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1.
Diabetes Obes Metab ; 2020 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-32239659

RESUMO

AIMS: To comprehensively evaluate the safety of dapagliflozin in patients with type 2 diabetes (T2DM) with emphasis placed on potential safety concerns related to the SGLT2-inhibitors class. METHODS: In DECLARE-TIMI 58, 17,160 patients with T2DM were randomized to dapagliflozin or placebo and followed for a median of 4.2 years. Safety was evaluated in 17,143 patients receiving at least one dose of study drug. RESULTS: Acute kidney injury occurred less frequently with dapagliflozin, and adverse events suggestive of volume depletion were balanced between treatment groups, both irrespective of baseline eGFR, blood pressure, diuretic or loop diuretic use (interaction-p-values >0.05). Fractures and malignancies were balanced irrespective of sex, diabetes duration or smoking (interaction p-values >0.05) and fewer cases of bladder cancer occurred in the dapagliflozin vs. placebo group. Diabetic ketoacidosis (DKA) was very rare, but more frequent with dapagliflozin vs. placebo (27 vs. 12 patients with events; p=0.02), yet signs, symptoms and contributing factors were similar in both groups. Major hypoglycemia occurred less frequently with dapagliflozin vs. placebo regardless of baseline use of either insulin or sulfonylureas (interaction p-values >0.05). There were more adverse events of genital infections leading to discontinuation of study drug in the dapagliflozin vs. placebo group, but serious genital infections were few and balanced between treatment groups. Urinary tract infections, acute pyelonephritis and urosepsis were also balanced between treatment groups. CONCLUSIONS: Dapagliflozin was well tolerated. The long duration and large number of patient-years in DECLARE-TIMI 58 comprehensively addressed previous safety questions, confirming the robust safety profile of dapagliflozin. This article is protected by copyright. All rights reserved.

2.
Eur J Endocrinol ; 182(4): C13-C15, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32061161

RESUMO

Endocrine disorders such as Cushing's syndrome and hypothyroidism may cause weight gain and exacerbate metabolic dysfunction in obesity. Other forms of endocrine dysfunction, particularly gonadal dysfunction (predominantly testosterone deficiency in men and polycystic ovarian syndrome in women), and abnormalities of the hypothalamic-pituitary-adrenal axis, the growth hormone-IGF-1 system and vitamin D deficiency are common in obesity. As a result, endocrinologists may be referred people with obesity for endocrine testing and asked to consider treatment with various hormones. A recent systematic review and associated guidance from the European Society of Endocrinology provide a useful evidence summary and clear guidelines on endocrine testing and treatment in people with obesity. With the exception of screening for hypothyroidism, most endocrine testing is not recommended in the absence of clinical features of endocrine syndromes in obesity, and likewise hormone treatment is rarely needed. These guidelines should help reduce unnecessary endocrine testing in those referred for assessment of obesity and encourage clinicians to support patients with their attempts at weight loss, which if successful has a good chance of correcting any endocrine dysfunction.


Assuntos
Doenças do Sistema Endócrino/complicações , Doenças do Sistema Endócrino/diagnóstico , Obesidade/etiologia , Síndrome de Cushing/complicações , Feminino , Glucocorticoides/metabolismo , Hormônios/análise , Hormônios/uso terapêutico , Humanos , Hipogonadismo/complicações , Hipotireoidismo/complicações , Masculino , Síndrome do Ovário Policístico/complicações
3.
Diabetes Obes Metab ; 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32072735

RESUMO

AIM: To assess the effects of dapagliflozin plus saxagliptin plus metformin versus glimepiride plus metformin on liver fat (proton density fat fraction) and visceral and subcutaneous adipose tissue volumes over 52 weeks of treatment. MATERIALS AND METHODS: This was a magnetic resonance imaging substudy of a 52-week, multicentre, randomized, double-blind, parallel-group trial that evaluated the efficacy and safety of dapagliflozin 10 mg/day plus saxagliptin 5 mg/day versus titrated glimepiride 1-6 mg (1, 2, 3, 4 or 6 mg) in 82 patients with type 2 diabetes (HbA1c 7.5%-10.5%) on metformin ≥1500 mg/day background. Analyses were exploratory and not controlled for multiplicity; P-values are nominal. RESULTS: Magnetic resonance imaging was performed on 59 patients; liver fat and adipose tissue volumes were analysed for 59 and 57 patients, respectively. There was a significant >30% reduction from baseline in liver fat (P = 0.007) and >10% reduction in adipose tissue volumes (P < 0.01) with dapagliflozin plus saxagliptin plus metformin at week 52 versus glimepiride plus metformin. In the full-study population, dapagliflozin plus saxagliptin plus metformin decreased body weight and serum alanine aminotransferase and aspartate aminotransferase levels over 52 weeks. CONCLUSIONS: Dapagliflozin plus saxagliptin significantly decreased liver fat and adipose tissue volume versus glimepiride, and reduced serum liver enzyme levels, indicating a favourable metabolic profile of dapagliflozin plus saxagliptin in patients with type 2 diabetes on metformin therapy.

4.
Diabetes Obes Metab ; 2020 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-32090404

RESUMO

AIM: To investigate whether the cardiovascular and renal benefits observed with dapagliflozin in the DECLARE-TIMI 58 trial are also observed in patients with short and long-standing diabetes. MATERIALS AND METHODS: This post hoc analysis studied the dual primary efficacy endpoints, a composite of cardiovascular death or hospitalization for heart failure (CVD/HHF) and major adverse cardiovascular events (MACE; CVD, myocardial infarction [MI], ischaemic stroke) by diabetes duration. RESULTS: Of the 17 160 patients, 3836 had diabetes duration of ≤5 years, 4731 >5-10 years, 3952 >10-15 years, 2433 >15-20 years and 2206 >20 years. Dapagliflozin reduced the risk of CVD/HHF by a similar amount across diabetes duration subgroups, ranging from HR 0.79 (0.58-1.06) in patients with diabetes duration of ≤5 years to 0.75 (0.55-1.03) in those patients with diabetes duration of >20 years (interaction trend P-value 0.76). Hazard ratios (HRs) for MACE ranged from 1.08 (0.87-1.35) in patients with diabetes duration of ≤5 years to 0.67 (0.52-0.86) in those patients with diabetes duration of >20 years (interaction trend P-value 0.004). This was driven by greater reductions in the risk of MI and ischaemic stroke with dapagliflozin in patients with long-standing diabetes (interaction trend P-values 0.019 and 0.015, respectively). The duration-based MACE heterogeneity was apparent in those with or without a history of prior MI and in those with multiple risk factors. The renal-specific outcome was reduced with dapagliflozin with HRs ranging from 0.79 (0.47-1.34) in patients with diabetes duration of ≤5 years to 0.42 (0.25-0.72) in those patients with diabetes duration of >20 years (interaction trend P-value 0.084). CONCLUSIONS: Dapagliflozin reduced the risk of CVD/HHF consistently, regardless of diabetes duration, whereas the treatment effect for MACE differed by duration subgroups, with significant reductions with dapagliflozin in patients with long-standing diabetes.

5.
Circulation ; 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-31983236

RESUMO

Background: Atrial fibrillation (AF) and atrial flutter (AFL) are associated with both diabetes and its related comorbidities including hypertension, obesity, and heart failure (HF). SGLT2i have been shown to lower blood pressure, reduce weight, have salutary effects on left ventricular remodeling and reduce hospitalization for HF and cardiovascular death in patients with type 2 diabetes (T2DM). We therefore investigated whether SGLT2i may also reduce the risk of AF/AFL. Methods: DECLARE-TIMI 58 studied the efficacy and safety of the SGLT2i dapagliflozin versus placebo in 17160 patients with T2DM and either multiple risk factors for (MRF, n=10186) or known atherosclerotic cardiovascular disease (ASCVD, n=6974). Here, we explore the effect of dapagliflozin on the first and total number of AF/AFL events in patients with (n=1,116) and without prevalent AF/AFL using Cox and negative binomial models, respectively. AF/AFL events were identified by search of the safety database using the MedDRA Preferred Terms ("atrial fibrillation", "atrial flutter"). Results: Dapagliflozin reduced the risk of AF/AFL events by 19% (264 versus 325 events, 7.8 versus 9.6 events per 1000 patient-years, hazard ratio 0.81, 95% CI 0.68 to 0.95, P=0.009). The reduction in AF/AFL events was consistent regardless of presence or absence of a history of AF/AFL at baseline (Prior AF/AFL: HR 0.79, 95% CI 0.58-1.09, No AF/AFL: HR 0.81, 95% CI 0.67-0.98; P-INT 0.89). Similarly, presence of ASCVD (HR 0.83, 95% CI 0.66-1.04) versus MRF (HR 0.78, 95% CI 0.62-0.99; P-INT 0.72), or a history of HF (HF: HR 0.78, 95% CI 0.55-1.11, No HF: HR 0.81, 95% CI 0.68-0.97; P-INT 0.88) did not modify the reduction in AF/AFL events observed with dapagliflozin. Moreover, there was no effect modification by sex, history of ischemic stroke, HbA1c, body mass index, blood pressure, or eGFR (all P-INT>0.20). Dapagliflozin also reduced the total number (first and recurrent) of AF/AFL events (337 versus 432; incidence rate ratio 0.77, 95% CI 0.64-0.92, P=0.005). Conclusions: Dapagliflozin decreased the incidence of reported episodes of AF/AFL adverse events in high-risk patients with T2DM. This effect was consistent regardless of the patients' prior history of AF, ASCVD, or HF. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT01730534.

6.
Lancet Diabetes Endocrinol ; 8(1): 27-35, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31862149

RESUMO

BACKGROUND: Cardiovascular and kidney outcome trials have shown that sodium-glucose co-transporter-2 (SGLT2) inhibitors slow progression of chronic kidney disease in patients with type 2 diabetes with or without chronic kidney disease. The aim of this study was to assess whether these benefits extend to patients with type 2 diabetes treated in routine clinical practice. METHODS: CVD-REAL 3 was a multinational observational cohort study in which new users of SGLT2 inhibitors and other glucose-lowering drugs with measurements of estimated glomerular filtration rate (eGFR) before and after (within 180 days) initiation were identified via claims, medical records, and national registries in Israel, Italy, Japan, Taiwan, and the UK. Propensity scores for SGLT2 inhibitor initiation were developed in each country, with 1:1 matching with initiators of other glucose-lowering drugs. Propensity score included (in addition to other clinical and demographic variables) baseline eGFR and eGFR slope before SGLT2 inhibitor or other glucose-lowering drug initiation. The main outcome measure was rate of eGFR decline (slope) calculated with a linear mixed regression model. Differences in eGFR slope between SGLT2 inhibitors and other glucose-lowering drugs were calculated and pooled. We also assessed a composite outcome of 50% eGFR decline or end-stage kidney disease. FINDINGS: After propensity matching, there were 35 561 episodes of treatment initiation in each group, from 65 231 individual patients. Dapagliflozin, empagliflozin, canagliflozin, ipragliflozin, tofogliflozin, and luseogliflozin accounted for 57·9%, 34·1%, 5·7%, 1·4%, 0·5%, and 0·4% of SGLT2 inhibitor initiation episodes, respectively. At baseline, 29 363 (41·3%) of 71 122 initiations were in women, mean age was 61·3 years, mean HbA1c was 72 mmol/mol (8·71%), and mean eGFR was 90·7 mL/min per 1·73 m2. During follow-up, SGLT2 inhibitor initiation was associated with reduced eGFR decline (difference in slope for SGLT2 inhibitors vs other glucose-lowering drugs 1·53 mL/min per 1·73 m2 per year, 95% CI 1·34-1·72, p<0·0001). During a mean follow-up of 14·9 months, 351 composite kidney outcomes occurred: 114 (3·0 events per 10 000 patient-years) among initiators of SGLT2 inhibitors and 237 (6·3 events per 10 000 patient-years) among initiators of other glucose-lowering drugs (hazard ratio 0·49, 95% CI 0·35-0·67; p<0·0001). These findings were consistent across countries (pheterogeneity 0·10) and prespecified subgroups. INTERPRETATION: In this large, international, real-world study of patients with type 2 diabetes, initiation of SGLT2 inhibitor therapy was associated with a slower rate of kidney function decline and lower risk of major kidney events compared with initiation of other glucose-lowering drugs. These data suggest that the benefits of SGLT2 inhibitors on kidney function identified in clinical trials seem to be largely generalisable to clinical practice. FUNDING: AstraZeneca.

7.
Diabetes Care ; 43(2): 468-475, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31843945

RESUMO

OBJECTIVE: Data regarding the effects of sodium-glucose cotransporter 2 inhibitors in the elderly (age ≥65 years) and very elderly (age ≥75 years) are limited. RESEARCH DESIGN AND METHODS: The Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 assessed cardiac and renal outcomes of dapagliflozin versus placebo in patients with type 2 diabetes. Efficacy and safety outcomes were studied within age subgroups for treatment effect and age-based treatment interaction. RESULTS: Of the 17,160 patients, 9,253 were <65 years of age, 6,811 ≥65 to <75 years, and 1,096 ≥75 years. Dapagliflozin reduced the composite of cardiovascular death or hospitalization for heart failure consistently, with a hazard ratio (HR) of 0.88 (95% CI 0.72, 1.07), 0.77 (0.63, 0.94), and 0.94 (0.65, 1.36) in age-groups <65, ≥65 to <75, and ≥75 years, respectively (interaction P value 0.5277). Overall, dapagliflozin did not significantly decrease the rates of major adverse cardiovascular events, with HR 0.93 (95% CI 0.81, 1.08), 0.97 (0.83, 1.13), and 0.84 (0.61, 1.15) in age-groups <65, ≥65 to <75, and ≥75 years, respectively (interaction P value 0.7352). The relative risk reduction for the secondary prespecified cardiorenal composite outcome ranged from 18% to 28% in the different age-groups with no heterogeneity. Major hypoglycemia was less frequent with dapagliflozin versus placebo, with HR 0.97 (95% CI 0.58, 1.64), 0.50 (0.29, 0.84), and 0.68 (0.29, 1.57) in age-groups <65, ≥65 to <75, and ≥75 years, respectively (interaction P value 0.2107). Safety outcomes, including fractures, volume depletion, cancer, urinary tract infections, and amputations were balanced with dapagliflozin versus placebo, and acute kidney injury was reduced, all regardless of age. Genital infections that were serious or led to discontinuation of the study drug and diabetic ketoacidosis were uncommon, yet more frequent with dapagliflozin versus placebo, without heterogeneity (interaction P values 0.1058 and 0.8433, respectively). CONCLUSIONS: The overall efficacy and safety of dapagliflozin are consistent regardless of age.

8.
Peptides ; : 170208, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31759125

RESUMO

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon like peptide (GLP-1) are the two incretin hormones secreted by the enteroendocrine system in response to nutrient ingestion. Compared with GLP-1, GIP is less well studied as a hormone or as a potential pharmacological treatment. Beyond its insulinotropic effects in the pancreas, GIP has important biological actions in many other tissues but its role in dietary fat metabolism and lipid storage in adipose tissue has been most studied. It is still unclear if such effects of GIP on adipose tissue/fat metabolism are protective or deleterious in the long term. Antagonising GIP actions through genetic and chemical disruption in mice models prevented diet induced obesity and improved insulin sensitivity. Whilst such effects of GIP antagonism are yet to be evaluated in humans, recent studies using combined GIP and GLP-1 agonists have shown weight reduction and improved glycaemic control in people with type 2 diabetes (T2D). Therapeutic manipulation of GIP physiology is intriguing in that both agonists and antagonists of GIP are being investigated to explore their potential weight-reducing and other metabolic benefits in people with obesity, T2D and non-alcoholic fatty liver disease (NAFLD). This review will discuss the physiological effects of GIP on fat metabolism in human adipose and other non-adipose tissues such as liver, pancreas, skeletal muscle and heart, describe where the actions of GIP may contribute to the pathophysiology of obesity, T2D and NAFLD and finally describe the therapeutic implications of GIP antagonism and agonism in these conditions.

9.
Diabetes Ther ; 10(6): 2023, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31583646

RESUMO

The authors of the article would like to amend the article title to 'Cardiac Autonomic Neuropathy in Obesity, Metabolic Syndrome and Prediabetes: A Narrative Review'.

10.
11.
Diabetes Ther ; 10(6): 2201-2217, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31606880

RESUMO

INTRODUCTION: Ipragliflozin is a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor approved for the treatment of type 2 diabetes mellitus (T2DM). The objective of this pooled analysis was to characterise the safety profile of ipragliflozin based on safety data from published randomised controlled trials. METHODS: Safety data from 12 randomised, phase II/III/IV placebo-controlled, parallel group, comparative studies of ipragliflozin in patients with T2DM were pooled. Treatment-emergent adverse events (TEAEs) were analysed for patients who had received at least one dose of ipragliflozin 50 mg (n = 1209) or placebo (n = 796) in studies lasting for up to 24 weeks. TEAEs of special interest and serious adverse events (SAEs) were assessed, as well as abnormal laboratory test and vital sign measurements. RESULTS: The overall incidences of TEAEs and SAEs between the ipragliflozin and placebo groups were similar, 63.8% vs 59.3% and 2.5% vs 3.3%, respectively. The incidence of TEAEs leading to permanent discontinuation was lower for ipragliflozin (3.6%) than placebo (6.5%). The incidences of TEAEs of special interest including those related to urinary tract infection, cardiovascular events, renal disorder, fracture, malignant tumours and hypoglycaemia were also similar between the groups. Genital infections were more frequent with ipragliflozin (2.4%) than placebo (0.6%), as were pollakiuria/polyuria (6.0% vs 2.0%), volume depletion (4.9% vs 1.8%) and skin/subcutaneous tissue disorders (7.7% vs 4.4%). There were no reported cases of diabetic ketoacidosis, fractures, lower-limb amputation or Fournier's gangrene in ipragliflozin-treated patients across the 12 studies. CONCLUSION: In randomised, placebo-controlled trials of patients with T2DM, ipragliflozin was well tolerated, with a similar overall incidence of TEAEs to placebo. No new safety signals were observed. TRIAL REGISTRATION NUMBERS: NCT01071850, NCT00621868, NCT01057628, NCT01117584, NCT01135433, NCT01225081, NCT01242215, NCT02175784, NCT01505426, NCT02452632, NCT02794792, NCT01316094. FUNDING: Astellas Pharma Inc.

12.
Circulation ; 140(19): 1569-1577, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31474116

RESUMO

BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) are at increased risk of developing heart failure. Sodium-glucose cotransporter-2 inhibitors reduce the risk of hospitalization for heart failure (HHF) in patients with T2DM. We aimed to develop and validate a practical clinical risk score for HHF in patients with T2DM and assess whether this score can identify high-risk patients with T2DM who have the greatest reduction in risk for HHF with a sodium-glucose cotransporter-2 inhibitor. METHODS: We developed a clinical risk score for HHF in 8212 patients with T2DM in the placebo arm of SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53). Candidate variables were assessed using multivariable Cox regression, and independent clinical risk indicators achieving statistical significance of P<0.001 were included in the risk score. We externally validated the score in 8578 patients with T2DM in the placebo arm of DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58). The relative and absolute risk reductions in HHF with the sodium-glucose cotransporter-2 inhibitor dapagliflozin were assessed by baseline HHF risk. RESULTS: Five clinical variables were independent risk predictors of HHF: prior heart failure, history of atrial fibrillation, coronary artery disease, estimated glomerular filtration rate, and urine albumin-to-creatinine ratio. A simple integer-based score (0-7 points) using these predictors identified a >20-fold gradient of HHF risk (P for trend <0.001) in both the derivation and validation cohorts, with C indices of 0.81 and 0.78, respectively. Although relative risk reductions with dapagliflozin were similar for patients across the risk scores (25%-34%), absolute risk reductions were greater in those at higher baseline risk (1-sided P for trend=0.04), with high-risk (2 points) and very-high-risk (≥3 points) patients having 1.5% and 2.7% absolute reductions in Kaplan-Meier estimates of HHF risk at 4 years, respectively. CONCLUSIONS: Risk stratification using a novel clinical risk score for HHF in patients with T2DM identifies patients at higher risk for HHF who derive greater absolute benefit from sodium-glucose cotransporter-2 inhibition. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01107886 and NCT01730534.

13.
Diabetes Ther ; 10(6): 1995-2021, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31552598

RESUMO

Cardiac autonomic neuropathy (CAN) is a major complication of type 1 and type 2 diabetes mellitus (T1DM and T2DM). The increased morbidity, cardiovascular and all-cause mortality associated with CAN is established from numerous epidemiological studies. However, CAN is increasingly recognised in people with prediabetes (pre-DM) and the metabolic syndrome (MetS) with a reported prevalence up to 11% and 24% respectively. CAN is associated with components of MetS including hypertension and obesity, predating hyperglycaemia. The aetiology of CAN is multifactorial and there is a reciprocal relationship with insulin resistance and MetS. Obstructive sleep apnoea (OSA) is also associated with CAN possibly through MetS and an independent mechanism. An estimated global prevalence of the impaired glucose tolerance (IGT) form of pre-DM of 587 million people by 2045 means CAN will become a major clinical problem. CAN is independently associated with silent myocardial ischaemia, major cardiovascular events, myocardial dysfunction and cardiovascular mortality. Screening for CAN in pre-DM using risk scores with analysis of heart rate variability (HRV) or Sudoscan is important to allow earlier treatment at a reversible stage. The link between obesity and CAN highlights the therapeutic potential of lifestyle interventions including diet and physical activity to reverse MetS and prevent CAN. Weight loss achieved using these dietary and exercise lifestyle interventions improves the sympathetic and parasympathetic HRV indices of cardiac autonomic function. Further research is needed to identify high-risk populations of people with pre-DM or obesity that might benefit from targeted pharmacotherapy including metformin, sodium/glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-1) analogues. Bariatric surgery also improves HRV through weight loss which might also prevent CAN in severe obesity. This article reviews the literature on CAN in obesity, pre-DM and MetS, to help determine a rationale for screening, early intervention treatment and formulate future research questions in this highly prevalent condition.

14.
Diabetes Res Clin Pract ; 155: 107791, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31325543

RESUMO

AIMS: Early treatment intensification for type 2 diabetes mellitus (T2DM) is often required to achieve glycaemic control and avoid longer-term complications. We assessed associations between early versus later dapagliflozin initiation with changes in glucose control, weight, and blood pressure using UK Clinical Practice Research Datalink (CPRD) data. METHODS: People with T2DM aged ≥18 years, initiating dapagliflozin between November 2012 and August 2016 and with prior oral T2DM therapy (N = 3774), were included. The relationship between early (first intensification after metformin or sulfonylurea monotherapy) and later (second or higher-order intensification) dapagliflozin use and baseline changes in glycated haemoglobin A1c (HbA1c; ≥1.0% absolute reduction), weight (≥5.0% relative loss), and systolic blood pressure (SBP; ≥2 mmHg absolute reduction) after 6-12 months were assessed. RESULTS: Overall, 25% of patients (951 of 3774) were early users and 75% (2823 of 3774) were later users. Later users were older, more likely to be men, and had longer disease duration. Early and later users had similar baseline mean HbA1c levels. For early versus later users, respectively, baseline-adjusted mean (95% confidence interval [CI]) reductions were 1.54% (-1.65, -1.44) versus 1.02% (-1.08, -0.97) in HbA1c, 3.31% (-4.37, -2.25) versus 4.06% (-5.05, -3.07) in weight, and 2.50 mm Hg (-3.89, -1.11) versus 2.84 mm Hg (-3.67, -2.01) in SBP. Early versus later use was associated with a greater likelihood of adjusted HbA1c reduction of ≥1% (odds ratio: 1.68, 95% CI: 1.15-2.45). CONCLUSIONS: Glycaemic benefits were greater with early versus later dapagliflozin intensification. These results support broader and earlier dapagliflozin use.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Glicemia/análise , Pressão Sanguínea , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/uso terapêutico , Hemoglobina A Glicada/análise , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Adulto , Idoso , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Atenção Primária à Saúde , Estudos Retrospectivos , Fatores de Tempo , Reino Unido/epidemiologia
16.
Lancet Diabetes Endocrinol ; 7(8): 606-617, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31196815

RESUMO

BACKGROUND: Sodium-glucose co-transporter-2 (SGLT2) inhibitors have shown beneficial effects on renal outcomes mainly in patients with established atherosclerotic cardiovascular disease. Here we report analyses of renal outcomes with the SGLT2 inhibitor dapagliflozin in the DECLARE-TIMI 58 cardiovascular outcomes trial, which included patients with type 2 diabetes both with and without established atherosclerotic cardiovascular disease and mostly with preserved renal function. METHODS: In DECLARE-TIMI 58, patients with type 2 diabetes, HbA1c 6·5-12·0% (47·5-113·1 mmol/mol), with either established atherosclerotic cardiovascular disease or multiple risk factors, and creatinine clearance of at least 60 mL/min were randomly assigned (1:1) to 10 mg dapagliflozin or placebo once daily. A prespecified secondary cardiorenal composite outcome was defined as a sustained decline of at least 40% in estimated glomerular filtration rate [eGFR] to less than 60 mL/min per 1·73m2, end-stage renal disease (defined as dialysis for at least 90 days, kidney transplantation, or confirmed sustained eGFR <15mL/min per 1·73 m2), or death from renal or cardiovascular causes; a prespecified renal-specific composite outcome was the same but excluding death from cardiovascular causes. In this renal analysis, we report findings for the components of these composite outcomes, subgroup analysis of these composite outcomes, and changes in eGFR at different timepoints. DECLARE-TIMI 58 is registered with ClinicalTrials.gov, number NCT01730534. FINDINGS: The trial took place between April 25, 2013, and Sept 18, 2018; median follow-up was 4·2 years (IQR 3·9-4·4). Of the 17 160 participants who were randomly assigned, 8162 (47·6%) had an eGFR of at least 90 mL/min per 1·73 m2, 7732 (45·1%) had an eGFR of 60 to less than 90 mL/min per 1·73 m2, and 1265 (7·4%) had an eGFR of less than 60 mL/min per 1·73 m2 at baseline (one participant had missing data for eGFR); 6974 (40·6%) had established atherosclerotic cardiovascular disease and 10 186 (59·4%) had multiple risk factors. As previously reported, the cardiorenal secondary composite outcome was significantly reduced with dapagliflozin versus placebo (hazard ratio [HR] 0·76, 95% CI 0·67-0.87; p<0·0001); excluding death from cardiovascular causes, the HR for the renal-specific outcome was 0·53 (0·43-0·66; p<0·0001). We identified a 46% reduction in sustained decline in eGFR by at least 40% to less than 60 mL/min per 1·73 m2 (120 [1·4% vs 221 [2·6%]; HR 0·54 [95% CI 0·43-0·67]; p<0·0001). The risk of end-stage renal disease or renal death was lower in the dapagliflozin group than in the placebo group (11 [0·1%] vs 27 [0·3%]; HR 0·41 [95% CI 0·20-0·82]; p=0·012). Both the cardiorenal and renal-specific composite outcomes were improved with dapagliflozin versus placebo across various prespecified subgroups, including those defined by baseline eGFR (cardiorenal outcome pinteraction=0·97; renal-specific outcome pinteraction=0·87) and the presence or absence of established atherosclerotic cardiovascular disease (cardiorenal outcome pinteraction=0·67; renal-specific outcome pinteraction=0·72). 6 months after randomisation, the mean decrease in eGFR was larger in the dapagliflozin group than in the placebo group. The mean change equalised by 2 years, and at 3 and 4 years the mean decrease in eGFR was less with dapagliflozin than with placebo. INTERPRETATION: Dapagliflozin seemed to prevent and reduce progression of kidney disease compared with placebo in this large and diverse population of patients with type 2 diabetes with and without established atherosclerotic cardiovascular disease, most of whom had preserved renal function. FUNDING: AstraZeneca.

17.
Diabetes Obes Metab ; 21 Suppl 2: 9-18, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31081592

RESUMO

Inhibition of glucose transport in the kidney, to produce glucosuria and thus directly lower blood glucose seems a remarkably simple way to treat diabetes (type 1 or type 2). The development of sodium-glucose co-transporter-2 (SGLT2) inhibitors and their subsequent clinical development has on one hand shown this to be true, but at another level has helped reveal a complex web of interacting effects starting in the kidney and modulating multiple metabolic pathways in a variety of other organs. These underlie the now clear benefits of this class of drugs in the management of type 2 diabetes from glucose lowering, weight loss and blood pressure reduction through to the reductions in cardiovascular and renal complications observed in long-term outcomes trials. They also explain some of the adverse effects that have emerged, including the risk of diabetic ketoacidosis. This review describes the effects of SGLT2 inhibition in relation to this complex physiology, and shows how this can favourably alter the pathophysiology of type 2 diabetes.

18.
Obes Rev ; 20(6): 816-828, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30972878

RESUMO

We are facing a global epidemic of obesity and type 2 diabetes. Weight loss, in the context of obesity and type 2 diabetes, may improve glycaemic control and weight-related comorbidities, and in some cases, induce diabetes remission. Although lifestyle-based weight loss strategies may be initially successful, most are not effective long-term. There is an increasing need to consider pharmacological approaches to assist weight loss in diabetes-obesity. Older glucose-lowering agents may cause weight gain, whereas the newer drug classes, sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide receptor agonists (GLP-1 RAs), concomitantly target weight loss and glycaemic control. Clinical trial data suggest that both SGLT2i and GLP1 RAs cause a mean weight loss of approximately 2 to 3 kg but real-world evidence and clinical experience suggests a significant heterogeneity in the magnitude of the weight loss (GLP-1 RAs) or the magnitude of the actual weight loss is significantly less than anticipated (SGLT2i). Why do some individuals lose more weight than others in response to these pharmacological treatments? This review will first explore mechanisms by which body weight is regulated through control of energy balance and its dysregulation in obesity, and then consider how these mechanisms may be modulated therapeutically with SGLT2i and GLP1 RAs.

19.
Circulation ; 139(22): 2516-2527, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-30882239

RESUMO

BACKGROUND: Sodium glucose transporter-2 inhibitors reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus and a history of atherosclerotic cardiovascular disease. Because of their baseline risk, patients with previous myocardial infarction (MI) may derive even greater benefit from sodium glucose transporter-2 inhibitor therapy. METHODS: DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58) randomized 17 160 patients with type 2 diabetes mellitus and either established atherosclerotic cardiovascular disease (n=6974) or multiple risk factors (n=10 186) to dapagliflozin versus placebo. The 2 primary end points were composite of MACE (cardiovascular death, MI, or ischemic stroke) and the composite of cardiovascular death or hospitalization for heart failure. Those with previous MI (n=3584) made up a prespecified subgroup of interest. RESULTS: In patients with previous MI (n=3584), dapagliflozin reduced the relative risk of MACE by 16% and the absolute risk by 2.6% (15.2% versus 17.8%; hazard ratio [HR], 0.84; 95% CI, 0.72-0.99; P=0.039), whereas there was no effect in patients without previous MI (7.1% versus 7.1%; HR, 1.00; 95% CI, 0.88-1.13; P=0.97; P for interaction for relative difference=0.11; P for interaction for absolute risk difference=0.048), including in patients with established atherosclerotic cardiovascular disease but no history of MI (12.6% versus 12.8%; HR, 0.98; 95% CI, 0.81-1.19). There seemed to be a greater benefit for MACE within 2 years after the last acute event ( P for interaction trend=0.007). The relative risk reductions in cardiovascular death/hospitalization for heart failure were more similar, but the absolute risk reductions tended to be greater: 1.9% (8.6% versus 10.5%; HR, 0.81; 95% CI, 0.65-1.00; P=0.046) and 0.6% (3.9% versus 4.5%; HR, 0.85; 95% CI, 0.72-1.00; P=0.055) in patients with and without previous MI, respectively ( P interaction for relative difference=0.69; P interaction for absolute risk difference=0.010). CONCLUSIONS: Patients with type 2 diabetes mellitus and previous MI are at high risk of MACE and cardiovascular death/hospitalization for heart failure. Dapagliflozin appears to robustly reduce the risk of both composite outcomes in these patients. Future studies should aim to confirm the large clinical benefits with sodium glucose transporter-2 inhibitors we observed in patients with previous MI. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01730534.

20.
Circulation ; 139(22): 2528-2536, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-30882238

RESUMO

BACKGROUND: In DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58), the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the composite end point of cardiovascular death/hospitalization for heart failure (HHF) in a broad population of patients with type 2 diabetes mellitus. However, the impact of baseline left ventricular ejection fraction (EF) on the clinical benefit of sodium-glucose cotransporter 2 inhibition is unknown. METHODS: In the DECLARE-TIMI 58 trial, baseline heart failure (HF) status was collected from all patients, and EF was collected when available. HF with reduced EF (HFrEF) was defined as EF <45%. Outcomes of interest were the composite of cardiovascular death/HHF, its components, and all-cause mortality. RESULTS: Of 17 160 patients, 671 (3.9%) had HFrEF, 1316 (7.7%) had HF without known reduced EF, and 15 173 (88.4%) had no history of HF at baseline. Dapagliflozin reduced cardiovascular death/HHF more in patients with HFrEF (hazard ratio [HR], 0.62 [95% CI, 0.45-0.86]) than in those without HFrEF (HR, 0.88 [95% CI, 0.76-1.02]; P for interaction=0.046), in whom the treatment effect of dapagliflozin was similar in those with HF without known reduced EF (HR, 0.88 [95% CI, 0.66-1.17]) and those without HF (HR, 0.88 [95% CI, 0.74-1.03]). Whereas dapagliflozin reduced HHF both in those with (HR, 0.64 [95% CI, 0.43-0.95]) and in those without HFrEF (HR, 0.76 [95% CI, 0.62-0.92]), it reduced cardiovascular death only in patients with HFrEF (HR, 0.55 [95% CI, 0.34-0.90]) but not in those without HFrEF (HR, 1.08 [95% CI, 0.89-1.31]; P for interaction=0.012). Likewise, dapagliflozin reduced all-cause mortality in patients with HFrEF (HR, 0.59 [95% CI, 0.40-0.88;) but not in those without HFrEF (HR, 0.97 [95% CI, 0.86-1.10]; P for interaction=0.016). CONCLUSIONS: In the first sodium-glucose cotransporter 2 inhibitor cardiovascular outcome trial to evaluate patients with type 2 diabetes mellitus stratified by EF, we found that dapagliflozin reduced HHF in patients with and without HFrEF and reduced cardiovascular death and all-cause mortality in patients with HFrEF. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01730534.

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