Changes in Albuminuria Predict Cardiovascular and Renal Outcomes in Type 2 Diabetes: A Post Hoc Analysis of the LEADER Trial

OBJECTIVE A post hoc analysis to investigate the association between 1-year changes in albuminuria and subsequent risk of cardiovascular and renal events. RESEARCH DESIGN AND METHODS LEADER was a randomized trial of liraglutide up to 1.8 mg/day versus placebo added to standard care for 3.5–5 years, in 9,340 participants with type 2 diabetes and high cardiovascular risk. We calculated change in urinary albumin-to-creatinine ratio (UACR) from baseline to 1 year in participants with >30% reduction (N=2,928), 30–0% reduction N=1,218) or any increase in UACR (N=4,124) irrespective of treatment. Using Cox regression, risks of major adverse cardiovascular events (MACE) and a composite nephropathy outcome (from 1 year to end of trial in subgroups by baseline UACR [<30 mg/g, 30–300 mg/g or ≥300 mg/g]) were assessed. The analysis was adjusted for treatment allocation alone as a fixed factor and for baseline variables associated with cardiovascular and renal outcomes. RESULTS For MACE, hazard ratios (HRs) for those with >30% and 30%–0% UACR reduction were 0.82 (95% CI 0.71–0.94; P=0.006) and 0.99 (0.82–1.19; P=0.912), respectively, compared with any increase in UACR (reference). For the composite nephropathy outcome, respective HRs (95% CI) were 0.67 (0.49–0.93; P=0.02) and 0.97 (0.66–1.43; P=0.881). Results were independent of baseline UACR and consistent in both treatment groups. After adjustment, HRs were significant and consistent in >30% reduction subgroups with baseline micro- or macroalbuminuria. CONCLUSIONS A reduction in albuminuria during the first year was associated with fewer cardiovascular and renal outcomes, independent of treatment. Albuminuria monitoring remains an important part of diabetes care, with great unused potential.

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Association of Baseline HbA1c With Cardiovascular and Renal Outcomes: Analyses From DECLARE-TIMI 58

10.2337/figshare.17118962 ◽

2022 ◽

Author(s):

Avivit Cahn ◽

Stephen D. Wiviott ◽

Ofri Mosenzon ◽

Sabina A. Murphy ◽

Erica L. Goodrich ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cardiovascular Events ◽

Cox Regression ◽

Major Adverse Cardiovascular Events ◽

Atherosclerotic Cardiovascular Disease ◽

Baseline Hba1c ◽

Renal Outcomes ◽

Increased Risk ◽

Hba1c Levels

Objective: Current guidelines recommend prescribing SGLT-2 inhibitors to patients with type 2 diabetes and established or at high risk for atherosclerotic cardiovascular disease (ASCVD), irrespective of HbA1c levels. We studied the association of HbA1c with cardiovascular and renal outcomes and whether the benefit of dapagliflozin varies by baseline HbA1c. Methods: In the Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 trial 17,160 patients with type 2 diabetes were randomized to dapagliflozin or placebo for a median follow up of 4.2 years. Cardiovascular and renal outcomes by baseline HbA1c in the overall population, and with dapagliflozin vs. placebo in HbA1c subgroups were studied by Cox regression models. Results: In the overall population, increasing HbA1c was associated with higher risk of cardiovascular death or hospitalization for heart failure (CVD/HHF), major adverse cardiovascular events (MACE; CVD, myocardial infarction, ischemic stroke) and of the cardiorenal outcome (adjusted HR [95% CI] 1.12 [1.06-1.19], 1.08 [1.04-1.13] and 1.17 [1.11-1.24] per 1% increase respectively). Elevated HbA1c was associated with an increased risk for MACE and for the cardiorenal outcome significantly more in patients with multiple risk factors (MRF), vs. patients with established ASCVD (P-interaction 0.0064 and 0.0093 respectively). Dapagliflozin led to a decrease in the risk of CVD/HHF, HHF and the cardiorenal outcome vs. placebo with no heterogeneity by baseline HbA1c (P-interaction >0.05). Conclusions: High HbA1c levels were associated with greater cardiovascular and renal risk, particularly in the MRF population, yet the benefits of dapagliflozin were observed in all subgroups irrespective of baseline HbA1c, including patients with HbA1c<7%.

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Association of Baseline HbA1c With Cardiovascular and Renal Outcomes: Analyses From DECLARE-TIMI 58

10.2337/figshare.17118962.v1 ◽

2022 ◽

Author(s):

Avivit Cahn ◽

Stephen D. Wiviott ◽

Ofri Mosenzon ◽

Sabina A. Murphy ◽

Erica L. Goodrich ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cardiovascular Events ◽

Cox Regression ◽

Major Adverse Cardiovascular Events ◽

Atherosclerotic Cardiovascular Disease ◽

Baseline Hba1c ◽

Renal Outcomes ◽

Increased Risk ◽

Hba1c Levels

Objective: Current guidelines recommend prescribing SGLT-2 inhibitors to patients with type 2 diabetes and established or at high risk for atherosclerotic cardiovascular disease (ASCVD), irrespective of HbA1c levels. We studied the association of HbA1c with cardiovascular and renal outcomes and whether the benefit of dapagliflozin varies by baseline HbA1c. Methods: In the Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 trial 17,160 patients with type 2 diabetes were randomized to dapagliflozin or placebo for a median follow up of 4.2 years. Cardiovascular and renal outcomes by baseline HbA1c in the overall population, and with dapagliflozin vs. placebo in HbA1c subgroups were studied by Cox regression models. Results: In the overall population, increasing HbA1c was associated with higher risk of cardiovascular death or hospitalization for heart failure (CVD/HHF), major adverse cardiovascular events (MACE; CVD, myocardial infarction, ischemic stroke) and of the cardiorenal outcome (adjusted HR [95% CI] 1.12 [1.06-1.19], 1.08 [1.04-1.13] and 1.17 [1.11-1.24] per 1% increase respectively). Elevated HbA1c was associated with an increased risk for MACE and for the cardiorenal outcome significantly more in patients with multiple risk factors (MRF), vs. patients with established ASCVD (P-interaction 0.0064 and 0.0093 respectively). Dapagliflozin led to a decrease in the risk of CVD/HHF, HHF and the cardiorenal outcome vs. placebo with no heterogeneity by baseline HbA1c (P-interaction >0.05). Conclusions: High HbA1c levels were associated with greater cardiovascular and renal risk, particularly in the MRF population, yet the benefits of dapagliflozin were observed in all subgroups irrespective of baseline HbA1c, including patients with HbA1c<7%.

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Trimethylamine N-oxide and incident atherosclerotic events in high-risk individuals with diabetes: an ACCORD trial post hoc analysis

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2019-000718 ◽

2019 ◽

Vol 7 (1) ◽

pp. e000718 ◽

Cited By ~ 3

Author(s):

Andrea Cardona ◽

Aaron O'Brien ◽

Matthew C Bernier ◽

Arpad Somogyi ◽

Vicki H Wysocki ◽

...

Keyword(s):

High Risk ◽

Cardiovascular Events ◽

Major Adverse Cardiovascular Events ◽

Atherosclerotic Cardiovascular Disease ◽

Antihypertensive Medications ◽

Ascvd Risk ◽

Post Hoc ◽

Design And Methods

IntroductionType 2 diabetes mellitus (T2D) confers high atherosclerotic cardiovascular disease (ASCVD) risk. The metabolite trimethylamine N-oxide (TMAO) derived via gut flora has been linked to excess ASCVD.Research design and methodsWe analyzed data, biospecimens, and major adverse cardiovascular events (MACEs) from the prospective multicenter randomized Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial to assess its value in 330 high-risk individuals with T2D without evident atherosclerotic disease at enrollment.ResultsIncident cardiovascular events occurred in 165 cases; 165 controls matched by age, sex, and treatment arm experienced no incident events during follow-up. Cases and controls (mean age 64.5 years) had similar mean glycated hemoglobin (HbA1c) (8.2%) and mean 10-year ASCVD risk (23.5%); groups also had similar use of statins and antihypertensive medications at baseline and follow-up. Baseline plasma TMAO levels did not differ between groups after adjusting for ASCVD risk score, HbA1c, and estimated glomerular filtration rate, nor did TMAO distinguish patients suffering incident MACE from those who remained event-free.ConclusionsTMAO’s prognostic value for incident ASCVD events may be blunted when applied to individuals with T2D with poor glycemic control and high baseline ASCVD risk. These results behoove further translational investigations of unique mechanisms of ASCVD risk in T2D.

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Risk of early mortality and cardiovascular disease in type 1 diabetes: a comparison with type 2 diabetes, a nationwide study

Cardiovascular Diabetology ◽

10.1186/s12933-019-0953-7 ◽

2019 ◽

Vol 18 (1) ◽

Cited By ~ 7

Author(s):

You-Bin Lee ◽

Kyungdo Han ◽

Bongsung Kim ◽

Seung-Eun Lee ◽

Ji Eun Jun ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cardiovascular Disease ◽

Type 1 Diabetes ◽

Cox Regression ◽

Early Mortality ◽

Hazard Ratios ◽

Epidemiological Characteristics

Abstract Background Both type 1 and type 2 diabetes are well-established risk factors for cardiovascular disease and early mortality. However, few studies have directly compared the hazards of cardiovascular outcomes and premature death among people with type 1 diabetes to those among people with type 2 diabetes and subjects without diabetes. Furthermore, information about the hazard of cardiovascular disease and early mortality among Asians with type 1 diabetes is sparse, although the clinical and epidemiological characteristics of Asians with type 1 diabetes are unlike those of Europeans. We estimated the hazard of myocardial infarction (MI), hospitalization for heart failure (HF), atrial fibrillation (AF), and mortality during follow-up in Korean adults with type 1 diabetes compared with those without diabetes and those with type 2 diabetes. Methods We used Korean National Health Insurance Service datasets of preventive health check-ups from 2009 to 2016 in this retrospective longitudinal study. The hazard ratios of MI, HF, AF, and mortality during follow-up were analyzed using the Cox regression analyses according to the presence and type of diabetes in ≥ 20-year-old individuals without baseline cardiovascular disease (N = 20,423,051). The presence and type of diabetes was determined based on the presence of type 1 or type 2 diabetes at baseline. Results During more than 93,300,000 person-years of follow-up, there were 116,649 MIs, 135,532 AF cases, 125,997 hospitalizations for HF, and 344,516 deaths. The fully-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for incident MI, hospitalized HF, AF, and all-cause death within the mean follow-up of 4.6 years were higher in the type 1 diabetes group than the type 2 diabetes [HR (95% CI) 1.679 (1.490–1.893) for MI; 2.105 (1.901–2.330) for HF; 1.608 (1.411–1.833) for AF; 1.884 (1.762–2.013) for death] and non-diabetes groups [HR (95% CI) 2.411 (2.138–2.718) for MI; 3.024 (2.730–3.350) for HF; 1.748 (1.534–1.993) for AF; 2.874 (2.689–3.073) for death]. Conclusions In Korea, the presence of diabetes was associated with a higher hazard of cardiovascular disease and all-cause death. Specifically, people with type 1 diabetes had a higher hazard of cardiovascular disease and all-cause mortality compared to people with type 2 diabetes.

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Metformin Use Is Associated with a Lower Risk of Inflammatory Bowel Disease in Patients with Type 2 Diabetes Mellitus

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjaa136 ◽

2020 ◽

Cited By ~ 1

Author(s):

Chin-Hsiao Tseng

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Inflammatory Bowel Disease ◽

Type 2 Diabetes Mellitus ◽

Bowel Disease ◽

Cox Regression ◽

Reference Group ◽

Hazard Ratios ◽

Inflammatory Bowel

Abstract Aim Our aim was to compare the risk of developing inflammatory bowel disease [IBD] between ever users and never users of metformin. Methods Patients with newly diagnosed type 2 diabetes mellitus from 1999 to 2005 were enrolled from Taiwan’s National Health Insurance. A total of 340 211 ever users and 24 478 never users who were free from IBD on January 1, 2006 were followed up until December 31, 2011. Hazard ratios were estimated by Cox regression incorporating the inverse probability of treatment weighting using a propensity score. Results New-onset IBD was diagnosed in 6466 ever users and 750 never users. The respective incidence rates were 412.0 and 741.3 per 100 000 person-years and the hazard ratio for ever vs never users was 0.55 [95% confidence interval: 0.51–0.60]. A dose–response pattern was observed while comparing the tertiles of cumulative duration of metformin therapy to never users. The respective hazard ratios for the first [<26.0 months], second [26.0–58.3 months] and third [>58.3 months] tertiles were 1.00 [0.93–1.09], 0.57 [0.52–0.62] and 0.24 [0.22–0.26]. While patients treated with oral antidiabetic drugs [OADs] without metformin were treated as a reference group, the hazard ratios for patients treated with OADs with metformin, with insulin without metformin [with/without other OADs] and with insulin and metformin [with/without other OADs] were 0.52 [0.42–0.66], 0.95 [0.76–1.20] and 0.50 [0.40–0.62], respectively. Conclusion A reduced risk of IBD is consistently observed in patients with type 2 diabetes mellitus who have been treated with metformin.

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Plasma Trimethylamine N-Oxide and Risk of Cardiovascular Events in Patients With Type 2 Diabetes

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa188 ◽

2020 ◽

Vol 105 (7) ◽

pp. 2371-2380 ◽

Cited By ~ 1

Author(s):

Mikael Croyal ◽

Pierre-Jean Saulnier ◽

Audrey Aguesse ◽

Elise Gand ◽

Stéphanie Ragot ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cardiovascular Events ◽

Tumor Necrosis Factor Receptor ◽

Density Lipoprotein ◽

Major Adverse Cardiovascular Events ◽

Cox Models ◽

Increased Risk ◽

All Cause Mortality ◽

Design And Methods

Abstract Objective Even though trimethylamine N-oxide (TMAO) has been demonstrated to interfere with atherosclerosis and diabetes pathophysiology, the association between TMAO and major adverse cardiovascular events (MACE) has not been specifically established in type 2 diabetes (T2D). Research Design and Methods We examined the association of plasma TMAO concentrations with MACE and all-cause mortality in a single-center prospective cohort of consecutively recruited patients with T2D. Results The study population consisted in 1463 SURDIENE participants (58% men), aged 65 ± 10 years. TMAO concentrations were significantly associated with diabetes duration, renal function, high-density lipoprotein cholesterol, soluble tumor necrosis factor receptor 1 (sTNFR1) concentrations (R2 = 0.27) and were significantly higher in patients on metformin, even after adjustment for estimated glomerular filtration rate (eGFR): 6.7 (8.5) vs 8.5 (13.6) µmol/L, respectively (PeGFR-adjusted = 0.0207). During follow-up (median duration [interquartile range], 85 [75] months), 403 MACE and 538 deaths were registered. MACE-free survival and all-cause mortality were significantly associated with the quartile distribution of TMAO concentrations, patients with the highest TMAO levels displaying the greatest risk of outcomes (P < 0.0001). In multivariate Cox models, compared with patients from the first 3 quartiles, those from the fourth quartile of TMAO concentration had an independently increased risk for MACE: adjusted hazard ratio (adjHR) 1.32 (1.02-1.70); P = 0.0325. Similarly, TMAO was significantly associated with mortality in multivariate analysis: adjHR 1.75 (1.17-2.09); P = 0.0124, but not when sTNFR1 and angiopoietin like 2 were considered: adjHR 1.16 (0.95-1.42); P = 0.1514. Conclusions We revealed an association between higher TMAO concentrations and increased risk of MACE and all-cause mortality, thereby opening some avenues on the role of dysbiosis in cardiovascular risk, in T2D patients.

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Fatty acid consumption and incident type 2 diabetes: an 18-year follow-up in the female E3N (Etude Epidémiologique auprès des femmes de la Mutuelle Générale de l’Education Nationale) prospective cohort study

British Journal Of Nutrition ◽

10.1017/s0007114516003883 ◽

2016 ◽

Vol 116 (10) ◽

pp. 1807-1815 ◽

Cited By ~ 4

Author(s):

Courtney Dow ◽

Marie Mangin ◽

Beverley Balkau ◽

Aurélie Affret ◽

Marie-Christine Boutron-Ruault ◽

...

Keyword(s):

Type 2 Diabetes ◽

Fatty Acid ◽

Cox Regression ◽

Positive Association ◽

Incident Type ◽

Overweight Women ◽

Hazard Ratios ◽

Acid Consumption ◽

Incident Cases

AbstractWe evaluated the association between dietary estimates of fatty acid (FA) consumption and type 2 diabetes (T2D) risk in the French E3N (Etude Epidémiologique auprès des femmes de la Mutuelle Générale de l’Education Nationale) cohort. In total, 71 334 women without diabetes at baseline were followed up from 1993 to 2011. Diabetes was identified using questionnaires and drug-reimbursement claims, and incident cases were validated. FA consumption in 1993 was estimated from a validated dietary questionnaire. Cox regression estimated hazard ratios (HR) and 95 % CI of diabetes risk, comparing the upper tertile group with the lowest. High n-3 PUFA consumption was associated with T2D even after adjustment for confounders, including other FA and BMI (HR 1·26; 95 % CI 1·13, 1·41; upper tertile compared with lowest). Upon stratification by overweight (BMI≥25 kg/m2)/non-overweight, a positive association between total PUFA consumption and T2D was observed, but it was restricted to non-overweight women (HR 1·22; 95 % CI 1·05, 1·42), whereas n-3 PUFA consumption was associated with increased T2D risk in both BMI strata (BMI<25 kg/m2: HR 1·19; 95 % CI 1·01, 1·40 and BMI≥25 kg/m2: HR 1·38; 95 % CI 1·20, 1·59). Within the n-3 PUFA, high DPA (HR 1·41; 95 % CI 1·23, 1·63) and α-linolenic acid (ALA) intakes were associated with increased T2D risk, but the effects of ALA were restricted to overweight women (HR 1·17; 95 % CI 1·01, 1·36). Within the n-6 PUFA, only arachidonic acid (AA) intake was associated with T2D risk (HR 1·49; 95 % CI 1·33, 1·66). The associations with DPA and AA persisted even after adjustment of their principal source in this cohort, the consumption of meat. The effects of PUFA are heterogeneous within the FA group. Intake of DPA and AA may contribute to T2D development.

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Cardiovascular and Renal Disease Burden in Type 1 Compared With Type 2 Diabetes: A Two-Country Nationwide Observational Study

10.2337/figshare.13721689 ◽

2021 ◽

Author(s):

Robin Kristófi ◽

Johan Bodegard ◽

Anna Norhammar ◽

Marcus Thuresson ◽

David Nathanson ◽

...

Keyword(s):

Heart Failure ◽

Type 2 Diabetes ◽

Renal Disease ◽

Cox Regression ◽

Cardiovascular Death ◽

Nationwide Observational Study ◽

Event Rates ◽

Design And Methods

Objective: Type 1 (T1D) and type 2 diabetes (T2D) increase risks of cardiovascular and renal disease (CVRD) compared to diabetes-free populations. Direct comparisons between T1D and T2D are scarce. We examined this by pooling full-population cohorts in Sweden and Norway. Research Design and Methods: 59,331 T1D and 484,241 T2D patients, aged 18-84 years, were followed over a mean period of 2.6 years from December 31, 2013. Patients were identified in nationwide prescribed drug and hospital registries in Norway and Sweden. Prevalence and event rates of myocardial infarction (MI), heart failure (HF), stroke, chronic kidney disease (CKD), all-cause death and cardiovascular death were assessed following age stratification in 5-year intervals. Cox regression analyses were used to estimate risk. Results: The prevalence of cardiovascular disease was similar in T1D and T2D across age strata, whereas CKD was more common in T1D. Age-adjusted event-rates comparing T1D versus T2D showed that HF risk was increased between the ages 65-79 years, MI between 55-79 years and stroke between 40-54 years, 1.3-1.4-fold, 1.3-1.8-fold and 1.4-1.7 fold respectively. CKD risk was 1.4-3.0-fold higher in T1D at all ages. The all-cause death risk was 1.2-1.5-fold higher in T1D above 50 years, with a similar trend for CV death. Conclusions: Adult T1D compared to T2D patients had an overall greater risk of cardiorenal disease (heart failure and CKD) across ages, of MI and all-cause death at middle-older ages and of stroke at younger ages. The total age-adjusted CVRD burden and risks were greater among T1D patients compared to T2D, highlighting their need for improved prevention strategies.

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Effects of exenatide and open-label SGLT2 inhibitor treatment, given in parallel or sequentially, on mortality and cardiovascular and renal outcomes in type 2 diabetes: insights from the EXSCEL trial

Cardiovascular Diabetology ◽

10.1186/s12933-019-0942-x ◽

2019 ◽

Vol 18 (1) ◽

Cited By ~ 11

Author(s):

Lindsay E. Clegg ◽

Robert C. Penland ◽

Srinivas Bachina ◽

David W. Boulton ◽

Marcus Thuresson ◽

...

Keyword(s):

Type 2 Diabetes ◽

Mixed Model ◽

Cox Regression ◽

Sglt2 Inhibitor ◽

Major Adverse Cardiovascular Event ◽

Cardiovascular Outcomes ◽

Open Label ◽

Adverse Cardiovascular Event ◽

Renal Outcomes

Abstract Background Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) improve cardiovascular and renal outcomes in patients with type 2 diabetes through distinct mechanisms. However, evidence on clinical outcomes in patients treated with both GLP-1 RA and SGLT2i is lacking. We aim to provide insight into the effects of open-label SGLT2i use in parallel with or shortly after once-weekly GLP-1 RA exenatide (EQW) on cardiorenal outcomes. Methods In the EXSCEL cardiovascular outcomes trial EQW arm, SGLT2i drop-in occurred in 8.7% of participants. These EQW+SGLT2i users were propensity-matched to: (1) placebo-arm participants not taking SGLT2i (n = 572 per group); and to (2) EQW-arm participants not taking SGLT2i (n = 575), based on their last measured characteristics before SGLT2i initiation, and equivalent study visit in comparator groups. Time-to-first major adverse cardiovascular event (MACE) and all-cause mortality (ACM) were compared using Cox regression analyses. eGFR slopes were quantified using mixed model repeated measurement analyses. Results In adjusted analyses, the risk for MACE with combination EQW+SGLT2i use was numerically lower compared with both placebo (adjusted hazard ratio 0.68, 95% CI 0.39–1.17) and EQW alone (0.85, 0.48–1.49). Risk of ACM was nominally significantly reduced compared with placebo (0.38, 0.16–0.90) and compared with EQW (0.41, 0.17–0.95). Combination EQW+SGLT2i use also nominally significantly improved estimated eGFR slope compared with placebo (+ 1.94, 95% CI 0.94–2.94 mL/min/1.73 m2/year) and EQW alone (+ 2.38, 1.40–3.35 mL/min/1.73 m2/year). Conclusions This post hoc analysis supports the hypothesis that combinatorial EQW and SGLT2i therapy may provide benefit on cardiovascular outcomes and mortality. Trial registration Clinicaltrials.gov, Identifying number: NCT01144338, Date of registration: June 15, 2010.

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