Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease: an exploratory analysis from the EMPA-REG OUTCOME randomised, placebo-controlled trial

Cherney, David Z.I.; Zinman, Bernard; Inzucchi, Silvio E.; Koïtka-Weber, Audrey; Mattheus, Michaela; Eynatten, Maximilian von; Wanner, Christoph

doi:10.1016/s2213-8587(17)30182-1

Cited by 326 publications

(326 citation statements)

References 39 publications

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“…Empagliflozin also reduced the development of acute renal failure . Further analysis showed empagliflozin to be associated with a reduction in albuminuria, regardless of the baseline urine albumin level …”

mentioning

confidence: 89%

The kidney and cardiovascular outcome trials

Bloomgarden

2018

Journal of Diabetes

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confidence: 89%

The kidney and cardiovascular outcome trials

Bloomgarden

2018

Journal of Diabetes

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“…This is akin to the impact of blood pressure and serum cholesterol, where therapeutic strategies have been designed and with the aim to lower blood pressure and serum cholesterol, respectively. Indeed, there are recognized therapeutic strategies that can reduce the degree of albuminuria, namely, antihypertensive agents such as ACE inhibitor and angiotensin-2 receptor blocker [5,6], tight glucose control [7], SGLT2 inhibitors [8,9], and low protein diet [27]. Since RAS blockade and SGLT2 inhibitor also lower blood pressure, it remained speculative whether the changes in albuminuria per se affect the CV/mortality endpoints independently of blood pressure.…”

Section: Discussionmentioning

confidence: 99%

“…ACR levels between 30 and 300 mg/g represent moderately increased levels of albuminuria, known as microalbumin-uria, while levels of more than 300 mg/g are associated with overt proteinuria. Several therapeutic strategies are available to reduce ACR, namely, via interruption of the renin-angiotensin system (RAS) with either angiotensinconverting enzyme (ACE) inhibitors or angiotensin II receptor blocker [5,6]; strict BP control; strategies to achieve tight glucose control [7]; and more recently, the sodium glucose co-transporter (SGLT)-2 inhibitor [8,9]. While these strategies are also associated with improvement in renal and CV outcomes, the precise impact of ACR reduction, independent of conventional CV risk parameters, in mediating the beneficial effect of cardio-renal outcome remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Albuminuria Regression and All-Cause Mortality among Insulin-Treated Patients with Type 2 Diabetes: Analysis of a Large UK Primary Care Cohort

2019

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Background: Overt albuminuria (urinary albumin-creatinine ratio [ACR] > 300 mg/g) is an established risk factor for progression of nephropathy and total mortality. However, whether a reduction in ACR translates into a reduction in mortality and/or cardiovascular (CV) events among insulin-treated patients with type 2 diabetes (T2D) in routine practice is currently not known. Methods: We obtained data on a large cohort of insulin users with T2D and nephropathy (baseline ACR ≥300 mg/g) from UK general practices between 2007 and 2014. Their corresponding ACR values after 1year of follow-up were thereafter categorized into: (1) < 300 mg/g (i.e., albuminuria regression) or (2) > 300 mg/g (i.e., nonregression of albuminuria), and the cohort was followed-up for 5 years for all-cause mortality and CV events. Cox proportional hazard models were fitted to estimate the risk of all-cause death. Results: A total of 11,074 patients with insulin-treated T2D met the inclusion criteria. Their mean age was 62.3 (13.6) years; mean HbA1c: 8.7 (1.8) and 53% were male. A total of 682 deaths occurred after a follow-up period of 43,393 person-years with a mortality rate of 16 per 1,000 person-years. Five-year survival was markedly reduced in the group whose proteinuria persisted or progressed (91 vs. 95%; log-rank p value < 0.001). Compared to patients whose ACR levels remained above 300 mg/g, all-cause mortality and CV events were 31 and 27% lower in those whose albuminuria regressed to < 300 mg/g (adjusted hazard ratio [aHR] 0.69; 95% CI 0.52–0.91; p = 0.008 and aHR 0. 73; 95% CI 0.54–0.98; p = 0.041), respectively. Conclusion: In patients with insulin-treated T2D and nephropathy in routine practice, a regression in albuminuria (e.g., via better BP or glycemic control) is associated with a significant reduction in all-cause mortality. Thus, albuminuria is not only simply a risk marker of renal and CV disease but also an independent target for therapy. Albuminuria reduction should be viewed as a goal for renal and CV protection.

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“…However, whether increased ACR or reduced eGFR is a cause or simply a marker of mortality risk such that reducing ACR or increasing eGFR would improve mortality outcomes remains unclear and is beyond the remit of this present study. Nonetheless, in the context of albuminuria in people with T2D, recent data suggest that in addition to renin-angiotensin system inhibitors, several glucose-lowering treatments, such as sodium-glucose cotransporter-2 inhibitors [27, 28] and glucagon-like peptide-1 agonist [29, 30], have been shown to improve ACR, as well as CV mortality outcomes and induce weight loss. While the mechanism for the reduction of mortality outcome remains unclear, concurrent use of a glucose-lowering therapy with insulin is used widely.…”

Section: Discussionmentioning

confidence: 99%

Individual and Combined Relationship between Reduced eGFR and/or Increased Urinary Albumin Excretion Rate with Mortality Risk among Insulin-Treated Patients with Type 2 Diabetes in Routine Practice

Anyanwagu¹,

Donnelly²,

Idris³

2018

Kidney Dis

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Background: A low estimated glomerular filtration rate (eGFR) and an increased urinary albumin-to-creatinine ratio (ACR) are well-recognised prognostic markers of cardiovascular (CV) risk, but their individual and combined relationship with CV disease and total mortality among insulin-treated type 2 diabetes (T2D) patients in routine clinical care is unclear. Methods: We analysed data for insulin users with T2D from UK general practices between 2007 and 2014 and examined the association between mortality rates and chronic kidney disease [categorised by low eGFR (< 60 mL/min/1.73 m²), high eGFR (≥60 mL/min/1.73 m²), low ACR (< 300 mg/g); and high ACR (≥300 mg/g) at insulin initiation] after a 5-year follow-up period using Cox proportional hazard models. Results: A total of 18,227 patients were identified (mean age: 61.5 ± 13.8 years, mean HbA1c: 8.6 ± 1.8%). After adjusting for confounders, when compared to adults on insulin therapy with an eGFR < 60 and an ACR ≥300 (low eGFR + high ACR) after a follow-up period of 5 years, patients with an eGFR < 60 and an ACR < 300 (low eGFR + low ACR) had a 6% lower mortality rate (aHR: 0.94; 95% CI 0.79–1.12); those with an eGFR > 60 and an ACR ≥300 (high eGFR + high ACR) had a 20% lower mortality rate (aHR: 0.80; 95% CI 0.68–0.96); and those with an eGFR > 60 and an ACR < 300 (high eGFR + low ACR) had the lowest death rate (28% less; aHR: 0.72; 95% CI 0.59–0.87). Conclusion: This study shows that among a large cohort of insulin-treated T2D patients in routine practice, the combination of reduced eGFR with increased ACR was associated with the greatest risk of premature death, followed closely by those with reduced eGFR and normal ACR levels. Adoption of aggressive CV risk management strategies to reduce mortality in patients with a low eGFR and albuminuria is essential in high-risk patients with T2D.

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Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease: an exploratory analysis from the EMPA-REG OUTCOME randomised, placebo-controlled trial

Cited by 326 publications

References 39 publications

The kidney and cardiovascular outcome trials

The kidney and cardiovascular outcome trials

Albuminuria Regression and All-Cause Mortality among Insulin-Treated Patients with Type 2 Diabetes: Analysis of a Large UK Primary Care Cohort

Individual and Combined Relationship between Reduced eGFR and/or Increased Urinary Albumin Excretion Rate with Mortality Risk among Insulin-Treated Patients with Type 2 Diabetes in Routine Practice

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