Journal: Cardiovasc Diabetol

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Abstract

Impact of myocardial scars on left ventricular deformation in type 2 diabetes mellitus after myocardial infarction by contrast-enhanced cardiac magnetic resonance.

Gao Y, Xu HY, Guo YK, Wen XL, ... Li Y, Yang ZG
Background
Type 2 diabetes mellitus (T2DM) is a major risk factor for coronary artery disease and myocardial infarction (MI). The interaction of diabetic cardiomyopathy and MI scars on myocardial deformation in T2DM patients is unclear. Therefore, we aimed to evaluate myocardial deformation using cardiac magnetic resonance (CMR) in T2DM patients with previous MI and investigated the influence of myocardial scar on left ventricular (LV) deformation.
Methods
Overall, 202 T2DM patients, including 46 with MI (T2DM(MI+)) and 156 without MI (T2DM(MI-)), and 59 normal controls who underwent CMR scans were included. Myocardial scars were assessed by late gadolinium enhancement. LV function and deformation, including LV global function index, LV global peak strain (PS), peak systolic strain rate (PSSR), and peak diastolic strain rate (PDSR), were compared among these groups. Correlation and multivariate linear regression analyses were used to investigate the relationship between myocardial scars and LV deformation.
Results
Decreases were observed in LV function and LV global PS, PSSR, and PDSR in the T2DM(MI+) group compared with those of the other groups. Reduced LV deformation (p < 0.017) was observed in the T2DM(MI+) group with anterior wall infarction. The increased total LV infarct extent and infarct mass of LV were related to decreased LV global PS (radial, circumferential, and longitudinal directions; p < 0.01) and LV global PSSR (radial and circumferential directions, p < 0.02). Multivariate analysis demonstrated that NYHA functional class and total LV infarct extent were independently associated with LV global radial PS (β =  - 0.400 and β =  - 0.446, respectively, all p < 0.01; model R2 = 0.37) and circumferential PS (β = 0.339 and β = 0.530, respectively, all p < 0.01; model R2 = 0.41), LV anterior wall infarction was independently associated with LV global longitudinal PS (β = 0.398, p = 0.006).
Conclusions
The myocardial scarring size in T2DM patients after MI is negatively correlated with LV global PS and PSSR, particularly in the circumferential direction. Additionally, different MI regions have different effects on the reduction of LV deformation, and relevant clinical evaluations should be strengthened.

© 2021. The Author(s).

Cardiovasc Diabetol: 24 Oct 2021; 20:215
Gao Y, Xu HY, Guo YK, Wen XL, ... Li Y, Yang ZG
Cardiovasc Diabetol: 24 Oct 2021; 20:215 | PMID: 34696783
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Abstract

Association of diabetes mellitus with clinical outcomes in patients with different coronary artery stenosis.

Zhang HW, Jin JL, Cao YX, Guo YL, ... Dong Q, Li JJ
Background
It has been demonstrated that patients with type 2 diabetes mellitus (DM) is associated with increased cardiovascular risk. However, little is known regarding the long-term prognosis in diabetic patients who experience mild-to-intermediate coronary artery stenosis (CAS). This study was to assess the clinical outcomes of diabetic patients with different severity of CAS.
Methods
We consecutively enrolled 10,940 patients hospitalized due to angina-like chest pain and followed up for major adverse cardiovascular events (MACEs) covering cardiac death, myocardial infarction, ischemic stroke, unplanned coronary revascularization and angina-related hospitalization. According to coronary angiography, patients were divided into non-obstructive CAS (NOCAS, < 50% stenosis), intermediate CAS (ICAS, 50-69% stenosis), and severe CAS (SCAS, 70-100% stenosis) subgroups, and were further categorized into six groups as NOCAS with DM and non-DM, ICAS with DM and non-DM, and SCAS with DM and non-DM.
Results
During a median follow-up of 40 months, 1,017 (11.1%) MACEs occurred. In patients with ICAS or SCAS, the incidence of events was higher when patients coexisted with DM (p < 0.05, respectively). In subgroup analyses, patients with ICAS and DM, SCAS and non-DM, SCAS and DM had increased risk of events [adjusted hazard ratio (HR): 1.709, 95% confidence interval (CI) 1.106-2.641, p = 0.016; HR: 1.911, 95% CI 1.460-2.501, p < 0.001; HR: 2.053, 95% CI 1.514-2.782, p < 0.001] compared to ones with NOCAS and non-DM. Besides, the Kaplan-Meier curves indicated the highest risk of MACEs in patients with SCAS and DM than others (p < 0.001).
Conclusions
Diabetic patients with ICAS had the worse outcome, which was comparable to patients with SCAS alone.

© 2021. The Author(s).

Cardiovasc Diabetol: 22 Oct 2021; 20:214
Zhang HW, Jin JL, Cao YX, Guo YL, ... Dong Q, Li JJ
Cardiovasc Diabetol: 22 Oct 2021; 20:214 | PMID: 34688289
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Abstract

Differences in outcomes of hospitalizations for heart failure after SGLT2 inhibitor treatment: effect modification by atherosclerotic cardiovascular disease.

Shao SC, Chang KC, Lin SJ, Chang SH, ... Chan YY, Lai EC
Background
The treatment effects on hospitalization for heart failure (hHF) from sodium-glucose cotransporter 2 (SGLT2) inhibitors may vary among type 2 diabetes (T2D) patients depending on whether or not they have established atherosclerotic cardiovascular diseases (ASCVD). We aimed to examine differences in hHF outcomes after dapagliflozin or empagliflozin use between T2D patients with and without a history of established ASCVD.
Methods
We conducted a retrospective multi-institutional cohort study in Taiwan. We included T2D patients newly receiving dapagliflozin or empagliflozin during 2016-2019, and followed them up until December 31, 2020. We implemented 1:1 propensity score matching to create homogenous groups for comparisons. We generated Cox proportional hazard models to compare the risk of hHF between dapagliflozin and empagliflozin (reference group). We included interaction terms of SGLT2 inhibitor and ASCVD history in the regression models to examine effect modification by ASCVD.
Results
We included a total cohort of 9,586 dapagliflozin new users and 9,586 matched empagliflozin new users. The overall hHF risks were similar for dapagliflozin and empagliflozin (HR: 0.90, 95% CI 0.74-1.09). However, differential hHF risks between dapagliflozin and empagliflozin were observed only in the subgroup without ASCVD (HR: 0.67, 95% CI 0.49-0.90), while not in the subgroup with ASCVD (HR: 1.12, 95% 0.87-1.45), and the p-value for examining interaction was 0.0097.
Conclusion
In this study, history of established ASCVD was associated with different hHF risks among SGLT2 inhibitors. For T2D patients without ASCVD, dapagliflozin may offer a more favorable hHF reduction effect, compared to empagliflozin, in clinical practice. Future prospective studies should be conducted to validate our findings.

© 2021. The Author(s).

Cardiovasc Diabetol: 22 Oct 2021; 20:213
Shao SC, Chang KC, Lin SJ, Chang SH, ... Chan YY, Lai EC
Cardiovasc Diabetol: 22 Oct 2021; 20:213 | PMID: 34688282
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Abstract

Association of left ventricular longitudinal myocardial function with subclinical right ventricular dysfunction in type 2 diabetes mellitus.

Todo S, Tanaka H, Yamauchi Y, Yokota S, ... Ogawa W, Hirata KI
Background
Left ventricular (LV) involvement in diabetic cardiomyopathy has been reported; however, only limited data exist on right ventricular (RV) involvement. Therefore, our purpose was to investigate RV systolic dysfunction and its association with LV longitudinal myocardial dysfunction in patients with type 2 diabetes mellitus (T2DM) and preserved LV ejection fraction (LVEF).
Methods
We studied 177 T2DM patients with preserved LVEF and 79 age-, sex-, and LVEF-matched healthy volunteers. LV longitudinal myocardial function was assessed as global longitudinal strain (GLS), and RV systolic function was assessed as RV free-wall strain, and predefined cutoff values for subclinical dysfunction were set at GLS < 18% and RV free-wall strain < 20%, respectively.
Results
RV free-wall strain in T2DM patients was significantly lower than that in normal controls (19.3% ± 4.8% vs. 24.4% ± 5.1%; P < 0.0001). RV free-wall strain in T2DM patients and LV longitudinal dysfunction was similar compared to that in T2DM patients without (19.0 ± 4.5% vs. 19.6 ± 5.0%, P = 0.40). Furthermore, multivariate logistic regression analyses showed that GLS was independently associated with RV systolic dysfunction as well as mitral inflow E and mitral e\' annular velocities ratio (odds ratio, 1.16; 95% confidence interval: 1.03-1.31; P < 0.05). Sequential logistic models evaluating the association of RV systolic dysfunction in T2DM patients showed an improvement in clinical variables (χ2 = 6.2) with the addition of conventional echocardiographic parameters (χ2 = 13.4, P < 0.001) and a further improvement with the addition of GLS (χ2 = 20.8, P < 0.001).
Conclusion
RV subclinical systolic dysfunction was observed in T2DM patients with preserved LVEF and was associated with LV longitudinal myocardial dysfunction. Our findings may provide additional findings for the management of T2DM patients.

© 2021. The Author(s).

Cardiovasc Diabetol: 22 Oct 2021; 20:212
Todo S, Tanaka H, Yamauchi Y, Yokota S, ... Ogawa W, Hirata KI
Cardiovasc Diabetol: 22 Oct 2021; 20:212 | PMID: 34688280
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Abstract

Optimal glucose, HbA1c, glucose-HbA1c ratio and stress-hyperglycaemia ratio cut-off values for predicting 1-year mortality in diabetic and non-diabetic acute myocardial infarction patients.

Sia CH, Chan MH, Zheng H, Ko J, ... Bulluck H, Hausenloy DJ
Background
Stress-induced hyperglycaemia at time of hospital admission has been linked to worse prognosis following acute myocardial infarction (AMI). In addition to glucose, other glucose-related indices, such as HbA1c, glucose-HbA1c ratio (GHR), and stress-hyperglycaemia ratio (SHR) are potential predictors of clinical outcomes following AMI. However, the optimal blood glucose, HbA1c, GHR, and SHR cut-off values for predicting adverse outcomes post-AMI are unknown. As such, we determined the optimal blood glucose, HbA1c, GHR, and SHR cut-off values for predicting 1-year all cause mortality in diabetic and non-diabetic ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI) patients.
Methods
We undertook a national, registry-based study of patients with AMI from January 2008 to December 2015. We determined the optimal blood glucose, HbA1c, GHR, and SHR cut-off values using the Youden\'s formula for 1-year all-cause mortality. We subsequently analyzed the sensitivity, specificity, positive and negative predictive values of the cut-off values in the diabetic and non-diabetic subgroups, stratified by the type of AMI.
Results
There were 5841 STEMI and 4105 NSTEMI in the study. In STEMI patients, glucose, GHR, and SHR were independent predictors of 1-year all-cause mortality [glucose: OR 2.19 (95% CI 1.74-2.76); GHR: OR 2.28 (95% CI 1.80-2.89); SHR: OR 2.20 (95% CI 1.73-2.79)]. However, in NSTEMI patients, glucose and HbA1c were independently associated with 1-year all-cause mortality [glucose: OR 1.38 (95% CI 1.01-1.90); HbA1c: OR 2.11 (95% CI 1.15-3.88)]. In diabetic STEMI patients, SHR performed the best in terms of area-under-the-curve (AUC) analysis (glucose: AUC 63.3%, 95% CI 59.5-67.2; GHR 68.8% 95% CI 64.8-72.8; SHR: AUC 69.3%, 95% CI 65.4-73.2). However, in non-diabetic STEMI patients, glucose, GHR, and SHR performed equally well (glucose: AUC 72.0%, 95% CI 67.7-76.3; GHR 71.9% 95% CI 67.7-76.2; SHR: AUC 71.7%, 95% CI 67.4-76.0). In NSTEMI patients, glucose performed better than HbA1c for both diabetic and non-diabetic patients in AUC analysis (For diabetic, glucose: AUC 52.8%, 95% CI 48.1-57.6; HbA1c: AUC 42.5%, 95% CI 37.6-47. For non-diabetic, glucose: AUC 62.0%, 95% CI 54.1-70.0; HbA1c: AUC 51.1%, 95% CI 43.3-58.9). The optimal cut-off values for glucose, GHR, and SHR in STEMI patients were 15.0 mmol/L, 2.11, and 1.68 for diabetic and 10.6 mmol/L, 1.72, and 1.51 for non-diabetic patients respectively. For NSTEMI patients, the optimal glucose values were 10.7 mmol/L for diabetic and 8.1 mmol/L for non-diabetic patients.
Conclusions
SHR was the most consistent independent predictor of 1-year all-cause mortality in both diabetic and non-diabetic STEMI, whereas glucose was the best predictor in NSTEMI patients.

© 2021. The Author(s).

Cardiovasc Diabetol: 18 Oct 2021; 20:211
Sia CH, Chan MH, Zheng H, Ko J, ... Bulluck H, Hausenloy DJ
Cardiovasc Diabetol: 18 Oct 2021; 20:211 | PMID: 34666746
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Abstract

A synergistic effect of variability in estimated glomerular filtration rate with chronic kidney disease on all-cause mortality prediction in patients with type 2 diabetes: a retrospective cohort study.

Chang YS, Li YH, Lee IT
Background
The combination of diabetes mellitus (DM) and chronic kidney disease (CKD) is associated with a high risk of mortality. Annual assessment of the estimated glomerular filtration rate (eGFR) is recommended for patients with DM. We investigated the effect of variability in annual eGFR values on all-cause mortality in patients with type 2 DM.
Methods
In this retrospective cohort study, we enrolled patients with eGFR data between 01 Aug 2017 and 31 July 2018. We defined the index eGFR as the first available eGFR value within the enrollment year and collected additional annual eGFR data from the previous three years. A total of 3592 patients with type 2 DM were enrolled, including 959 patients with CKD (index eGFR < 60 mL/min/1.73 m2) and 2633 patients without CKD. We assessed eGFR variability by using the standard deviation (SD) of the three annual eGFR and index eGFR values. We divided patients into subgroups according to the median SD of their annual eGFR (7.62 mL/min/1.73 m2). The primary endpoint was all-cause mortality after the index eGFR was assessed.
Results
During a median follow-up of 19 months (interquartile range: 18‒20 months), 127 (3.5%) deaths occurred among all 3592 enrolled patients. The highest mortality risk was observed in the high SD with CKD group, with a hazard ratio (HR) of 2.382 [95% confidence interval (CI) 1.346‒4.215] in comparison to the low SD without CKD group after adjusting for the associated factors. In patients without CKD, a high SD was an independent risk factor for mortality (HR = 2.105, 95% CI 1.256‒3.528). According to the C-index, the mortality prediction ability was better for the index eGFR + SD model than for the index eGFR alone model (0.671 vs. 0.629, P < 0.001).
Conclusion
There was a synergistic effect of eGFR variability with single-measured eGFR for the prediction of mortality in patients with type 2 DM. The SD of the annual eGFR values was also an independent predictor of mortality in patients with an eGFR > 60 mL/min/1.73 m2.

© 2021. The Author(s).

Cardiovasc Diabetol: 17 Oct 2021; 20:209
Chang YS, Li YH, Lee IT
Cardiovasc Diabetol: 17 Oct 2021; 20:209 | PMID: 34663321
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Impact:
Abstract

Improvement of glycemic control and reduction of major cardiovascular events in 18 cardiovascular outcome trials: an updated meta-regression.

Maiorino MI, Longo M, Scappaticcio L, Bellastella G, ... Esposito K, Giugliano D
Background
Besides providing reassurance about cardiovascular (CV) safety of newer diabetes drugs, cardiovascular outcome trials (CVOTs) have also shown encouraging benefits on some CV endpoints. The contribution of the better glycemic control in the reduction of major cardiovascular events (MACE) remains an open question. The aim of this study is to evaluate the associations between the reduction of HbA1c and risk of MACE, MACE components, hospitalization for heart failure (HF) and all-cause death in CVOTs.
Methods
An electronic search up to July 2021 was conducted to determine eligible trials. Systematic review identified eighteen CVOTs reporting prespecified CV outcomes. Pooled summary estimates and 95% confidence intervals (CI) were calculated according to the random effects model using the Paule-Mandel method; restricted maximum likelihood estimators were used to estimate model parameters in the metaregression.
Results
The eighteen CVOTs evaluated 161,156 patients and included four trials with dipeptidyl-peptidase-4 inhibitors (DPP-4i), eight trials with glucagon-like peptide-1 receptor agonists (GLP-1RA) and six trials with sodium-glucose cotransporter-2 inhibitors (SGLT-2i). Random-effects model meta-analysis showed an association between treatment and risk of MACE (hazard ratio [HR] 0.90; 95% CI 0.86, 0.94, P < 0.001), with significant heterogeneity between studies (I2 = 45.2%, Q statistic P = 0.040). In meta-regression, there was an association between the reduction in HbA1c at the end of the trial and the HR reduction for MACE (beta =  - 0.298, P = 0.007), with significant heterogeneity (I2 = 40%, Q statistic P = 0.04); this association was totally driven by the risk reduction of non-fatal stroke, which explained 100% of between-study variance (beta =  - 0.531, R2 = 100%), without heterogeneity (I2 = 24%, Q statistic P = 0.206). There was no association between the reduction in HbA1c and the HR for heart failure or all-cause death.
Conclusions
The reduction of HbA1c in eighteen CVOTs was significantly associated with reduction of non-fatal stroke, explaining all (R2 = 100%) of the between-study variance. While the contribution of glucose lowering in some CV benefits of newer agents does not influence their indications for the patient with type 2 diabetes, it may hopefully facilitate their use.

© 2021. The Author(s).

Cardiovasc Diabetol: 17 Oct 2021; 20:210
Maiorino MI, Longo M, Scappaticcio L, Bellastella G, ... Esposito K, Giugliano D
Cardiovasc Diabetol: 17 Oct 2021; 20:210 | PMID: 34663316
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Abstract

Relationship between skin autofluorescence levels and clinical events in patients with heart failure undergoing cardiac rehabilitation.

Kunimoto M, Yokoyama M, Shimada K, Matsubara T, ... Daida H, Minamino T
Background
Advanced glycation end-products, indicated by skin autofluorescence (SAF) levels, could be prognostic predictors of all-cause and cardiovascular mortality in patients with diabetes mellitus (DM) and renal disease. However, the clinical usefulness of SAF levels in patients with heart failure (HF) who underwent cardiac rehabilitation (CR) remains unclear. This study aimed to investigate the associations between SAF and MACE risk in patients with HF who underwent CR.
Methods
This study enrolled 204 consecutive patients with HF who had undergone CR at our university hospital between November 2015 and October 2017. Clinical characteristics and anthropometric data were collected at the beginning of CR. SAF levels were noninvasively measured with an autofluorescence reader. Major adverse cardiovascular event (MACE) was a composite of all-cause mortality and unplanned hospitalization for HF. Follow-up data concerning primary endpoints were collected until November 2017.
Results
Patients\' mean age was 68.1 years, and 61% were male. Patients were divided into two groups according to the median SAF levels (High and Low SAF groups). Patients in the High SAF group were significantly older, had a higher prevalence of chronic kidney disease, and more frequently had history of coronary artery bypass surgery; however, there were no significant between-group differences in sex, prevalence of DM, left ventricular ejection fraction, and physical function. During a mean follow-up period of 590 days, 18 patients had all-cause mortality and 36 were hospitalized for HF. Kaplan-Meier analysis showed that patients in the high SAF group had a higher incidence of MACE (log-rank P < 0.05). After adjusting for confounding factors, Cox regression multivariate analysis revealed that SAF levels were independently associated with the incidence of MACE (odds ratio, 1.86; 95% confidence interval, 1.08-3.12; P = 0.03).
Conclusion
SAF levels were significantly associated with the incidence of MACE in patients with HF and may be useful for risk stratification in patients with HF who underwent CR.

© 2021. The Author(s).

Cardiovasc Diabetol: 15 Oct 2021; 20:208
Kunimoto M, Yokoyama M, Shimada K, Matsubara T, ... Daida H, Minamino T
Cardiovasc Diabetol: 15 Oct 2021; 20:208 | PMID: 34656131
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Abstract

Visit-to-visit fasting blood glucose variability and lifetime risk of cardiovascular disease: a prospective study.

Bi J, Song L, Wang L, Wu M, ... Wu S, Tian Y
Aims
Previous studies suggested an adverse association between higher fasting blood glucose (FBG) variability and cardiovascular disease (CVD). Lifetime risk provides an absolute risk assessment during the remainder of an individual\'s life. However, the association between FBG variability and the lifetime risk of CVD is uncertain.
Objective
We aimed to investigate the effect of the visit-to-visit FBG variability on the lifetime risk of CVD.
Methods
This study included participants from the Kailuan Study who did not have CVD at index ages 35, 45, and 55 years. The FBG variability was defined as the coefficient of variation (CV) of three FBG values that were measured during the examination periods of 2006-2007, 2008-2009, and 2010-2011. We used a modified Kaplan-Merrier method to estimate lifetime risk of CVD according to tertiles of FBG variability.
Results
At index age 35 years, the study sample comprised 46,018 participants. During a median follow-up of 7.0 years, 1889 participants developed CVD events. For index age 35 years, participants with high FBG variability had higher lifetime risk of CVD (32.5%; 95% confidence interval [CI]: 28.9-36.1%), compared with intermediate (28.3%; 95% CI: 25.5 -31.1%) and low (26.3%; 95% CI: 23.0-29.5%) FBG variability. We found that higher FBG variability was associated with increased lifetime risk of CVD in men but not women. Similar patterns were observed at index ages 45 and 55 years.
Conclusions
Higher FBG variability was associated with increased lifetime risk of CVD at each index age. Focusing on the FBG variability may provide an insight to the clinical utility for reducing the lifetime risk of CVD.

© 2021. The Author(s).

Cardiovasc Diabetol: 15 Oct 2021; 20:207
Bi J, Song L, Wang L, Wu M, ... Wu S, Tian Y
Cardiovasc Diabetol: 15 Oct 2021; 20:207 | PMID: 34656122
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Abstract

Gender difference in the association between TyG index and subclinical atherosclerosis: results from the I-Lan Longitudinal Aging Study.

Lu YW, Chang CC, Chou RH, Tsai YL, ... Huang PH, Lin SJ
Background
Insulin resistance (IR) is a known risk factor for cardiovascular disease (CVD) in non-diabetic patients through the association of hyperglycemia or associated metabolic factors. The triglyceride glucose (TyG) index, which was defined by incorporating serum glucose and insulin concentrations, was developed as a surrogate marker of insulin resistance. We aimed to investigate the association between the TyG index and the early phase of subclinical atherosclerosis (SA) between the sexes.
Methods
The I-Lan Longitudinal Aging Study (ILAS) enrolled 1457 subjects aged 50-80 years. For each subject, demographic data and the TyG index {ln[fasting triglyceride (mg/dL)  ×  fasting plasma glucose (mg/dL)]/2} were obtained. Patients were further stratified according to sex and the 50th percentile of the TyG index (≥  8.55 or  <  8.55). SA was defined as the mean carotid intima-media thickness (cIMT) at the 75th percentile of the entire cohort. Demographic characteristics and the presence of SA were compared between the groups. Logistic regression analysis was performed to assess the relationship between TyG index and SA.
Results
Patients with a higher TyG index (≥  8.55) had a higher body mass index (BMI), hypertension (HTN) and diabetes mellitus (DM). They had higher lipid profiles, including total cholesterol (T-Chol) and low-density lipoprotein (LDL), compared to those with a lower TyG index (<  8.55). Gender disparity was observed in non-diabetic women who had a significantly higher prevalence of SA in the high TyG index group than in the low TyG index group. In multivariate logistic regression analysis, a high TyG index was independently associated with SA in non-diabetic women after adjusting for traditional risk factors [adjusted odds ratio (OR): 1.510, 95% CI 1.010-2.257, p  =  0.045] but not in non-diabetic men. The TyG index was not associated with the presence of SA in diabetic patients, irrespective of sex.
Conclusion
A high TyG index was significantly associated with SA and gender disparity in non-diabetic patients. This result may highlight the need for a sex-specific risk management strategy to prevent atherosclerosis.

© 2021. The Author(s).

Cardiovasc Diabetol: 12 Oct 2021; 20:206
Lu YW, Chang CC, Chou RH, Tsai YL, ... Huang PH, Lin SJ
Cardiovasc Diabetol: 12 Oct 2021; 20:206 | PMID: 34645432
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Abstract

GLP-1 receptor agonists vs. SGLT-2 inhibitors: the gap seems to be leveling off.

Giugliano D, Scappaticcio L, Longo M, Bellastella G, Esposito K
Cardiovascular disease (CVD) remains the leading cause of death in patients with type 2 diabetes (T2D). Older age, prior heart failure (HF) and CV events, peripheral artery disease, and kidney complications can identify a subgroup of patients with T2D at high risk of mortality who are likely to achieve the greatest benefit from newer glucose-lowering agents. Both glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose cotransporter-2 (SGLT-2) inhibitors can reduce CV risk in patients with T2D, and both are recommended by the American Diabetes Association to reduce the risk of major cardiovascular events (MACE). The magnitude of the benefits of GLP-1RA and SGLT-2 inhibitors on MACE are similar, ranging from 12 to 14% reduction of risk, but only GLP-1RA may reduce the risk of stroke. The most striking difference between the two classes of drugs relates to the amelioration on hospitalization for HF, as the benefit of SGLT-2 inhibitors surpass by threefold that obtained with GLP-1RA. Despite this, GLP-1RA also exert a significant benefit on HF which suggest their use when SGLT-2 inhibitors are contraindicated or not tolerated. The difference between the two classes is less impressive for the kidney outcome. Overall, the results of CVOTs published so far seems to suggest that the gap between the cardiorenal benefits of SGLT-2 and GLP-1RA is narrowing.

© 2021. The Author(s).

Cardiovasc Diabetol: 11 Oct 2021; 20:205
Giugliano D, Scappaticcio L, Longo M, Bellastella G, Esposito K
Cardiovasc Diabetol: 11 Oct 2021; 20:205 | PMID: 34641876
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Impact:
Abstract

Cost-effectiveness evaluation of add-on dapagliflozin for heart failure with reduced ejection fraction from perspective of healthcare systems in Asia-Pacific region.

Liao CT, Yang CT, Toh HS, Chang WT, ... Strong C, Ou HT
Background
With emerging evidence on the efficacy of adding dapagliflozin to standard care for patients with heart failure with reduced ejection fraction (HFrEF), this study assessed the cost-effectiveness of add-on dapagliflozin to standard care versus standard care alone for HFrEF from the perspective of healthcare systems in the Asia-Pacific region.
Methods
A Markov model was applied to project the outcomes of treatment in terms of lifetime medical cost and quality-adjusted life-years. The transition probabilities between health states in the model were obtained from the Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction trial. Country-specific costs and utilities were extracted for modeling. The incremental cost-effectiveness ratio against a country-specific willingness-to-pay threshold was applied to determine the cost-effectiveness of treatment. A series of sensitivity analyses were performed to ensure the robustness of the study results. Costs are presented in 2020 United States dollars.
Results
The incremental cost-effectiveness ratios for add-on dapagliflozin versus standard care alone were $5277, $9980, $12,305, $16,705, and $23,227 per quality-adjusted life-year gained in Korea, Australia, Taiwan, Japan, and Singapore, respectively. When using add-on dapagliflozin to standard care versus standard care alone, ~ 100% of simulations were cost-effective at a willingness-to-pay threshold of one gross domestic product per capita of the given Asia-Pacific country; however, the probability of being cost-effective for using add-on dapagliflozin decreased when the time horizon for simulation was restricted to 18 months and when the cardiovascular mortality for the two treatments (43.8% and 33.0%, respectively) was assumed to be the same. The cost-effectiveness results were most sensitive to cardiovascular mortality of treatment.
Conclusions
Adding dapagliflozin to standard care is cost-effective for HFrEF in healthcare systems in the Asia-Pacific region, which supports the rational use of dapagliflozin for HFrEF in this region.

© 2021. The Author(s).

Cardiovasc Diabetol: 08 Oct 2021; 20:204
Liao CT, Yang CT, Toh HS, Chang WT, ... Strong C, Ou HT
Cardiovasc Diabetol: 08 Oct 2021; 20:204 | PMID: 34627231
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Impact:
Abstract

Renoprotective effect of SGLT-2 inhibitors among type 2 diabetes patients with different baseline kidney function: a multi-center study.

Lin FJ, Wang CC, Hsu CN, Yang CY, Wang CY, Ou HT
Background
To assess the effect of sodium glucose cotransporter-2 inhibitors (SGLT-2is) for type 2 diabetes on kidney outcomes stratified by patient baseline estimated glomerular filtration rate (eGFR) levels (i.e., eGFR ≤ 60, 60 < eGFR ≤ 90, and eGFR > 90 mL/min/1.73 m2).
Methods
Patients from three large healthcare delivery systems in Taiwan who had initiated SGLT-2is or other glucose-lowering drugs (oGLDs) between May 2016 and December 2017 were included. Main outcomes were the times to 30%, 40%, and 50% eGFR reduction after treatment initiation. One-to-one propensity score matching in the overall study cohort and in each eGFR subgroup between SGLT-2i and oGLD users was applied to ensure between-group comparability in baseline characteristics.
Results
There were 13,666 matched pairs of SGLT-2is and oGLD users in the overall cohort. While a sustained eGFR decline was revealed in oGLD-treated patients (mean values [standard errors] from 85.61 [0.43] to 82.49 [0.44] mL/min/1.73 m2 during the 12 months after treatment initiation), the mean eGFR values of SGLT-2i users decreased in the first 3 months (85.68 [0.37] to 79.71 [0.41] mL/min/1.73 m2) but then improved and sustained until the end of follow-up. There were 2300, 5705, and 5509 matched SGLT-2i and oGLD users in the eGFR ≤ 60, 60 < eGFR ≤ 90, and eGFR > 90 subgroups, respectively. Using SGLT-2is versus oGLDs was significantly associated with slower eGFR declines; hazard ratios (HRs) were 0.51 (95% CI 0.37-0.69), 0.51 (0.37-0.70), and 0.47 (0.31-0.71) for 40% eGFR reduction in the eGFR ≤ 60, 60 < eGFR ≤ 90, and eGFR > 90 subgroups, respectively. The renoprotective effect of SGLT-2is versus oGLDs was confirmed in the outcomes of 30% and 50% eGFR reduction across the three eGFR subgroups.
Conclusions
This study supports the renoprotective benefit of real-world SGLT-2i use irrespective of patient baseline kidney function.

© 2021. The Author(s).

Cardiovasc Diabetol: 06 Oct 2021; 20:203
Lin FJ, Wang CC, Hsu CN, Yang CY, Wang CY, Ou HT
Cardiovasc Diabetol: 06 Oct 2021; 20:203 | PMID: 34620182
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Impact:
Abstract

Estimated glucose disposal rate and risk of stroke and mortality in type 2 diabetes: a nationwide cohort study.

Zabala A, Darsalia V, Lind M, Svensson AM, ... Jonsson M, Nyström T
Background:
and aims
Insulin resistance contributes to the development of type 2 diabetes (T2D) and is also a cardiovascular risk factor. The aim of this study was to investigate the potential association between insulin resistance measured by estimated glucose disposal rate (eGDR) and risk of stroke and mortality thereof in people with T2D.
Materials and methods
Nationwide population based observational cohort study that included all T2D patients from the Swedish national diabetes registry between 2004 and 2016 with full data on eGDR and categorised as following: < 4, 4-6, 6-8, and ≥ 8 mg/kg/min. We calculated crude incidence rates and 95% confidence intervals (CIs) and used multiple Cox regression to estimate hazard ratios (HRs) to assess the association between the risk of stroke and death, according to the eGDR categories in which the lowest category < 4 (i.e., highest grade of insulin resistance), served as a reference. The relative importance attributed of each factor in the eGDR formula was measured by the R2 (± SE) values calculating the explainable log-likelihoods in the Cox regression.
Results
A total of 104 697 T2D individuals, 44.5% women, mean age of 63 years, were included. During a median follow up-time of 5.6 years, 4201 strokes occurred (4.0%). After multivariate adjustment the HRs (95% CI) for stroke in patients with eGDR categories between 4-6, 6-8 and > 8 were: 0.77 (0.69-0.87), 0.68 (0.58-0.80) and 0.60 (0.48-0.76), compared to the reference < 4. Corresponding numbers for the risk of death were: 0.82 (0.70-0.94), 0.75 (0.64-0.88) and 0.68 (0.53-0.89). The attributed relative risk R2 (± SE) for each variable in the eGDR formula and stroke was for: hypertension (0.045 ± 0.0024), HbA1c (0.013 ± 0.0014), and waist (0.006 ± 0.0009), respectively.
Conclusion
A low eGDR (a measure of insulin resistance) is associated with an increased risk of stroke and death in individuals with T2D. The relative attributed risk was most important for hypertension.

© 2021. The Author(s).

Cardiovasc Diabetol: 05 Oct 2021; 20:202
Zabala A, Darsalia V, Lind M, Svensson AM, ... Jonsson M, Nyström T
Cardiovasc Diabetol: 05 Oct 2021; 20:202 | PMID: 34615525
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Impact:
Abstract

Atherogenic index of plasma is associated with major adverse cardiovascular events in patients with type 2 diabetes mellitus.

Fu L, Zhou Y, Sun J, Zhu Z, ... Wang Y, Tai S
Background
Previous studies reported the prognostic value of the atherogenic index of plasma (AIP) in the course of atherosclerosis and other cardiovascular diseases (CVDs). Still, the predictive utility of the AIP is unknown among patients with type 2 diabetes mellitus (T2DM).
Methods
This was a secondary analysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, which randomized 10,251 patients with long-lasting T2DM. ROC curve analysis was used to determine an optimal threshold for AIP, and the study population was divided into high and low AIP groups. Univariable and multivariable Cox proportional hazards regression analyses were used to determine the association between AIP and primary (major adverse cardiovascular events [MACEs], including nonfatal myocardial infarction, nonfatal stroke, and/or death from cardiovascular causes) and secondary outcomes (all-cause mortality). Stratified analyses were performed to control for the confounding factors.
Results
AIP was an independent risk factor for the prognosis of T2DM (HR = 1.309; 95% CI 1.084-1.581; P = 0.005). The threshold for AIP was determined to be 0.34 in the study population. After adjustments for confounding factors, multivariable analysis showed that AIP was associated with the risk of MACEs (Model 1: HR = 1.333, 95% CI 1.205-1.474, P < 0.001; Model 2: HR = 1.171, 95% CI 1.030-1.333, P = 0.016; Model 3: HR = 1.194, 95% CI 1.049-1.360, P = 0.007), all-cause mortality (Model 1: HR = 1.184, 95% CI 1.077-1.303, P < 0.001), cardiovascular death (Model 1: HR = 1.422, 95% CI 1.201-1.683, P < 0.001; Model 3: HR = 1.264, 95% CI 1.015-1.573, P = 0.036), and nonfatal myocardial infarction (Model 1: HR = 1.447, 95% CI 1.255-1.669, P < 0.001; Model 2: HR = 1.252, 95% CI 1.045-1.499, P = 0.015; Model 3: HR = 1.284, 95% CI 1.071-1.539, P = 0.007). Subgroup stratified analyses showed that AIP might interact with sex, a classical risk factor of cardiovascular events.
Conclusions
This study showed that AIP might be a strong biomarker that could be used to predict the risk of cardiovascular events in patients with T2DM.
Trial registration
URL: http://www.clinicaltrials.gov . Unique identifier: NCT00000620.

© 2021. The Author(s).

Cardiovasc Diabetol: 04 Oct 2021; 20:201
Fu L, Zhou Y, Sun J, Zhu Z, ... Wang Y, Tai S
Cardiovasc Diabetol: 04 Oct 2021; 20:201 | PMID: 34610830
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Impact:
Abstract

Impact of empagliflozin on right ventricular parameters and function among patients with type 2 diabetes.

Sarak B, Verma S, David Mazer C, Teoh H, ... Connelly KA, Yan AT
Background
Sodium-glucose cotransporter 2 (SGLT2) inhibition reduces cardiovascular events in type 2 diabetes (T2DM) and is associated with a reduction in left ventricular (LV) mass index. However, the impact on right ventricular (RV) remodeling is unknown. Accordingly, the objective of this study was to assess the impact of SGLT2 inhibition on RV parameters and function in T2DM and coronary artery disease (CAD).
Methods
In EMPA-HEART CardioLink-6, 97 patients with T2DM and CAD were randomly assigned to empagliflozin 10 mg (n = 49) once daily or placebo (n = 48). Cardiac magnetic resonance imaging was performed at baseline and after 6 months. RV mass index (RVMi), RV end-diastolic and end-systolic volume index (RVEDVi, RVESVi) and RV ejection fraction (RVEF) were assessed in blinded fashion.
Results
At baseline, mean RVMi (± SD) (11.8 ± 2.4 g/m2), RVEF (53.5 ± 4.8%), RVEDVi (64.3 ± 13.2 mL/m2) and RVESVi (29.9 ± 6.9 mL/m2) were within normal limits and were similar between the empagliflozin and placebo groups. Over 6 months, there were no significant differences in RVMi (- 0.11 g/m2, [95% CI - 0.81 to 0.60], p = 0.76), RVEF (0.54%, [95% CI - 1.4 to 2.4], p = 0.58), RVEDVi (- 1.2 mL/m2, [95% CI - 4.1 to 1.7], p = 0.41) and RVESVi (- 0.81 mL/m2, [95% CI - 2.5 to 0.90], p = 0.35) in the empaglifozin group as compared with the placebo group. In both groups, there was no significant correlation between RVMi and LVMi changes from baseline to 6 months.
Conclusions
In this post-hoc analysis, SGLT2 inhibition with empagliflozin had no impact on RVMi and RV volumes in patients with T2DM and CAD. The potentially differential effect of empagliflozin on the LV and RV warrants further investigation.
Clinical trial registration
URL:  https://www.clinicaltrials.gov/ct2/show/NCT02998970?cond=NCT02998970&draw=2&rank=1 . Unique identifier: NCT02998970.

© 2021. The Author(s).

Cardiovasc Diabetol: 03 Oct 2021; 20:200
Sarak B, Verma S, David Mazer C, Teoh H, ... Connelly KA, Yan AT
Cardiovasc Diabetol: 03 Oct 2021; 20:200 | PMID: 34607574
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Impact:
Abstract

Empagliflozin protects the heart against ischemia/reperfusion-induced sudden cardiac death.

Hu Z, Ju F, Du L, Abbott GW
Background
Empagliflozin is a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor used to lower blood sugar in adults with type 2 diabetes. Empagliflozin also exerts cardioprotective effects independent from glucose control, but its benefits on arrhythmogenesis and sudden cardiac death are not known. The purpose of this study was to examine the effect of empagliflozin on myocardial ischemia/reperfusion-provoked cardiac arrhythmia and sudden cardiac death in vivo.
Methods
Male Sprague Dawley rats were randomly assigned to sham-operated, control or empagliflozin groups. All except for the sham-operated rats were subjected to 5-min left main coronary artery ligation followed by 20-min reperfusion. A standard limb lead II electrocardiogram was continuously measured throughout the experiment. Coronary artery reperfusion-induced ventricular arrhythmogenesis and empagliflozin therapy were evaluated. The hearts were used for protein phosphorylation analysis and immunohistological assessment.
Results
Empagliflozin did not alter baseline cardiac normal conduction activity. However, empagliflozin eliminated myocardial vulnerability to sudden cardiac death (from 69.2% mortality rate in the control group to 0% in the empagliflozin group) and reduced the susceptibility to reperfusion-induced arrhythmias post I/R injury. Empagliflozin increased phosphorylation of cardiac ERK1/2 after reperfusion injury. Furthermore, inhibition of ERK1/2 using U0126 abolished the anti-arrhythmic action of empagliflozin and ERK1/2 phosphorylation.
Conclusions
Pretreatment with empagliflozin protects the heart from subsequent severe lethal ventricular arrhythmia induced by myocardial ischemia and reperfusion injury. These protective benefits may occur as a consequence of activation of the ERK1/2-dependent cell-survival signaling pathway in a glucose-independent manner.

© 2021. The Author(s).

Cardiovasc Diabetol: 03 Oct 2021; 20:199
Hu Z, Ju F, Du L, Abbott GW
Cardiovasc Diabetol: 03 Oct 2021; 20:199 | PMID: 34607570
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Impact:
Abstract

The association of hepatic steatosis and fibrosis with heart failure and mortality.

Park J, Kim G, Kim H, Lee J, ... Hur KY, Kim JH
Background
Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic disease and independently affects the development of cardiovascular (CV) disease. We investigated whether hepatic steatosis and/or fibrosis are associated with the development of incident heart failure (iHF), hospitalized HF (hHF), mortality, and CV death in both the general population and HF patients.
Methods
We analyzed 778,739 individuals without HF and 7445 patients with pre-existing HF aged 40 to 80 years who underwent a national health check-up from January 2009 to December 2012. The presence of hepatic steatosis and advanced hepatic fibrosis was determined using cutoff values for fatty liver index (FLI) and BARD score. We evaluated the association of FLI or BARD score with the development of iHF, hHF, mortality and CV death using multivariable-adjusted Cox regression models.
Results
A total of 28,524 (3.7%) individuals in the general population and 1422 (19.1%) pre-existing HF patients developed iHF and hHF respectively. In the multivariable-adjusted model, participants with an FLI ≥ 60 were at increased risk for iHF (hazard ratio [HR], 95% confidence interval [CI], 1.30, 1.24-1.36), hHF (HR 1.54, 95% CI 1.44-1.66), all-cause mortality (HR 1.62, 95% CI 1.54-1.70), and CV mortality (HR 1.41 95% CI 1.22-1.63) in the general population and hHF (HR 1.26, 95% CI 1.21-1.54) and all-cause mortality (HR 1.54 95% CI 1.24-1.92) in the HF patient group compared with an FLI < 20. Among participants with NAFLD, advanced liver fibrosis was associated with increased risk for iHF, hHF, and all-cause mortality in the general population and all-cause mortality and CV mortality in the HF patient group (all p < 0.05).
Conclusion
Hepatic steatosis and/or advanced fibrosis as assessed by FLI and BARD score was significantly associated with the risk of HF and mortality.

© 2021. The Author(s).

Cardiovasc Diabetol: 27 Sep 2021; 20:197
Park J, Kim G, Kim H, Lee J, ... Hur KY, Kim JH
Cardiovasc Diabetol: 27 Sep 2021; 20:197 | PMID: 34583706
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Impact:
Abstract

Effects of GLP-1 receptor agonists and SGLT-2 inhibitors on cardiac structure and function: a narrative review of clinical evidence.

Natali A, Nesti L, Tricò D, Ferrannini E
The impressive results of recent clinical trials with glucagon-like peptide-1 receptor agonists (GLP-1Ra) and sodium glucose transporter 2 inhibitors (SGLT-2i) in terms of cardiovascular protection prompted a huge interest in these agents for heart failure (HF) prevention and treatment. While both classes show positive effects on composite cardiovascular endpoints (i.e. 3P MACE), their actions on the cardiac function and structure, as well as on volume regulation, and their impact on HF-related events have not been systematically evaluated and compared. In this narrative review, we summarize and critically interpret the available evidence emerging from clinical studies. While chronic exposure to GLP-1Ra appears to be essentially neutral on both systolic and diastolic function, irrespective of left ventricular ejection fraction (LVEF), a beneficial impact of SGLT-2i is consistently detectable for both systolic and diastolic function parameters in subjects with diabetes with and without HF, with a gradient proportional to the severity of baseline dysfunction. SGLT-2i have a clinically significant impact in terms of HF hospitalization prevention in subjects at high and very high cardiovascular risk both with and without type 2 diabetes (T2D) or HF, while GLP-1Ra have been proven to be safe (and marginally beneficial) in subjects with T2D without HF. We suggest that the role of the kidney is crucial for the effect of SGLT-2i on the clinical outcomes not only because these drugs slow-down the time-dependent decline of kidney function and enhance the response to diuretics, but also because they attenuate the meal-related anti-natriuretic pressure (lowering postprandial hyperglycemia and hyperinsulinemia and preventing proximal sodium reabsorption), which would reduce the individual sensitivity to day-to-day variations in dietary sodium intake.

© 2021. The Author(s).

Cardiovasc Diabetol: 27 Sep 2021; 20:196
Natali A, Nesti L, Tricò D, Ferrannini E
Cardiovasc Diabetol: 27 Sep 2021; 20:196 | PMID: 34583699
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Impact:
Abstract

Diabetes status-related differences in risk factors and mediators of heart failure in the general population: results from the MORGAM/BiomarCaRE consortium.

Vuori MA, Reinikainen J, Söderberg S, Bergdahl E, ... Kuulasmaa K, Niiranen TJ
Background
The risk of heart failure among diabetic individuals is high, even under tight glycemic control. The correlates and mediators of heart failure risk in individuals with diabetes need more elucidation in large population-based cohorts with long follow-up times and a wide panel of biologically relevant biomarkers.
Methods
In a population-based sample of 3834 diabetic and 90,177 non-diabetic individuals, proportional hazards models and mediation analysis were used to assess the relation of conventional heart failure risk factors and biomarkers with incident heart failure.
Results
Over a median follow-up of 13.8 years, a total of 652 (17.0%) and 5524 (6.1%) cases of incident heart failure were observed in participants with and without diabetes, respectively. 51.4% were women and the mean age at baseline was 48.7 (standard deviation [SD] 12.5) years. The multivariable-adjusted hazard ratio (HR) for heart failure among diabetic individuals was 2.70 (95% confidence interval, 2.49-2.93) compared to non-diabetic participants. In the multivariable-adjusted Cox models, conventional cardiovascular disease risk factors, such as smoking (diabetes: HR 2.07 [1.59-2.69]; non-diabetes: HR 1.85 [1.68-2.02]), BMI (diabetes: HR 1.30 [1.18-1.42]; non-diabetes: HR 1.40 [1.35-1.47]), baseline myocardial infarction (diabetes: HR 2.06 [1.55-2.75]; non-diabetes: HR 2.86 [2.50-3.28]), and baseline atrial fibrillation (diabetes: HR 1.51 [0.82-2.80]; non-diabetes: HR 2.97 [2.21-4.00]) had the strongest associations with incident heart failure. In addition, biomarkers for cardiac strain (represented by nT-proBNP, diabetes: HR 1.26 [1.19-1.34]; non-diabetes: HR 1.43 [1.39-1.47]), myocardial injury (hs-TnI, diabetes: HR 1.10 [1.04-1.16]; non-diabetes: HR 1.13 [1.10-1.16]), and inflammation (hs-CRP, diabetes: HR 1.13 [1.03-1.24]; non-diabetes: HR 1.29 [1.25-1.34]) were also associated with incident heart failure. In general, all these associations were equally strong in non-diabetic and diabetic individuals. However, the strongest mediators of heart failure in diabetes were the direct effect of diabetes status itself (relative effect share 43.1% [33.9-52.3] and indirect effects (effect share 56.9% [47.7-66.1]) mediated by obesity (BMI, 13.2% [10.3-16.2]), cardiac strain/volume overload (nT-proBNP, 8.4% [-0.7-17.4]), and hyperglycemia (glucose, 12.0% [4.2-19.9]).
Conclusions
The findings suggest that the main mediators of heart failure in diabetes are obesity, hyperglycemia, and cardiac strain/volume overload. Conventional cardiovascular risk factors are strongly related to incident heart failure, but these associations are not stronger in diabetic than in non-diabetic individuals. Active measurement of relevant biomarkers could potentially be used to improve prevention and prediction of heart failure in high-risk diabetic patients.

© 2021. The Author(s).

Cardiovasc Diabetol: 27 Sep 2021; 20:195
Vuori MA, Reinikainen J, Söderberg S, Bergdahl E, ... Kuulasmaa K, Niiranen TJ
Cardiovasc Diabetol: 27 Sep 2021; 20:195 | PMID: 34583686
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Impact:
Abstract

Exploring potential mediators of the cardiovascular benefit of dulaglutide in type 2 diabetes patients in REWIND.

Konig M, Riddle MC, Colhoun HM, Branch KR, ... Raha S, Gerstein HC
Background
The REWIND trial demonstrated cardiovascular (CV) benefits to patients with type 2 diabetes and multiple CV risk factors or established CV disease. This exploratory analysis evaluated the degree to which the effect of dulaglutide on CV risk factors could statistically account for its effects on major adverse cardiovascular events (MACE) in the REWIND trial.
Methods
Potential mediators of established CV risk factors that were significantly reduced by dulaglutide were assessed in a post hoc analysis using repeated measures mixed models and included glycated hemoglobin (HbA1c), body weight, waist-to-hip ratio, systolic blood pressure, low-density lipoprotein (LDL), and urine albumin/creatinine ratio (UACR). These factors, for which the change in level during follow-up was significantly associated with incident MACE, were identified using Cox regression modeling. Each identified variable was then included as a covariate in the Cox model assessing the effect of dulaglutide on MACE to estimate the degree to which the hazard ratio of dulaglutide vs placebo was attenuated. The combined effect of the variables associated with attenuation was assessed by including all variables in an additional Cox model.
Results
Although all evaluated variables were significantly improved by treatment, only changes in HbA1c and UACR were associated with MACE and a reduction in the effect of dulaglutide on this outcome was observed. The observed hazard ratio for MACE for dulaglutide vs placebo reduced by 36.1% by the updated mean HbA1c, and by 28.5% by the updated mean UACR. A similar pattern was observed for change from baseline in HbA1c and UACR and a reduction of 16.7% and 25.4%, respectively in the hazard ratio for MACE with dulaglutide vs placebo was observed. When HbA1c and UACR were both included, the observed hazard ratio reduced by 65.4% for the updated mean and 41.7% for the change from baseline with no HbA1c-UACR interaction (P interaction = 0.75 and 0.15, respectively).
Conclusions
Treatment-induced improvement in HbA1c and UACR, but not changes in weight, systolic blood pressure, or LDL cholesterol, appear to partly mediate the beneficial effects of dulaglutide on MACE outcomes. These observations suggest that the proven effects of dulaglutide on cardiovascular disease benefit are partially related to changes in glycemic control and albuminuria, with residual unexplained benefit. Clinicaltrials.gov; Trial registration number: NCT01394952. URL: https://clinicaltrials.gov/ct2/show/NCT01394952.

© 2021. The Author(s).

Cardiovasc Diabetol: 24 Sep 2021; 20:194
Konig M, Riddle MC, Colhoun HM, Branch KR, ... Raha S, Gerstein HC
Cardiovasc Diabetol: 24 Sep 2021; 20:194 | PMID: 34563178
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Impact:
Abstract

Impact of admission hyperglycemia on short and long-term prognosis in acute myocardial infarction: MINOCA versus MIOCA.

Paolisso P, Foà A, Bergamaschi L, Angeli F, ... Galiè N, Pizzi C
Background
The prognostic role of hyperglycemia in patients with myocardial infarction and obstructive coronary arteries (MIOCA) is acknowledged, while data on non-obstructive coronary arteries (MINOCA) are still lacking. Recently, we demonstrated that admission stress-hyperglycemia (aHGL) was associated with a larger infarct size and inflammatory response in MIOCA, while no differences were observed in MINOCA. We aim to investigate the impact of aHGL on short and long-term outcomes in MIOCA and MINOCA patients.
Methods
Multicenter, population-based, cohort study of the prospective registry, designed to evaluate the prognostic information of patients admitted with acute myocardial infarction to S. Orsola-Malpighi and Maggiore Hospitals of Bologna metropolitan area. Among 2704 patients enrolled from 2016 to 2020, 2431 patients were classified according to the presence of aHGL (defined as admission glucose level ≥ 140 mg/dL) and AMI phenotype (MIOCA/MINOCA): no-aHGL (n = 1321), aHGL (n = 877) in MIOCA and no-aHGL (n = 195), aHGL (n = 38) in MINOCA. Short-term outcomes included in-hospital death and arrhythmias. Long-term outcomes were all-cause and cardiovascular mortality.
Results
aHGL was associated with a higher in-hospital arrhythmic burden in MINOCA and MIOCA, with increased in-hospital mortality only in MIOCA. After adjusting for age, gender, hypertension, Killip class and AMI phenotypes, aHGL predicted higher in-hospital mortality in non-diabetic (HR = 4.2; 95% CI 1.9-9.5, p = 0.001) and diabetic patients (HR = 3.5, 95% CI 1.5-8.2, p = 0.003). During long-term follow-up, aHGL was associated with 2-fold increased mortality in MIOCA and a 4-fold increase in MINOCA (p = 0.032 and p = 0.016). Kaplan Meier 3-year survival of non-hyperglycemic patients was greater than in aHGL patients for both groups. No differences in survival were found between hyperglycemic MIOCA and MINOCA patients. After adjusting for age, gender, hypertension, smoking, LVEF, STEMI/NSTEMI and AMI phenotypes (MIOCA/MINOCA), aHGL predicted higher long-term mortality.
Conclusions
aHGL was identified as a strong predictor of adverse short- and long-term outcomes in both MIOCA and MINOCA, regardless of diabetes. aHGL should be considered a high-risk prognostic marker in all AMI patients, independently of the underlying coronary anatomy. Trial registration data were part of the ongoing observational study AMIPE: Acute Myocardial Infarction, Prognostic and Therapeutic Evaluation. ClinicalTrials.gov Identifier: NCT03883711.

© 2021. The Author(s).

Cardiovasc Diabetol: 23 Sep 2021; 20:192
Paolisso P, Foà A, Bergamaschi L, Angeli F, ... Galiè N, Pizzi C
Cardiovasc Diabetol: 23 Sep 2021; 20:192 | PMID: 34560876
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Impact:
Abstract

Prognostic impact of liver fibrosis and steatosis by transient elastography for cardiovascular and mortality outcomes in individuals with nonalcoholic fatty liver disease and type 2 diabetes: the Rio de Janeiro Cohort Study.

Cardoso CRL, Villela-Nogueira CA, Leite NC, Salles GF
Background
Liver stiffness measurement (LSM, which reflects fibrosis) and controlled attenuation parameter (CAP, which reflects steatosis), two parameters derived from hepatic transient elastography (TE), have scarcely been evaluated as predictors of cardiovascular complications and mortality in individuals with type 2 diabetes and nonalcoholic fatty liver disease (NAFLD).
Methods
Four hundred type 2 diabetic patients with NAFLD had TE examination (by Fibroscan®) performed at baseline. Multivariate Cox analyses evaluated the associations between TE parameters and the occurrence of cardiovascular events (CVEs) and mortality. TE parameters were assessed as continuous variables and dichotomized at low/high values reflecting advanced liver fibrosis (LSM > 9.6 kPa) and severe steatosis (CAP > 296 or > 330 dB/m). Improvements in risk discrimination were assessed by C-statistic and by the relative Integrated Discrimination Improvement (IDI) index.
Results
During a median follow-up of 5.5 years, 85 patients died (40 from cardiovascular causes), and 69 had a CVE. As continuous variables, an increasing LSM was a risk marker for total CVEs (hazard ratio [HR]: 1.05; 95% CI: 1.01-1.08) and all-cause mortality (HR: 1.04; 95% CI: 1.01-1.07); whereas an increasing CAP was a protective factor for both outcomes (HR: 0.93; 95% CI: 0.89-0.98; and HR: 0.92; 95% CI: 0.88-0.97; respectively). As dichotomized variables, a high LSM remained a risk marker of adverse outcomes (with HRs ranging from 2.5 to 3.0) and a high CAP was protective (with HRs from 0.3 to 0.5). The subgroup of individuals with low-LSM/high-CAP had the lowest risks while the opposite subgroup with high-LSM/low-CAP had the highest risks. Both LSM and CAP improved risk discrimination, with increases in C-statistics up to 0.037 and IDIs up to 52%.
Conclusions
Measured by hepatic TE, advanced liver fibrosis is a risk marker and severe steatosis is a protective factor for cardiovascular complications and mortality in individuals with type 2 diabetes and NAFLD.

© 2021. The Author(s).

Cardiovasc Diabetol: 23 Sep 2021; 20:193
Cardoso CRL, Villela-Nogueira CA, Leite NC, Salles GF
Cardiovasc Diabetol: 23 Sep 2021; 20:193 | PMID: 34560854
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Impact:
Abstract

Hypofibrinolysis in type 2 diabetes and its clinical implications: from mechanisms to pharmacological modulation.

Bryk-Wiązania AH, Undas A
A prothrombotic state is a typical feature of type 2 diabetes mellitus (T2DM). Apart from increased platelet reactivity, endothelial dysfunction, hyperfibrinogenemia, and hypofibrinolysis are observed in T2DM. A variety of poorly elucidated mechanisms behind impaired fibrinolysis in this disease have been reported, indicating complex associations between platelet activation, fibrin formation and clot structure, and fibrinolysis inhibitors, in particular, elevated plasminogen antigen inhibitor-1 levels which are closely associated with obesity. Abnormal fibrin clot structure is of paramount importance for relative resistance to plasmin-mediated lysis in T2DM. Enhanced thrombin generation, a proinflammatory state, increased release of neutrophil extracellular traps, elevated complement C3, along with posttranslational modifications of fibrinogen and plasminogen have been regarded to contribute to altered clot structure and impaired fibrinolysis in T2DM. Antidiabetic agents such as metformin and insulin, as well as antithrombotic agents, including anticoagulants, have been reported to improve fibrin properties and accelerate fibrinolysis in T2DM. Notably, recent evidence shows that hypofibrinolysis, assessed in plasma-based assays, has a predictive value in terms of cardiovascular events and cardiovascular mortality in T2DM patients. This review presents the current data on the mechanisms underlying arterial and venous thrombotic complications in T2DM patients, with an emphasis on hypofibrinolysis and its impact on clinical outcomes. We also discuss potential modulators of fibrinolysis in the search for optimal therapy in diabetic patients.

© 2021. The Author(s).

Cardiovasc Diabetol: 21 Sep 2021; 20:191
Bryk-Wiązania AH, Undas A
Cardiovasc Diabetol: 21 Sep 2021; 20:191 | PMID: 34551784
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Impact:
Abstract

Comparison of various insulin resistance surrogates on prognostic prediction and stratification following percutaneous coronary intervention in patients with and without type 2 diabetes mellitus.

Zhao Q, Cheng YJ, Xu YK, Zhao ZW, ... Sun TN, Zhou YJ
Background
Insulin resistance (IR), evaluation of which is difficult and complex, is closely associated with cardiovascular disease. Recently, various IR surrogates have been proposed and proved to be highly correlated with IR assessed by the gold standard. It remains indistinct whether different IR surrogates perform equivalently on prognostic prediction and stratification following percutaneous coronary intervention (PCI) in non-ST-segment elevation acute coronary syndrome (NSTE-ACS) patients with and without type 2 diabetes mellitus (T2DM).
Methods
The present study recruited patients who were diagnosed with NSTE-ACS and successfully underwent PCI. IR surrogates evaluated in the current study included triglyceride-glucose (TyG) index, visceral adiposity index, Chinese visceral adiposity index, lipid accumulation product, and triglyceride-to-high density lipoprotein cholesterol ratio, calculations of which were conformed to previous studies. The observational endpoint was defined as the major adverse cardiovascular and cerebrovascular events (MACCE), including cardiac death, non-fatal myocardial infarction, and non-fatal ischemic stroke.
Results
2107 patients (60.02 ± 9.03 years, 28.0% female) were ultimately enrolled in the present study. A total of 187 (8.9%) MACCEs were documented during the 24-month follow-up. Despite regarding the lower median as reference [hazard ratio (HR) 3.805, 95% confidence interval (CI) 2.581-5.608, P < 0.001] or evaluating 1 normalized unit increase (HR 1.847, 95% CI 1.564-2.181, P < 0.001), the TyG index remained the strongest risk predictor for MACCE, independent of confounding factors. The TyG index showed the most powerful diagnostic value for MACCE with the highest area under the receiver operating characteristic curve of 0.715. The addition of the TyG index, compared with other IR surrogates, exhibited the maximum enhancement on risk stratification for MACCE on the basis of a baseline model (Harrell\'s C-index: 0.708 for baseline model vs. 0.758 for baseline model + TyG index, P < 0.001; continuous net reclassification improvement: 0.255, P < 0.001; integrated discrimination improvement: 0.033, P < 0.001). The results were consistent in subgroup analysis where similar analyses were performed in patients with and without T2DM, respectively.
Conclusion
The TyG index, which is most strongly associated with the risk of MACCE, can be served as the most valuable IR surrogate for risk prediction and stratification in NSTE-ACS patients receiving PCI, with and without T2DM.

© 2021. The Author(s).

Cardiovasc Diabetol: 17 Sep 2021; 20:190
Zhao Q, Cheng YJ, Xu YK, Zhao ZW, ... Sun TN, Zhou YJ
Cardiovasc Diabetol: 17 Sep 2021; 20:190 | PMID: 34537077
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Abstract

GLP-1 receptor agonists and cardiorenal outcomes in type 2 diabetes: an updated meta-analysis of eight CVOTs.

Giugliano D, Scappaticcio L, Longo M, Caruso P, ... Chiodini P, Esposito K
Background
A meta-analysis is presented of cardiovascular outcome trials (CVOTs) comparing glucagon-like peptide-1 receptor agonists (GLP-1RA) versus placebo on cardiorenal outcomes in patients with type 2 diabetes mellitus (T2DM).
Methods
We did an electronic search up to June 30, 2021, for eligible trials. We did a meta-analysis of available trial data using a random-effects model to calculate overall hazard ratios (HRs) and 95% CI (confidence intervals). We included data from 8 CVOTs and 60,080 patients (72.4% with established cardiovascular disease).
Results
GLP-1RA reduced major cardiovascular events (MACE) by 14% (HR = 0.86, 95% CI 0.79-0.94, P = 0.006) with a non-significant heterogeneity between subgroups of patients with and without cardiovascular disease (P = 0.127). GLP-1RA also reduced the risk of cardiovascular death by 13% (P = 0.016), nonfatal stroke by 16% (P = 0.007), hospitalization for heart failure by 10% (P = 0.023), all-cause mortality by 12% (P = 0.012), and the broad composite kidney outcome by 17% (P = 0.012), which was driven by a reduction in macroalbuminuria only (HR = 0.74, 0.67-0.82, P < 0.001).
Conclusions
GLP-1RA have moderate benefits on MACE, and also reduce hospitalization for heart failure and all-cause mortality; they also have robust benefits on reducing the incidence of macroalbuminuria.

© 2021. The Author(s).

Cardiovasc Diabetol: 14 Sep 2021; 20:189
Giugliano D, Scappaticcio L, Longo M, Caruso P, ... Chiodini P, Esposito K
Cardiovasc Diabetol: 14 Sep 2021; 20:189 | PMID: 34526024
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Abstract

Association between apolipoprotein B/A1 ratio and coronary plaque vulnerability in patients with atherosclerotic cardiovascular disease: an intravascular optical coherence tomography study.

Deng F, Li D, Lei L, Yang Q, ... Zheng Q, Jiang W
Background
Apolipoprotein (Apo) A1 and Apo B are strongly associated with the risk of atherosclerotic cardiovascular disease (ASCVD). However, the relationship between the Apo B/A1 ratio and the morphology of coronary vulnerable plaques has not been fully elucidated in patients with ASCVD.
Methods
A total of 320 patients with ASCVD undergoing percutaneous coronary intervention were enrolled and assigned into acute coronary syndrome (ACS) or chronic coronary syndrome (CCS) group. The morphology of culprit plaque was analyzed by intravascular optical coherence tomography. Association between the Apo B/A1 ratio and coronary vulnerable plaques were evaluated using logistic regression models and receiver operator characteristic (ROC) curve analyses.
Results
The Apo B/A1 ratio was higher in ACS patients than CCS patients (0.77 ± 0.28 vs. 0.64 ± 0.22, P < 0.001) and it was also higher in patients with plaque rupture, erosion or thrombus than those without culprit plaques. The high Apo B/A1 ratio was associated with high percent of vulnerable plaques compared with low ratio group. The Apo B/A1 ratio was negatively related to fibrous cap thickness in lipid-rich plaque (r = - 0.228, P = 0.043). Univariate and multivariate logistic regression analyses revealed that the Apo B/A1 ratio was an independent factor of plaque rupture, erosion, and thrombus. The area under the ROC curve of the Apo B/A1 ratio for plaque rupture, erosion, and thrombus were 0.632, 0.624, and 0.670 respectively (P < 0.001 for all), which were higher than that of low-density lipoprotein cholesterol.
Conclusions
The Apo B/A1 ratio is an independent predictor for plaque rupture, erosion, and thrombus in patients with ASCVD.

© 2021. The Author(s).

Cardiovasc Diabetol: 14 Sep 2021; 20:188
Deng F, Li D, Lei L, Yang Q, ... Zheng Q, Jiang W
Cardiovasc Diabetol: 14 Sep 2021; 20:188 | PMID: 34526013
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Abstract

Effects of canagliflozin on NT-proBNP stratified by left ventricular diastolic function in patients with type 2 diabetes and chronic heart failure: a sub analysis of the CANDLE trial.

Kusunose K, Imai T, Tanaka A, Dohi K, ... Node K, CANDLE Trial Investigators
Background
Identification of the effective subtypes of treatment for heart failure (HF) is an essential topic for optimizing treatment of the disorder. We hypothesized that the beneficial effect of SGLT2 inhibitors (SGLT2i) on the levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) might depend on baseline diastolic function. To elucidate the effects of SGLT2i in type 2 diabetes mellitus (T2DM) and chronic HF we investigated, as a post-hoc sub-study of the CANDLE trial, the effects of canagliflozin on NT-proBNP levels from baseline to 24 weeks, with the data stratified by left ventricular (LV) diastolic function at baseline.
Methods
Patients (n = 233) in the CANDLE trial were assigned randomly to either an add-on canagliflozin (n = 113) or glimepiride treatment groups (n = 120). The primary endpoint was a comparison between the two groups of the changes from baseline to 24 weeks in NT-pro BNP levels, stratified according to baseline ventricular diastolic function.
Results
The change in the geometric mean of NT-proBNP level from baseline to 24 weeks was 0.98 (95% CI 0.89-1.08) in the canagliflozin group and 1.07 (95% CI 0.97-1.18) in the glimepiride group. The ratio of change with canagliflozin/glimepiride was 0.93 (95% CI 0.82-1.05). Responder analyses were used to investigate the response of an improvement in NT-proBNP levels. Although the subgroup analyses for septal annular velocity (SEP-e\') showed no marked heterogeneity in treatment effect, the subgroup with an SEP-e\' < 4.7 cm/s indicated there was an association with lower NT-proBNP levels in the canagliflozin group compared with that in the glimepiride group (ratio of change with canagliflozin/glimepiride (0.83, 95% CI 0.66-1.04).
Conclusions
In the subgroup with a lower LV diastolic function, canagliflozin showed a trend of reduced NT-pro BNP levels compared to that observed with glimepiride. This study suggests that the beneficial effects of canagliflozin treatment may be different in subgroups classified by the severity of LV diastolic dysfunction.

© 2021. The Author(s).

Cardiovasc Diabetol: 13 Sep 2021; 20:186
Kusunose K, Imai T, Tanaka A, Dohi K, ... Node K, CANDLE Trial Investigators
Cardiovasc Diabetol: 13 Sep 2021; 20:186 | PMID: 34521417
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Abstract

Effect of diabetes mellitus on the development of left ventricular contractile dysfunction in women with heart failure and preserved ejection fraction.

Shi K, Yang MX, Huang S, Yan WF, ... Guo YK, Yang ZG
Background
Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome with sex-specific pathophysiology. Estrogen deficiency is believed to be responsible for the development of HFpEF in women. However, estrogen deficiency does not seem to be completely responsible for the differences in HFpEF prevalence between sexes. While diabetes mellitus (DM) frequently coexists with HFpEF in women and is associated with worse outcomes, the changes in myocardial contractility among women with HFpEF and the DM phenotype is yet unknown. Therefore, we aimed to investigate sex-related differences in left ventricular (LV) contractility dysfunction in HFpEF comorbid with DM.
Methods
A total of 224 patients who underwent cardiac cine MRI were included in this study. Sex-specific differences in LV structure and function in the context of DM were determined. LV systolic strains (global longitudinal strain [GLS], circumferential strain [GCS] and radial strain [GRS]) were measured using cine MRI. The determinants of impaired myocardial strain for women and men were assessed.
Results
The prevalence of DM did not differ between sexes (p > 0.05). Despite a similar LV ejection fraction, women with DM demonstrated a greater LV mass index than women without DM (p = 0.023). The prevalence of LV geometry patterns by sex did not differ in the non-DM subgroup, but there was a trend toward a more abnormal LV geometry in women with DM (p = 0.072). The magnitudes of systolic strains were similar between sexes in the non-DM group (p > 0.05). Nevertheless, in the DM subgroup, there was significant impairment in women in systolic strains compared with men (p < 0.05). In the multivariable analysis, DM was associated with impaired systolic strains in women (GLS [β = 0.26; p = 0.007], GCS [β = 0.31; p < 0.001], and GRS [β = -0.24; p = 0.016]), whereas obesity and coronary artery disease were associated with impaired systolic strains in men (p < 0.05).
Conclusions
Women with DM demonstrated greater LV contractile dysfunction, which indicates that women with HFpEF comorbid with DM have a high-risk phenotype of cardiac failure that may require more aggressive and personalized medical treatment.

© 2021. The Author(s).

Cardiovasc Diabetol: 13 Sep 2021; 20:185
Shi K, Yang MX, Huang S, Yan WF, ... Guo YK, Yang ZG
Cardiovasc Diabetol: 13 Sep 2021; 20:185 | PMID: 34521391
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Abstract

Body weight changes in patients with type 2 diabetes and a recent acute coronary syndrome: an analysis from the EXAMINE trial.

Ferreira JP, Rossignol P, Bakris G, Mehta C, White WB, Zannad F
Background
Patients with type 2 diabetes (T2D) may experience frequent body weight changes over time. The prognostic impact of these weight changes (gains or losses) requires further study.
Aims
To study the associations between changes in body weight (intentional or unintentional) with subsequent outcomes.
Methods
The EXAMINE trial included 5380 patients with T2D and a recent acute coronary syndrome, who were randomized to alogliptin or placebo. Time-updated Cox models and mixed effects models were used to test the associations between changes in body weight and subsequent outcomes over a median follow-up of 1.6 (1.0-2.1) years.
Results
During the post-randomization follow-up period, 1044 patients (19.4%) experienced a weight loss ≥ 5% of baseline weight, 2677 (49.8%) had a stable weight, and 1659 (30.8%) had a ≥ 5 % weight gain. Patients with weight loss were more frequently women and had more co-morbid conditions. In contrast, patients who gained ≥ 5% weight were more frequently men with less co-morbid conditions. A weight loss ≥ 5% was independently associated with a higher risk of subsequent adverse outcomes, including all-cause mortality: adjusted HR (95% CI) = 1.79 (1.33-2.42), P < 0.001. Similar associations were found for cardiovascular mortality, the composite of cardiovascular mortality or heart failure hospitalization, and the primary outcome. A weight gain ≥ 5% was independently associated with an increase in the risk of subsequent cardiovascular mortality or heart failure hospitalization only: adjusted HR (95% CI) = 1.34 (1.02-1.76), P = 0.033.
Conclusions
In patients with T2D who had a recent ACS/MI, a ≥ 5% loss of body weight was associated with a higher risk of subsequent cardiovascular events and mortality.

© 2021. The Author(s).

Cardiovasc Diabetol: 13 Sep 2021; 20:187
Ferreira JP, Rossignol P, Bakris G, Mehta C, White WB, Zannad F
Cardiovasc Diabetol: 13 Sep 2021; 20:187 | PMID: 34521390
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This program is still in alpha version.