiency (GHD). PARTICIPANTS:The chair of the Task Force was selected by the Clinical Guidelines Subcommittee of The Endocrine Society (TES). The chair selected five other endocrinologists and a medical writer, who were approved by the Council. One closed meeting of the group was held. There was no corporate funding, and members of the group received no remuneration. EVIDENCE:Only fully published, peer-reviewed literature was reviewed. The Grades of Evidence used are outlined in the Appendix. CONSENSUS PROCESS:Consensus was achieved through one group meeting and e-mailing of drafts that were written by the group with grammatical/style help from the medical writer. Drafts were reviewed successively by the Clinical Guidelines Subcommittee, the Clinical Affairs Committee, and TES Council, and a version was placed on the TES web site for comments. At each level, the writing group incorporated needed changes. CONCLUSIONS:GHD can persist from childhood or be newly acquired. Confirmation through stimulation testing is usually required unless there is a proven genetic/structural lesion persistent from childhood. GH therapy offers benefits in body composition, exercise capacity, skeletal integrity, and quality of life measures and is most likely to benefit those patients who have more severe GHD. The risks of GH treatment are low. GH dosing regimens should be individualized. The final decision to treat adults with GHD requires thoughtful clinical judgment with a careful evaluation of the benefits and risks specific to the individual.

Acromegaly is associated with significantly increased morbidity and mortality.As a consequence, treatment of the disease is indicated in almost all cases once the diagnosis is established.Studies published between 1970 and 1988 reported standardized mortality rates in patients with acromegaly to be 1.6 -3.3; more recent studies, published in the past 3 yr, reported the rate to be lower, ranging from 1.3-1.8.However, when disease activity is controlled in patients with acromegaly, the relative mortality risk is reduced toward normal.Changes brought about by improvements in assay methodology for GH and IGF-I mean that hormone levels reported from these retrospective analyses cannot be simply converted by formula to draw conclusions about the outcome of acromegaly assessed biochemically using current assays.For these reasons The Growth Hormone Research Society and The Pituitary Society formed a joint program committee and invited international experts to address the current status of both biochemical assessment and long-term monitoring in patients with acromegaly at a consensus conference held in Feldafing, Germany, in April 2003. Biochemical assessment of the patient with acromegaly