JULY 2019 I 1

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Katherine R Tuttle, MD, FASN, FACP, FNKFExecutive Director for Research,Providence Health CareProfessor of Medicine,Institute of Translational Health SciencesUniversity of Washington

Cross-talk between the kidneys and circulation in diabetes

KEY MESSAGES

• The rising prevalence of diabetes in the world is creating a global health emergency

• Chronic kidney disease (CKD) in diabetics is a serious matter with a prevalence of ~30% and ~40% in type 1 and type 2 diabetics respectively

• CKD amplifies cardiovascular disease (CVD) risk, and most diabetes-associated excess CVD risk occurs in those with CKD

• Intensive glycaemic control is a proven strategy for CKD prevention in early diabetes, but less stringent glycaemic control is recommended once CKD develops, due to high risks and nominal benefit

• SGLT-2 inhibition reduces macroalbuminuria, slope of eGFR decline, serum creatinine doubling and end-stage kidney disease (ESKD); it also protects against CVD, principally heart failure and CV death

• GLP-1 receptor agonists lower the risk of albuminuria, slow eGFR decline and protect against CVD

• Mechanistic-based and individualised treatments are still urgently needed to mitigate the global impact of CKD in diabetes.

IntroductionThe rising prevalence of diabetes in the world is creating a global health emergency. According to the International Diabetes Federation there were 425 million diabetics worldwide in 2017 and that figure is predicted to escalate to 629 million by 2045. The development of chronic kidney disease (CKD) in diabetics is a serious matter, with a prevalence of ~30% and ~40% in type 1 and type 2 diabetics, respectively. Diabetes is responsible for nearly half of all cases of CKD and end-stage kidney disease (ESKD) worldwide. CKD amplifies cardiovascular disease (CVD) risk, and most diabetes-associated excess CVD risk occurs in those with CKD. Paradoxically only 10% progress to ESKD while 90% die of other causes prior to reaching ESKD, mainly CVD and infections. Structure of nephron

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Cross-talk between the kidneys and circulation in diabetes

Prevention of diabetic kidney disease (DKD)Glycaemic control Intensive glycaemic control prevents CKD when initiated in early diabetes; the benefits take about a decade to appear and accrue over subsequent decades in both type 1 and type 2 diabetes (DCCT/EDIC, UKPDS, and Kumamoto studies). When initiated in longstanding type 2 diabetes, CKD onset and progression are largely not averted (ACCORD, ADVANCE and VADT studies).

In the ACCORD study mortality and CVD outcomes were studied in relation to severe hypoglycaemia and CKD in type 2 diabetes. Most CKD patients had microalbuminuria only (69%) and 22% had an eGFR <60ml/min/1.73m2. In patients with CKD, severe hypoglycae-mia occurred in 21.5%, compared to 9.1% without CKD; the hazard ratio for major adverse CV events (MACE) was 1.96 and for CVD death 2.19.1

The American Diabetes Association (ADA) issued the following recommenda-tions for glycaemic targets. A reasonable A1C goal for many nonpregnant adults is <7% (level A evidence) with the follow-ing exceptions: less stringent A1C goals (<8%) may be appropriate for patients with a history of severe hypoglycaemia, limited life expectancy, advanced micro-vascular or macrovascular complications and extensive comorbid conditions (level B). More stringent A1C goals (<6.5 %) are recommended for selected individual patients if these goals can be achieved without significant hypoglycaemia or other adverse effects; these patients might include those with short duration of dia-betes, type 2 diabetes treated only with lifestyle or metformin, long life expec-tancy and no significant CVD (level C).

Consensus report: management of hyperglycaemia in type 2 diabetes (European Association for the Study of Diabetes (EASD) and ADA)In a major departure from previous guide-lines the ADA/EASD issued a consen-sus report in 2018 based on recent CV outcome studies involving glucagon-like peptide 1 (GLP-1) receptor agonists and sodium glucose transporter 2 (SGLT-2) inhibitors (Figure 1).2 This was prompted by the publication of major CV outcomes studies involving GLP-1 receptor agonists and SGLT-2 inhibitors. Although met-formin was retained as first-line treatment,

the next step was dependent on the pres-ence of underlying CVD, heart failure and CKD. If atherosclerotic cardiovascular dis-ease (ASCVD) was present, then a GLP-1 receptor agonist was preferred or alterna-tively an SGLT-2 inhibitor with evidence of protection against ASCVD if eGFR was maintained. However, if heart failure (HF) or CKD predominated, an SGLT-2 inhibitor was preferred or a GLP-1 recep-tor agonist with proven CVD benefit.

Strategies to prevent CVD and progression of DKDThere is a wide range of pharmacologi-cal agents under development, or that have ceased to be developed, to prevent CVD and progression of DKD in type 2 diabetes. These include protein kinase C (PKC) inhibition, anti-advanced gly-cation end products (AGE) treatment, renin-angiotensin system (RAS) inhi-bition (especially aldosterone antago-nists), anti-fibrotic treatments, uric acid and gout treatments, antioxidants and anti-inflammatories, chemokine CCL2 (MCP-1) receptor antagonists, endothelin antagonists, supplements, diet and weight loss, and the newer treatments (SGLT-2 inhibitors, GLP-1 receptor agonists and DPP-4 inhibitors).

MetforminIn 2017 a meta-analysis was performed on outcomes in moderate to severe CKD with metformin usage.3 In 17 observa-tional studies, metformin use was associ-ated with reduced all-cause mortality in patients with CKD and chronic HF.

SGLT-2 inhibitorsIn the EMPA-REG OUTCOME study performed in patients with established or at high risk for CVD, empagliflozin com-pared to placebo was associated with a 14% reduction in MACE mainly driven by a 35% reduction in hospitalisation for HF and a 38% in reduction in CV death.4 Furthermore, there was decreased

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Cross-talk between the kidneys and circulation in diabetes

development of macroalbuminuria and reduced slope of eGFR decline; it also prevented serum creatinine doubling and ESKD. The CVD and CKD benefits of empagliflozin occurred in subgroups with and without pre-existing CKD.

Additional benefits of SGLT-2 inhibi-tor treatment included lower blood glucose without increased risk for hypo-glycaemia, reduction in blood pressure, weight loss and natriuresis. The latter is an important mechanism for preventing HF.

The mechanisms for the renoprotection observed in this study were probably due to the restoration of autoregulation in the diabetic kidney (Figure 2).5 In controlled diabetes, the SGLT-2 is upregulated, resulting in increased glucose and sodium

reabsorption in the proximal tubule and reduced sodium delivery to the macula densa. This results in tubuloglomerular feedback (TGF) causing afferent dilata-tion and efferent constriction, which raises intraglomerular pressure and eGFR. SGLT-2 inhibition results in natriuresis and increased delivery of sodium to the macula densa. Glomerular autoregulation through the afferent and efferent arterioles is restored, reducing glomerular pressure. Increased glomerular pressure is strongly linked to progression of DKD. This is well illustrated in EMPA-REG OUTCOME where empagliflozin caused an initial decline in eGFR compared to placebo, but ultimately brought about long-term stabilisation of eGFR (Figure 3).4

Figure 1. The 2018 EASD/ADA consensus statement2

Use metformin unless contraindicated or not toleratedIf not at HbA1c target: • Continue metformin unless contraindicated (remember to adjust dose/stop metformin with declining eGFR)• Add SGLT-2i or GLP-1 RA with proven cardiovascular benefit (see below)If at HbA1c target: • If already on dual therapy, or multiple glucose-lowering therapies and not on an SGLT-2i or GLP-1 RA, consider switching

to one of these agents with proven cardiovascular benefit (see below)OR reconsider/lower individualised target and introduce SGLT-2i or GLP-1 RAOR reassess HbA1c at 3-month intervals and add SGLT-2i or GLP-1 RA if HbA1c goes above target

If further intensification is required or patient is unable to tolerate GLP-1 RA and/or SGLT-2i, choose agents demonstrating CV safety:• Consider adding the other class (GLP-1 RA or SGLT-2i)

with proven CVD benefit• DPP-4i if not on GLP-1 RA• Basal insulin• TZD• SU

ASCVD predominates

If HbA1c above target

GLP-1 RA with proven benefit

SGLT-2i with proven CVD

benefit, if eGFR adequate

EITHER/OR

• Avoid TZD in the setting of HFChoose agents demonstrating CV safety:• Consider adding the other class with proven CVD

benefit• DPP-4i (not saxagliptin) in the setting of HF (if not

GLP-1 RA)• Basal insulin• SU

PREFERABLYSGLT-2i with evidence of reducing HF and/or CKD

progression in CVOTs if eGFR adequate

OR

If SGLT-2i not tolerated or contraindicated or if eGFR less than adequate add GLP-1 RA with proven CVD benefit

HF or CKD predominates

If HbA1c above target

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Cross-talk between the kidneys and circulation in diabetes

The CREDENCE study was a dedi-cated DKD study presented at the International Society of Nephrology meeting in Melbourne and showed sig-nificant benefits in respect of kidney and CV endpoints.6 The primary outcome was a composite of the progression to ESKD (defined as the need for chronic dialysis or renal transplant); doubling of serum creatinine; and renal or CV death. There was a highly significant relative risk (RR) of the primary outcome which was 30% lower for those taking 100mg of canagli-flozin compared with placebo, 34% for the renal-specific elements (event rates

of 43.2 and 61.2 per 1 000 patient years respectively), and 32% for ESKD.

Among secondary endpoints, those taking canagliflozin also had a lower risk of CV death, myocardial infarction and stroke (HR, 0.80; 95% CI, 0.67-0.95; P=0.01), and hospitalisation for HF (HR, 0.61; 95% CI, 0.47 to 0.80; P<0.001).

Based on renal outcome studies with dapagliflozin, the FDA has recently approved a label update for this SGLT-2 inhibitor expanding its use for patients with type 2 diabetes and moderate renal impairment.

GLP-1 receptor agonistsGLP-1 receptors in the kidney are located in glomerular endothelial cells, mesangial cells, and macrophages, and proximal tubular cells. GLP-1 receptor agonists in

experimental models reduce albuminu-ria, decrease mesangial expansion and glomerular basement membrane thick-ness, protect endothelial cells and restore

A. Diabetic nephron B. Diabetic nephron with SGLT inhibition

Figure 2. SGLT-2 inhibition: restoration of autoregulation in the diabetic kidney5

normalized PGChigh PGC

increased feedback from macula densa

reduced feedback from macula densa

reversed afferent

vasodilation

afferent vasodilation

normalised distal delivery

of NACI

decreased distal delivery

of NACI decreased NaCI and glucose

reabsorption via SGLT-2 inhibition

increased NaCI and glucose

reabsorption via SGLT-2

increased NaCI and glucose

filtration

Sodium-glucose co-transporter-2 (SGLT-2)

Sodium-glucose co-transporter-1 (SGLT-1)

PGC = pressure in glomerular capillaryGlucose

Sodium (Na)Chloride (Cl)

Adenosine activation of (A1) receptor

Afferent arteriole

Tubular lumen

ATP cleavage of adenosine

Tubular epithelial cell

Basolateral ATP release

ATP

ADP + Pi

Na+/K+ – ATPase

H2O [CI–]

[Na+][K+]

3 Na–

2 K–

[Ca2+] Vaso-

constriction

Adenosine activation of (A1) receptor

Afferent arteriole

Tubular lumen

ATP cleavage of adenosine

Tubular epithelial cell

Basolateral ATP release

ATP

ADP + Pi

Na+/K+ – ATPase

H2O [CI–]

[Na+][K+]

3 Na–

2 K–

[Ca2+] Vaso-

constriction

JULY 2019 I 5

Cross-talk between the kidneys and circulation in diabetes

podocytes. Mediators for effects of GLP-1 receptor agonists probably include reduc-tion in oxidative stress and inflammation.

In the SUSTAIN-6 study, performed in type 2 diabetics at high risk for CVD, there was a 26% reduction in MACE, 26% in myocardial infarction, and 36% in stroke, but no reduction in CV deaths.7

Clinical trials in diabetics with CKD demonstrate reduced risk of albuminuria onset and progression across GLP-1 ago-nists (lira-, sema-, dula- glutides). In the LEADER study liraglutide significantly reduced the progression of CKD, mainly in the group with eGFR between 30-60ml/

min/1.73m2 and there was a graded risk reduction of CVD by eGFR categories except in the <30ml/min/1.73m2 group where there were inadequate numbers.8 In the AWARD-7 study performed in diabetic patients with moderate to severe CKD, dulaglutide compared to insulin glargine showed comparable glycaemic control with a significantly reduced decline in eGFR.9 Furthermore, on harder kidney endpoints significantly more patients on glargine showed a 40% decline in eGFR or reached ESKD (Tuttle KR et al. ASN Kidney Week, October 25, 2018).

New drugs for CKD in diabetesDKD is a complex disease with many faces. Histological characteristics can range from diffuse mesangial expansion with mesangial cell proliferation; promi-nent mesangial expansion with early nod-ularity and mesangiolysis; accumulation of mesangial matrix forming Kimmelstiel-Wilson nodules; dilation of capillaries forming microaneurysms, with subintimal hyaline (plasmatic insudation) and obso-lescent glomeruli (Figure 4).10 There is the opportunity to use systems biology to tar-get therapeutic opportunities.

Many JAK/STAT mRNAs are over-expressed in both human and mouse dia-betic kidney disease, and these mRNAs

correlate closely with DKD severity. Over-expression of JAK2 appears to ‘humanise’ mouse models by producing a phenotype akin to DKD. Gene expression in human kidney tissue points to a JAK2 inflam-matory pathway. Baricitinib is a JAK1/2 inhibitor, and a phase 2, double-blind, dose-ranging study was conducted, where participants were randomised 1:1:1:1:1 to receive placebo or baricitinib (0.75mg daily; 0.75mg twice daily; 1.5mg daily; or 4mg daily), for 24 weeks followed by 4-8 weeks of washout. Baricitinib resulted in a significant reduction in albuminuria, which is an important surrogate endpoint of progression of kidney disease.11

Based on renal outcome studies with dapagliflozin, the FDA has recently approved a label update for this SGLT-2 inhibitor expanding its use for patients with type 2 diabetes and moderate renal impairment

78

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70

68

66

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eG

FR (

ml/

min

/1.7

3m2 )

Week

Empagliflozin 10mgEmpagliflozin 25mg

Change in eGFR over 192 wk

Baseline

Placebo

4 12 52 66 80 94 108 122 136 150 164 178 19228

Figure 3. eGFR over time in the EMPA-REG OUTCOME study4

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DisclaimerThe views and opinions expressed in the article are those of the presenters and do not necessarily reflect those of the publisher or its sponsor. In all clinical instances, medical practitioners are referred to the product insert documentation as approved by relevant control authorities.

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Cross-talk between the kidneys and circulation in diabetes

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ConclusionsIntensive glycaemic control is a proven strategy for CKD prevention in early dia-betes. Less stringent glycaemic control is recommended once CKD develops in diabetes due to high risks and nominal benefit. SGLT-2 inhibition reduces mac-roalbuminuria, slope of eGFR decline,

serum creatinine doubling and ESKD. GLP-1 receptor agonists lower the risk of albuminuria and slow eGFR decline. Mechanistic-based and individualised treatments are urgently needed to mitigate the global impact of CKD in diabetes.

ReferencesClick on reference to access the scientific article1. Papademetriou V, Lovato L, Doumas M, et al. Chronic

kidney disease and intensive glycemic control increase cardiovascular risk in patients with type 2 diabetes. Kidney Int 2015; 87(3): 649-659.

2. Davies MJ, D’Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2018; 41(12): 2669-2701.

3. Crowley MJ, Diamantidis CJ, McDuffie JR, et al. Clinical outcomes of metformin use in populations with chronic kidney disease, congestive heart failure, or chronic liver disease: A systematic review. Ann Intern Med 2017; 166(3): 191-200.

4. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016; 375(4): 323-334.

5. Alicic RZ, Johnson EJ, Tuttle KR. SGLT-2 inhibition for the prevention and treatment of diabetic kidney disease: A review. Am J Kidney Dis 2018; 72(2): 267-277.

6. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and

renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019. [Epub ahead of print]

7. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016; 375(19): 1834-1844.

8. Mann JFE, Orsted DD, Brown-Frandsen K, et al. Liraglutide and renal outcomes in type 2 diabetes. N Engl J Med 2017; 377(9): 839-848.

9. Tuttle KR, Lakshmanan MC, Rayner B, et al. Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial. Lancet Diabetes Endocrinol 2018; 6(8): 605-617.

10. Alicic RZ, Rooney MT, Tuttle KR. Diabetic kidney disease: challenges, progress, and possibilities. Clin J Am Soc Nephrol 2017; 12(12): 2032-2045.

11. Tuttle KR, Brosius FC 3rd, Adler SG, et al. JAK1/JAK2 inhibition by baricitinib in diabetic kidney disease: results from a Phase 2 randomized controlled clinical trial. Nephrol Dial Transplant 2018; 33(11): 1950-1959.

Figure 4. The many faces of DKD10

Diabetic glomerulopathy. Changes in glomerular histology in diabetic glomerulopathy (A) Normal glomerulus. (B) Diffuse mesangial expansion with mesangial cell proliferation. (C) Prominent mesangial expansion with early nodularity and mesangiolysis. (D) Accumulation of mesangial matrix forming Kimmelstiel-Wilson nodules. (E) Dilation of capillaries forming microaneurysms, with subintimal hyaline (plasmatic insudation). (F) Obsolescent glomerulus. A-D and F were stained with Periodic acid–Schiff stain, and E was stained with Jones stain. Original magnification, ×400.

This CPD report from the Cardiology, Diabetes and Nephrology At the Limits 2019 meeting at the Royal College of Physicians, London, UK, was written by Professor Brian Rayner for deNovo Medica.Professor Rayner is Emeritus Professor and Senior Scholar, Division of Nephrology and Hypertension, Kidney and Hypertension Research Unit, University of Cape Town.

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1. In type 2 diabetes, what percentage of patients is expected to develop CKD?

A 30% B 40% C 50%

2. Early intensive glycaemic control is a proven strategy for CKD prevention.

A True B False

3. Most diabetic patients with CKD die of:

A CVD B Infection C ESKD D A and C E A and B

4. A more stringent HbA1c target of <6.5% can be selected for:

A Patients with a short duration of diabetes B Type 2 diabetes mellitus patients on lifestyle measures and metformin C Patients with long life expectancy D Patients with no significant CVD E All of the above

5. In controlled diabetes, SGLT-2 is:

A Up-regulated B Down-regulated

6. SGLT-2 inhibitors’ mechanism of renoprotection is likely to be due to:

A Reduction in blood pressure B Restoration of autoregulation of the kidney C Weight loss D A and C

7. In the CV outcomes trial (EMPA-REG OUTCOME), SGLT-2 inhibition was associated with a 14% reduction in MACE due mainly to:

A Reduction in HF hospitalisation B Reduction in CV death C Reduction in ESKD C A and B

8. The CREDENCE study of DKD showed that treatment with canagliflozin resulted in a relative risk reduction in the primary outcomes (renal and cardiovascular) of:

A 20% B 30% C >30%

9. Based on renal outcome studies with dapagliflozin, the FDA has expanded its use in type 2 diabetes to patients with:

A Serious renal impairment B Moderate renal impairment C An eGFR of 90 or more

10. The GLP-1 receptor agonist studies in type 2 diabetes patients at high risk showed a reduction in CV deaths.

A True B False

11. In the LEADER study, the GLP-1 receptor agonist liraglutide reduced the progression of CKD mainly in the group with an eGFR of:

A 30-60ml/min/1.73m2 B 60-90ml/min/1.73m2 C >90ml/min/1.73m2

12. Type 2 diabetes patients with moderate to severe CKD treated with insulin glargine showed a:

A 20% decline in eGFR B 30% decline in eGFR C 40% decline in eGFR

13. Once CKD develops in diabetic patients, the HbA1c target should be:

A <6.5% B <7% C <8%

14. SGLT-2 inhibitors reduce:

A Macroalbuminuria B Slope of eGFR decline C Doubling of serum creatinine D ESKD E All of the above

15. GLP-1 receptor agonists reduce:

A Macroalbuminuria B Slope of eGFR decline C Doubling of serum creatinine D ESKD E A and B F C and D