Blog entry by Meguid El Nahas

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J Am Soc Nephrol. 2016 Aug 18. pii: ASN.2016030278. [Epub ahead of print]

Canagliflozin Slows Progression of Renal Function Decline Independently of Glycemic Effects.

Sodium-glucose cotransporter 2 inhibition with canagliflozin decreases HbA1c, body weight, BP, and albuminuria, implying that canagliflozinconfers renoprotection. We determined whether canagliflozin decreases albuminuria and reduces renal function decline independently of its glycemic effects in a secondary analysis of a clinical trial in 1450 patients with type 2 diabetes receiving metformin and randomly assigned to either once-daily canagliflozin 100 mg, canagliflozin 300 mg, or glimepiride uptitrated to 6-8 mg. End points were annual change in eGFR and albuminuria over 2 years of follow-up. Glimepiride, canagliflozin 100 mg, and canagliflozin 300 mg groups had eGFR declines of 3.3 ml/min per 1.73 m2 per year (95% confidence interval [95% CI], 2.8 to 3.8), 0.5 ml/min per 1.73 m2 per year (95% CI, 0.0 to 1.0), and 0.9 ml/min per 1.73 m2per year (95% CI, 0.4 to 1.4), respectively (P<0.01 for each canagliflozin group versus glimepiride). In the subgroup of patients with baseline urinary albumin-to-creatinine ratio ≥30 mg/g, urinary albumin-to-creatinine ratio decreased more with canagliflozin 100 mg (31.7%; 95% CI, 8.6% to 48.9%; P=0.01) or canagliflozin 300 mg (49.3%; 95% CI, 31.9% to 62.2%; P<0.001) than with glimepiride. Patients receiving glimepiride,canagliflozin 100 mg, or canagliflozin 300 mg had reductions in HbA1c of 0.81%, 0.82%, and 0.93%, respectively, at 1 year and 0.55%, 0.65%, and 0.74%, respectively, at 2 years. In conclusion, canagliflozin 100 or 300 mg/d, compared with glimepiride, slowed the progression of renal disease over 2 years in patients with type 2 diabetes, and canagliflozin may confer renoprotective effects independently of its glycemic effects.

Copyright © 2016 by the American Society of Nephrology.

COMMENTS:

Spectacular effect of Canaglifozin a SGLT2 inhibitor and effectively a potent diuretic on the progression of T2Diabetic nephropathy.

Effective slowing of the rate of eGFR decline compared to Glimepiride. 

This has led some to beleive that this is a major breakthrough in the management of DN. 

However, a number of limitations, some highlighted by the authors, should be considered:

1. This was NOT a study on DN progression; it was a study powered to ascertain the comparative efficacy of canaglifozin on diabetes control. Therefore, it can only be HYPOTHESIS GENERATING  as it is unsuitable for testing the hypothesis that it is superior or inferior to Glimepiride on the progression of CKD in T2DM.

2. Morevover, SGLT2 inhibitors are potent diuretics, and no diuretic control for the osmotic diuresis induced by the drug was included in this study.

3. As a potent diuretic, canaglifozin did what most diuretics do....lower BP; in fact the reduction of systolic BP was 10-20 fold more significant in patients treated with Canaglifozine compared to Glimepiride... Therefore, is it suprising that DN progression was improved with better BP control. This has been known since the original observations of Mogensen in the 70s: BP control slows the progression of diabetic nephropathy!

Statistical analysis doesnt mitigate that fact.

A more suitable control would have included equal diuresis and equal BP control to determine whether the effect of the SGLT2 inhibitor was specifically renoprotective independently of its anti-hypertensive effect.

3. Progression, as usual these days, was measured by eGFR and NOT MEASURED...?! An agent that interferes with proximal tubular transport and function may interfere with tubular secretion of creatinine and may therefore lower serum creatinine, and eGFR changes, through that mechanism rather than TRUE GFR CHANGES. It seems as if the lessons of Bardoxolone and its effects on eGFR have not been learnt...?!

http://www.ncbi.nlm.nih.gov/pubmed/?term=Bardoxolone%2C+quarterback

So as far as I am concerned, SGLT2 inhibitor are effective oral hypoglycemic agents with a potent glycosuric, osmotic diuretic effect. These agents have been associated with serious side effects including urogenital infections and cancer. http://www.ncbi.nlm.nih.gov/pubmed/27541294

Their renal and cardioprotective effects need to be evaluated by comparison with comparable diuretic and anti-hypertensive agents.

Their reno-protective effecst need to be properly evaluated by measuring GFR rather than the fudge of calculating it...

The jury is out on any specific, BP reduction independent, renal and cardiovascular protective effects of these potentially harmful agents.

[ Modified: Thursday, 1 January 1970, 1:00 AM ]