Dapagliflozin in nondiabetic Chronic Kidney Disease recent evidences from review.ppt

Dapagliflozin in nondiabetic CKD

1. DAPA CKD TRIAL PRESENTER : DR. SANGYA BAJRACHARYA MODERATOR : DR SANTOSH SUBEDI

2. JOURNAL CLUB DAPAGLIFLOZIN IN PATIENTS WITH CHRONIC KIDNEY DISEASE DAPA- CKD TRIAL

3. Chronic kidney disease is an important contributor to illness and is associated with a diminished quality of life and a reduced life expectancy Type 2 diabetes mellitus is the leading cause of kidney failure worldwide , but few effective long-term treatments are available. Sodium – glucose co-transporter -2 (SGLT2) inhibitors are a newly diagnosed class of oral anti-diabetic drugs and a unique mechanism of action and having various pleotropic effects in addition to lowering the blood sugars

4. RENOPROTECTIVE PATHWAYS In patients with Type 2 DM , eGFR changes are characterized by acute , dose dependent reductions of =5 ml/min /1.73 m2 over several weeks After this initial dip , eGFR subsequently tends to return toward baseline and remains stable over time The impact of SGLT2 inhibition on eGFR is consistent in patients with and without CKD, in those with established cardiovascular disease , and is observed after treatemt for 3-4 weeks eGFR dip is reversible within 2 weeks of drug discontinuation , an effect also observed in the EMPA-REG OUTCOME trial

5. The initial decline in eGFR observed with SGLT2 inhibitors is likely related to afferent arteriolar vasoconstriction through feedback mechanism. In nondiabetic conditions, SGLT2 is responsible for =5 % of total renal NaCl reabsorption. In hyperglycemia , SGLT2 and SGLT1 mRNA expression increase by 36% and 20% respectively ----- SGLT1/2 activity accounts for as much as 14% of total renal NaCl reabsorption … marked reduction in distal NaCl delivery to macula densa

6. SGLT 2 inhibitor has been associated with 10=15% reduction in plasma uric acid levels Increased glysosuria --- leading to secretion of uric acid in exchange for glucose reabsorption via GLUT9 transporter

7. an increase in NaCl delivery to macula densa --- increased uptake of Na Cl by macula densa cells occurs via Na/K/2Cl cotransporter (which is an energy requiring process )--- leading to breakdown of adenosine triphosphate to adenosine ---adenosine then acts in a paracrine fashion via adenosine type 1 receptors on afferent arteriolar vascular smooth muscle cells causing vasoconstriction As increase in intraglomerular pressure and resultant increase in glomerular wall tension are associated with glomerular fibrosis and inflammation--- SGLT2 inhibitor mediated reductions in hyperfiltration would suppress markers of inflammation and fibrosis

8. Renal cardio hypothesis for cardiovascular protection with SGLT2 inhibitors

9. Published on : September 24, 2020

10. GOAL To assess the safety and efficacy of dapagliflozin in reducing renal events among patients with chronic kidney disease (CKD) with or without diabetes mellitus(DM)

11. Trial Design and Oversight Randomized , double –blind , placebo controlled , multicenter clinical trial The trial was sponsored by AstraZeneca and conducted at 386 sites in 21 countries from February 2,2017 through June 12 , 2020

12. STUDY DESIGN Eligible patients were randomized in a 1:1 fashion to either dapagliflozin 10mg daily (n=2,152) or placebo (n= 2152) Total number of enrolles : 4,304 Duration of follow up :2.4 years Mean patient age: 61.8 years Percentage female : 33.1%

13. Inclusion criteria : >= 18 years of age Urinary albumin : creatinine ratio >=200mg/g Estimated glomerular filtration rate ( eGFR ) between 25 and 75 ml/min/1.73 m 2 Stable and for patient , maximum tolerated labelled dose of angiotensin-converting enzyme inhibitors or angiotensin – receptor blockers for>= 4 weeks , unless contraindicated

14. EXCLUSION CRITERIA : Type I Diabetes Mellitus Autosomal dominant or autosomal recessive polycystic kidney disease , lupus nephritis , or ANCA – associated vasculitis Receiving cytotoxic therapy , immunosuppressive therapy , or other immunotherapy for primary or secondary renal disease within 6 months prior to enrollment New York Heart Association class IV congestive heart failure (HF) Myocardial infarction , unstable angina , stroke , or transient ischaemic attack within 8 weeks prior enrollment Coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting ) or valvular repair / replacement within 8 weeks prior to enrollment

15. Other salient features Mean Arterial pressure :138/78 mm Hg Mean eGFR : 43 ml/min/1.73m2 ; eGFR <30 : 14% , 30- <45 :44% , 45-<60% :31% Urinary albumin to creatinine ratio > 1000 :48%

16. METHODS Randomly 4304 participants were assigned with : an estimated glomerular filtration rate (GFR) of 25 to 75 ml per minute per 1.73 m2 of body-surface area a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of 200 to 5000 to receive dapagliflozin (10 mg once daily) or placebo. The primary outcome was a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes.

17. Trial procedure Participants were randomly assigned to receive dapagliflozin (10mg once daily) or matching placebo Randomization was stratified according to the diagnosis of type 2 DM (yes/No) and the urinary albumin to creatinine ratio(<=1000 or >1000) After randomization , in person trial visits were performed at 2 weeks , at 2 , 4 and 8 months , at 4 month intervals thereafter

18. At each follow up visit Vital signs were recorded Blood and urine samples were sent for laboratory assessment Information on potential trial outcomes , adverse events , concomitant therapies , and adherence to the trial regimen was collected Dapagliflozin or placebo was to be discontinued if pregnancy or DKA occured

19. OUTCOMES Primary composite endpoint assessed in a time to event analysis , was the first occurrence of any of the following A decline of at least 50% in the estimated GFR (confirmed by a second serum creatinine measurement after >=28 days) The onset of end-stage kidney disease (defined as maintenance dialysis for >= 28 days , kidney transplantation or an estimated GFR of<15ml per minute per 1.73 m2 confirmed by a second measurement after >=28 days) Death from renal or cardiovascular causes.

20. Secondary endpoints Time to a composite renal endpoint >=50% eGFR decline from baseline (confirmed by>= 28 day serum creatinine) ESRD defined as eGFR <15ml/min/1.73m2 , need for chronic dialysis or renal transplantation Renal death Time to the first occurrence of either cardiovascular death or hospitalization for heart failure Time to death from any cause

21. Safety outcomes These included serious adverse events , adverse events resulting in the discontinuation of dapagliflozin or placebo Adverse events of interest (symptoms of volume depletion , renal events , major hypoglycemia , bone fractures, amputations and potential diabetic ketoacidosis)

22. Statistical Analysis Event –driven trial With the recruitment of at least 4000 patients, the trial will have 90% power to detect a relative risk reduction of 22 % in the primary endpoint based on primary events being observed in 681 pts and a two sided p value of 0-05 Assumptions underlying the sample size calculation included a placebo event rate of 7.5% events per yr (based on event rates observed in relevant pts in prior trials) , an annual drug discontinuation rate of 6% , 1% loss to follow up , a recruitment period of 24 months and a total study duration of 45 months The primary efficacy analysis was based on the intention to traet population , which include all the participants who had undergone randomisation

23. The baseline characteristics , including medications for type 2 DM and kidney disease , were balanced between dapagliflozin and placebo groups After a regular review meeting on March 26 , 2020 , the independent data monitoring committee recommended to the two coprincipal investigators that the trial be discontinued because of clear efficacy , on the basis of 408 primary outcome events At the conclusion of the trial , the median follow up was 2.4 years

24. Secondary outcomes

25. The number of participants who needed to be treated during the trial period to prevent one primary outcome event was 19 (95% CI, 15 to 27) The effect of dapagliflozin on the primary outcome was generally consistent across prespecified subgroups

26. Safety Outcomes and Adverse Events The incidence of adverse events and serious adverse events were similar overall in tha dapagliflozin and placebo groups DKA was not reported in any participants who received dapagliflozin and in two participants who received placebo Neither DKA nor severe hypoglycemia was observed in participants without type 2 DM There was one confirmed case of Fournier’s gangrene in the placebo group and none in dapagliflozin group

27. RESULTS The independent data monitoring committee recommended stopping the trial because of efficacy. Over a median of 2.4 years, a primary outcome event occurred in 197 of 2152 participants (9.2%) in the dapagliflozin group and 312 of 2152 participants (14.5%) in the placebo group (hazard ratio, 0.61; 95% confidence interval [CI], 0.51 to 0.72; P <0.001; number needed to treat to prevent one primary outcome event, 19 [95% CI, 15 to 27]) The hazard ratio for the composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes was 0.56 (95% CI, 0.45 to 0.68; P<0.001 and the hazard ratio for the composite of death from cardiovascular causes or hospitalization for heart failure was 0.71 (95% CI, 0.55 to 0.92; P=0.009). Death occurred in 101 participants (4.7%) in the dapagliflozin group and 146 participants (6.8%) in the placebo group (hazard ratio, 0.69; 95% CI, 0.53 to 0.88; P=0.004). The effects of dapagliflozin were similar in participants with type 2 diabetes and in those without type 2 diabetes. The known safety profile of dapagliflozin was confirmed.

28. Principal findings Trial has to be stopped early due to benefit The primary endpoint , decline in eGFR >=50% , ESRD , death from renal causes , or cardiovascular death for dapagliflozin vs placebo , was 9.2% vs 14.5% (hazard ratio [HR] 0.61 , 95% confidence interval (CI) 0.51 -0.72 ; p=0.000000028) The benefit of dapagliflozin on the primary endpoint was consistent in patients with without type 2 DM Decline in eGFR >=50% : 5.2 % vs 9.3% End stage kidney disease : 5.1% vs 7.5% CV death :3.0% vs 3.7% (p>0.05)

29. Secondary outcomes for dapagliflozin vs placebo : CV death /HF hospitalization :4.6% vs 6.4% (p=0.0009) All cause mortality :4.7% vs 6.8% (p=0.003) Amputation :1.6% vs 1.8% (p=0.73) Major hypoglycemia :0.7 % vs 1.3% (p=0.04)

30. Presence of CV disease : Results for primary endpoint, CV disease / HF , all cause mortality and other CV outcomes for dapaglifozin vs placebo were maintained among patients with and without known CV disease at baseline (p for interaction >0.05 for all) events rate were higher among patients with known CV disease Cause of specific mortality : 36.8% due to CV causes , 41.3% due to non CV causes , remainder undetermined For dapagliflozin vs placebo , CV death :1.9 % vs 2.3% ; non CV death : 1.7% vs 3.1% (p =0.003) Serious infections :9.0 % vs 9.6% (p=0.49) ; mortality in this subgroup for dapagliflozin vs placebo: 7.8% vs 15% (p< 0.05) Malignancy :2.7% vs 3.3% (p=0.29); mortality in this subgroup :15.3% vs 23.9% (p>0.05)

31. Presence of heart failure : Dapagliflozin reduces the risk of primary endpoint equally in patients with heart failure (HR 0.58 , 95 % CI 0.37 -0.91) and without HF (HR 0.62 , 95% CI 0.51- 0.75)( P For interaction =0.59) Similar results were noted for HF/CV hospitalization , all cause mortality , and heart failure hospitalization (p for interaction >0.05) Event rates were higher among patients with HF Effect on hospitalization : First hospitalization for any cause for dapagliflozin vs placebo : HR 0.84 , 95% CI 0.75-0.94 ; first hospitalization or death :HR 0.83 ,95% CI 0.75-0.93; all hospitalizations or death :rate ratio 0.70-0.89. There was no interaction by diabetes status

32. Interpretation Result of this trial : dapagliflozin results in salutary effects on renal function among patients with CKD, with or without DM , who are already on maximal tolerated doses of angiotensin – converting enzyme inhibitors/angiotensin receptor blocker Beneficial effects noted on non CV and all- cause mortality and all -cause hospitalizations Results were sustained among patients with or without known CV disease or HF at baseline Even though SGLT2 inhibitors were introduced as Type 2 DM drugs ,results of DAPA –CKD , similar studies indicated benefit in CKD management , irrespective of DM status These drugs will likely change practice and have a prominent role in future CKD management guidelines CREDENCE trial similar benefit to pts with CKD with or without DM status and with low GFR Benefit in reduction of heart failure independent of DM status

33. Discussion - Participants with CKD with or without type 2 DM , who were randomly assigned to receive dapagliflozin had a lower risk of the primary composite outcome of a sustained decline in the eGFR of at least 50% , end stage kidney disease , or death from renal or cardiovascular causes than the participants who were assigned to receive placebo - In contrast to the CREDENCE Trial , the present trial examined the effects of SGLT2 inhibitor in pts with CKD of whom 32.5% didn’t have type 2 DM and 14.5% had an eGFR below 30ml /min /1.73 m2. - The lower risk of hospitalization for heart failure or death from cardiovascular causes in the dapagliflozin group than in placebo is consistent with the results of two previous trials of dapagliflozin , the DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58) and DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trials - Dapagliflozin had an acceptable safety profile in this population , which included pt with an eGFR as low as 25ml /min/1.73m2. -There was no cases of DKA with Dapagliflozin , and hypoglycemic episodes did not occur in participants without diabetes.

34. As in other trials of SGLT2 inhibitors , there was initial dip in eGFR , followed by a stabilization of kidney function decline. This dip in eGFR reflects favourable hemodynamic changes in glomerulus.

35. LIMITATIONS Type 1 DM patients were excluded , the safety profile of dapagliflozin regarding DKA could not be excluded for sure Patients on ESRD and on HD were excluded , so that it is not clear whether dapagliflozin can be used in such pts.

36. CONCLUSIONS Among patients with chronic kidney disease, regardless of the presence or absence of diabetes, the risk of a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes was significantly lower with dapagliflozin than with placebo. (Funded by AstraZeneca; DAPA-CKD ClinicalTrials )

37. CONCLUSION In patients with CKD , with or without type 2 DM , dapagliflozin compared to placebo : Reduced the risk of kidney failure Reduced the risk of death from CV causes or hospitalization for heart failure Prolonged survival Dapagliflozin was well tolerated in keeping with its established safety profile

38. Other trials

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