Diabetes and CKD: is it all about managing glucose

Melanie J Davies CBE FMedSci Professor of Diabetes Medicine

Agenda

• Metabolic-cardio-renal cross-talk and role of GLP-1RA

• Glucose lowering in T2D and CKD

• Summary

Patients with T2D are at increased risk of complications such as CV disease, HF and CKD

*Patients with T2D aged <55 years CKD, chronic kidney disease; CV, cardiovascular; DKD, diabetic kidney disease; ESKD, end-stage kidney disease; HF, heart failure; HHF, hospitalisation for heart failure; T2D, type 2 diabetes

1. Younossi ZM et al. J Hepatology 2019;71:793; 2. Masmiquel L et al. Cardiovasc Diabetol 2016;15:29; 3. International Diabetes Foundation. Diabetes Atlas 8th Edition. http://www.diabetesatlas.org (accessed Jan 2020); 4. Rosengren A et al. Diabetologia 2018;61:2300; 5. Mozaffarian D et al. Circulation 2016;133:e38; 6. MacDonald MR et al. Eur Heart J 2008;29:1377; 7. Thomas M et al. Nat Rev Nephrol 2016;12:73; 8. Toth-Manikowski S & Atta MG. J Diabetes Res 2015;2015:697010; 9. World Health Organisation. https://www.who.int/bulletin/volumes/96/6/17-206441/en/ (accessed Jan 2020); 10. Ather S et al. J Am Coll Cardiol 2012;59:998.

T2D

CKD CV disease/ HF

• CKD affects ∽50% of patients with T2D7

• Diabetes is the most common reason for progression to ESKD, accounting for 30-50% of ESKD8

• Approximately one in three patients with T2D has CV disease3

• 2- to 5-fold increased risk of HF in patients with T2D*4

• 60–80% greater probability of CV death and all-cause mortality in those with T2D and established HF5,6

• 17–21% of patients with CKD also have HF9

• Presence of CKD in patients with HF increases risk of mortality by ~25–30%10

• ~55% with T2D have NAFLD1

• Over half of patients with T2D are reported to be obese2

Regulation of energy metabolism is essential for

healthy function, especially in the heart and kidneys1,2

The heart is the most metabolically demanding organ, susceptible to changes

in volume or metabolism1

The kidneys play a key role in glucose and volume homeostasis3,4

1. Lopashuk GD & Ussher JR. Circ Res 2016;119:1173; 2. de Boer IH & Utzschneider KM. Nephrol Dial Transplant 2017;32:588; 3. García-Donaire JA & Ruilope LM. Int J Nephrol 2011;2011:975782; 4. Alsahli M & Gerich JE Diabetes Res Clin Pract 2017;133:1

The cardiovascular, renal and metabolic systems are interrelated

• Diseases of the CRM system share many of the same risk factors3

• Dysfunction in one system leads to progression of interrelated diseases4 such as T2D, CV disease, HF, and CKD, which in turn lead to an increased risk of CV death5

CKD, chronic kidney disease; CRM, cardio-renal-metabolic; CV, cardiovascular; HF, heart failure; T2D, type 2 diabetes CRM, cardio-renal-metabolic; CV, cardiovascular; HF, heart failure; T2D, type 2 diabetes 1. García-Donaire JA & Ruilope LM. Int J Nephrol 2011;2011:975782; 2. Thomas G et al. Clin J Am Soc Nephrol 2011;6:2364; 3. Sarafidis PA et al. J Cardiometab Syndr 2006:58; 4. Ronco C et al. Contrib Nephrol 2010;165:54; 5. Leon BM and Maddox TM. World J Diabetes 2015;6:1246

Dysfunction of the heart, kidneys or metabolism contributes to the dysfunction of the others1,2

Energy metabolism

Cardiovascular

Renal

Fluid retention2

Albuminuria1

Renal failure1

1. Connell AW & Sowers JR. J Am Soc Hypertens 2014;8:604; 2. Ronco C et al. J Am Coll Cardiol 2008;52:1527

Metabolic dysfunction adds to cardio–renal disease progression and outcomes1,2

Glucotoxicity Lipotoxicity1

↑ Insulin resistance1

Altered hormonal milieu1

↑ Adipokines1

Energy metabolism

Cardiac failure2

Vascular dysfunction1

Atherosclerosis2

FFA, free fatty acids 1. Connell AW & Sowers JR. J Am Soc Hypertens 2014;8:604; 2. Ronco C et al. J Am Coll Cardiol 2008;52:1527; 4. Lopashuk GD & Ussher JR. Circ Res 2016;119:1173

Cardiac abnormalities affect renal/metabolic disease progression and outcomes1,2

Cardiac dysfunction adds to the renal/metabolic burden1,2

Cardiovascular Hypoperfusion2 Volume overload2

↑ Arterial resistance2

Neurohormonal activation1,2

∆ Substrate utilisation3

Autonomic dysfunction1,2

↑ Insulin resistance1

↑ FFA and lipotoxicity4

Hypertension1,2

Albuminuria1,2 Renal failure1

Ventricular hypertrophy2

Cardiac failure2 Vascular dysfunction1,2

Atherosclerosis2

↑ Insulin resistance1

↑ Hypoglycaemia

RAAS, renin–angiotensin–aldosterone system; SNS, sympathetic nervous system 1. Connell AW & Sowers JR. J Am Soc Hypertens 2014;8:604; 2. Cabundugama PK et al. Med Clin North Am 2017;101:129

Renal abnormalities affect cardiac and metabolic disease progression and outcomes1,2

Renal dysfunction adds to cardiac and metabolic burden

Renal1,2

Hypertension Fluid retention

Oxidative stress Arterial calcification

Activation of the RAAS & SNS

GLP-1 in the treatment of diabetes

Lowering of blood glucose Increased insulin, lowered glucagon, gastric emptying

Lowering of body weight Lowered food intake, increased satiety, reduced hunger

Cardiovascular effects Reduced blood pressure, lipids, inflammation

GLP-1, the conductor of the diabetes orchestra…

…that works on many important organs

Drucker D. Cell Metab 2016;24:15–30

GLP-1 RA, glucagon-like peptide-1 receptor agonist Adapted from Drucker D. Cell Metab 2018;27:740; Rizzo M et al. Biochim Biophys Acta Mol Basis Dis 2018;1864:2814

Effects of GLP-1 receptor agonists on the cardio-renal-metabolic systems

Intermediate Effects

Natriuresis

Diuresis

Downstream observed effects

GLP-1 RA

Coagulation Inflammation

CV events

Blood pressure

Body weight

HbA1c Postprandial lipids

Insulin secretion

Glucagon suppression

LV function

Agenda

• Metabolic-cardio-renal cross-talk and role of GLP-1RA

• Glucose lowering in T2D and CKD

• Summary

Turnbull FM et al. Diabetologia 2009;52:2288

Meta-analysis of the ACCORD, ADVANCE, UKPDS and VADT studies

Limited CV benefits have been observed with intensive glycaemic control in patients with T2D

Objective: to generate precise estimates of the effects of glucose-lowering

therapy on major CV events Major CV

events

Limited benefit HR 0.91 (0.84, 0.99)

All-cause mortality

No effect HR 1.04 (0.90, 1.20)

Patients with T2D (N=27,049) allocated to ‘More intensive’ or ‘Less intensive’ glycaemic

control

Composite end-point: time to incident CVD, number of CV events, mortality and CVD rates CV, cardiovascular; CVD, cardiovascular disease; T2D, type 2 diabetes Gaede P et al. Diabetologia 2016;59:2298

Steno-2: Intensive multifactorial control of CV risk factors reduces CV risk in patients with T2D and microalbuminuria

Multifactorial control of CV risk factors reduced CV risk in T2D patients

Conventional (51 events)

Intensive (35 events)

Unadjusted HR 0.55 (95% CI 0.39, 0.77); p=<0.001

*Existing ASCVD or 10-year ASCVD risk ≥15%; †10-year ASCVD risk <15%; ‡Empagliflozin, canagliflozin, and dapagliflozin reduce CV events in patients with DM and CVD or are at very high/high CV risk; §Liraglutide, semaglutide and dulaglutide reduce CV events in patients with DM and CVD, or who are at very high/high CV risk ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ASCVD, atherosclerotic cardiovascular disease; CV, cardiovascular; HbA1c, glycated haemoglobin; LDL, low-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; PCSK9, proprotein convertase subtilisin/kexin type 9; T2D, Type 2 Diabetes; RAAS, renin-angiotensin-aldosterone system 1. American Diabetes Association. Diabetes Care 2020;43:S1; 2. Cosentino F et al. Eur Heart J 2020;7:255

Management approaches focus on reducing the risk of CV death in patients with T2D1,2

Multifactorial management established as standard of care for patients with T2D1,2

Target Treatment

Blood pressure-lowering

For individuals with T2D and hypertension, a blood pressure target of: • <130/80 mmHg if at higher CV risk*1

• <140/90 mmHg if at lower risk for CV disease†1

• RAAS blocker, and a calcium channel blocker or diuretic

• Dual therapy is recommended as first-line treatment

LDL cholesterol-lowering

• <1.8 mmol/l (<70 mg/dl) with LDL-C reduction of ≥50% if at high CV risk

• <2.6 mmol/l (<100 mg/dl) if at moderate CV risk • Statins, ezetimibe or a PCSK9 inhibitor

Glucose control Targets are individualised – generally HbA1c <7% • SGLT2 inhibitors‡, GLP-1 RA§, DPP-4

inhibitors, metformin, sulfonylureas, thiazolidinediones, insulin

Individualised diet and lifestyle Weight loss and smoking cessation

• Diet • Physical activity • Behavioural therapy

Not intended for direct comparison; comparison of trials should be interpreted with caution due to differences in study design, populations and methodology *Empagliflozin only; †Liraglutide only; ‡Most commonly doubling serum creatinine, ESKD, renal death ACEi, angiotensin-converting-enzyme inhibitor; ARB, angiotensin receptor blocker; ARNi, angiotensin receptor-neprilysin inhibitor; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; GLP1-RA, glucagon-like peptide-1 receptor agonist; HHF, hospitalisation for heart failure; MACE, major adverse cardiovascular events; SGLT2i, sodium-glucose co-transporter-2 inhibitor

Effects of drug classes on CV, HF and kidney outcomes

SGLT2i GLP1-RA ACEi ARB Statins

MACE

CV death * †

HHF

Hard renal endpoints

Albuminuria

All-cause mortality

Decision cycle for patient-centred glycaemic management in Type 2 diabetes

Davies MJ et al. Diabetes Care 2018. Sep; dci180033. https://doi.org/10.2337/dci18-0033; Davies MJ et al. Diabetologia 2018. https://doi.org/10.1007/s00125-018-4729-5

Presence of ASCVD, CKD or HF is a compelling indication

Buse et al. Diabetes Care. 2019 Dec 19. https://doi.org/10.2337/dci19-0066. Davies MJ et al. Diabetes Care 2018. Sep; dci180033. https://doi.org/10.2337/dci18-0033; Davies MJ et al. Diabetologia 2018. https://doi.org/10.1007/s00125-018-4729-5

Step 1: Assess cardiovascular disease

“In appropriate high-risk individuals with established T2D, the decision to treat with a GLP-1 RA or SGLT2 inhibitor to reduce MACE, HHF, CV death or CKD progression should be considered independently of baseline HbA1c or individualised HbA1c target”1

ASCVD, atherosclerotic cardiovascular disease; HHF, hospitalisation for heart failure 1. Buse JB et al. Diabetes Care 2020;43:487; 2. American Diabetes Association. Diabetes Care 2020;43:S1; 3. Davies MJ et al. Diabetes Care 2018;41:2669

ADA–EASD 2019 Consensus Report update

ADA–EASD consensus for Management of Hyperglycaemia

These recommendations have been also incorporated into the ADA Standards of Medical Care in Diabetes 20202 and should be considered in conjunction with the ADA–EASD 2018 consensus report3

Characteristics of approved GLP-1 Receptor Agonists

Dosing for available GLP-1RA and dose modification for CKD

1. KDIGO Dec 2019 kdigo.com

GLP-1 RAs in T2D: HbA1c

BID, twice daily; BW, body weight; GLP-1 RA, glucagon-like peptide-1 receptor agonist; OD, once daily; QW, once a week; T2D, type 2 diabetes. *Liraglutide 0.6–1.8 mg, lixisenatide 10–20 µg; †liraglutide 1.2 mg. 1. Madsbad S. Diabetes Obes and Metab 2016;18(4):317–32; 2. Trujillo M, et al. Ther Adv Endocrinol Metab 2015;6(1)19–28; 3. Nauck M, et al. Diabetes Care 2016:39(9):1501–9; 4. Ahmann AJ et al. Diabetes Care 2018;41:258–66; 5. Pratley RE et al. Lancet Diabetes Endocrinol 2018;6:275–86; 6. Capehorn M et al. Diabetes UK Annual Conference 2019;P439.

-1.9

-1.6

-1.4

-0.8

-1.5 -1.4

-1.1

-1.5

-1.8

-0.5

-1

-1.5

-1.8 -1.7

-1.5

-0.9

-1.1 -1 -1

-1.4

-0.8

-1.3 -1.2

-0.3

-0.8 -0.9

-1.4

-1

-2.5

-2

-1.5

-1

-0.5

0DURATION-1 DURATION-5 Ji et al GetGoal-X AWARD-1 AWARD-6 LEAD-6 DURATION-6 Nauck et al Kapitza et al HARMONY-7 SUSTAIN 3 SUSTAIN 7 SUSTAIN 10

8.3 8.3 Baseline

HbA1c

Cha

nge

from

bas

elin

e in

HbA

1c (%

)

8.5 8.4 8.7 8.7 8.0 8.0 8.1 8.1 8.1 8.1 8.2 8.1 8.4 8.5 8.4 8.4 7.4 7.2 8.2 8.2 8.4 8.3 8.2 8.2 8.2 8.3

Exenatide 10 µg BID Exenatide 2 mg QW

Liraglutide 1.8 mg OD Lixisenatide 20 µg OD

Albiglutide 50 mg QW Dulaglutide 1.5 mg QW

Semaglutide 1.0 mg QW

Choosing glucose-lowering medication if compelling need to minimise weight gain or promote weight loss

1. Semaglutide > liraglutide > dulaglutide > exenatide > lixisenatide 2. Be aware that SGLT2i vary by region and individual agent with regard to indicated level of eGFR for initiation and continued use 3. Choose later generation SU with lower risk of hypoglycaemia 4. Low dose may be better tolerated though less well studied for CVD effects

Davies MJ et al. Diabetes Care 2018. Sep; dci180033. https://doi.org/10.2337/dci18-0033 Davies MJ et al. Diabetologia 2018. https://doi.org/10.1007/s00125-018-4729-5

Semaglutide Liraglutide Exenatide Lixisenatide Dulaglutide

GLP-1 RAs in T2D: weight

BID, twice daily; BW, body weight; GLP-1 RA, glucagon-like peptide-1 receptor agonist; OD, once daily; QW, once a week; T2D, type 2 diabetes. *Liraglutide 0.6–1.8 mg, lixisenatide 10–20 µg; †liraglutide 1.2 mg. 1. Madsbad S. Diabetes Obes and Metab 2016;18(4):317–32; 2. Trujillo M, et al. Ther Adv Endocrinol Metab 2015;6(1)19–28; 3. Nauck M, et al. Diabetes Care 2016:39(9):1501–9; 4. Ahmann AJ et al. Diabetes Care 2018;41:258–66; 5. Pratley RE et al. Lancet Diabetes Endocrinol 2018;6:275–86; 6. Capehorn M et al. Diabetes UK Annual Conference 2019;P439.

-3.7

-2.3

-1.6

-3

-1.3

-3.6

-3.2

-3.6

-4.3

-2.4 -2.2

-5.6

-6.5

-5.8

-3.6

-1.4

-2.5

-4

-1.1

-2.9 -2.9 -2.7

-3.7

-1.6

-0.6

-1.9

-3

-1.9

-7

-6

-5

-4

-3

-2

-1

0DURATION-1 DURATION-5 Ji et al GetGoal-X AWARD-1 AWARD-6 LEAD-6 DURATION-6 Nauck et al Kapitza et al HARMONY-7 SUSTAIN 3 SUSTAIN 7 SUSTAIN 10

102 102 Baseline

BW

Cha

nge

from

bas

elin

e in

BW

(kg)

97 94 70 70 94 96 96 97 94 94 93 93 91 91 102 101 93 91 93 92 96 95 96 93 97 97

Exenatide 10 µg BID Exenatide 2 mg QW

Liraglutide 1.8 mg OD Lixisenatide 20 µg OD

Albiglutide 50 mg QW Dulaglutide 1.5 mg QW

Semaglutide 1.0 mg QW

Possible cardiorenal mechanistic interactions between SGLT2 inhibitors and GLP-1RAs

SGLT2 inhibition GLP1-RA

Anticipated impact of Combination SGLT2 inhibitor-GLP1 RA

therapy Renal parameters Renal hemodynamics ↓ Glomerular hypertension ↔ ↓ Glomerular hypertension

Albuminuria ↓30%–50% ↓20%–30% ↓↓

Inflammation ↓MCP-1, IL-6, NF-kB, ROS ↓ Inflammation, ROS ↓↓

Natriuresis ↑Proximal natriuresis (FENa+) ↑Proximal natriuresis (FENa+) ↑↑

Blood pressure ↓4–6 mm Hg ↔/↓ ↓↓

Cardiovascular events

Ischemic events ↔/↓ ↓ ↓/↓↓

Heart failure ↓/↓ ↔ ↓/↓↓

Metabolic parameters

HbA1c ↓ ↓ ↓↓

Weight ↓ ↓ ↓↓

Heerspink, Kidney International. 2018

Agenda

• Metabolic-cardio-renal cross-talk and role of GLP-1RA

• Glucose lowering in T2D and CKD

• Summary

Summary

• Type 2 diabetes is associated with increased cardio-renal morbidity and mortality

• CVOTs with glucose lowering agents reveal between and within class difference in cardio-renal protection

• The ADA/EASD consensus suggests the new evidence should fundamentally change how we manage patients with T2DM and CKD