scholarly journals Effects of canagliflozin in patients with type 2 diabetes and chronic heart failure: a randomized trial (CANDLE)

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A Tanaka ◽  
I Hisauchi ◽  
I Taguchi ◽  
A Sezai ◽  
S Toyoda ◽  
...  

Abstract Background Little is known about the impacts of sodium glucose co-transporter 2 inhibitors on cardiac functional parameters, such as natriuretic peptides, in type 2 diabetes (T2D) patients with concomitant chronic heart failure (CHF). Purpose To compare the effect of canagliflozin with glimepiride, based on changes in N-terminal pro-brain natriuretic peptide (NT-proBNP), in that patient population. Methods This trial was an investigator-initiated, multicenter, prospective, randomized, open-label, blinded-endpoint trial at 34 centers in Japan. Patients with T2D and clinically stable CHF excluding NYHA class IV, randomized to receive canagliflozin 100 mg or glimepiride (starting dose: 0.5 mg), were examined using the primary endpoint of non-inferiority of canagliflozin versus glimepiride, defined as a margin of 1.1 in the upper-limit of the 2-sided 95% confidence interval (95% CI) for the group ratio of percentage change in NT-proBNP at 24 weeks. Results Data analysis of 233 patients (mean age 68.6±10.1 yrs; 75% male) showed mean left ventricular ejection fraction (LVEF) at randomization was 57.6±14.6%, with 71% of patients having a preserved LVEF (≥50%). The ratio of NT-proBNP percentage change was 0.48 (95% CI, −0.13 to 1.59, P=0.226), and therefore did not meet the prespecified non-inferiority margin. However, data stratified according to baseline NT-proBNP levels showed a trend that canagliflozin treatment reduced NT-proBNP levels to a greater extent than in subgroups with elevated levels of NT-proBNP (Figure A). Furthermore, NT-proBNP levels in the canagliflozin group did show a nonsignificant trend lower in the subgroup with preserved LVEF (Figure B), but not in the subgroup with reduced LVEF (Figure C). Additionally, the changes in the NYHA class were comparable between groups (P=0.061) in the overall cohort, whereas in the subgroup with a preserved LVEF canagliflozin caused a significant improvement in NYHA classes compared to that found for glimepiride treatment (P=0.027). Conclusions This trial did not meet the predefined primary endpoint of changes in NT-proBNP levels, with 24 weeks of treatment with canagliflozin relative to glimepiride which together with other recent studies would question the value of continuing to monitor NT-proBNP levels after the initial diagnosis of heart failure. Nevertheless, in a subgroup with preserved LVEF, there was a non-significant trend for canagliflozin treatment to reduce NT-proBNP levels and improve symptoms even in stable HF patients. Further research is therefore warranted to determine whether patients with preserved LVEF, regardless of diabetes status, could potentially benefit from treatment with SGLT2 inhibitors. Changes in NT-proBNP Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Mitsubishi Tanabe Pharma Corporation

2019 ◽  
Vol 5 (1) ◽  
pp. 1-13
Author(s):  
Irina V. Askari ◽  
Olga A. Osipova

Introduction: Diastolic dysfunction (DD) and cardiac dyssynchrony (DS) are involved in the progression of chronic heart failure (CHF). A comparative analysis was conducted of the effect of a 6-month course of nebivolol and bisoprolol on DD, DS and metalloproteinase-9 (MMP-9) level in patients with ischemic chronic heart failure with preserved ejection fraction (HFpEF) and with midrange ejection fraction (HFmrEF), as well as in patients with comorbid type 2 diabetes mellitus (T2DM) in the setting of coronary artery bypass grafting (CABG) after 6 months of therapy. Materials and methods: The study included 308 patients with CHFFC I-II, left ventricular ejection fraction (LVEF) >40%, who had undergone CABG. The average dose of nebivolol in patients with DS 6 months later was 5.1±2.6 mg/day, and bisoprolol – 4.9±2.4 mg/day. Echocardiography (EchoCG) and evaluation of MMP-9 in blood plasma were performed. Mechanical myocardial asynchrony was determined by calculating the standard deviation of time to peak systolic myocardial velocity (TS-SD) and maximum segment delay (TS12) using a 6-basal and-midsegment model. Results and discussion: MMP-9 level in patients with CHF before CABG was 4.7 times higher (p<0.001). MMP-9 correlated with LVEF (r=-0.60, p<0.001), E/A (r=-0.49, p<0.001), DT (r=0.43, p<0.001), E` (r=-0.58, p<0.001) and DS: TS12 (r=0.54, p<0.001), TS-SD (r=0.49, p<0.001). The six-month course of nebivolol improved the values of DS: TS12 – by 30% (p<0.001), TS-SD – by 32% (p<0.01) and reduced the MMP-9 level by 11% (p<0.001). In patients with HFmrEF without DSnebivolol increased E/A by 19% (p<0.01), E` – by 16% (P<0.05), and decreased E/E’ by 9% (p<0.05), DT – by 12% (p<0.05). In patients with HFpEF and DM2, nebivolol reduced TS12 by 37% (p<0.01), TS-SD – by 29% (p<0.05) and MMP-9 – by 13% (p<0.05). Conclusion: The positive effect of nebivolol on the DS, DD of the LV in patients with HFpEF, HFmrEF and with comorbid type 2 diabetes mellitus. The six-month course of nebivolol decreased the MMP-9 level in patients with ischemic CHF after CABG, including patients with T2DM.


2013 ◽  
Vol 16 (2) ◽  
pp. 17-25 ◽  
Author(s):  
Tatiana Nikolaevna Kochegura ◽  
P I Makarevich ◽  
A G Ovchinnikov ◽  
L V Zhigunova ◽  
Elena Leonidovna Lahova ◽  
...  

AIM: To evaluate the plasma level of circulating heptocyte growth factor (HGF) in patients with comorbidity of post-infarction chronic heart failure (CHF), type 2 diabetes mellitus (T2DM) and obesity. We also aimed to assess possible correlations between HGF levels and parameters of carbohydrate and lipid metabolism, as well as myocardial functional characteristics and classic biochemical severity markers for CHF.17Сахар ный диабет КардиологияСахарный диабет. 2013;(2):17-25 MATERIALS AND METHODS: We enrolled 100 patients for participation in this study, including the following subgroups: 20 individuals with- out cardiovascular and glycemic disorders, 30 patients with CHF, 25 patients with CHF/T2DM comorbidity and 25 diabetic patients with no signs of heart failure. Quantitative plasma HGF analysis was performed with enzyme-linked immunosorbent assay (ELISA). RESULTS: Plasma HGF was elevated both in patients with CHF and T2DM as measured against healthy control group. The elevation was most prominent in patients with CHF/T2DM comorbidity and was found to correlate with HbA1c level (r=0.52, p=0.03). Plasma HGF also correlated with BMI (r=0.42, p=0007) in a unified study group, though we observed no statistically significant difference between subgroups with a trend toward higher HGF in obese patients with CHF/T2DM comorbidity (626.1?254.1 pg/ml vs 742.0?210.7 pg/ml respectively; p 0.05). Interestingly, plasma HGF was also significantly higher in controls with BMI 30 km/m2 (324.1?107.7 pg/ml vs 436.9?112.3 pg/ml, p=0.03).Circulating HGF correlated with plasma levels of N-terminal fragment of B-type natriuretic peptide (NT-proBNP) and such structural and functional myocardial characteristics as left atrial size and maximum volume along with left ventricular ejection fraction (EF), end-diastolic volume (EDV) and end-diastolic dimension (EDD). CONCLUSION: These findings suggest that HGF may potentially serve as a prediction marker for unfavorable myocardial remodeling and poor prognosis in CHF patients with T2DM and obesity, though this possibility should be further investigated in follow-up studies.


2021 ◽  
Vol 1 (223) ◽  
pp. 2-14
Author(s):  
Gulmira Alipova ◽  
◽  
Anna Bazarova ◽  
Nazira Bazarova ◽  
Rimma Bazarbekova ◽  
...  

The article presents the results of the DAPA-HF study - evaluating the efficacy of dapagliflozin, used at a dose of 10 mg once a day, in addition to the standard treatment for patients with chronic heart failure with reduced left ventricular ejection fraction, compared to placebo. An analysis of current clinical recommendations related to this issue was carried out, the results of recent clinical studies and metaanalyses conducted were highlighted. Based on the results of the study, the need is postulated to optimize drug therapy of this category to patients with persistent symptoms of heart failure, despite standard therapy, with the addition of dapagliflozin to reduce the risk of cardiovascular death and hospitalizations for heart failure, improve the course of the disease. Keywords: chronic heart failure, dapagliflozin, low ejection fraction, effects of type 2 sodium-glucose co transporter inhibitors, diabetes mellitus.


2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
R Lahoz ◽  
S Corda ◽  
C Proudfoot ◽  
A.F Fonseca ◽  
S Cotton ◽  
...  

Abstract Background and purpose The majority of patients with heart failure (HF) have difficulties in independently carrying out activities of daily living and hence, require support from caregivers (CGs). This study assessed the quality of life (QoL) of CGs of HF patients with sub-normal LVEF (≤60%). Methods A cross-sectional survey of HF patients and their CGs was conducted in France, Germany, Italy, Spain and the UK. Cardiologists and primary care physicians completed patient record forms (PRF) between June and November 2019. Caregivers of the same patients were invited to complete a caregiver self-completion survey, which included the Family Caregiver QoL Scale (FAMQOL) and EQ-5D. Patient demographics were derived from PRFs. Results 361 CGs (73.1% female, mean age: 58.8 yrs) and HF patients (39.9% female, mean age: 71.2 yrs) were included. 58.2% of the CGs were spouses, 23.4% a child of the patient. On average, CGs devoted 20 hrs/week in the care of HF patients; this CG time increased from 12 to 26 hrs/week with NYHA class I to III/IV of the HF patient. Further, anxiety/stress was experienced overall by 29/31% of CGs which increased from 27/17% for NYHA I to 40/41% for NYHA III/IV of the HF patient (Table 1). Conclusions Caregivers of patients with HF and LVEF ≤60% spend a significant amount of time to provide daily support to HF patients. Patients with progressive disease were older, more polymorbid and had a higher disease duration. These factors likely contributed towards increased caregiver burden of HF patients with increased NYHA class. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Novartis Pharma AG


2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M Polovina ◽  
I Milinkovic ◽  
G Krljanac ◽  
I Veljic ◽  
I Petrovic-Djordjevic ◽  
...  

Abstract Background Type 2 diabetes (T2DM) portends adverse prognosis in patients with atrial fibrillation (AF). Whether T2DM independently increases the risk of incident heart failure (HF) in AF is uncertain. Also, HF phenotype developing in patients with vs. those without T2DM has not been characterised. Purpose In AF patients without a history of prior HF, we aimed to assess: 1) the impact of T2DM on the risk of new-onset HF; and 2) the association between T2DM and HF phenotype developing during the prospective follow-up. Methods We included diabetic and non-diabetic AF patients, without a history of HF. Baseline T2DM status was inferred from medical history, haemoglobin A1c levels and oral glucose tolerance test. Study outcome was the first hospital admission or emergency department treatment for new-onset HF during the prospective follow-up. The phenotype of new-onset HF was determined by echocardiographic exam performed following clinical stabilisation (at hospital discharge, or within a month after HF diagnosis). HF phenotype was defined as HFrEF (left ventricular ejection fraction [LVEF] <40%), HFmrEF (LVEF 40–49%) or HFpEF (LVEF≥50%). Cox regression analyses adjusted for age, sex, baseline LVEF, comorbidities, smoking status, alcohol intake, AF type (paroxysmal vs. non-paroxysmal) and T2DM treatment was used to analyse the association between T2DM and incident HF. Results Among 1,288 AF patients without prior HF (mean age: 62.1±12.7 years; 61% male), T2DM was present in 16.5%. Diabetic patients had higher mean baseline LVEF compared with nondiabetic patients (50.0±6.2% vs. 57.6±9.0%; P<0.001). During the median 5.5-year follow-up, new-onset HF occurred in 12.4% of patients (incidence rate, 2.9; 95% confidence interval [CI], 2.5–3.3 per 100 patient-years). Compared with non-diabetic patients, those with T2DM had a hazard ratio of 2.1 (95% CI, 1.6–2.8; P<0.001) for new-onset HF, independent of baseline LVEF or other factors. In addition, diabetic patients had a significantly greater decline in covariate-adjusted mean LVEF (−10.4%; 95% CI, −9.8% to −10.8%) at follow-up, compared with nondiabetic patients (−4.0%; 95% CI, −3.8% to −4.2%), P<0.001. The distribution of HF phenotypes at follow-up is presented in Figure. Among patients with T2DM, HFrEF (56.9%) was the most common phenotype of HF, whereas in patients without T2DM, HF mostly took the phenotype of HFpEF (75.0%). Conclusions T2DM is associated with an independent risk of new-onset HF in patients with AF and confers a greater decline in LVEF compared to individuals without T2DM. HFrEF was the most prevalent presenting phenotype of HF in AF patients with T2DM.


2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
K Ejiri ◽  
T Miyoshi ◽  
H Kihara ◽  
Y Hata ◽  
T Nagano ◽  
...  

Abstract Background Recent randomized, placebo-controlled trial in patients with type 2 diabetes demonstrated that the sodium-glucose cotransporter 2 inhibitors reduced mortality, cardiovascular events and hospitalization for heart failure. However, those trials were not specialized design to investigate the effect of sodium-glucose cotransporter 2 inhibitors in patients with heart failure, in particular with heart failure with preserved ejection fraction. Purpose The aim of this study was to evaluate the drug efficacy of luseogliflozin, a sodium-glucose cotransporter 2 inhibitor, compared with voglibose, an alpha-glucosidase inhibitor, using brain natriuretic peptide (BNP) in type 2 diabetes patients with heart failure with preserved ejection fraction. Methods This study was a prospective, multicenter, open-label, randomized-controlled trial, comparing luseogliflozin 2.5 mg once daily or voglibose 0.2 mg three times daily in patients with type 2 diabetes suffering from heart failure with preserved ejection fraction (left ventricular ejection fraction >45% and BNP ≥35 pg/ml2) in a 1:1 randomization fashion. Randomization was undertaken using a computer-generated random sequence web response system. The primary outcome was the difference from baseline in BNP after 12 weeks of treatment between two drugs. The key secondary outcomes were the change from baseline in left ventricular ejection fraction and E/e' in echocardiographic parameters, body weight, glycohemoglobin level after 12 weeks of treatment. The safety outcomes included the incidence of major adverse cardiovascular events, hypoglycemic adverse events, and urinary tract infection. Results Between December 2015 and September 2018, 173 patients from 16 hospitals and clinics have been included in this study. Of those, 83 patients were assigned to receive luseogliflozin and 82 to receive voglibose. There was no significant difference in the reduction in the BNP concentration after 12 weeks from baseline between the two groups; the ratio of the average values at week 12 to the baseline value was 0.91 in the luseoglifllzin group as compared with 0.98 in the voglibose group (percent change, −9.0% vs. −1.9%, ratio of change with luseogliflozin vs. voglibose, 0.93; 95% confidence interval, 0.78 to 1.10; p=0.26). The key secondary outcomes including left ventricular ejection fraction, E/e', body weight, glycohemoglobin level and the safety outcomes did not differ significantly between the two groups. Conclusions In type 2 diabetes patients with heart failure with preserved ejection fraction, the administration of luseogliflozin did not lead to a significant reduction in the BNP concentration than that of voglibose. Left ventricular ejection fraction, E/e', body weight and glycohemoglobin level after 12 weeks of treatment, comparing with at baseline did not differ significantly between the two groups. (UMIN Clinical Trial Registry number, UMINehz748.005618395) Acknowledgement/Funding Novartis


Author(s):  
D.V. Grazhdankina ◽  
◽  
A.A. Demin ◽  
I.A. Bondar ◽  
◽  
...  

Introduction. Type 2 diabetes mellitus (T2DM) is considered to be the equivalent of cardiovascular disease due to its micro- and macrovascular complications. Insulin resistance and hyperinsulinemia, impaired glucose tolerance and fasting glucose, and their subsequent maladaptive responses lead to myocardial dysfunction several years before the onset of T2DM. Pathological changes in the cardiovascular system in T2DM can progress without any symptoms for a long time. Aim. To identify clinical, laboratory, echocardiographic predictors of the early manifestations of chronic heart failure (CHF) in patients with T2DM. Materials and methods. The study included 94 patients with T2DM with and without initial symptoms of CHF at the age of 40 to 65 years. All patients had obesity or excess body weight and arterial hypertension (AH), 37 patients had stable coronary heart disease (CHD). Patients underwent general clinical and laboratory examination, a 6-minute walk test (6MWT), echocardiography. The concentration of N-terminal pro-B-type natriuretic peptide (NT-proBNP ) was also determined. The patients were divided into 2 groups: without CHF symptoms (group 1, n = 54) and with initial symptoms of CHF (group 2, n = 40) and then these groups were compared. Results. Differences were revealed between the second and first groups in the duration of T2DM (10.5 vs 7.5 years, p = 0.02) and AH (15 vs 10 years, p = 0.009); the incidence of stable CHD (70 vs 16.7%, p < 0.0001); distance covered during 6MWT (375 vs 425 m, p < 0.0001); the median level of NT-proBNP (38.5 vs 27.2 pg/ml, p = 0.031); the left atrium (LA) size (4.4 vs 4.2 cm, p = 0.044); the left ventricular posterior wall thickness (PWT) (1.05 vs 0.95 cm, p = 0.02); the level of triglycerides (2.3 vs 1.6 mmol/l, p = 0.03) and the glomerular filtration rate (GFR) (74.1 vs 79.1 ml/min/1.73 m2, r = 0.04). The discriminant analysis revealed combination of factors associated with initial symptoms of CHF: the duration of CHD (taken as 0, if absent, p < 0.00001), PWT of the LV (p = 0.000007), GFR (p = 0.0009), the LA size (p = 0.005), the level of triglycerides (p = 0.03), the duration of T2DM (p = 0.046). The NT-proBNP level > 125 pg/ml was detected in 16% of patients with T2DM and correlated with the duration of diabetes over 10 years (p = 0.0085), the presence of stable CHD (p < 0.0001), and left ventricular mass index (p = 0.0005) and the ejection fraction of the LV (p < 0.0001). Conclusion. Predictors of the initial manifestations of chronic heart failure in patients with type 2 diabetes mellitus were the presence and duration of stable CHD, an increase in the PWT of the LV, the LA size, the level of triglycerides, and the duration of diabetes. An elevated level of NT-proBNP (more than 125 pg/ml) in patients with T2DM was detected in 16% of cases and was associated with the duration of diabetes for more than 10 years, presence of stable CHD, initial symptoms of CHF, left ventricular myocardial hypertrophy, and a lower left ventricular ejection fraction according to echocardiography.


Author(s):  
Sergey V. Povetkin

The objective is to provide an overview of the literature data concerning the optimization of pharmacotherapy of comorbid pathology - chronic heart failure and diabetes mellitus. The article discusses the pathogenetic mechanisms of the negative mutual influence of chronic heart failure (CHF) and type 2 diabetes mellitus (T2DM) on their course and prognosis in patients with this comorbid pathology. Along with the discussion of the leading groups of drugs used for the treatment of CHF with a reduced left ventricular ejection fraction in patients with T2DM, priority classes of drugs for the treatment of patients with diastolic heart failure and their effect on the prognosis in the discussed contingent of patients are considered. An important area of therapy for people with CHF and T2DM is the use of hypoglycemic drugs that can have a positive effect on the course of cardiac pathology and change the prognosis in such patients. The article discusses the results of a number of randomized clinical trials evaluating the cardioprotective effect of modern classes of hypoglycemic agents: dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter-2 (SGLT-2) inhibitors. According to the presented studies, DPP-4 inhibitors, GLP-1 receptor agonists had a neutral or favorable effect on the prognosis in patients with cardiovascular diseases of atherosclerotic genesis and/or risk factors for their development, but did not affect the course of CHF. For the current period, the most significant drugs in terms of a positive effect on the prognosis in patients with diabetes mellitus and CHF are those from the SGLT-2 inhibitors group. The paper discusses in detail the results of clinical studies on the use of agents of the above-mentioned group in persons with CHF and diabetes mellitus and reviews the pharmacodynamic mechanisms that determine the cardioprotective effect of these drugs. The paper presents modern data that allow discussing the prospects for the use of SGLT-2 inhibitors in patients with CHF without T2DM.


2018 ◽  
Vol 15 (6) ◽  
pp. 494-503 ◽  
Author(s):  
Isabelle Johansson ◽  
Ulf Dahlström ◽  
Magnus Edner ◽  
Per Näsman ◽  
Lars Rydén ◽  
...  

Objective: To study the characteristics and prognostic implications of type 2 diabetes in different heart failure entities from a nationwide perspective. Methods: This observational study comprised 30,696 heart failure patients prospectively included in the Swedish Heart Failure Registry (SwedeHF) 2003–2011 from specialist care, with mortality information available until December 2014. Patients were categorized into three heart failure entities by their left ventricular ejection fraction (heart failure with preserved ejection fraction: ⩾50%, heart failure with mid-range ejection fraction: 40%–49% and heart failure with reduced ejection fraction: <40%). All-cause mortality stratified by type 2 diabetes and heart failure entity was studied by Cox regression. Results: Among the patients, 22% had heart failure with preserved ejection fraction, 21% had heart failure with mid-range ejection fraction and 57% had heart failure with reduced ejection fraction. The proportion of type 2 diabetes was similar, ≈25% in each heart failure entity. Patients with type 2 diabetes and heart failure with preserved ejection fraction were older, more often female and burdened with hypertension and renal impairment compared with heart failure with mid-range ejection fraction and heart failure with reduced ejection fraction patients among whom ischaemic heart disease was more common. Type 2 diabetes remained an independent mortality predictor across all heart failure entities after multivariable adjustment, somewhat stronger in heart failure with left ventricular ejection fraction below 50% (hazard ratio, 95% confidence interval; heart failure with preserved ejection fraction: 1.32 [1.22–1.43], heart failure with mid-range ejection fraction: 1.51 [1.39–1.65], heart failure with reduced ejection fraction: 1.46 [1.39–1.54]; p-value for interaction, p = 0.0049). Conclusion: Type 2 diabetes is an independent mortality predictor across all heart failure entities increasing mortality risk by 30%–50%. In type 2 diabetes, the heart failure with mid-range ejection fraction entity resembles heart failure with reduced ejection fraction in clinical characteristics, risk factor pattern and prognosis.


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