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Ali K Abu-Alfa,MD, FASN, FAHA

Dr Abu-Alfa is a Professor of Medicine, Head of the Division of Nephrology and Hypertension at the American University of Beirut (AUB). He is the Director for the Human Research Protection Program and for Research Affairs. He joined AUB in 2010 after spending 2 decades at the Yale School of Medicine.He is founding President of the Middle East Chapter of the International Society for Peritoneal Dialysis, is currently the President for the Lebanese Society of Nephrology and Hypertension, and Chair-Elect of the International Society of Nephrology (ISN)-Middle East Regional Board, and is serving as an ISN council member. Dr Abu-Alfa’s scientific interests are in areas of CKD, Peritoneal Dialysis, complex hypertension, Mineral and Bone Disorder in CKD (CKD-MBD), imaging issues in renal patients and use of Gadolinium Based Contrast Agents. He is also very active in the sphere of research ethics.

Ali K. Abu-Alfa, MD, FASN, FASHProfessor of Medicine

Head, Division of Nephrology & HypertensionDirector, Human Research Protection Program

American University of Beirut

Diabetes Management inChronic Kidney Disease

Chinese Society of Nephrology 2019Hangzhou

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Disclosures and Acknowledgements

No financial or intellectual conflict of interest, or affiliations, of relevance to content.

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Dr Sara Jdiaa  (Nephrology‐AUB, Lebanon)

Dr Imad Kibbe  (Endocrinology‐AUB, Lebanon)

Dr Adrian Liew (Nephrology‐Tan Tock Seng Hospital, Singapore)

Objectives• Special issues in CKD:

• Hypoglycemia• Reliability of HbA1C• Safety of commonly used hypoglycemic agents

• SGLT2 inhibitors and renal protection:• Major Trials of SGLT2i• CREDENCE trial in CKD patients• Use in transplant recipients

• GLP1‐RA, DDP‐4 inhibitors and renal protection

• Conclusions

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Hypoglycemia Risk in CKD

Moen MF et al: CJASN 2009: 4; 1121-1127

Retrospective cohort 243,222 patients who had 2,040,206 glucose measurements

CKD defined as eGFR < 60 ml/min per 1.73 m2

Jung M et al: Journal of Diabetes 2018: 10; 276–285

Accuracy of HbA1c in CKD

Scatterplots of HbA1c with fasting glucose or HbA1c by chronic kidney disease (CKD) category.

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Tuttle KR: Diabetes care 2014: 37; 2864-83

Use of Metformin in CKD: Lactic Acidosis

Arnouts P et al: Nephrology Dialysis Transplantation 2014: 29; 1284-300.

Use of Sulphonylureas and other agents in CKD

Thiazolidinediones: PioglitazoneIncreased risk for causing or aggravating CHF (water retention, edema, dyspnea, weight gain)

DDP-4 inhibitors:Linagliptin: No adjustment needed with CKDSaxagliptin: Adjustments needed with CKD

GLP-1 Receptor Agonists:Liraglutide: No adjustment needed Dulaglutide: No adjustments needed

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Objectives

• Special issues in CKD: • Hypoglycemia• Reliability of HbA1C• Safety of commonly used hypoglycemic agents

• SGLT2 inhibitors and renal protection:• Major Trials of SGLT2i• CREDENCE trial in CKD patients• Use in transplant recipients

• GLP1‐RA, DDP‐4 inhibitors and renal protection

• Conclusion

Sodium-Glucose Co-transporter 2 (SGLT2) Inhibitors

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Wanner C. AM J Med 2017: 130; S63-S72

Renal Hemodynamic Effects of SGLT2 Inhibition

Mechanisms for SGLT2i Protective Effects

Heerspink HJL et al: Circulation 2016; 134: 752-772

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Canagliflozin DapagliflozinEmpagliflozin

CANVAS Trial(n=10,142)

N Eng J Med 2017; 377:644-657.

DECLARE-TIMI Trial(n=10,186)

N Eng J Med 2019; 380:347-357.

EMPA-REG OUTCOME Trial

(n=7,020)

N Engl J Med 2015; 373:2117-2128.N Eng J Med 2016; 375:323-334.

Primary Outcome:1. Composite of Death from cardiovascular causes, nonfatal myocardial infarction, nonfatal

stroke (EMPA-REG OUTCOME and CANVAS Trials)2. MACE and a composite of cardiovascular death or hospitalization for heart failure.

(DECLARE-TIMI Trial)

CREDENCE Trial - Canagliflozin

Primary Outcome:1. Composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated

GFR < 15 ml/min/1.73m2), doubling of serum creatinine, or death from renal or cardiovascular causes.

SGLT2 Inhibitors: 4 RCTs beyond Glucose Control

SGLT2 Inhibitors RCTs: CKD Inclusivity

Kluger et al. Cardiovasc Diabetol 2019: 18; 99

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SGLT2 Inhibitors RCTs: Renal Outcomes

Kluger et al. Cardiovasc Diabetol 2019: 18; 99

Wanner C et al. N Engl J Med 2016; 375: 323-334

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EMPA-REG: Change in GFR over time

Wanner C et al. N Engl J Med 2016; 375: 323-334

EMPA-REG: Main Renal Outcomes

Wanner C et al. N Engl J Med 2016; 375: 323-334

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EMPA-REG: Detailed Renal Outcomes by Strata

Wanner C et al. N Engl J Med 2016; 375: 323-334

Perkovic V et al. N Engl J Med 2019: 380; 2295-2306

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CREDENCE: Design, Criteria and OutcomesKey inclusion criteria• ≥30 years of age • T2DM and HbA1c 6.5% to 12.0%• eGFR 30 to 90 mL/min/1.73 m2

• UACR 300 to 5000 mg/g• Stable max tolerated labelled dose of

ACEi or ARB for ≥4 weeks

Key exclusion criteria• Other kidney diseases, dialysis, or kidney transplant• Dual ACEi and ARB; direct renin inhibitor; MRA• Serum K+ >5.5 mmol/L• CV events within 12 weeks of screening • NYHA class IV heart failure• Diabetic ketoacidosis or T1DM

2-week placebo run-in

Placebo

Canagliflozin 100 mg R

Double-blind randomization

(1:1)

Follow-up at Weeks 3, 13, and 26 (Face to Face) then every 13 weeks (alternating phone/Face to Face)

• Participants continued treatment if eGFR was <30 mL/min/1.73 m2 until chronic dialysis was initiated or kidney transplant occurred

Perkovic V et al. N Engl J Med 2019: 380; 2295-2306

Primary outcome was a composite of ESRD, Doubling of creatinine, or Death from renal or CV causes

N=4401

CREDENCE: Changes in GFR and UACR

Perkovic V et al. N Engl J Med 2019: 380; 2295-2306

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CREDENCE: Non-Renal Outcomes

Perkovic V et al. N Engl J Med 2019: 380; 2295-2306

Trial stopped at median follow-up of 2.62 years

CREDENCE: Renal-Specific Outcomes

Perkovic V et al. N Engl J Med 2019: 380; 2295-2306

Trial stopped at median follow-up of 2.62 years

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CREDENCE: Detailed Outcomes by Strata

Perkovic V et al. N Engl J Med 2019: 380; 2295-2306

CREDENCE: Detailed Outcomes by Strata

Perkovic V et al. N Engl J Med 2019: 380; 2295-2306

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CREDENCE: Detailed Outcomes by Strata

Perkovic V et al. N Engl J Med 2019: 380; 2295-2306

SGLT2 Inhibitors: Meta-analysis | Renal Outcomes

Neuen BL et al. Lancet Diabetes Endocrinol. 2019 ePub Sept 2019

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SGLT2 Inhibitors: Adverse Events

Kluger et al. Cardiovasc Diabetol 2019: 18; 99

SGLT2 Inhibitors: Use post-Transplantation

Halden TAS et al: Diabetes Care 2019: 42; :1067-1074

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Objectives

• Special issues in CKD: • Hypoglycemia• Reliability of HbA1C• Safety of commonly used hypoglycemic agents

• SGLT2 inhibitors and renal protection:• Major Trials of SGLT2i• CREDENCE trial in CKD patients• Use in transplant recipients

• GLP1‐RA, DDP‐4 inhibitors and renal protection

• Conclusion

Glucagon-like Peptide Receptor Agonists (GLP1-RA)

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• Randomized 9,340 patients with high cardiovascular risks.

• Median Follow-up of 3.84 years.

• Pre-specified secondary renal outcomes which was a composite of new-onset persistent albuminuria, doubling of serum creatinine, ESRD or death to renal causes.

Marso SP et al. N Engl J Med 2016; 375: 311-322.

LEADER Trial: Liraglutide

Tuttle KR : Lancet Diabetes Endocrinol 2018: 6; 605-617

AWARD-7 Trial: Dulaglutide in CKD Stages 3-4KDIGO

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Tuttle KR : Lancet Diabetes Endocrinol 2018: 6; 605-617

AWARD-7 Trial: Dulaglutide | Albuminuria

DPP-4 (dipeptidyl peptidase-4) Inhibitors

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Mosenzon et al: Diabetes Care 2017: 40; 69–76

SAVOR-TIMI 53: Saxagliptin

Rosenstock J: JAMA 2019321(1): 69-79

CARMELINA: Linagliptin in CKDKDIGO

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Sarafidis P et al. Nephrol Dial Transplant 2019: 34; 208–230

EURECA-m and DIABESITY: ERA-EDTA Consensus

Sarafidis P et al. Nephrol Dial Transplant 2019: 34; 208–230

EURECA-m and DIABESITY: ERA-EDTA ConsensusKDIGO

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Summary and Conclusion• Management of diabetes mellitus in CKD patients, especially in 

advanced stages, requires close coordination between nephrologist and endocrinologist.

• Newer classes of agents with reno‐protective and cardio‐protective attributes are important to include in regimens when feasible and indicated.

• SGLT2 inhibitors have had consistent outcomes among various RCTs with CREDENCE trial lending strong support for their safe and beneficial use in CKD.

• The use of SGLT2 inhibitors GLP‐1 receptor inhibitors need to be advocated for by the nephrologist in diabetic CKD patients as a reno‐cardio‐protective drugs, besides RAS blockade, even if glycemic control is being achieved.

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