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Diabetes and CKD- The update

Diabetes and CKD- The update. Dr Ching Chen Hua. Kidneys play a critical role in the management of glucose reabsorption and maintaining the overall metabolic balance in humans.

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Diabetes and CKD- The update

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  1. Diabetes and CKD- The update Dr Ching Chen Hua

  2. Kidneys play a critical role in the management of glucose reabsorption and maintaining the overall metabolic balance in humans

  3. Meta-analyses of large clinical trials have suggested that a 30% reduction in albuminuria might translate into a 30% reduction in the risk of ESRD, assuming no changes in other markers of kidney disease

  4. The study ran from August 28, 2009 until January 30, 2013. • Randomized controlled trial comparing canagliflozin (100mg &300mg daily) and glimepiride (up-titrated to 6–8 mg) in 1450 patients with type 2 diabetes receiving metformin • Aim was to determine whether canagliflozin decreases albuminuria and slows the progression of kidney function decline independent of glycemic control • End points were annual change in eGFR and albuminuria over 2 years of follow-up. (Secondary analysis)

  5. Glimepiride, canagliflozin 100 mg, and canagliflozin 300 mg groups had eGFR declines of 3.3 , 0.5 and 0.3 ml/min per 1.73 m2 per year (P<0.01 for each canagliflozin group versus glimepiride).

  6. Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) at high risk for cardiovascular events who were receiving standard care • A total of 7020 patients at 590 sites in 42 countries received at least one dose of a study drug. According to the trial design, more than 99% of the patients had established cardiovascular disease. • All patients had eGFR ≥30 ml/min/1.73m2.

  7. The primary outcome was a composite of three major adverse cardiovascular events (3-point MACE) (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) • A secondary outcome was a composite microvascular outcome, the first occurrence of any of the following: the initiation of retinal photo-coagulation, vitreous hemorrhage, diabetes-related blindness, or incident or worsening nephropathy. • The incident or worsening nephropathy defined as • - progression to macroalbuminuria (urinary albumin- to-creatinine ratio>300 mg of albumin per gram of creatinine); • - a doubling of the serum creatinine level, accompanied by an eGFR of ≤45 ml per minute per 1.73 m2 (MDRD formula) ; • - the initiation of renal-replacement therapy; or death from renal disease

  8. 39% reduction in the development or worsening of nephropathy - the endpoint occurred among 525/4,124 patients (12.7%) who received empagliflozin compared with 388/2,061 patients (18.8%) with placebo: HR=0.61; P<0.001. • 46% relative reduction in composite outcome of doubling of serum creatinine, initiation of renal replacement therapy, or death due to renal disease - 44% relative risk reduction in doubling of the serum creatinine level - 70 of 4645 patients (1.5%) in the empagliflozin group and 60 of 2323 (2.6%) in the placebo group - 55% lower relative risk in initiation of renal-replacement therapy,13 of 4687 patients (0.3%) in the empagliflozin group and in 14 of 2333 patients (0.6%) in the placebo group P=0.04)

  9. The CANVAS Program integrated data from two trials involving a total of 10,142 participants (4330 in CANVAS and 5812 in CANVAS-R ) with type 2 diabetes and high cardiovascular risk. • Participants in each trial were randomly assigned to receive canagliflozin or placebo and were followed for a mean of 188.2 weeks • (eGFR) at entry of more than 30 ml per minute per 1.73 m2 • Primary outcome: 3 MACE • Secondary outcome: albuminuria reduction • Study started 2009 (CANVAS) and 2014 (CANVAS-R) - completed on Feb 2017

  10. CANVAS-R were randomly assigned in a 1:1 ratio to receive canagliflozin, administered at an initial dose of 100 mg daily with an optional increase to 300 mg starting from week 13, or matching placebo. • CANVAS R: the key prespecified exploratory renal outcomes were regression of albuminuria (using criteria comparable to those defined for category progression) and • The renal composite comprising a 40% reduction in eGFR sustained for at least two consecutive measures, the need for renal-replacement therapy (dialysis or transplantation), or death from renal causes (defined as death with a proximate renal cause).

  11. Ongoing trial looking at hard primary renal endpoint…. • CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation [clinical trial reg. no. NCT02065791]) - designed to assess whether canagliflozin 100 mg compared with placebo delays or prevents kidney failure (Primary outcome) or cardiovascular death (secondary outcome) in patients with type 2 diabetes with CKD stages 2 and 3 and established nephropathy on top of maximum dose of ACE inhibitors or angiotensin receptor blocker • the primary composite end point include end-stage renal disease, doubling of serum creatinine, and cardiovascular death. • Start Feb 2014 • Estimated date of completion Jun 2019

  12. FDA CAUTION • From March 2013, when canagliflozin was approved, to October 2015, FDA received reports of 101 confirmable cases* of acute kidney injury, some requiring hospitalization and dialysis, with canagliflozin or dapagliflozin use •  In approximately half of the cases, the events of acute kidney injury occurred within 1 month of starting the drug, and most patients improved after stopping it. • Some cases occurred in patients who were younger than 65 years. Some patients were dehydrated, had low blood pressure, or were taking other medicines that can affect the kidneys.

  13. Consider factors that may predispose patients to acute kidney injury prior to starting canagliflozin or dapagliflozin: • decreased blood volume; chronic kidney insufficiency; congestive heart failure; • taking other medications such as diuretics, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), and nonsteroidal anti-inflammatory drugs (NSAIDs). • Assess kidney function prior to starting canagliflozin or dapagliflozin and monitor periodically thereafter. • If acute kidney injury occurs, promptly discontinue the drug and treat the kidney impairment.

  14. Summary • GLT2 inhibitors are a new class of glucose-lowering agents, with important influences on risk factors for DN: • improvement in glycemic control • reduction in both systolic and diastolic blood pressure • weight loss • reduction in uric acid • Preclinical and clinical studies have shown that SGLT2 inhibitors have potentially beneficial renal hemodynamic effects, with reduction of hyperfiltration and intraglomerular pressure. • In clinical trials, a positive influence on albuminuria has consistently been documented.

  15. Evidence is increasing that these drugs have substantial nephroprotective effects. • Careful in patient at risk of AKI especially in patient with intravascular depletion such as : dehydration, severe CCF, advanced renal failure • Monitor renal function at the initiation of medication

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