Evaluating the Effects of Canagliflozin on Cardiovascular and Renal Events in Patients With Type 2 Diabetes Mellitus and Chronic Kidney Disease According to Baseline HbA1c, Including Those With HbA1c &lt;7%

Cannon, Christopher P.; Perkovic, Vlado; Agarwal, Rajiv; Baldassarre, James; Bakris, George L.; Charytan, David M.; Zeeuw, Dick de; Edwards, Robert; Greene, Tom; Heerspink, Hiddo J.L.; Jardine, Meg; Levin, Adeera; Li, Jing Wei; Neal, Bruce; Pollock, Carol; Wheeler, David C.; Zhang, Hong; Zinman, Bernard; Mahaffey, Kenneth W.

doi:10.1161/circulationaha.119.044359

Cited by 108 publications

(67 citation statements)

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“…Nevertheless, kidney protection is consistent and substantial in this population (14). SGLT2 inhibitors also have kidney benefits in people with well-controlled glycemia (HbA 1c ,7%) in whom further glucose lowering was minimal (15). In the DAPA-HF trial, which included people with or without diabetes, the effects on HF and kidney disease end points were consistent regardless of diabetes status (16).…”

Section: Mechanisms Of Kidney Protection By Sglt2 Inhibitorsmentioning

confidence: 97%

“…SGLT2 inhibitors promote diuresis due to glucosuria and natriuresis (34). Diuresis is an important mechanism for reducing blood pressure and risk for HF events (11)(12)(13)(14)(15)(16)35). Lack of a compensatory increase in heart rate suggests commensurate blunting of sympathetic nervous system activity, which may also contribute to salutary effects of SGLT2 inhibitors compared with other diuretics (36,37).…”

Section: Diuresis and Natriuresismentioning

confidence: 99%

“…Three SGLT2 inhibitors (empagliflozin, canagliflozin, and dapagliflozin) were studied across six large-scale completed CVD and CKD clinical trials (12)(13)(14)(15)(16)35), with assessment of ertugliflozin (45) in a subsequent clinical trial.…”

Section: Cardiovascular Protection By Sglt2 Inhibitorsmentioning

confidence: 99%

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SGLT2 Inhibition for CKD and Cardiovascular Disease in Type 2 Diabetes: Report of a Scientific Workshop Sponsored by the National Kidney Foundation

et al. 2020

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Diabetes is the most frequent cause of chronic kidney disease (CKD), leading to nearly half of all cases of kidney failure requiring replacement therapy. The principal cause of death among patients with diabetes and CKD is cardiovascular disease (CVD). Sodium/glucose cotransporter 2 (SGLT2) inhibitors were developed to lower blood glucose levels by inhibiting glucose reabsorption in the proximal tubule. In clinical trials designed to demonstrate the CVD safety of SGLT2 inhibitors in type 2 diabetes mellitus (T2DM), consistent reductions in risks for secondary kidney disease end points (albuminuria and a composite of serum creatinine doubling or 40% estimated glomerular filtration rate decline, kidney failure, or death), along with reductions in CVD events, were observed. In patients with CKD, the kidney and CVD benefits of canagliflozin were established by the CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial in patients with T2DM, urinary albumin-creatinine ratio >300 mg/g, and estimated glomerular filtration rate of 30 to <90 mL/min/1.73 m2. To clarify and support the role of SGLT2 inhibitors for treatment of T2DM and CKD, the National Kidney Foundation convened a scientific workshop with an international panel of more than 80 experts. They discussed the current state of knowledge and unanswered questions in order to propose therapeutic approaches and delineate future research. SGLT2 inhibitors improve glomerular hemodynamic function and are thought to ameliorate other local and systemic mechanisms involved in the pathogenesis of CKD and CVD. SGLT2 inhibitors should be used when possible by people with T2DM to reduce risks for CKD and CVD in alignment with the clinical trial entry criteria. Important risks of SGLT2 inhibitors include euglycemic ketoacidosis, genital mycotic infections, and volume depletion. Careful consideration should be given to the balance of benefits and harms of SGLT2 inhibitors and risk mitigation strategies. Effective implementation strategies are needed to achieve widespread use of these life-saving medications.

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Section: Mechanisms Of Kidney Protection By Sglt2 Inhibitorsmentioning

confidence: 97%

Section: Diuresis and Natriuresismentioning

confidence: 99%

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SGLT2 Inhibition for CKD and Cardiovascular Disease in Type 2 Diabetes: Report of a Scientific Workshop Sponsored by the National Kidney Foundation

et al. 2020

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“…However, for patients attaining glycemic targets with metformin alone, addition of an SGLT2i (particularly, if both agents are used in low doses) is not likely to cause hypoglycemia and may still provide kidney and cardiovascular benefits. Kidney and cardiovascular benefits are not proven in this specific population but are supported by the observations that SGLT2i reduce kidney and cardiovascular events similarly across the full range of studied HbA1c levels ($6.5%) [239][240][241][242][243][244] and that beneficial effects of dapagliflozin and empagliflozin on heart failure (among patients with heart failure with reduced ejection fraction [HFrEF]) did not require presence of diabetes. 240,244a More data are needed to confirm or correct use of this approach in CKD.…”

Section: Research Recommendationsmentioning

confidence: 98%

KDIGO 2020 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease

Boer¹,

Caramori²,

Chan³

et al. 2020

Kidney International

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825

549

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S20 Introduction S22 Summary of recommendation statements and practice points S30 Chapter 1: Comprehensive care in patients with diabetes and CKD S39 Chapter 2: Glycemic monitoring and targets in patients with diabetes and CKD S47 Chapter 3: Lifestyle interventions in patients with diabetes and CKD S58 Chapter 4: Antihyperglycemic therapies in patients with type 2 diabetes (T2D) and CKD S79 Chapter 5: Approaches to management of patients with diabetes and CKD S87 Methods for guideline development S96 Biographic and disclosure information S106 Acknowledgments S107 References The development and publication of this guideline were supported by KDIGO. The opinions or views expressed in this professional education supplement are those of the authors and do not necessarily reflect the opinions or recommendations of the International Society of Nephrology or Elsevier. Dosages, indications, and methods of use for products that are referred to in the supplement by the authors may reflect their clinical experience or may be derived from the professional literature or other clinical sources. Because of the differences between in vitro and in vivo systems and between laboratory animal models and clinical data in humans, in vitro and animal data may not necessarily correlate with clinical results.

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“…Authors found a 30% reduction in the primary composite outcome (end-stage kidney disease, doubling of serum creatinine, or death from renal or CV causes) [54]. Additionally, similar results were found in patients with more advanced renal impairment (eGFR 30e45 ml/min/1.73 m 2 ) at baseline and across all levels of baseline HbA1c, including 650 patients with HbA1c levels below 7% [55]. The results translate into a number-neededto-treat (NNT) of 19, which is lower than that reported in previous studies with ARB alone [56].…”

Section: On Renal Functionmentioning

confidence: 68%

Sodium-glucose co-transporter-2 inhibitors: peculiar “hybrid” diuretics that protect from target organ damage and cardiovascular events

Sarzani

Giulietti

Pentima

et al. 2020

Nutrition, Metabolism and Cardiovascular Diseases

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Sodium-glucose co-transporter-2 inhibitors (SGLT2i) have been proven to lead to relevant cardiovascular benefits, regardless of glycemic control function. SGLT2i have on the one hand led to reduction in cardiovascular events such as heart failure and on the other hand to renal protection. Blood pressure reduction and kidney function play a central role in these outcomes. This focused review describes the main mechanisms and clinical aspects of SGLT2i. Data synthesis: These drugs act on the proximal renal tubule and behave as diuretics with a "hybrid" mechanism, as they can favour both natriuresis and enhanced diuresis due to an osmotic effect dependent on glycosuria, resulting in blood pressure decrease. The exclusive peculiarity of these "diuretics", which distinguishes them from loop and thiazide diuretics, lies also in the activation of the tubule-glomerular feedback. Conclusions: This mechanism, resulting in modulation of arterioles' tone and renin secretion, contributes to the favorable outcomes, suggesting a wider use of SGLT2i in internal medicine, nephrology and cardiology.

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Evaluating the Effects of Canagliflozin on Cardiovascular and Renal Events in Patients With Type 2 Diabetes Mellitus and Chronic Kidney Disease According to Baseline HbA1c, Including Those With HbA1c <7%

Cited by 108 publications

References 6 publications

SGLT2 Inhibition for CKD and Cardiovascular Disease in Type 2 Diabetes: Report of a Scientific Workshop Sponsored by the National Kidney Foundation

SGLT2 Inhibition for CKD and Cardiovascular Disease in Type 2 Diabetes: Report of a Scientific Workshop Sponsored by the National Kidney Foundation

KDIGO 2020 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease

Sodium-glucose co-transporter-2 inhibitors: peculiar “hybrid” diuretics that protect from target organ damage and cardiovascular events

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