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1.
Kidney Int ; 101(5): 874-877, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35461613

RESUMO

The progression of chronic kidney disease is difficult to stop once established. Metformin and sodium-glucose cotransporter 2 inhibitors show promise, but clinical trials with a head-to-head comparison in patients with more advanced (stage 3b-4) chronic kidney disease are largely lacking, partly for safety reasons. In this issue, Corremans et al. compare the effects of metformin and canagliflozin in rats with adenine-induced moderate (stage 2-4) chronic kidney disease. Metformin halted progression, whereas canagliflozin did not. This commentary puts the results in a wider clinical context.


Assuntos
Diabetes Mellitus Tipo 2 , Metformina , Insuficiência Renal Crônica , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Canagliflozina/efeitos adversos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Humanos , Hipoglicemiantes/efeitos adversos , Masculino , Metformina/farmacologia , Metformina/uso terapêutico , Ratos , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
3.
Kidney Int ; 101(5): 929-944, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35271933

RESUMO

Current treatment strategies for chronic kidney disease (CKD) mainly focus on controlling risk factors. Metformin, a first-line drug for type 2 diabetes, exerts beneficial pleiotropic actions beyond its prescribed use and incipient data have revealed protective effects against the development of kidney impairment. This study evaluated the therapeutic efficacy of metformin and canagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor recently approved by the United States Food and Drug Administration to treat diabetic nephropathy, in slowing the progression of established non-diabetic CKD. Rats with adenine-induced CKD were assigned to different treatment groups to receive either 200 mg/kg metformin, four or five weeks after the start of the adenine diet (established mild-moderate CKD), or 25 mg/kg canagliflozin four weeks after the start of the diet, by daily oral gavage administered during four weeks. Each treatment group was compared to a vehicle group. Chronic adenine dosing resulted in severe CKD in vehicle-treated rats as indicated by a marked rise in serum creatinine levels, a marked decrease in creatinine clearance, and a disturbed mineral metabolism. Metformin, but not canagliflozin, halted functional kidney decline. Additionally, kidneys of metformin-treated animals showed less interstitial area and inflammation as compared to the vehicle group. Proteomic analyses revealed that metformin's kidney-protective effect was associated with the activation of the Hippo signaling pathway, a highly conserved multiprotein kinase cascade that controls tissue development, organ size, cell proliferation, and apoptosis. Thus, metformin demonstrated therapeutic efficacy by halting the progression of established CKD in a rat model.


Assuntos
Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Metformina , Insuficiência Renal Crônica , Adenina/efeitos adversos , Animais , Canagliflozina/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/tratamento farmacológico , Feminino , Humanos , Masculino , Metformina/farmacologia , Metformina/uso terapêutico , Proteômica , Ratos , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico
4.
Nat Med ; 28(4): 809-813, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35228753

RESUMO

Large traditional clinical trials suggest that sodium-glucose co-transporter 2 inhibitors improve symptoms in patients with heart failure and reduced ejection fraction (HFrEF) and in patients with heart failure and preserved ejection fraction (HFpEF). In the midst of the Coronavirus Disease 2019 pandemic, we sought to confirm these benefits in a new type of trial that was patient centered and conducted in a completely remote fashion. In the CHIEF-HF trial ( NCT04252287 ), 476 participants with HF, regardless of EF or diabetes status, were randomized to 100 mg of canagliflozin or placebo. Enrollment was stopped early due to shifting sponsor priorities, without unblinding. The primary outcome was change in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ TSS) at 12 weeks. The 12-week change in KCCQ TSS was 4.3 points (95% confidence interval, 0.8-7.8; P = 0.016) higher with canagliflozin than with placebo, meeting the primary endpoint. Similar effects were observed in participants with HFpEF and in those with HFrEF and in participants with and without diabetes, demonstrating that canagliflozin significantly improves symptom burden in HF, regardless of EF or diabetes status. This randomized, double-blind trial, conducted without in-person interactions between doctor and patient, can serve as a model for future all-virtual clinical trials.


Assuntos
COVID-19 , Insuficiência Cardíaca , Inibidores do Transportador 2 de Sódio-Glicose , Disfunção Ventricular Esquerda , Canagliflozina/farmacologia , Canagliflozina/uso terapêutico , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Assistência Centrada no Paciente , Qualidade de Vida , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Volume Sistólico
5.
Arch Endocrinol Metab ; 66(1): 68-76, 2022 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-35263050

RESUMO

The lowest dosage of empagliflozin (10 mg) showed similar benefits on glycated hemoglobin (HbA1c) level, body weight, blood pressure, and total and cardiovascular mortality in comparison with the highest available dose (25 mg) in the EMPAREG trial. These findings have not been clearly demonstrated for canagliflozin and dapagliflozin. The objective was to compare the effect of different doses of SGLT2 inhibitors commercially available in Brazil on HbA1c and body weight of patients with type 2 diabetes. MEDLINE, Cochrane and Embase databases were searched from inception until 11th October 2021 for randomized controlled trials of SGLT2 inhibitors in type 2 diabetes patients, lasting at least 12 weeks. HbA1c and body weight variations were described using standard mean difference. We performed direct and indirect meta-analysis, as well as a meta-regression with medication doses as covariates. Eighteen studies were included, comprising 16,095 patients. In the direct meta-analysis, SGLT2 inhibitors reduced HbA1c by 0.62% (95% CI -0.66 to -0.59) and body weight by 0.60 kg (95% CI -0.64 to -0.55). In the indirect meta-analysis, canagliflozin 300 mg ranked the highest regarding reductions in HbA1c and body weight. The remaining medications and dosages were clinically similar, despite some statistically significant differences among them. Canagliflozin 300 mg seems to be more potent in reducing HbA1c and body weight in patients with type 2 diabetes. The remaining SGLT2 inhibitors at different doses lead to similar effects for both outcomes. Whether these glycemic and weight effects are reflected in lower mortality and cardiovascular events is still uncertain and may be a topic for further studies.


Assuntos
Diabetes Mellitus Tipo 2 , Hipoglicemiantes , Inibidores do Transportador 2 de Sódio-Glicose , Glicemia , Peso Corporal , Brasil , Canagliflozina/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hemoglobina A Glicada/análise , Humanos , Hipoglicemiantes/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
6.
Diabetes ; 71(5): 881-893, 2022 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-35108373

RESUMO

Chronic hyperglycemia is associated with low response to aerobic exercise training in rodent models and humans, including reduced aerobic exercise capacity and impaired oxidative remodeling in skeletal muscle. Here, we investigated whether glucose lowering with the sodium-glucose cotransporter 2 inhibitor (SGLT2i), canagliflozin (Cana; 30 mg/kg/day), could restore exercise training response in a model of hyperglycemia (low-dose streptozotocin [STZ]). Cana effectively prevented increased blood glucose in STZ-treated mice. After 6 weeks of voluntary wheel running, Cana-treated mice displayed improvements in aerobic exercise capacity, higher capillary density in striated muscle, and a more oxidative fiber-type in skeletal muscle. In contrast, these responses were blunted or absent in STZ-treated mice. Recent work implicates glucose-induced accumulation of skeletal muscle extracellular matrix (ECM) and hyperactivation of c-Jun N-terminal kinase (JNK)/SMAD2 mechanical signaling as potential mechanisms underlying poor exercise response. In line with this, muscle ECM accretion was prevented by Cana in STZ-treated mice. JNK/SMAD2 signaling with acute exercise was twofold higher in STZ compared with control but was normalized by Cana. In human participants, ECM accumulation was associated with increased JNK signaling, low VO2peak, and impaired metabolic health (oral glucose tolerance test-derived insulin sensitivity). These data demonstrate that hyperglycemia-associated impairments in exercise adaptation can be ameliorated by cotherapy with SGLT2i.


Assuntos
Hiperglicemia , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Canagliflozina/farmacologia , Canagliflozina/uso terapêutico , Matriz Extracelular/metabolismo , Glucose/metabolismo , Humanos , Hiperglicemia/tratamento farmacológico , Hiperglicemia/prevenção & controle , Camundongos , Atividade Motora , Músculo Esquelético/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Estreptozocina
8.
Adv Ther ; 39(4): 1642-1658, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35138572

RESUMO

INTRODUCTION: Teneligliptin/canagliflozin combination tablets, which combine a dipeptidyl peptidase-4 (DPP-4) inhibitor (teneligliptin) and a sodium-glucose cotransporter 2 (SGLT2) inhibitor (canagliflozin), are a treatment option for type 2 diabetes mellitus (T2DM) in Japan. This post-marketing surveillance evaluated the real-world safety and effectiveness of teneligliptin/canagliflozin combination tablets, and changes in self-reported adherence to oral antihyperglycaemic agents. METHODS: Japanese patients with T2DM who were prescribed the combination tablets for the first time between December 2017 and June 2018 were registered and followed up for 12 months. Safety and effectiveness were assessed in terms of adverse drug reactions (ADRs) and the changes in haemoglobin A1c (HbA1c) and body weight from baseline to 12 months with the last observation carried forward, respectively. Adherence was assessed using the Morisky Medication Adherence Scale 8. RESULTS: Overall, 821 patients were eligible for the analyses, including 733 who were prescribed the combination tablets for 12 months. ADRs and serious ADRs were reported in 4.38% and 0.85% of patients, respectively. Gastrointestinal disorders (0.97%) were the most common class of ADRs. No new safety concerns were identified beyond those described in the Japanese package insert. The changes in HbA1c and body weight from baseline to 12 months were - 0.43 ± 0.93% and - 1.29 ± 5.57 kg, respectively. The reductions in HbA1c at 12 months tended to be greater among patients who switched from either DPP-4 inhibitors (- 0.71 ± 0.89%) or SGLT2 inhibitors (- 0.51 ± 1.00%) relative to patients who switched from both (- 0.22 ± 0.88%). The decrease in body weight was greatest among patients who switched from DPP-4 inhibitors. An improvement in self-reported adherence to oral antihyperglycaemic agents occurred after switching to the combination tablets. CONCLUSION: Teneligliptin/canagliflozin combination tablets were effective and associated with an improvement in adherence without new safety concerns in Japanese patients with T2DM in real-world clinical practice. TRIAL REGISTRATION: JapicCTI-173778.


Teneligliptin/canagliflozin combination tablets are used as an option for the treatment of type 2 diabetes mellitus in Japan. We performed this surveillance to obtain data on the frequency of side effects (adverse drug reactions) and effectiveness (in terms of changes in haemoglobin A1c and body weight) in Japanese patients treated with teneligliptin/canagliflozin combination tablets in real-world clinical practice. We also asked patients to evaluate their adherence to oral antihyperglycaemic agents as part of their prescribed therapies. We collected data for up to 12 months. We detected no new safety concerns, other than those already described in the Japanese package insert for the combination tablets. In terms of effectiveness, we observed improvements in both haemoglobin A1c and body weight over 12 months of treatment. Furthermore, self-reported adherence to oral antihyperglycaemic agents improved after treatment with the combination tablets.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Glicemia , Peso Corporal , Canagliflozina/uso terapêutico , Diabetes Mellitus Tipo 2/epidemiologia , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Hemoglobina A Glicada/análise , Humanos , Hipoglicemiantes/efeitos adversos , Japão/epidemiologia , Vigilância de Produtos Comercializados , Pirazóis , Tiazolidinas
9.
J Hypertens ; 40(5): 996-1001, 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35221325

RESUMO

BACKGROUND: Canagliflozin is a sodium glucose-cotransporter-2 receptor inhibitor approved for the treatment of type 2 diabetes mellitus (T2DM). However, it is less prescribed due to increased LDL cholesterol (LDL-C), high incidence of urinary tract infection (UTI), high cost. Data on the effect of canagliflozin on blood pressure (BP) are also limited. We conducted a meta-analysis of randomized controlled trials (RCTs) to review dosedependent effects of canagliflozin on BP and lipids in patients with T2DM. METHODS: A meta-analysis of RCTs in patients with T2DM was conducted. MEDLINE, the Cochrane Library of Trials and Clinicaltrials.gov were searched for relevant studies from January 2008 to May 2021. RESULTS: Compared with placebo, canagliflozin 100 mg reduced SBP by 3.43 mmHg and DBP by 1.05 mmHg. Canagliflozin 100 mg increased LDL-C by 0.10mmol/l and HDL cholesterol (HDL-C) by 0.05 mmol/l. Compared with placebo, canagliflozin 300 mg reduced SBP by 4.75 mmHg and DBP by 1.69 mmHg. Canagliflozin 300 mg increased LDL-C by 0.16 mmol/l and HDL-C by 0.06 mmol/l. Compared with canagliflozin 100 mg, canagliflozin 300 mg further reduced SBP by 1.21 mmHg and DBP by 0.64 mmHg, and further increased LDL-C by 0.06 mmol/l and HDL-C by 0.02 mmol/l. Compared with placebo and canagliflozin 100 mg, canagliflozin 300 mg increased the risk of UTI. CONCLUSION: The current meta-analysis provides new evidence on different doses of canagliflozin as an antihypertensive agent in T2DM complicated by hypertension; however, LDL-C and the risk of UTI should be monitored.


Assuntos
Diabetes Mellitus Tipo 2 , Hipertensão , Pressão Sanguínea , Canagliflozina/uso terapêutico , LDL-Colesterol , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Hipertensão/tratamento farmacológico
10.
Diabetes Care ; 45(4): 965-974, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35120199

RESUMO

OBJECTIVE: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have well-documented cardioprotective effects but are underused, partly because of high cost. We aimed to develop a machine learning-based decision support tool to individualize the atherosclerotic cardiovascular disease (ASCVD) benefit of canagliflozin in type 2 diabetes. RESEARCH DESIGN AND METHODS: We constructed a topological representation of the Canagliflozin Cardiovascular Assessment Study (CANVAS) using 75 baseline variables collected from 4,327 patients with type 2 diabetes randomly assigned 1:1:1 to one of two canagliflozin doses (n = 2,886) or placebo (n = 1,441). Within each patient's 5% neighborhood, we calculated age- and sex-adjusted risk estimates for major adverse cardiovascular events (MACEs). An extreme gradient boosting algorithm was trained to predict the personalized ASCVD effect of canagliflozin using features most predictive of topological benefit. For validation, this algorithm was applied to the CANVAS-Renal (CANVAS-R) trial, comprising 5,808 patients with type 2 diabetes randomly assigned 1:1 to canagliflozin or placebo. RESULTS: In CANVAS (mean age 60.9 ± 8.1 years; 33.9% women), 1,605 (37.1%) patients had a neighborhood hazard ratio (HR) more protective than the effect estimate of 0.86 reported for MACEs in the original trial. A 15-variable tool, INSIGHT, trained to predict the personalized ASCVD effects of canagliflozin in CANVAS, was tested in CANVAS-R (mean age 62.4 ± 8.4 years; 2,164 [37.3%] women), where it identified patient phenotypes with greater ASCVD canagliflozin effects (adjusted HR 0.60 [95% CI 0.41-0.89] vs. 0.99 [95% CI 0.76-1.29]; Pinteraction = 0.04). CONCLUSIONS: We present an evidence-based, machine learning-guided algorithm to personalize the prescription of SGLT2 inhibitors for patients with type 2 diabetes for ASCVD effects.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Canagliflozina/uso terapêutico , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Fatores de Risco de Doenças Cardíacas , Humanos , Masculino , Fatores de Risco
11.
Diabetes Obes Metab ; 24(6): 1072-1083, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35166429

RESUMO

AIM: To define the proportional and absolute benefits of the sodium-glucose co-transporter-2 inhibitor canagliflozin in patients with type 2 diabetes (T2D) with and without peripheral arterial disease (PAD). MATERIALS AND METHODS: We pooled individual participant data from the CANVAS Program (n = 10 142) and CREDENCE trial (n = 4401). In this post hoc analysis, the main outcomes of interest were major adverse cardiovascular events (MACE: non-fatal myocardial infarction, non-fatal stroke or cardiovascular death), kidney outcomes, and extended major adverse limb events (MALE). Cox proportional hazards models were used to assess canagliflozin treatment effects in those with and without PAD. Absolute risk reductions per 1000 patients treated for 2.5 years were estimated using Poisson regression. RESULTS: Of 14 543 participants, 3159 (21.7%) had PAD at baseline. In patients with PAD, canagliflozin reduced MACE (hazard ratio, 0.76; 95% confidence interval, 0.62-0.92), with similar relative benefits for other cardiovascular and kidney outcomes in participants with or without PAD at baseline (all Pinteraction  > .268). There was no increase in the relative risk of extended MALE with canagliflozin, irrespective of baseline PAD history (Pinteraction  > .864). The absolute benefits of canagliflozin were greater in those with PAD. CONCLUSIONS: Patients with T2D and PAD derived similar relative cardiorenal benefits from canagliflozin treatment but higher absolute benefits compared with those without PAD, with no increase in extended MALE.


Assuntos
Canagliflozina , Diabetes Mellitus Tipo 2 , Doença Arterial Periférica , Canagliflozina/efeitos adversos , Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Nefropatias/epidemiologia , Doença Arterial Periférica/complicações , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos
12.
J Diabetes Res ; 2022: 7520632, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35224108

RESUMO

BACKGROUND: Several trials have assessed the antihyperglycemic effects of sodium/glucose cotransporter-2 inhibitors (SGLT2i) in patients with type 2 diabetes mellitus (T2DM). We conducted a quantitative analysis to assess the impact of SGLT2is on serum uric acid (SUA) in patients with T2DM. METHODS: Placebo-controlled trials published before 13 August 2021 were identified by searching PubMed, Embase, Web of Science, and Scopus. The intervention group received SGLT2i as monotherapy or add-on treatment, and the control group received a placebo that was replaced with SGLT2i. Clinical trials providing changes in SUA were included. The mean change of SUA, glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), and body weight were calculated (PROSPERO CRD42021287019). RESULTS: After screening of 1172 papers, 59 papers were included in the systematic review. A total of 55 trials (122 groups) of 7 types of SGLT2i on patients with T2DM were eligible for meta-analysis. All SGLT2is significantly decreased SUA levels compared with the placebo groups: empagliflozin mean difference (MD) = -40.98 µmol/L, 95% CI [-47.63, -34.32], dapagliflozin MD = -35.17 µmol/L, 95% CI [-39.68, -30.66], canagliflozin MD = -36.27 µmol/L, 95% CI [-41.62, -30.93], luseogliflozin MD = -24.269 µmol/L, 95% CI [-33.31, -15.22], tofogliflozin MD = -19.47 µmol/L, 95% CI [-27.40, -11.55], and ipragliflozin MD = -18.85 µmol/L, 95% CI [-27.20, -10.49]. SGLT2i also decreased FPG, body weight, and HbA1c levels. SUA reduction persisted during long-term treatment with SGLT2i (except for empagliflozin), while the SUA reduction was affected by the duration of diabetes. CONCLUSIONS: SGLT2i can be a valid therapeutic strategy for patients with T2DM and comorbid hyperuricemia. Besides reducing FPG, body weight, and HbA1c, SGLT2i can significantly decrease SUA levels compared to placebo (Total MD = -34.07 µmol/L, 95% CI [-37.00, -31.14]).


Assuntos
Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Ácido Úrico/metabolismo , Compostos Benzidrílicos/metabolismo , Compostos Benzidrílicos/farmacologia , Canagliflozina/metabolismo , Canagliflozina/farmacologia , Glucosídeos/metabolismo , Glucosídeos/farmacologia , Humanos , Hipoglicemiantes/metabolismo , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Tiofenos/metabolismo , Tiofenos/farmacologia
14.
BMC Endocr Disord ; 22(1): 37, 2022 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-35144596

RESUMO

BACKGROUND: The current study was to evaluate the effects of canagliflozin and metformin on insulin resistance and visceral adipose tissue in people with newly-diagnosed type 2 diabetes. METHODS: This is an open-label, parallel and controlled study. Participants were divided into canagliflozin (100 mg/qd) or metformin (1000 mg/bid) groups. At baseline and after 12 weeks' therapy, insulin resistance [Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)], subcutaneous and visceral adipose tissue, fasting blood glucose (FBG), glycated hemoglobin A1c (HbA1c), C-reactive protein (CRP) and nitric oxide (NO) were evaluated and compared. RESULTS: There was no significant between-group difference in baseline characteristics. After 12 weeks' therapy, in canagliflozin group (n = 67), compared to baseline, FBG, HbA1c and HOMA-IR were decreased, accompanying with reduction of visceral adipose tissue. Compared to metformin group (n = 73), FBG, HbA1c and HOMA-IR were lower in canagliflozin group, accompanying with less visceral adipose tissue and lower serum CRP level and higher NO level. After multivariable regression analysis, age, visceral adipose tissue and CRP remained associated with increased insulin resistance, while canagliflozin treatment and higher NO level were associated with reduced insulin resistance. Body mass index, waist/hip ratio, CRP and HOMA-IR remained associated with increased visceral adipose tissue, while canagliflozin treatment and higher NO level were associated with reduced visceral adipose tissue. There was no difference in adverse event between these two groups. CONCLUSION: Canagliflozin reduces visceral adipose tissue and improves blood glucose, insulin resistance and systemic inflammation in people with newly-diagnosed type 2 diabetes.


Assuntos
Canagliflozina/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Resistência à Insulina , Gordura Intra-Abdominal/metabolismo , Metformina/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
15.
J Am Coll Cardiol ; 79(5): 432-444, 2022 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-35115099

RESUMO

BACKGROUND: Circulating biomarkers reflecting different mechanistic pathways may identify at-risk individuals with diabetes who may benefit from sodium-glucose cotransporter-2 (SGLT2) inhibitors. OBJECTIVES: The purpose of this study was to determine if high-sensitivity cardiac troponin T (hs-cTnT), soluble suppression of tumorigenesis-2 (sST2), and insulin-like growth factor binding protein 7 (IGFBP7) levels, either alone or in combination, may modify the treatment benefits of canagliflozin. METHODS: In the CANVAS (CANagliflozin cardioVascular Assessment Study) biomarker substudy, we evaluated the prognostic significance of baseline biomarker measurements, the long-term trajectory of each, and response to canagliflozin on key cardiovascular and kidney outcomes. RESULTS: Among the 4,330 study participants, baseline hs-cTnT, sST2, and IGFBP7 were available in 3,503 (81%), 3,084 (71%), and 3,577 (83%). In total, 39% had elevated hs-cTnT ≥14 pg/mL, 6% had sST2 >35 ng/mL, and 49% had IGFBP7 >96.5 ng/mL. Canagliflozin significantly slowed increases of hs-cTnT (P = 0.027) and sST2 (P = 0.033) through 6 years. Each biomarker was significantly associated with cardiovascular and kidney outcomes, independent of clinical covariates. Canagliflozin reduced heart failure and kidney events regardless of baseline biomarker concentration. Patients with hs-cTnT ≥14 ng/L and those with sST2 >35 ng/mL derived greater relative benefit for major adverse cardiovascular events (MACE) (both Pinteraction ≤0.05). A panel of all 3 biomarkers predicted each cardiac and kidney outcome evaluated; participants with an increasing number of abnormal circulating biomarkers appeared to have greater relative reductions in MACE from canagliflozin treatment (Pinteraction trend = 0.005). CONCLUSIONS: Canagliflozin delays longitudinal rise in hs-cTnT and sST2 compared with placebo out to 6 years. Canagliflozin reduced heart failure and kidney events regardless of baseline biomarker concentration. Elevated cardiovascular biomarkers, either alone or in combination, may identify individuals who may derive greater MACE benefit from SGLT2 inhibition. CANVAS (CANagliflozin cardioVascular Assessment Study; NCT01032629).


Assuntos
Canagliflozina/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insuficiência Cardíaca/tratamento farmacológico , Rim/metabolismo , Troponina T/sangue , Adulto , Biomarcadores/sangue , Diabetes Mellitus Tipo 2/complicações , Feminino , Insuficiência Cardíaca/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
16.
Am J Nephrol ; 53(1): 21-31, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35016188

RESUMO

INTRODUCTION: KidneyIntelX is a composite risk score, incorporating biomarkers and clinical variables for predicting progression of diabetic kidney disease (DKD). The utility of this score in the context of sodium glucose co-transporter 2 inhibitors and how changes in the risk score associate with future kidney outcomes are unknown. METHODS: We measured soluble tumor necrosis factor receptor (TNFR)-1, soluble TNFR-2, and kidney injury molecule 1 on banked samples from CANagliflozin cardioVascular Assessment Study (CANVAS) trial participants with baseline DKD (estimated glomerular filtration rate [eGFR] 30-59 mL/min/1.73 m2 or urine albumin-to-creatinine ratio [UACR] ≥30 mg/g) and generated KidneyIntelX risk scores at baseline and years 1, 3, and 6. We assessed the association of baseline and changes in KidneyIntelX with subsequent DKD progression (composite outcome of an eGFR decline of ≥5 mL/min/year [using the 6-week eGFR as the baseline in the canagliflozin group], ≥40% sustained decline in the eGFR, or kidney failure). RESULTS: We included 1,325 CANVAS participants with concurrent DKD and available baseline plasma samples (mean eGFR 65 mL/min/1.73 m2 and median UACR 56 mg/g). During a mean follow-up of 5.6 years, 131 participants (9.9%) experienced the composite kidney outcome. Using risk cutoffs from prior validation studies, KidneyIntelX stratified patients to low- (42%), intermediate- (44%), and high-risk (15%) strata with cumulative incidence for the outcome of 3%, 11%, and 26% (risk ratio 8.4; 95% confidence interval [CI]: 5.0, 14.2) for the high-risk versus low-risk groups. The differences in eGFR slopes for canagliflozin versus placebo were 0.66, 1.52, and 2.16 mL/min/1.73 m2 in low, intermediate, and high KidneyIntelX risk strata, respectively. KidneyIntelX risk scores declined by 5.4% (95% CI: -6.9, -3.9) in the canagliflozin arm at year 1 versus an increase of 6.3% (95% CI: 3.8, 8.7) in the placebo arm (p < 0.001). Changes in the KidneyIntelX score at year 1 were associated with future risk of the composite outcome (odds ratio per 10 unit decrease 0.80; 95% CI: 0.77, 0.83; p < 0.001) after accounting for the treatment arm, without evidence of effect modification by the baseline KidneyIntelX risk stratum or by the treatment arm. CONCLUSIONS: KidneyIntelX successfully risk-stratified a large multinational external cohort for progression of DKD, and greater numerical differences in the eGFR slope for canagliflozin versus placebo were observed in those with higher baseline KidneyIntelX scores. Canagliflozin treatment reduced KidneyIntelX risk scores over time and changes in the KidneyIntelX score from baseline to 1 year associated with future risk of DKD progression, independent of the baseline risk score and treatment arm.


Assuntos
Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Inibidores do Transportador 2 de Sódio-Glicose , Canagliflozina/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/complicações , Nefropatias Diabéticas/etiologia , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
17.
Clin J Am Soc Nephrol ; 17(3): 361-373, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35063969

RESUMO

BACKGROUND AND OBJECTIVES: The effect of including race in the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation on screening, recruitment, and outcomes of clinical trials is unclear. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The inclusion and outcomes of participants in the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial, which randomized individuals with type 2 diabetes and CKD to canagliflozin or placebo, were evaluated after calculating eGFR using the 2009 CKD-EPI creatinine equation with and without a race-specific coefficient or the 2021 CKD-EPI creatinine equation. Treatment effects were estimated using proportional hazards models and piecewise linear mixed effects models for eGFR slope. RESULTS: Of 4401 randomized participants, 2931 (67%) were White participants, 224 (5%) were Black participants, 877 (20%) were Asian participants, and 369 (8%) participants were other race. Among randomized participants, recalculation of screening eGFR using the 2009 equation without a race-specific coefficient had no effect on the likelihood of non-Black participants meeting inclusion criteria but would have excluded 22 (10%) randomized Black participants for eGFR<30 ml/min per 1.73 m2. Recalculation with the 2021 equation would have excluded eight (4%) Black participants for low eGFR and one (0.4%) Black participant for eGFR≥90 ml/min per 1.73 m2, whereas 30 (0.7%) and 300 (7%) non-Black participants would have been excluded for low and high eGFR, respectively. A high proportion (eight of 22; 36%) of end points in Black participants occurred in individuals who would have been excluded following recalculation using the race-free 2009 equation but not when recalculated with the 2021 equation (one of eight; 13%). Cardiovascular and kidney treatment effects remained consistent across eGFR categories following recalculation with either equation. Changes in estimated treatment effects on eGFR slope were modest but were qualitatively larger following recalculation using the 2021 equation. However, the effect of canagliflozin on chronic change in eGFR was attenuated by 7% among Black participants and increased 6% in non-Black participants. CONCLUSIONS: In the CREDENCE trial, eGFR recalculation without the race-specific coefficient had small but potentially important effects on event rates and the relative proportion of Black participants without substantially changing efficacy estimates. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE), NCT02065791.


Assuntos
Diabetes Mellitus Tipo 2 , Insuficiência Renal Crônica , Inibidores do Transportador 2 de Sódio-Glicose , Canagliflozina/farmacologia , Creatinina , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/epidemiologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
18.
Biochem J ; 479(3): 425-444, 2022 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-35048967

RESUMO

There has been a concern that sodium-glucose cotransporter 2 (SGLT2) inhibitors could reduce skeletal muscle mass and function. Here, we examine the effect of canagliflozin (CANA), an SGLT2 inhibitor, on slow and fast muscles from nondiabetic C57BL/6J mice. In this study, mice were fed with or without CANA under ad libitum feeding, and then evaluated for metabolic valuables as well as slow and fast muscle mass and function. We also examined the effect of CANA on gene expressions and metabolites in slow and fast muscles. During SGLT2 inhibition, fast muscle function is increased, as accompanied by increased food intake, whereas slow muscle function is unaffected, although slow and fast muscle mass is maintained. When the amount of food in CANA-treated mice is adjusted to that in vehicle-treated mice, fast muscle mass and function are reduced, but slow muscle was unaffected during SGLT2 inhibition. In metabolome analysis, glycolytic metabolites and ATP are increased in fast muscle, whereas glycolytic metabolites are reduced but ATP is maintained in slow muscle during SGLT2 inhibition. Amino acids and free fatty acids are increased in slow muscle, but unchanged in fast muscle during SGLT2 inhibition. The metabolic effects on slow and fast muscles are exaggerated when food intake is restricted. This study demonstrates the differential effects of an SGLT2 inhibitor on slow and fast muscles independent of impaired glucose metabolism, thereby providing new insights into how they should be used in patients with diabetes, who are at a high risk of sarcopenia.


Assuntos
Fibras Musculares de Contração Rápida/efeitos dos fármacos , Fibras Musculares de Contração Lenta/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Adenilato Quinase/biossíntese , Adenilato Quinase/genética , Tecido Adiposo Branco/efeitos dos fármacos , Aminoácidos/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Canagliflozina/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Ácidos Graxos não Esterificados/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Ontologia Genética , Glicólise , Força da Mão , Fígado/efeitos dos fármacos , Masculino , Metaboloma/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Fibras Musculares de Contração Rápida/metabolismo , Músculo Esquelético/efeitos dos fármacos , Tamanho do Órgão/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transportador 2 de Glucose-Sódio/fisiologia , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Serina-Treonina Quinases TOR/biossíntese , Serina-Treonina Quinases TOR/genética
19.
Clin J Am Soc Nephrol ; 17(2): 251-259, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34876454

RESUMO

BACKGROUND AND OBJECTIVES: Clinical trials in nephrology are enriched for patients with micro- or macroalbuminuria to enroll patients at risk of kidney failure. However, patients with normoalbuminuria can also progress to kidney failure. TNF receptor-1, TNF receptor-2, and kidney injury marker-1 (KIM-1) are known to be associated with kidney disease progression in patients with micro- or macroalbuminuria. We assessed the value of TNF receptor-1, TNF receptor-2, and KIM-1 as prognostic biomarkers for CKD progression in patients with type 2 diabetes and normoalbuminuria. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: TNF receptor-1, TNF receptor-2, and KIM-1 were measured using immunoassays in plasma samples from patients with type 2 diabetes at high cardiovascular risk participating in the Canagliflozin Cardiovascular Assessment Study trial. We used multivariable adjusted Cox proportional hazards analyses to estimate hazard ratios per doubling of each biomarker for the kidney outcome, stratified the population by the fourth quartile of each biomarker distribution, and assessed the number of events and event rates. RESULTS: In patients with normoalbuminuria (n=2553), 51 kidney outcomes were recorded during a median follow-up of 6.1 (interquartile range, 5.8-6.4) years (event rate, 3.5; 95% confidence interval, 2.6 to 4.6 per 1000 patient-years). Each doubling of baseline TNF receptor-1 (hazard ratio, 4.2; 95% confidence interval, 1.8 to 9.6) and TNF receptor-2 (hazard ratio, 2.3; 95% confidence interval, 1.5 to 3.6) was associated with a higher risk for the kidney outcome. Baseline KIM-1, urinary albumin-creatinine ratio, and eGFR were not associated with kidney outcomes. The event rates in the highest quartile of TNF receptor-1 (≥2992 ng/ml) and TNF receptor-2 (≥11,394 ng/ml) were 5.6 and 7.0 events per 1000 patient-years, respectively, compared with 2.8 and 2.3, respectively, in the lower three quartiles. CONCLUSIONS: TNF receptor-1 and TNF receptor-2 are associated with kidney outcomes in patients with type 2 diabetes and normoalbuminuria. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: CANagliflozin cardioVascular Assessment Study (CANVAS), NCT01032629.


Assuntos
Diabetes Mellitus Tipo 2/etiologia , Nefropatias Diabéticas/etiologia , Receptor Celular 1 do Vírus da Hepatite A/fisiologia , Receptores do Fator de Necrose Tumoral/fisiologia , Insuficiência Renal Crônica/etiologia , Idoso , Canagliflozina/uso terapêutico , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Nefropatias Diabéticas/complicações , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Insuficiência Renal Crônica/complicações , Índice de Gravidade de Doença , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
20.
Drug Res (Stuttg) ; 72(2): 86-93, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34729722

RESUMO

The objective of this study is to investigate the regulations of FFA with canagliflozin in relation to metabolic parameters. Drug naïve subjects with T2DM were administered 50-100 mg/day canagliflozin monotherapy (n=70) for 3 months. Significant correlations between the changes of (Δ) FFA and Δadipo-IR (R=0.496), but no correlations between ΔFFA and ΔHOMA-R were observed. The subjects were divided into three groups with similar numbers according to Δ FFA: group A: highest tertile: (ΔFFA=38.7%, n=23); group B: intermediate tertile: (ΔFFA=2%, n=23); group C: lowest tertile: (ΔFFA=-36%, n=24). Metabolic parameters were compared between group A and group C. At baseline, FFA was higher in group C than group A (p<0.002). Greater degrees of HbA1c reduction and increases of insulin were observed in group C than group A (both p<0.05). In group A, significant reductions of BMI (-2.6%) and HOMA-R (-30%) were seen. In group C, significant reductions of non-HDL-C (-6.2%), UA (-7.6%) or adipo-IR (-28.7%), and increases of HOMA-B (+85.6%) were observed. Taken together, 1) certain population treated with canagliflozin showed decreased FFA. 2) beta-cell function increased while atherogenic cholesterol, UA and adipo-IR decreased in those with reduced FFA. Better glycemic efficacies were seen in these populations. 3) body weight and whole body insulin resistance (HOMA-R) significantly decreased in those with elevated FFA. 4) FFA is linked to adipose insulin resistance (adipo-IR), while it does not appear to impact whole body insulin resistance (HOMA-R).


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Preparações Farmacêuticas , Glicemia , Canagliflozina/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Ácidos Graxos não Esterificados , Humanos , Insulina
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