JOSE AUGUSTO SGARBI
@famema.br
Professor of Medicine, Division of Endocrinology and Metabolism
Faculdade de Medicina de Marilia
EDUCATION
Medical Doctor, Faculdade de Medicina de Vassouras, BR, 1984
M.Sc, Internal Medicine, Faculdade de Medicina de Botucatu, Universidade do Estado de São Paulo, UNESP
PhD., Clinical Endocrinology, Escola Paulista de Medicina, Univesidade Federal de São Paulo, UNESP
RESEARCH, TEACHING, or OTHER INTERESTS
Medicine, Endocrinology, Diabetes and Metabolism, Epidemiology, Internal Medicine
Scopus Publications
Scholar Citations
Scholar h-index
Scholar i10-index
Scopus Publications
Vandrize Meneghini, William Rodrigues Tebar, Itamar Souza Santos, Carolina Castro Porto Silva Janovsky, Bianca de Almeida-Pititto, Marina Gabriela Birck, Paulo Andrade Lotufo, Alessandra Carvalho Goulart, José Augusto Sgarbi, Patrícia de Fátima dos Santos Teixeira,et al.
The Endocrine Society
Abstract Context The presence of thyroid peroxidase antibodies (TPOAbs) may be considered as an indicator of adverse health outcomes. Objective We aimed to investigate the potential determinants of TPOAb levels and to analyze the association between TPOAb titers and the risk of all- and specific-cause mortality. Methods Baseline and longitudinal data of 13 187 participants from the ELSA-Brasil Study were analyzed. We investigated the association of TPOAb, detectability, positivity, and persistent positivity with sociodemographic and lifestyle factors using logistic regressions. Cox proportional hazards and Fine-Gray subdistribution hazard regression analyses were used to verify the association of TPOAbs with mortality. Results The determinants of TPOAb detectability and positivity were younger age, higher body mass index, female sex, and former and current smoking status. Black, mixed, and other self-reported races, intermediate and higher education, and heavy drinking were determinants of detectable and positive TPOAb levels. Female sex, White race, and former smoking were determinants of persistent TPOAb positivity at 2 visits, although only the female sex maintained its association at 3 visits. Moreover, after multivariate adjustment, there were associations between higher levels of TPOAbs and higher risk of cancer-related mortality among men, and TPOAb detectability and mortality by other causes among women. Conclusion Sociodemographic and lifestyle-related factors were determinants of multiple TPOAb categories. TPOAb levels were associated with mortality risk; however, the low mortality rate in this sample might have compromised this finding. We suggest further studies to explore the clinical importance of detectable TPOAb levels, not only its positivity, as a potential marker of inflammation.
Yanning Xu, Arash Derakhshan, Ola Hysaj, Lea Wildisen, Till Ittermann, Alessandro Pingitore, Nazanin Abolhassani, Marco Medici, Lambertus A L M Kiemeney, Niels P Riksen,et al.
Elsevier BV
Jesselina Francisco dos Santos Haber, Sandra Maria Barbalho, Jose Augusto Sgarbi, Rafael Santos de Argollo Haber, Roger William de Labio, Lucas Fornari Laurindo, Eduardo Federighi Baisi Chagas, and Spencer Luiz Marques Payão
MDPI AG
Type 1 diabetes mellitus (T1DM) is one of the major chronic diseases in children worldwide. This study aimed to investigate interleukin-10 (IL-10) gene expression and tumor necrosis factor-alpha (TNF-α) in T1DM. A total of 107 patients were included, 15 were T1DM in ketoacidosis, 30 patients had T1DM and HbA1c ≥ 8%; 32 patients had T1DM and presented HbA1c < 8%; and 30 were controls. The expression of peripheral blood mononuclear cells was performed using the reverse transcriptase–polymerase chain reaction in real time. The cytokines gene expression was higher in patients with T1DM. The IL-10 gene expression increased substantially in patients with ketoacidosis, and there was a positive correlation with HbA1c. A negative correlation was found for IL-10 expression and the age of patients with diabetes, and the time of diagnosis of the disease. There was a positive correlation between TNF-α expression with age. The expression of IL-10 and TNF-α genes showed a significant increase in DM1 patients. Once current T1DM treatment is based on exogenous insulin, there is a need for other therapies, and inflammatory biomarkers could bring new possibilities to the therapeutic approach of the patients.
Gabriela Brenta, Marco António Campinho, Celia Regina Nogueira, and Jose Sgarbi
Frontiers Media SA
Jose Augusto Sgarbi, Celia Regina Nogueira, Gabriela Brenta, and Marco Antonio Campinho
Frontiers Media SA
COPYRIGHT © 2022 Sgarbi, Nogueira, Brenta and Campinho. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. TYPE Editorial PUBLISHED 23 December 2022 DOI 10.3389/fendo.2022.1112695
Marina Gabriela Birck, Bianca de Almeida-Pititto, Carolina C.P.S. Janovsky, Alessandra Carvalho Goulart, Itamar S. Santos, Patrícia de Fátima dos Santos Teixeira, Jose A. Sgarbi, Sandhi M. Barreto, Bruce B. Duncan, Maria Inês Schmidt,et al.
Thyroid Mary Ann Liebert Inc
BACKGROUND
There are conflicting data regarding the association of thyroid function with incident diabetes. We prospectively investigated thyroid-stimulating hormone (TSH), free-thyroxine (FT4), free-triiodothyronine (FT3), and its conversion ratio (FT3:FT4), with the risk of developing diabetes in euthyroid subjects and those with subclinical thyroid dysfunction. Our hypothesis is that this relationship is a U-shaped curve since both subclinical thyroid diseases may be associated with diabetes.
METHODS
ELSA-Brasil is a highly admixed cohort study aged 35-74 years at baseline (2008-2010). Levels of TSH, FT4, FT3, and FT3:FT4 ratio were evaluated at baseline and incident diabetes was estimated over an 8.2-year follow-up (2017-2019). Diabetes was identified based on medical diagnosis, prescriptions and laboratory tests. The risk of diabetes was evaluated according to quintiles of TSH, FT4, FT3 and FT3:FT4 ratio using Poisson Regression with robust variance presented as relative risk (RR) with 95% Confidence Interval (95%CI) after multivariable adjustment for sociodemographic and cardiovascular risk factors (reference 3rd quintile) and also as continuous variables Results: We included 7,948 participants (mean age, 50.2 (SD8.6) years; 54.4% female): 7,177 euthyroid, 726 with subclinical hypothyroidism, and 45 with subclinical hyperthyroidism. Incidence of diabetes was 14.8%. No association was found for TSH, FT4, FT3, and FT3:FT4 ratio quintiles with incident diabetes. Using continuous variables, the increase of 1-unit of FT4 decreased the risk of diabetes (RR 0.94; 95%CI 0.91-0.99) while the increase of 1-unit of the FT3:FT4 ratio increased the diabetes risk (RR 1.37; 95%CI, 1.15-1.63). The increase of 1-unit of FT3 was associated with an increased risk of diabetes, but without significance after multivariable adjustment. In BMI stratified analysis, people with overweight or obesity presented a modest significantly higher risk of diabetes in the lowest quintile of FT4 (RR 1.04; 95%CI 1.01-1.07) and an inverse association with incident diabetes in the 1st quintile of FT3:FT4 ratio (RR, 0.95; 95%CI 0.93-0.98). The analyses using continuous variables presented similar findings.
CONCLUSION
These findings suggest that FT4 and FT3 levels and the conversion rate might be additional risk factors associated with incident diabetes specially in the presence of overweight or obesity. However, they need to be confirmed in future studies.
Lamprini Syrogiannouli, Lea Wildisen, Christiaan Meuwese, Douglas C. Bauer, Anne R. Cappola, Jacobijn Gussekloo, Wendy P. J. den Elzen, Stella Trompet, Rudi G. J. Westendorp, J. Wouter Jukema,et al.
Frontiers Media SA
BackgroundIn non-randomized studies (NRSs) where a continuous outcome variable (e.g., depressive symptoms) is assessed at baseline and follow-up, it is common to observe imbalance of the baseline values between the treatment/exposure group and control group. This may bias the study and consequently a meta-analysis (MA) estimate. These estimates may differ across statistical methods used to deal with this issue. Analysis of individual participant data (IPD) allows standardization of methods across studies. We aimed to identify methods used in published IPD-MAs of NRSs for continuous outcomes, and to compare different methods to account for baseline values of outcome variables in IPD-MA of NRSs using two empirical examples from the Thyroid Studies Collaboration (TSC).MethodsFor the first aim we systematically searched in MEDLINE, EMBASE, and Cochrane from inception to February 2021 to identify published IPD-MAs of NRSs that adjusted for baseline outcome measures in the analysis of continuous outcomes. For the second aim, we applied analysis of covariance (ANCOVA), change score, propensity score and the naïve approach (ignores the baseline outcome data) in IPD-MA from NRSs on the association between subclinical hyperthyroidism and depressive symptoms and renal function. We estimated the study and meta-analytic mean difference (MD) and relative standard error (SE). We used both fixed- and random-effects MA.ResultsTen of 18 (56%) of the included studies used the change score method, seven (39%) studies used ANCOVA and one the propensity score (5%). The study estimates were similar across the methods in studies in which groups were balanced at baseline with regard to outcome variables but differed in studies with baseline imbalance. In our empirical examples, ANCOVA and change score showed study results on the same direction, not the propensity score. In our applications, ANCOVA provided more precise estimates, both at study and meta-analytical level, in comparison to other methods. Heterogeneity was higher when change score was used as outcome, moderate for ANCOVA and null with the propensity score.ConclusionANCOVA provided the most precise estimates at both study and meta-analytic level and thus seems preferable in the meta-analysis of IPD from non-randomized studies. For the studies that were well-balanced between groups, change score, and ANCOVA performed similarly.
Jesselina Francisco dos Santos Haber, Eduardo Federighi Baisi Chagas, Sandra Maria Barbalho, Jose Augusto Sgarbi, Rafael Santos De Argollo Haber, Roger William de Labio, and Spencer Luiz Marques Payão
Elsevier BV
Gláucia Maria Ferreira da Silva Mazeto, José Augusto Sgarbi, Helton Estrela Ramos, Danilo Glauco Pereira Villagelin, Célia Regina Nogueira, Mario Vaisman, Hans Graf, and Gisah Amaral de Carvalho
Archives of Endocrinology and Metabolism
ABSTRACT Primary hypothyroidism is a common disorder in clinical practice. The management of most cases of hypothyroidism is usually straightforward, but the best approach in some special situations may raise questions among physicians. This position statement was prepared by experts from the Brazilian Society of Endocrinology and Metabolism to guide the management of three special situations, namely, hypothyroidism in the elderly, subclinical hypothyroidism in patients with heart disease, and difficult-to-control hypothyroidism. The authors prepared the present statement after conducting a search on the databases MEDLINE/PubMed, LILACS, and SciELO and selecting articles with the best evidence quality addressing the selected situations. The statement presents information about the current approach to patients in these special situations.
Isabela M. Bensenor, Alessandra C. Goulart, Alexandre C. Pereira, André R. Brunoni, Airlane Alencar, Raul D. Santos, Márcio S. Bittencourt, Rosa W. Telles, Luciana Andrade Carneiro Machado, Sandhi Maria Barreto,et al.
Clinics Elsevier BV
Isabela M. Benseñor, Fernando Barbosa Junior, Carolina Castro Porto Silva Janovsky, Dirce Marchioni, Maria de Fátima Haueisen Sander Diniz, Itamar de Souza Santos, Bianca de Almeida-Pititto, José Augusto Sgarbi, Maria del Carmen B. Molina, José Geraldo Mill,et al.
Journal of Trace Elements in Medicine and Biology Elsevier BV
OBJECTIVES
To evaluate urinary iodine concentration (UIC) in civil servants aged 35-74 years of the Brazilian Study of Adults Health (ELSA-Brasil) to analyze its relationship with sociodemographic, clinical risk factors, lifestyle, urinary Na and thyroid status.
DESIGN
Cross-sectional study in six Brazilian cities.
METHODS
This analysis included 792 participants with information about urinary iodine concentration (UIC). Thyroid status was defined by serum levels of TSH/FT4 and the current use of antithyroid drugs for treatment of overt hyperthyroidism or levothyroxine to treat overt hypothyroidism. The determination of UIC was carried out with an inductively coupled plasma mass spectrometer (ICP-MS) and was expressed as median with Interquartile Range (IQR).
RESULTS
In 792 participants, thereof 52% women, mean age was 51.9 (9.0) years. The median UIC was 219 (IQR, 166-291) for all persons studied, thereof 211 (IQR, 157-276) for women and 231 (IQR, 178-304) for men. According to the WHO classification, for all persons studied, 60% had more than adequate iodine-supply (UIC ≥200 μg/L), 37% were adequately supplied (UIC 100-199 μg/L) and <3% had a deficient iodine status (<100 μg/L). In the 35-44-year age strata, which includes women of childbearing age, 23.2% of women presented less than 150 μg/L of UIC. No differences in UIC were detected according to thyroid status. (P = 0.39) The correlation between Ur-Na and UIC showed a Spearman coefficient of 0.52 (P < 0.0001) and it was also found an association of Ur-Na with UIC: Beta of 1.76 (95% Confidence Interval (95% CI): 1.01 to 2.51. The urinary Na concentration showed a synergy with the UIC, that means medians of 57, 72, 107 and 141 mmol Na/L urine (P < 0.001) in the groups with the four UIC classes according to the WHO grading mentioned above. The very low Na content in the persons exhibiting <100 μg/L UIC seems to reflect also a higher urine volume due to the frequent use of diuretics. The strong relationship between the urinary Na concentration and the UIC points to a dependence of the UIC on the individual consumption of iodized salt, which should be more considered in future studies. The strong relationship between the urinary Na concentration and the UIC points to a dependence of the UIC on the individual consumption of iodized salt, which should be more considered in future studies.
CONCLUSIONS
Euthyroid persons were dominating by more than four fifths and no significant association was found between UIC and thyroid status. Although most of the persons studied present more than adequate iodine intake it was observed that nearly a quarter of women in childbearing age are iodine deficient.
Isabela M. Benseñor, José Augusto Sgarbi, Carolina Castro Porto Silva Janovsky, Bianca Almeida Pittito, Maria de Fátima Haueisen Sander Diniz, Maria da Conceição Chagas de Almeida, Sheila Maria Alvim, Sandhi M. Barreto, Luana Giatti, Bruce B. Duncan,et al.
Archives of endocrinology and metabolism Archives of Endocrinology and Metabolism
Objective
To evaluate incidence of subclinical and overt hyperthyroidism and hypothyroidism.
Methods
The Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) is a prospective cohort study of 15,105 civil servants, examined at baseline and over a 4-year follow-up. This analysis included 9,705 participants with normal thyroid function at baseline, follow-up information about thyroid function and with no report of using drugs that may interfere in the thyroid function. Thyroid function was defined by TSH/FT4 levels or routine use of thyroid hormones/anti-thyroid medications. Annual and cumulative (over 4-year) incidence rates were presented as percentages (95% Confidence Intervals).
Results
The incidence of all overt and subclinical thyroid disease was 6.7% (1.73%/year): 0.19% for overt hyperthyroidism (0.048%/year), 0.54% for subclinical hyperthyroidism (0.14%/year), 1.98% for overt hypothyroidism (0.51%/year), and 3.99% for subclinical hypothyroidism (1.03%/year). The incidence of all thyroid diseases was higher in women, when compared to men, with a low women:men ratio (1.36). For Blacks the highest incidence was for overt hyperthyroidism, while for Whites, the highest incidence was for overt hypothyroidism. However, the highest incidence of overt hyperthyroidism was detected in Asian descendants. The presence of antithyroperoxidase antibodies at baseline was associated with higher incidence of overt thyroid diseases.
Conclusion
These results showed a high incidence of hypothyroidism, which is compatible with a country with a more-than-adequate iodine intake. The low women:men ratio of the incidence of thyroid dysfunction highlights the importance of the diagnosis of thyroid diseases among men in Brazil.
Isabela M. Benseñor, Carolina Castro Porto Silva Janovsky, Alessandra C. Goulart, Itamar de Souza Santos, Maria de Fátima Haueisen Sander Diniz, Bianca de Almeida-Pititto, José Augusto Sgarbi, and Paulo A. Lotufo
Archives of Endocrinology and Metabolism
ABSTRACT Objective: Although some previous data have suggested a high iodine intake in Brazil, the prevalence of antithyroperoxidase antibodies (TPOAb) in the country is compatible with rates from countries with adequate iodine intake. This observation emphasizes the importance of knowing the incidence of TPOAb in Brazil. Materials and methods: This prospective analysis included euthyroid participants with negative TPOAb at baseline and a thyroid function assessment at a 4-year follow-up. TPOAb was measured by electrochemiluminescence and considered positive when titers were ≥34 IU/mL. TSH and free T4 (FT4) levels were determined by a third-generation immunoenzymatic assay. The incidence of TPOAb is expressed in percentage per year or as a cumulative incidence within the 4-year follow-up period. Results: Of 8,922 euthyroid participants (mean age 51.1 years; 50.9% women) with a negative TPOAb test at baseline, 130 presented incident TPOAb at the 4-year follow-up, yielding an annual incidence of TPOAb of 0.38%/year (95% confidence interval [95% CI], 0.37-0.39%/year) and a cumulative incidence over 4 years of 1.46% (95% CI, 1.21-1.71%). In men, the annual incidence was 0.32% (95% CI, 0.31-0.33%), and the cumulative incidence over 4 years was 1.23% (95% CI, 0.90-1.56%). In women, the annual incidence was 0.43%/year (95% CI, 0.42-0.44%/year) and the cumulative incidence over 4 years was 1.67% (95% CI, 1.30-2.04%). The only factor associated with incident TPOAb was the occurrence of thyroid diseases at follow-up. No differences in TPOAb incidence were detected across ELSA-Brasil research centers. Conclusion: Based on the results of this study, the incidence of TPOAb per year and at a 4-year follow-up period are compatible with those of a country with adequate iodine intake.
João Roberto M. Martins, Danilo G. P. Villagelin, Gisah A. Carvalho, Fernanda Vaisman, Patrícia F. S. Teixeira, Rafael S. Scheffel, and José A. Sgarbi
Archives of Endocrinology and Metabolism
ABSTRACT This position statement was prepared to guide endocrinologists on the best approach to managing thyroid disorders during the coronavirus disease (COVID-19) pandemic. The most frequent thyroid hormonal findings in patients with COVID-19, particularly in individuals with severe disease, are similar to those present in the non-thyroidal illness syndrome and require no intervention. Subacute thyroiditis has also been reported during COVID-19 infection. Diagnosis and treatment of hypothyroidism during the COVID-19 pandemic may follow usual practice; however, should avoid frequent laboratory tests in patients with previous controlled disease. Well-controlled hypo and hyperthyroidism are not associated with an increased risk of COVID-19 infection or severity. Newly diagnosed hyperthyroidism during the pandemic should be preferably treated with antithyroid drugs (ATDs), bearing in mind the possibility of rare side effects with these medications, particularly agranulocytosis, which requires immediate intervention. Definitive treatment of hyperthyroidism (radioiodine therapy or surgery) may be considered in those cases that protective protocols can be followed to avoid COVID-19 contamination or once the pandemic is over. In patients with moderate Graves’ ophthalmopathy (GO) not at risk of visual loss, glucocorticoids at immunosuppressive doses should be avoided, while in those with severe GO without COVID-19 and at risk of vision loss, intravenous glucocorticoid is the therapeutic choice. Considering that most of the thyroid cancer cases are low risk and associated with an excellent prognosis, surgical procedures could and should be postponed safely during the pandemic period. Additionally, when indicated, radioiodine therapy could also be safely postponed as long as it is possible.
José Augusto Sgarbi and Laura Sterian Ward
Archives of Endocrinology and Metabolism
ABSTRACT Subclinical hypothyroidism (Shypo) is an increasingly frequent condition in common medical practice. Its diagnosis continues to pose a challenge since a series of non-thyroidal and temporary conditions can elevate serum TSH levels. In addition, the consequences of Shypo are still up for debate. Although detrimental cardiovascular effects have been consistently demonstrated in the young, they are less evident in older adults (65-79 years), and even more so in the oldest old (≥80 years). In the absence of evidence of any benefits of treating Shypo in patients’ clinical manifestations and unfavorable outcomes, the most effective decision-making approach should include a thorough investigation of the patient's condition integrating all relevant clinical data, such as TSH levels, age, quality of life, comorbidities, cardiovascular risk, safety, and personal preferences. The decision-making process needs to take into account the risk of levothyroxine overtreatment and the resulting adverse consequences, such as reduction of bone mineral density, heart failure, and atrial fibrillation. Hence, current evidence suggests that individuals with TSH > 10 mU/L, who test positive for TPO Ab or are symptomatic may benefit from levothyroxine treatment. However, a more cautious and conservative approach is required in older (≥65 years of age), and oldest-old (≥80 years) patients, particularly those with frailty, in which the risk of treatment can outweigh potential benefits. The latter may benefit from a wait-and-see approach.
José Augusto Sgarbi
Springer International Publishing
M.A. Czepielewski, Q. Garret, S.A.C. Vencio, N. Rassi, J.S. Felicio, M.S. Faria, C.C.P. Senn, M.D. Bronstein, M.J.A.G. Cerqueira, A.C.L. Neves,et al.
Elsevier BV
Christiaan L Meuwese, Merel van Diepen, Anne R Cappola, Mark J Sarnak, Michael G Shlipak, Douglas C Bauer, Linda P Fried, Massimo Iacoviello, Bert Vaes, Jean Degryse,et al.
Oxford University Press (OUP)
Abstract Background Chronic kidney disease (CKD) is frequently accompanied by thyroid hormone dysfunction. It is currently unclear whether these alterations are the cause or consequence of CKD. This study aimed at studying the effect of thyroid hormone alterations on renal function in cross-sectional and longitudinal analyses in individuals from all adult age groups. Methods Individual participant data (IPD) from 16 independent cohorts having measured thyroid stimulating hormone, free thyroxine levels and creatinine levels were included. Thyroid hormone status was defined using clinical cut-off values. Estimated glomerular filtration rates (eGFR) were calculated by means of the four-variable Modification of Diet in Renal Disease (MDRD) formula. For this IPD meta-analysis, eGFR at baseline and eGFR change during follow-up were computed by fitting linear regression models and linear mixed models in each cohort separately. Effect estimates were pooled using random effects models. Results A total of 72 856 individuals from 16 different cohorts were included. At baseline, individuals with overt hypothyroidism (n = 704) and subclinical hypothyroidism (n = 3356) had a average (95% confidence interval) −4.07 (−6.37 to −1.78) and −2.40 (−3.78 to −1.02) mL/min/1.73 m2 lower eGFR as compared with euthyroid subjects (n = 66 542). In (subclinical) hyperthyroid subjects (n = 2254), average eGFR was 3.01 (1.50–4.52) mL/min/1.73 m2 higher. During 329 713 patient years of follow-up, eGFR did not decline more rapidly in individuals with low thyroid function compared with individuals with normal thyroid function. Conclusions Low thyroid function is not associated with a deterioration of renal function. The cross-sectional association may be explained by renal dysfunction causing thyroid hormone alterations.
José Augusto Sgarbi
Archives of Endocrinology and Metabolism
Layal Chaker, Christine Baumgartner, Wendy P. J. den Elzen, Tinh-Hai Collet, M. Arfan Ikram, Manuel R. Blum, Abbas Dehghan, Christiane Drechsler, Robert N. Luben, Marileen L. P. Portegies,et al.
The Endocrine Society
CONTEXT
The currently applied reference ranges for thyroid function are under debate. Despite evidence that thyroid function within the reference range is related with several cardiovascular disorders, its association with the risk of stroke has not been evaluated previously.
DESIGN AND SETTING
We identified studies through a systematic literature search and the Thyroid Studies Collaboration, a collaboration of prospective cohort studies. Studies measuring baseline TSH, free T4, and stroke outcomes were included, and we collected individual participant data from each study, including thyroid function measurements and incident all stroke (combined fatal and nonfatal) and fatal stroke. The applied reference range for TSH levels was between 0.45 and 4.49 mIU/L.
RESULTS
We collected individual participant data on 43 598 adults with TSH within the reference range from 17 cohorts, with a median follow-up of 11.6 years (interquartile range 5.1-13.9), including 449 908 person-years. Age- and sex-adjusted pooled hazard ratio for TSH was 0.78 (95% confidence interval [CI] 0.65-0.95 across the reference range of TSH) for all stroke and 0.83 (95% CI 0.62-1.09) for fatal stroke. For the free T4 analyses, the hazard ratio was 1.08 (95% CI 0.99-1.15 per SD increase) for all stroke and 1.10 (95% CI 1.04-1.19) for fatal stroke. This was independent of cardiovascular risk factors including systolic blood pressure, total cholesterol, smoking, and prevalent diabetes.
CONCLUSION
Higher levels of TSH within the reference range may decrease the risk of stroke, highlighting the need for further research focusing on the clinical consequences associated with differences within the reference range of thyroid function.
Christoph Wanner, Silvio E. Inzucchi, John M. Lachin, David Fitchett, Maximilian von Eynatten, Michaela Mattheus, Odd Erik Johansen, Hans J. Woerle, Uli C. Broedl, and Bernard Zinman
Massachusetts Medical Society
BACKGROUND
Diabetes confers an increased risk of adverse cardiovascular and renal events. In the EMPA-REG OUTCOME trial, empagliflozin, a sodium-glucose cotransporter 2 inhibitor, reduced the risk of major adverse cardiovascular events in patients with type 2 diabetes at high risk for cardiovascular events. We wanted to determine the long-term renal effects of empagliflozin, an analysis that was a prespecified component of the secondary microvascular outcome of that trial.
METHODS
We randomly assigned patients with type 2 diabetes and an estimated glomerular filtration rate of at least 30 ml per minute per 1.73 m(2) of body-surface area to receive either empagliflozin (at a dose of 10 mg or 25 mg) or placebo once daily. Prespecified renal outcomes included incident or worsening nephropathy (progression to macroalbuminuria, doubling of the serum creatinine level, initiation of renal-replacement therapy, or death from renal disease) and incident albuminuria.
RESULTS
Incident or worsening nephropathy occurred in 525 of 4124 patients (12.7%) in the empagliflozin group and in 388 of 2061 (18.8%) in the placebo group (hazard ratio in the empagliflozin group, 0.61; 95% confidence interval, 0.53 to 0.70; P<0.001). Doubling of the serum creatinine level occurred in 70 of 4645 patients (1.5%) in the empagliflozin group and in 60 of 2323 (2.6%) in the placebo group, a significant relative risk reduction of 44%. Renal-replacement therapy was initiated in 13 of 4687 patients (0.3%) in the empagliflozin group and in 14 of 2333 patients (0.6%) in the placebo group, representing a 55% lower relative risk in the empagliflozin group. There was no significant between-group difference in the rate of incident albuminuria. The adverse-event profile of empagliflozin in patients with impaired kidney function at baseline was similar to that reported in the overall trial population.
CONCLUSIONS
In patients with type 2 diabetes at high cardiovascular risk, empagliflozin was associated with slower progression of kidney disease and lower rates of clinically relevant renal events than was placebo when added to standard care. (Funded by the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance; EMPA-REG OUTCOME ClinicalTrials.gov number, NCT01131676.).
Jennifer B. Green, M. Angelyn Bethel, Paul W. Armstrong, John B. Buse, Samuel S. Engel, Jyotsna Garg, Robert Josse, Keith D. Kaufman, Joerg Koglin, Scott Korn,et al.
Massachusetts Medical Society
BACKGROUND
Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease.
METHODS
In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina.
RESULTS
During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P=0.98). There were no significant between-group differences in rates of acute pancreatitis (P=0.07) or pancreatic cancer (P=0.32).
CONCLUSIONS
Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events. (Funded by Merck Sharp & Dohme; TECOS ClinicalTrials.gov number, NCT00790205.).
Layal Chaker, Christine Baumgartner, Wendy P. J. den Elzen, M. Arfan Ikram, Manuel R. Blum, Tinh-Hai Collet, Stephan J. L. Bakker, Abbas Dehghan, Christiane Drechsler, Robert N. Luben,et al.
The Endocrine Society
OBJECTIVE
The objective was to determine the risk of stroke associated with subclinical hypothyroidism.
DATA SOURCES AND STUDY SELECTION
Published prospective cohort studies were identified through a systematic search through November 2013 without restrictions in several databases. Unpublished studies were identified through the Thyroid Studies Collaboration. We collected individual participant data on thyroid function and stroke outcome. Euthyroidism was defined as TSH levels of 0.45-4.49 mIU/L, and subclinical hypothyroidism was defined as TSH levels of 4.5-19.9 mIU/L with normal T4 levels.
DATA EXTRACTION AND SYNTHESIS
We collected individual participant data on 47 573 adults (3451 subclinical hypothyroidism) from 17 cohorts and followed up from 1972-2014 (489 192 person-years). Age- and sex-adjusted pooled hazard ratios (HRs) for participants with subclinical hypothyroidism compared to euthyroidism were 1.05 (95% confidence interval [CI], 0.91-1.21) for stroke events (combined fatal and nonfatal stroke) and 1.07 (95% CI, 0.80-1.42) for fatal stroke. Stratified by age, the HR for stroke events was 3.32 (95% CI, 1.25-8.80) for individuals aged 18-49 years. There was an increased risk of fatal stroke in the age groups 18-49 and 50-64 years, with a HR of 4.22 (95% CI, 1.08-16.55) and 2.86 (95% CI, 1.31-6.26), respectively (p trend 0.04). We found no increased risk for those 65-79 years old (HR, 1.00; 95% CI, 0.86-1.18) or ≥ 80 years old (HR, 1.31; 95% CI, 0.79-2.18). There was a pattern of increased risk of fatal stroke with higher TSH concentrations.
CONCLUSIONS
Although no overall effect of subclinical hypothyroidism on stroke could be demonstrated, an increased risk in subjects younger than 65 years and those with higher TSH concentrations was observed.
Bjørn O. Åsvold, Lars J. Vatten, Trine Bjøro, Douglas C. Bauer, Alexandra Bremner, Anne R. Cappola, Graziano Ceresini, Wendy P. J. den Elzen, Luigi Ferrucci, Oscar H. Franco,et al.
American Medical Association (AMA)
IMPORTANCE
Some experts suggest that serum thyrotropin levels in the upper part of the current reference range should be considered abnormal, an approach that would reclassify many individuals as having mild hypothyroidism. Health hazards associated with such thyrotropin levels are poorly documented, but conflicting evidence suggests that thyrotropin levels in the upper part of the reference range may be associated with an increased risk of coronary heart disease (CHD).
OBJECTIVE
To assess the association between differences in thyroid function within the reference range and CHD risk.
DESIGN, SETTING, AND PARTICIPANTS
Individual participant data analysis of 14 cohorts with baseline examinations between July 1972 and April 2002 and with median follow-up ranging from 3.3 to 20.0 years. Participants included 55,412 individuals with serum thyrotropin levels of 0.45 to 4.49 mIU/L and no previously known thyroid or cardiovascular disease at baseline.
EXPOSURES
Thyroid function as expressed by serum thyrotropin levels at baseline.
MAIN OUTCOMES AND MEASURES
Hazard ratios (HRs) of CHD mortality and CHD events according to thyrotropin levels after adjustment for age, sex, and smoking status.
RESULTS
Among 55,412 individuals, 1813 people (3.3%) died of CHD during 643,183 person-years of follow-up. In 10 cohorts with information on both nonfatal and fatal CHD events, 4666 of 48,875 individuals (9.5%) experienced a first-time CHD event during 533,408 person-years of follow-up. For each 1-mIU/L higher thyrotropin level, the HR was 0.97 (95% CI, 0.90-1.04) for CHD mortality and 1.00 (95% CI, 0.97-1.03) for a first-time CHD event. Similarly, in analyses by categories of thyrotropin, the HRs of CHD mortality (0.94 [95% CI, 0.74-1.20]) and CHD events (0.97 [95% CI, 0.83-1.13]) were similar among participants with the highest (3.50-4.49 mIU/L) compared with the lowest (0.45-1.49 mIU/L) thyrotropin levels. Subgroup analyses by sex and age group yielded similar results.
CONCLUSIONS AND RELEVANCE
Thyrotropin levels within the reference range are not associated with risk of CHD events or CHD mortality. This finding suggests that differences in thyroid function within the population reference range do not influence the risk of CHD. Increased CHD risk does not appear to be a reason for lowering the upper thyrotropin reference limit.
Rhonda Bentley-Lewis, David Aguilar, Matthew C. Riddle, Brian Claggett, Rafael Diaz, Kenneth Dickstein, Hertzel C. Gerstein, Peter Johnston, Lars V. Køber, Francesca Lawson,et al.
Elsevier BV