The effects of macronutrients composition on hormones and substrates during a meal tolerance test in drug-naive and sitagliptin-treated individuals with type 2 diabetes: a randomized crossover study

ABSTRACT Objectives: To evaluate the effect of sitagliptin treatment in early type 2 diabetes mellitus (T2DM) and the impact of different macronutrient compositions on hormones and substrates during meal tolerance tests (MTT). Materials and methods: Half of the drug-naive patients with T2DM were randomly assigned for treatment with 100 mg of sitagliptin, q.d., or placebo for 4 weeks and then submitted to 3 consecutive MTT intercalated every 48 h. The MTTs differed in terms of macronutrient composition, with 70% of total energy from carbohydrates, proteins, or lipids. After 4 weeks of washout, a crossover treatment design was repeated. Both patients and researchers were blinded, and a repeated-measures ANOVA was employed for statistical analysis. Results: Sitagliptin treatment reduced but did not normalize fasting and post-meal glucose values in the three MTTs, with lowered area-under-glucose-curve values varying from 7% to 15%. The sitagliptin treatment also improved the insulinogenic index (+86%) and the insulin/glucose (+25%), glucagon-like peptide-1/glucose (+46%) incremental area under the curves. Patients with early T2DM maintained the lowest glucose excursion after a protein- or lipid-rich meal without any major change in insulin, C-peptide, glucagon, or NEFA levels. Conclusion: We conclude that sitagliptin treatment is tolerable and contributes to better control of glucose homeostasis in early T2DM, irrespective of macronutrient composition. The blood glucose excursion during meal ingestion is minimal in protein- or fat-rich meals, which can be a positive ally for the management of T2DM. Clinical trial no: NCT00881543

The effects of macronutrients composition on hormones and substrates during a meal tolerance test in drugnaive and sitagliptin-treated individuals with type 2 diabetes: a randomized crossover study.

Objective: To evaluate the effect of sitagliptin treatment in early type 2 diabetes mellitus (T2DM) and the impact of different macronutrient compositions on hormones and substrates during meal tolerance tests (MTT). Methods: Half of the drug-naive patients with T2DM were randomly assigned for treatment with 100 mg of sitagliptin, q.d., or placebo for 4 weeks and then submitted to 3 consecutive MTT intercalated every 48 h. The MTTs differed in terms of macronutrient composition, with 70% of total energy from carbohydrates, proteins, or lipids. After 4 weeks of washout, a crossover treatment design was repeated. Both patients and researchers were blinded, and a repeated-measures ANOVA was employed for statistical analysis. Results: Sitagliptin treatment reduced but did not normalize fasting and post-meal glucose values in the three MTTs, with lowered area-under-glucose-curve values varying from 7% to 15%. The sitagliptin treatment also improved the insulinogenic index (+86%) and the insulin/glucose (+25%), glucagon-like peptide-1/glucose (+46%) incremental area under the curves. Patients with early T2DM maintained the lowest glucose excursion after a protein- or lipid-rich meal without any major change in insulin, C-peptide, glucagon, or NEFA levels. Conclusion: We conclude that sitagliptin treatment is tolerable and contributes to better control of glucose homeostasis in early T2DM, irrespective of macronutrient composition. The blood glucose excursion during meal ingestion is minimal in protein- or fat-rich meals, which can be a positive ally for the management of T2DM. Clinical trial no: NCT00881543.

Machine learning for the identification of decision boundaries during the transition from radial to vertical growth phase superficial spreading melanomas.

The objective of this study was to compute threshold values for the diameter of superficial spreading melanomas (SSMs) at which the radial growth phase (RGP) evolves into an invasive vertical growth phase (VGP). We examined reports from 1995 to 2019 of 834 primary SSMs. All the patients underwent complete surgical removal of the tumor and the diagnosis was confirmed after histologic examination. Machine learning was used to compute the thresholds. For invasive non-naevus-associated SSMs, a threshold for the diameter was found at 13.2 mm (n = 634). For the lower limb (n = 209) the threshold was at 9.8 mm, whereas for the upper limb (n = 117) at 14.1 mm. For the back (n = 106) and the trunk (n = 173), the threshold was at 16.2 mm and 17.1 mm, respectively. When considering non-naevus-associated and naevus-associated SSMs together (n = 834) a threshold for the diameter was found at 16.8 mm. For the lower limb (n = 248) the threshold was at 11.7 mm, whereas for the upper limb (n = 146) at 16.4 mm. For the back (n = 170) and the trunk (n = 236), the threshold was at 18.6 mm and 14.1 mm, respectively. Thresholds for various anatomic locations and for each gender were defined. They were based on the diameter of the melanoma and computed to suggest a transition from RGP to VGP. The transition from a radial to a more invasive vertical phase is detected by an increase of tumor size with a numeric cutoff. Besides the anamnestic, clinical and dermatoscopic findings, our proposed approach may have practical relevance in vivo during clinical presurgical inspections.

Portuguese-Brazilian evidence-based guideline on the management of hyperglycemia in type 2 diabetes mellitus.

BACKGROUND: In current management of type 2 diabetes (T2DM), cardiovascular and renal prevention have become important targets to be achieved. In this context, a joint panel of four endocrinology societies from Brazil and Portugal was established to develop an evidence-based guideline for treatment of hyperglycemia in T2DM. METHODS: MEDLINE (via PubMed) was searched for randomized clinical trials, meta-analyses, and observational studies related to diabetes treatment. When there was insufficient high-quality evidence, expert opinion was sought. Updated positions on treatment of T2DM patients with heart failure (HF), atherosclerotic CV disease (ASCVD), chronic kidney disease (CKD), and patients with no vascular complications were developed. The degree of recommendation and the level of evidence were determined using predefined criteria. RESULTS AND CONCLUSIONS: In non-pregnant adults, the recommended HbA1c target is below 7%. Higher levels are recommended in frail older adults and patients at higher risk of hypoglycemia. Lifestyle modification is recommended at all phases of treatment. Metformin is the first choice when HbA1c is 6.5-7.5%. When HbA1c is 7.5-9.0%, dual therapy with metformin plus an SGLT2i and/or GLP-1RA (first-line antidiabetic agents, AD1) is recommended due to cardiovascular and renal benefits. If an AD1 is unaffordable, other antidiabetic drugs (AD) may be used. Triple or quadruple therapy should be considered when HbA1c remains above target. In patients with clinical or subclinical atherosclerosis, the combination of one AD1 plus metformin is the recommended first-line therapy to reduce cardiovascular events and improve blood glucose control. In stable heart failure with low ejection fraction (< 40%) and glomerular filtration rate (eGFR) > 30 mL/min/1.73 m2, metformin plus an SGLT-2i is recommended to reduce cardiovascular mortality and heart failure hospitalizations and improve blood glucose control. In patients with diabetes-associated chronic kidney disease (CKD) (eGFR 30-60 mL/min/1.73 m2 or eGFR 30-90 mL/min/1.73 m2 with albuminuria > 30 mg/g), the combination of metformin and an SGLT2i is recommended to attenuate loss of renal function, reduce albuminuria and improve blood glucose control. In patients with severe renal failure, insulin-based therapy is recommended to improve blood glucose control. Alternatively, GLP-1RA, DPP4i, gliclazide MR and pioglitazone may be considered to reduce albuminuria. In conclusion, the current evidence supports individualizing anti-hyperglycemic treatment for T2DM.

Diretriz brasileira baseada em evidências sobre prevenção de doenças cardiovasculares em pacientes com diabetes: posicionamento da Sociedade Brasileira de Diabetes (SBD), da Sociedade Brasileira de Cardiologia (SBC) e da Sociedade Brasileira de Endocrinologia e Metabologia (SBEM) / Brazilian evidence-based guideline on cardiovascular disease prevention in patients with diabetes: positioning of the Brazilian Society of Diabetes (SBD), the Brazilian Society of Cardiology (SBC) and the Brazilian Society of Endocrinology and Metabology (SBEM)

Resumo Fundamentação: desde o primeiro posicionamento da Sociedade Brasileira de Diabetes (SBD) sobre diabetes e prevenção cardiovascular, em 2014,1 importantes estudos têm sido publicados na área de prevenção cardiovascular e tratamento do diabetes,2 os quais contribuíram para a evolução na prevenção primária e secundária nos pacientes com diabetes. Ferramentas de estratificação de risco mais precisas, novos fármacos hipolipemiantes e novos antidiabéticos com efeitos cardiovasculares e redução da mortalidade, são parte desta nova abordagem para os pacientes com diabetes. O reconhecimento de que o diabetes é uma doença heterogênea foi fundamental, sendo claramente demonstrado que nem todos os pacientes diabéticos pertencem a categorias de risco alto ou muito alto. Um porcentual elevado é composto por pacientes jovens, sem os fatores de risco clássicos, os quais podem ser classificados adequadamente em categorias de risco intermediário ou mesmo em baixo risco cardiovascular. O presente posicionamento revisa as melhores evidências atualmente disponíveis e propõe uma abordagem prática, baseada em risco, para o tratamento de pacientes com diabetes. Estruturação: perante este desafio e reconhecendo a natureza multifacetada da doença, a SBD uniu-se à Sociedade Brasileira de Cardiologia (SBC) e à Sociedade Brasileira de Endocrinologia e Metabolismo (SBEM), e formou um painel de especialistas, constituído por 28 cardiologistas e endocrinologistas, para revisar as melhores evidências disponíveis e elaborar uma diretriz contendo recomendações práticas para a estratificação de risco e prevenção da Doença Cardiovascular (DVC) no Diabetes Melito (DM). As principais inovações incluem: (1) considerações do impacto de novos hipolipemiantes e das novas medicações antidiabéticas no risco cardiovascular; (2) uma abordagem prática, baseada em fator de risco, para orientar o uso das estatinas, incluindo novas definições das metas da Lipoproteína de Baixa Densidade-colesterol (LDL-colesterol) e colesterol não Lipoproteína de Alta Densidade HDL; (3) uma abordagem baseada em evidências, para avaliar a isquemia miocárdica silenciosa (IMS) e a aterosclerose subclínica em pacientes com diabetes; (4) as abordagens mais atuais para o tratamento da hipertensão; e (5) recomendação de atualizações para o uso de terapia antiplaquetária. Esperamos que esta diretriz auxilie os médicos no cuidado dedicado aos pacientes com diabetes. Métodos: inicialmente, os membros do painel foram divididos em sete subcomitês para definirem os tópicos principais que necessitavam de uma posição atualizada das sociedades. Os membros do painel pesquisaram e buscaram no PubMed estudos clínicos randomizados e metanálises de estudos clínicos e estudos observacionais de boa qualidade, publicados entre 1997 e 2017, usando termos MeSH: [diabetes], [diabetes tipo 2], [doença cardiovascular], [estratificação de risco cardiovascular] [doença arterial coronária], [rastreamento], [isquemia silenciosa], [estatinas], [hipertensão], [ácido acetilsalicílico]. Estudos observacionais de baixa qualidade, metanálises com alta heterogeneidade e estudos transversais não foram incluídos, embora talvez tenham impactado no Nível de Evidência indicado. A opinião de especialistas foi usada quando os resultados das buscas não eram satisfatórios para um item específico. É importante salientar que este posicionamento não teve a intenção de incluir uma revisão sistemática rigorosa. Um manuscrito preliminar, destacando recomendações de graus e níveis de evidência (Quadro 1), foi esboçado. Este passo levou a várias discussões entre os membros dos subcomitês, que revisaram os achados e fizeram novas sugestões. O manuscrito foi, então, revisto pelo autor líder, encarregado da padronização do texto e da inclusão de pequenas alterações, sendo submetido à apreciação mais detalhada pelos membros dos comitês, buscando uma posição de consenso. Depois desta fase, o manuscrito foi enviado para a banca editorial e edição final, sendo encaminhado para publicação. Quadro 1 Graus de recomendações e níveis de evidências adotados nesta revisão Grau de recomendação Classe I A evidência é conclusiva ou, se não, existe consenso de que o procedimento ou tratamento é seguro e eficaz Classe II Há evidências contraditórias ou opiniões divergentes sobre segurança, eficácia, ou utilidade do tratamento ou procedimento Classe IIa As opiniões são favoráveis ao tratamento ou procedimento. A maioria dos especialistas aprova Classe IIb A eficácia é bem menos estabelecida, e as opiniões são divergentes Classe III Há evidências ou consenso de que o tratamento ou procedimento não é útil, eficaz, ou pode ser prejudicial Níveis de Evidência A Múltiplos estudos clínicos randomizados concordantes e bem elaborados ou metanálises robustas de estudos clínicos randomizados B Dados de metanálises menos robustas, um único estudo clínico randomizado ou estudos observacionais C Opinião dos especialistas

Brazilian guidelines on prevention of cardiovascular disease in patients with diabetes: a position statement from the Brazilian Diabetes Society (SBD), the Brazilian Cardiology Society (SBC) and the Brazilian Endocrinology and Metabolism Society (SBEM).

BACKGROUND: Since the first position statement on diabetes and cardiovascular prevention published in 2014 by the Brazilian Diabetes Society, the current view on primary and secondary prevention in diabetes has evolved as a result of new approaches on cardiovascular risk stratification, new cholesterol lowering drugs, and new anti-hyperglycemic drugs. Importantly, a pattern of risk heterogeneity has emerged, showing that not all diabetic patients are at high or very high risk. In fact, most younger patients who have no overt cardiovascular risk factors may be more adequately classified as being at intermediate or even low cardiovascular risk. Thus, there is a need for cardiovascular risk stratification in patients with diabetes. The present panel reviews the best current evidence and proposes a practical risk-based approach on treatment for patients with diabetes. MAIN BODY: The Brazilian Diabetes Society, the Brazilian Society of Cardiology, and the Brazilian Endocrinology and Metabolism Society gathered to form an expert panel including 28 cardiologists and endocrinologists to review the best available evidence and to draft up-to-date an evidence-based guideline with practical recommendations for risk stratification and prevention of cardiovascular disease in diabetes. The guideline includes 59 recommendations covering: (1) the impact of new anti-hyperglycemic drugs and new lipid lowering drugs on cardiovascular risk; (2) a guide to statin use, including new definitions of LDL-cholesterol and in non-HDL-cholesterol targets; (3) evaluation of silent myocardial ischemia and subclinical atherosclerosis in patients with diabetes; (4) hypertension treatment; and (5) the use of antiplatelet therapy. CONCLUSIONS: Diabetes is a heterogeneous disease. Although cardiovascular risk is increased in most patients, those without risk factors or evidence of sub-clinical atherosclerosis are at a lower risk. Optimal management must rely on an approach that will cover both cardiovascular disease prevention in individuals in the highest risk as well as protection from overtreatment in those at lower risk. Thus, cardiovascular prevention strategies should be individualized according to cardiovascular risk while intensification of treatment should focus on those at higher risk.

Brazilian guidelines on prevention of cardiovascular disease in patients with diabetes: a position statement from the Brazilian Diabetes Society (SBD), the Brazilian Cardiology Society (SBC) and the Brazilian Endocrinology and Metabolism Society (SBEM)

BACKGROUND: Since the first position statement on diabetes and cardiovascular prevention published in 2014 by the Brazilian Diabetes Society, the current view on primary and secondary prevention in diabetes has evolved as a result of new approaches on cardiovascular risk stratification, new cholesterol lowering drugs, and new anti-hyperglycemic drugs. Importantly, a pattern of risk heterogeneity has emerged, showing that not all diabetic patients are at high or very high risk. In fact, most younger patients who have no overt cardiovascular risk factors may be more adequately classified as being at intermediate or even low cardiovascular risk. Thus, there is a need for cardiovascular risk stratification in patients with diabetes. The present panel reviews the best current evidence and proposes a practical risk-based approach on treatment for patients with diabetes. MAIN BODY: The Brazilian Diabetes Society, the Brazilian Society of Cardiology, and the Brazilian Endocrinology and Metabolism Society gathered to form an expert panel including 28 cardiologists and endocrinologists to review the best available evidence and to draft up-to-date an evidence-based guideline with practical recommendations for risk stratification and prevention of cardiovascular disease in diabetes. The guideline includes 59 recommendations covering: (1) the impact of new anti-hyperglycemic drugs and new lipid lowering drugs on cardiovascular risk; (2) a guide to statin use, including new definitions of LDL-cholesterol and in non-HDL-cholesterol targets; (3) evaluation of silent myocardial ischemia and subclinical atherosclerosis in patients with diabetes; (4) hypertension treatment; and (5) the use of antiplatelet therapy.

An observational study regarding the rate of growth in vertical and radial growth phase superficial spreading melanomas.

The natural history of superficial spreading melanomas (SSMs) involves the progression from a radial growth phase (RGP) to a vertical growth phase (VGP). Currently, a patient's history represents the only method to estimate the rate of tumor growth. The present study aimed to verify whether the estimated rate of growth (ROG) of SSMs with a RGP or VGP exhibited any differences, and to evaluate the possible implications for the most important prognostic determinants. ROG was quantified as the ratio between Breslow's thickness in millimeters (mm) and the time of tumor growth in months, defined as the time between the date that the patient had first noticed the lesion in which melanoma subsequently developed and the date on which the patient first felt this lesion changed. A total of 105 patients (58 male and 47 female) were studied. Of these, 66 had VGP-SSMs, whilst 39 had RGP-only SSMs (RGP-SSMs). No significant differences in age and gender were observed between these groups. The mean Breslow's thickness in patients with VGP-SSMs was significantly greater than in patients with RGP-SSMs (0.78±0.68 vs. 0.48±0.22 mm, P=0.0096). Similarly, the ROG was observed to be higher in VGP-SSM vs. RGP-SSM patients (0.13±0.16 vs. 0.065±0.09 mm/month, P=0.0244). In patients with VGP-SSMs, Breslow's thickness and ROG were significantly higher for tumors with a mitotic rate of ≥1 mitosis/mm2 compared with those with <1 mitosis/mm2 (1.15±0.96 vs. 0.56±0.30 mm, P=0.0005; and 0.188±0.20 vs. 0.09±0.12 mm/month, P=0.0228, respectively). According to these results, two subsets of SSMs exist: The first is characterized by the presence of mitosis and a higher ROG, while the second exhibits a more indolent behavior and is characterized by an RGP only. Given the differences in the Breslow's thickness and ROG, clinicians must be aware of the possible diagnostic delay in these subsets of melanoma that, differently from true nodular melanomas, generally fulfill the classical ABCD clinical criteria.

Preoperative margin detection by digital dermoscopy in the traditional surgical excision of cutaneous squamous cell carcinomas.

BACKGROUND: The incomplete excision rate is a useful clinical and performance indicator, as it correlates with the treatment, the recurrence rate, the patient's morbidity and mortality. Methods of preoperative assessment of tumoral margins are therefore of paramount importance. Dermoscopy is a simple, non-invasive method, and can also be used for the diagnosis of epithelial tumors. OBJECTIVE: The aim of the study is to assess the preoperative evaluation of margins with digital dermoscopy, and compare it with clinical evaluation; to ameliorate the surgical performance. PATIENTS AND METHODS: Ninety-four patients with histologically confirmed squamous cell carcinomas were initially selected for traditional surgical excision. Subsequently, the margin of excision was determined by both clinical (group A, 46 patients) and dermoscopy evaluation (group B, 48 patients). RESULTS: In group A, margin involvement was observed in eight (17%) patients. Positive margins were seen in three (6%) patients of group B. CONCLUSIONS: Preoperative digital dermoscopy is a better method for detecting tumoral margins than clinical evaluation, and is an effective, simple, non-invasive method for the presurgical evaluation of margins.

Basosquamous cell carcinoma: a survey of 76 patients and a comparative analysis of basal cell carcinomas and squamous cell carcinomas.

BACKGROUND: Basosquamous carcinoma (BSC) is a rare epithelial tumor with a still confusing terminology. Since 2005 a more comprehensive and broader classification has existed. AIM: To retrospectively review our cases of BSC according to the new WHO definition and to re-evaluate their clinical and demographic characteristics and the margin involvement after traditional surgical excision. The data were compared with the same results obtained by basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs). PATIENTS AND METHODS: Histologically confirmed carcinomas observed in our Department during a sixteen-year period (1994-2011) were studied. Surgical excision was evaluated following the international guidelines. Histopathologic subtypes of BSC were classified in accordance with accepted criteria. RESULTS: Seventy-six patients had a BSC, 305 a SCC, 3,643 a BCC. There were significant differences among the median age of BSCs, the total BCCs and Non-Aggressive BCCs (74.7, 68.8 and 68.3 years respectively; p<0.05). BSC was more significantly located on head-neck region than Non-Aggressive BCC (p<0.04), and less on trunk than Mixed Histology BCC (p<0.01) and Non-Aggressive BCC (p<0.005). BSC has higher prevalence of positive margins after excision than total (p<0.03) and Non-Aggressive BCC (p<0.001). CONCLUSION: Basosquamous carcinoma fits to a tumor type with a different behavior pattern from non-aggressive basal cell carcinoma and more similar to squamous cell carcinoma or aggressive variants of basal cell carcinoma. Its infiltrative growth and the stromal reaction patterns give enough evidence to support the notion of considering basosquamous carcinoma as a relatively aggressive tumor.

Usefulness of margin detection by digital dermoscopy in the traditional surgical excision of basal cell carcinomas of the head and neck including infiltrative/morpheaform type.

Incomplete or suboptimal surgical excision of basal cell carcinoma of the head and neck is a relatively frequent occurrence. Methods of preoperative assessment of tumoral margins are therefore of paramount importance. The aim of this study was to compare the preoperative evaluation of margins with digital dermoscopy and clinical definition. One hundred and 12 patients with histologically confirmed basal cell carcinoma were selected for surgical excision. Subsequently, the margin of excision was determined by either clinical (45 patients) or dermoscopic evaluation (67 patients). After pre-surgical clinical evaluation, 22% of histological specimens of excised basal cell carcinoma showed suboptimal margins of excision. Pre-surgical dermoscopic evaluation had only 7% suboptimal excision. Preoperative digital dermoscopy is a better method to determine tumoral margins than clinical evaluation alone. Indeed, preoperative digital dermoscopy is an effective, simple, non-invasive procedure for the pre-surgical determination of margins.