Diabetes and CKD- The update Dr Ching Chen Hua

Kidney disease develops in approximately 35% of patients with type 2 diabetes and is associated with increased mortality.

Kidneys play a critical role in the management of glucose reabsorption and maintaining the overall metabolic balance in humans 90% of the plasma glucose reabsorption in the kidney take place at S1 segment of the proximal renal tubule Treatment for DKD is mainly aimed at controlling metabolic and hemodynamic abnormalities kidneys play a critical role in the management of glucose reabsorption and maintaining the overall metabolic balance in humans SGLT2 inhibitors would contribute to increased sodium levels delivered to the macula densa and secondary autoregulatory vasoconstriction of afferent glomerular arteriolae to neutralize the vascular imbalance driven by local Ang II characterized by glomerular hypertension in T2DM SGLT2, a low-a nity, high- capacity glucose transporter, is located primarily in the brush border membrane of the S1 segment of the proximal renal tubule and is responsible for approximated 90% of the plasma glucose reabsorption in the kidney

Despite the low-pressure environment of renal glomeruli, a reduction in glomerular hypertension of approximately 6 to 8 mm Hg was observed with empagliflozin.

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 In patients with type 2 diabetes and CKD, empagliflozin decreased albuminuria by approximately 30%, whereas dapagliflozin decreased albuminuria by 33% com- pared with placebo in patients with type 2 diabetes and micro- or macroalbuminuria treated with an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. The albuminuria reduction achieved by empagliflozin was completely reversible 4 weeks after treatment discontinuation, which suggests that albuminuria reduction is mediated through changes in renal hemodynamics , predominantly glucose-independent mechanism 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

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) Published Jun 2016

urinary ACR 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.

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).

(Secondary analysis) The albuminuria reduction achieved by empagliflozin was com- pletely reversible 4 weeks after treatment discontinuation, which suggests that albuminuria reduction is mediated through changes in renal hemodynamics , predominantly glucose-independent mechanism 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

All patients had eGFR ≥30 ml/min/1.73m2. 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. Published Jun 2016

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

At baseline, the eGFR was 45 to 59 ml per minute per 1. 73 m2 in 17 At baseline, the eGFR was 45 to 59 ml per minute per 1.73 m2 in 17.8% of the patients and 30 to 44 ml per minute per 1.73 m2 in 7.7%; - 28.7% had microalbuminuria, and 11.0% had macroalbuminuria. - In total, 80.7% of the patients were taking angiotensin-converting–enzyme inhibitors or angiotensin-receptor blockers at baseline.

CKD-EPI creatinine equation CKD-EPI creatinine equation. From baseline to week 4 (period 1), there was a short-term decrease in the eGFR in the empagliflozin groups long-term administration (period 2; from week 4 to the last week of treatment), the eGFR remained stable in the empagliflozin groups and declined steadily in the placebo group, with adjusted estimates of annual decreases of 0.19±0.11 ml per minute per 1.73 m2 in the 10-mg and 25-mg empagliflozin groups, as compared with a decrease of 1.67±0.13 ml per minute per 1.73 m2 in the placebo group (P<0.001 for both comparisons with placebo). After the cessation of the study drug (period 3; last week of treatment to follow-up), the eGFR increased with both doses of empagliflozin,

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) (Nephropathy here defined as a UACR >300 mg/g, doubling of serum creatinine with an eGFR of 45 mL/min/1.73 m2 or less, initiation of renal replacement therapy, or death due to renal disease)

(eGFR) at entry of more than 30 ml per minute per 1.73 m2 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 Published Jun 2017 The Canagliflozin Cardiovascular Assessment Study (CANVAS)8 was initiated in December 2009, before the approval of canagliflozin by the Food and Drug Administration (FDA) The first approval of the compound by the FDA occurred in March 2013, with interim data from CANVAS. CANVAS–Renal (CANVAS-R)9 was designed as a second CANVAS- like, double-blind, randomized, placebo-controlled trial to be analyzed jointly with CANVAS, to meet a post-approval cardiovascular safety com- mitment to regulatory agencies. CANVAS-R, which commenced in 2014, was also designed to assess effects on albuminuria.

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).

The renal composite outcome occurred less frequently among participants in the canagliflozin group than among those in the placebo group (5.5 vs. 9.0 participants with the outcome per 1000 patient-years, HR of 0.60; 95% CI, 0.47 to 0.77) Regression of albuminuria also occurred more frequently among those assigned to canagliflozin (293.4 vs. 187.5 participants with regression per 1000 patient-years; HR 1.70; 95% CI, 1.51 to 1.91)

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

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.

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.

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.

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