https://pure.rug.nl/ws/files/178375118/1_s2.0_S1550413121000723_main.pdf

A kidney perspective on the mechanism of action of sodium glucose co-transporter 2 inhibitors

Empagliflozin Improves Cardiovascular and Renal Outcomes in Heart Failure Irrespective of Systolic Blood Pressure.

Kidney and heart failure outcomes associated with SGLT2 inhibitor use

Are SGLT2 Inhibitors New Hypertension Drugs

There is currently an unmet need for effective treatment of chronic kidney disease (CKD) that slows disease progression, prevents development of end-stage kidney disease and cardiovascular disease, and prolongs survival of patients with CKD. In the last 20 years, the only agents to show a reduction in the risk of CKD progression in patients with and without type 2 diabetes (T2D) were angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, but neither drug class has provided a decreased risk of all-cause mortality in patients with CKD and evidence for their use in patients with CKD without T2D is relatively limited. This review discusses the mechanisms underlying the progression of CKD, its associated risk factors, and summarizes the potential therapeutic approaches for managing CKD. There is increasing evidence to support the role of sodium–glucose cotransporter 2 (SGLT2) inhibitor therapy in patients with CKD, including data from the designated kidney outcome trials in patients with T2D (CREDENCE) and in patients with or without T2D (DAPA-CKD). These studies showed a significant reduction in the risk of CKD progression with canagliflozin (in patients with T2D) or dapagliflozin (in patients with or without T2D), respectively, with DAPA-CKD being the first trial to show a reduced risk of all-cause mortality. On the basis of these data, individualized treatment with SGLT2 inhibitors represents a promising therapeutic option for patients with diabetic and nondiabetic CKD to slow disease progression. Chronic kidney disease is a common condition in which the ability of the kidneys to work correctly gradually decreases over time. It is a major risk factor for a number of other serious conditions, including cardiovascular disease and end-stage kidney disease, and for early death. Several treatments have been shown to reduce the risk of chronic kidney disease progressing (particularly in patients with type 2 diabetes), but there have been no treatments that slow chronic kidney disease progression, prevent the development of end-stage kidney disease and cardiovascular disease, and prolong survival. However, evidence is now accumulating to suggest that some drugs initially developed to treat other diseases may be potential treatments for chronic kidney disease. The sodium–glucose cotransporter 2 inhibitors, which are commonly used to lower blood sugar levels in people with type 2 diabetes, are examples of such drugs. Data from two studies of sodium–glucose cotransporter 2 inhibitors—the CREDENCE study of canagliflozin in patients with chronic kidney disease and type 2 diabetes and the DAPA-CKD study of dapagliflozin in patients with chronic kidney disease with or without type 2 diabetes—have shown that these drugs reduce the risk of chronic kidney disease progression in these patients. More importantly, the DAPA-CKD study showed that patients with chronic kidney disease who were taking dapagliflozin had a reduced risk of death compared with placebo. These results show that sodium–glucose cotransporter 2 inhibitors are slowing the progression of chronic kidney disease and improve overall outcomes for properly selected patients.

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Chronic Kidney Disease and SGLT2 Inhibitors: A Review of the Evolving Treatment Landscape.

Background: People with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) experience a high burden of hypertension but the magnitude and consistency of blood pressure (BP) lowering with canagliflozin in this population is uncertain Whether the effects of canagliflozin on kidney and cardiovascular outcomes vary by baseline BP or BP lowering therapy is also unknown Methods: The CREDENCE trial randomized people with T2DM and CKD to canagliflozin or placebo Post-hoc, we investigated the effect of canagliflozin on systolic BP across subgroups defined by baseline systolic BP, number of BP lowering drug classes, and history of apparent treatment-resistant hypertension (BP ≥130/80 mmHg while receiving ≥3 classes of BP lowering drugs, including a diuretic) We also assessed whether effects on clinical outcomes differed across these subgroups Results: The trial included 4,401 participants of whom 3,361 (764%) had baseline systolic BP ≥130 mmHg, and 1371 (312%) had resistant hypertension By week 3, canagliflozin reduced systolic BP by 350mmHg (95% CI, -427 to -272), an effect maintained over the duration of the trial, with similar reductions across BP and BP lowering therapy subgroups (all P-interaction ≥005) Canagliflozin also reduced the need for initiation of additional BP lowering agents during the trial (HR 068, 95% CI 061-075) The effect of canagliflozin on kidney failure, doubling of serum creatinine, or death due to kidney or cardiovascular disease (HR 070, 95% CI 059-082) was consistent across BP and BP lowering therapy subgroups (all P-interaction ≥035), as were effects on other key kidney, cardiovascular and safety outcomes Conclusions: In people with T2DM and CKD, canagliflozin lowers systolic BP across all BP defined subgroups and reduces the need for additional BP lowering agents These findings support use of canagliflozin for end-organ protection and as an adjunct BP lowering therapy in people with CKD Clinical Trial Registration: URL: https://clinicaltrialsgov Unique Identifier: NCT02065791

Nan Ye

Papers

Blood Pressure Effects of Canagliflozin and Clinical Outcomes in Type 2 Diabetes and Chronic Kidney Disease: Insights from the CREDENCE Trial