Recent advancement in managing diabetic nephropathy

RECENT ADVANCES IN

MANAGING AND UNDERSTANDING

DIABETIC NEPHROPATHY

Presented by :

Mr. Prashant Shivgunde

Assistant Professor,

University Department of Interdisciplinary Research and Technology,

Maharashtra University Health Sciences, Nashik1/25/2017

Contents

• Introduction

• Pathophysiology of Diabetic Nephropathy

• Current Standard of Approach to Diabetic Nephropathy

• Novel Therapeutic Modalities

• Some of the Newer Drugs and Terminated RCTs 1/25/2017

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Introduction

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Diabetes Mellitus

• Prevalence of diabetes mellitus (DM) is 8.5% and increasing

• Most affected with Type 2 DM• Epidemic for several decades • Associated with many complications

• Diabetic kidney disease (DKD) is a leading complication of diabetes, which can lead to serious consequences, including kidney failure and cardiovascular morbidity and mortality

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Chronic Kidney Disease

• 8% to 16% prevalence of CKD globally and is steadily rising

• QOL

• Medical expenses are costly

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CKD prognosis example

100%

Patients

Stage 3 CKD 1/25/2017

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27%

8%65%

Patients

Stage 3 CKD RRT Dead Patients

After 10 Years

CKD and Diabetes

• As a cause of ESRD, diabetic nephropathy (DN) ranks first

• DN is clinically characterized by • Proteinuria (mostly albuminuria), • Elevated serum creatinine levels, and • Decreased eGFR

• More than 20% of patients starting dialysis are dead within the first year and more than 70% of diabetic patients starting dialysis are dead within 5 years

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Percentage of diabetic patients who are likely to progress through each stage

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Normal albumin excretion

Persistent MicroalbuminuriaMicroalbuminuria

Proteinuria

Renal Failure

20-30%~50% (2-4% per annum)

40%

30%

Raising blood pressure and cardiovascular disease risk

Table 1: Likelihood of DKD based on UACR and GFR

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Albuminuria

GFR* CKD Stage† None‡ UACR 30-299 mg/g UACR ≥300 mg/g

>60 1+2 At risk Possible DKD DKD

30–60 3 Unlikely DKD Possible DKD DKD

<30 4+5 Unlikely DKD Unlikely DKD DKD

*GFR expressed in mL/min.†The NKF recommends using albuminuria data before initiation of RAAS inhibitor therapy to determine the

staging.‡UACR <30 mg/g

Diabetic Nephropathy

• Affects approx. one-third of individuals with diabetes mellitus

• NHANES program during 1988–2008

• Prevalence of DKD increased (2.2%–3.3%) in proportion to the prevalence

of diabetes (6.0%–9.4%)

• The excess mortality risk of DM is practically exclusively

correlated with the occurrence of DN

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Diabetic Nephropathy

• Burden of ESRD from type 2 diabetes mellitus(T2DM) is expected to burgeon by four fold

• Why some diabetic patients develop nephropathy whereas others do not- ?

• DN pathogenesis remains obscure

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Drug Development

• Fewer interventional trials to develop therapeutics

• Obstacles are• Slow patient enrolment (in part because of a lack of disease awareness), • Regulatory requirements for hard patient outcomes for drug

registration, and • Lack of payer engagement

• Only unmet medical need attract some pharmaceutical companies.

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Pathophysiology of Diabetic Nephropathy

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Pathogenetic Mechanisms

• Heavy inflammatory element triggered by metabolic disorders,

protein overload, and hemodynamic abnormalities

• Traditionally, Glomerular in origin

• Emerging data suggest that the tubular epithelial cell

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Effects of - High Glucose

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IncreasesNADH:NAD

Ratio

High Glucose

Aldose ReductasePathway

DAG synthesis

PKC

ROS

AGE

RAGE

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16Free Amino Groups (Proteins , Lipids, & Nucleic Acids

Reducing Sugar

Under High Glucose

Ambience

Non-Enzymatic Interaction

Labile Schiff Base

Amadori Rearrangement

Dehydration

Polymerization

AGE’s

ROS

Interact With

RAGE and Other Binding Protein

(OST-48, 80 K-H, Galectin)

Induce Various Intracellular

Events

Activate PKC, MAP Kinase and Transcription factor

such as NF-κβ

Increased synthesis of Type I & IV Collagens

Activate Transcription factor such as TGF-β and alter expression of ECM

proteins

Decreased Expression Of Proteoglycans

Anomalous ECM polymerization and

expansion

Covalently Bind With Proteins Thus Compounding With Various Deleterious Effect in Tissues

17

18Membrane Barrier

High Glucose and Ang II-induced JAK/STAT pathway in kidney mesangial cell growth

O2

NADPH oxidase

Angiotensin II

AT1

High Glucose

Polyol Pathway

RAGE

PKC-beta

AGE

PLD2

JAK2 and STATs

SHP-1 and SHP-2

PLC-gamma1

DAG

AldoseReductase

Current Standard of Approach to Diabetic Nephropathy

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The Triumvirate

• Intensive control of Blood Glucose

• Intensive control of Blood Pressure

• RAAS Blockade

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What Can be Achieved with Glycaemic Control?

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Glycaemic Optimization

• Study - EDIC (Epidemiology of Diabetes Interventions and Complications- Cohort)

• Type 1 diabetics clearly demonstrated a legacy effect of early intensive diabetic control-• 44% reduction in developing CKD with eGFR lower than 60 ml/min/1.73m2

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• Study- UK Prospective Diabetes Study (UKPDS)

• 3,867 Patients (newly diagnosed)

• Conventional Group HbA1c 7.9%

• For type 2 diabetics the risk in the intensive group was • 12% lower for any diabetes-related endpoint; • 10% lower for any diabetes-related death; and • 6% lower for all-cause mortality

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• Study- ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) trial

• 11,140 patients

• Demonstrated the value of tight glycaemic control• Reduction of albuminuria (9% and 30% for micro- and macro-albuminuria,

respectively) and 65% risk reduction of ESRD

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• Encouraging data must be interpreted with caution

• UKPDS, patients in the intensive group had significantly more hypoglycaemic episodes

• Study - ACCORD (Action to Control Cardiovascular Risk in Diabetes)• Terminated early due to excess mortality in the intensive therapy arm

(HbA1c target <6.0%) versus the standard arm (HbA1c 7.0–7.9%)

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• What constitutes optimal diabetic control?

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Aim- to strike a balance between the risk of hypoglycaemia and the clear benefit of reno-protection

The American Association of Clinical Endocrinologists

Target of HbA1c <6.5%

American Diabetes Association

Target of HbA1c <7%


• The Steno-2 study (microalbuminuria)-

• Target-driven, long-term, intensified intervention aimed at multiple risk factors• Blood pressure < 130/80 mmHg, • Proteinuria < 0.3 g/day, • Low density lipoprotein [LDL] < 100 mg/dL, • ldl + very low density lipoprotein < 130 mg/dL, • HbA1c < 7.0%, smoking cessation, and • Near normalization of anemia of hemoglobin of 11 to 13 g/dL

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• Reduced the risks of cardiovascular and microvascular events, by approximately 50%

• In elderly, stricter established target levels • hypoglycaemia and cerebrovascular ischemic events chances

• Thus, treatment targets should be tailored

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Glycaemic Vs Blood Pressure Control

• Depends on the clinical circumstances of the individual

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Significance

Glycaemic control

Normoalbuminuria to microalbuminuria progression

Blood pressure control

Once microalbuminuria has shifted into a macroalbu-

minuric state

Blood Pressure Control

• Hypertension an independent, modifiable variable • Predisposes individuals to the development and acceleration of micro- and

macro-vascular problems• Various attempts to optimize RAAS inactivation

• Several trials have been conducted to validate the efficacy• Angiotensin converting enzyme inhibitors (ACEI) or Angiotensin II type 1

receptor blockers (ARBs) alone, • Combined use of ACEI and ARBs, • Renin inhibitors (aliskiren), • Aldosterone inhibitors (spironolactone or eplerenone), and • Angiotensin II type 2 receptor enhancement 1/25/2017

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Blood Pressure Control

• UKPDS showed for every 10 mmHg reduction in SBP, there was a decrease in • All DM-related complications by 12%• Death by 15%

• Echoed in the RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan) trial• 1,513 type 2 DM patients with confirmed DN and hypertension• Risk of ESRD or death was raised by 6.7% for each 10 mmHg increase in

baseline SBP

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Renin-angiotensin-aldosterone Axis Blockade

• Type 2 DM-• ACEi or ARB is superior to using other anti-hypertensive agents• Provide other renoprotective benefits, (MARVAL -Micro-Albuminuria

Reduction with Valsartan study)

• Type 1 DM –• Study- meta-analysis of 698 non-hypertensive type 1 DM patients with

micro-albuminuria• Treatment with ACEi restricted development to macro-albuminuria by

60%

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• Sub-study of the IRMA-2 (Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria) trial • Reduction in micro-albuminuria by RAS blockade persisted even after

treatment withdrawal

• IDNT (Irbesartan Diabetic Nephropathy Trial)• 1,715 hypertensive type 2 DN patients • 33% decrease in the risk of serum creatinine doubling• 23% decrease in progression to ESRD

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• Similar observations of RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan)• 50% decrease in albuminuria after 6 months of losartan treatment

correlated with a 45% decreased risk for ESRD

• Findings recapitulate the renoprotective effect of captopril in type 1 diabetics with overt nephropathy

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Drug Trial Notes

Valsartan MARVAL

(Micro-Albuminuria Reduction with

Valsartan)

Reduction in BP +

micro-albuminuria

Irbesartan IRMA-2

(Irbesartan in Patients with Type 2

Diabetes and Microalbuminuria)

Reduction in micro-albuminuria

persisted, even after treatment withdrawal,

implies that glomerular structural normalization

may be occurring

Irbesartan IDNT

(Irbesartan Diabetic Nephropathy

Trial)

GFR decline,

33% and 23% Risk reduction of serum creatinine

doubling and progression to ESRD respectively

losartan RENAAL

RENAAL (Reduction of Endpoints in

NIDDM with the Angiotensin II

Antagonist Losartan)

GFR decline,

50% & 45% decrease in albuminuria & risk for

ESRD respectively after 6 months treatment

Renin-Angiotensin-Aldosterone Axis Blockade

• Comparison between ACEi and ARB • Appear to have comparable efficacy in DN, • Intractable dry cough may be associated with ACE inhibition

• Findings are reinforced by the DETAIL (Diabetics Exposed to Telmisartan and Enalapril) trial • RCT in 250 type 2 DN patients• No difference after 5 years- degree of GFR decline, albuminuria and

ESRD incidence

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Renin-Angiotensin-Aldosterone Axis Blockade

• Secondary prevention trials have so far provided all existing data for RAS blockade

• The NKF KDOQI clinical practice guidelines have not recommended using ACEi or ARB for the primary prevention of DN in normotensive individuals with normo-albuminuria

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Exploiting the Renin-Angiotensin-Aldosterone Axis

• Combining ACEi and ARB to maximize RAS blockade

• CALM (Candesartan and Lisinopril Micro-albuminuria) study• A combination of candesartan and lisinopril• Lowered micro-albuminuria more effectively than either drug alone at 12

weeks

• Longer follow-up studies were never able to reproduce these short-term results

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• RCT—ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial),

• Ramipril, telmisartan or both were administered to 25,620 high vascular risk patients (37.5% diabetics)

• Combination therapy was shown to increase the composite outcome of dialysis, doubling of serum creatinine and death

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• VA NEPHRON-D (Veterans Affairs Nephropathy in Diabetes)

• 1,448 type 2 DN patients with eGFR 30–89.9 mL/min/1.73m2

• Treated with losartan alone or in combination with lisinopril• Trial ended early- no renal benefit and an excessive risk of hyperkalemia

(9.9% vs. 4.4%) and acute kidney injury (18% vs. 11%)

• In DN patients with more advanced CKD, dual RAS inhibition would carry an even greater risk

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Aldosterone Antagonism

• Mineralocorticoid receptor antagonist (MRA) • Meta-analyses have demonstrated that a supplement of MRA given to

those treated with ACEi or ARB produces a decrease in proteinuria

• Likewise beneficial effects observed in administration of non-selective and selective MRA

• But, Several studies, in combination with RAS inhibition showed• A greater risk of hyperkalemia

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Non-steroidal MRA Antagonism

• Finerenone• Increased receptor selectivity compared to spironolactone and • Greater receptor affinity than eplerenone in vitro, • A less frequent occurrence of hyperkalemia than spironolactone

• Finerenone added to ACEi or ARB• Produced a dose-dependent decrease in UACR without inducing

hyperkalemia at day 90• The study had several important limitations

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Lipid Lowering Therapy

• Statins are the most widely used class of drug for lipid lowering in individuals with type 2 diabetes• reflects the indisputable evidence

• The role of lipid-lowering treatments in renoprotection for patients with diabetes, however, is debatable.

• In the Heart Protection Study by MRC/BHF with subgroup analysis for participants with diabetes, allocation to simvastatin (40 mg/day)• Significantly decreased the rise in serum creatinine values• Limitation- Subjects with late stage CKD were not studied

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• SHARP• comprising 23% diabetic subjects did not produce significant reductions

in any of the prespecified measures of renal disease progression among the subgroup of 6,247 nondialysis patients with a mean eGFR of 26.6 ml/min/1.73m2.

• Whether lipid lowering could only confer tangible renoprotection during early rather than late CKD requires further investigation

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• GREACE study• Patients given atorvastatin had a significant reduction in urinary albumin

excretion; • However, separate analysis for type2 diabetes was not included in the study

• Findings echoed by the PLANET I study • Treatment with atorvastatin 80 mg lowered UPCR substantially more than

rosuvastatin 10 mg or rosuvastatin 40 mg

• It must be cautioned that such doses of atorvastatin are unusually high for the average CKD patient.

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• Statins-

• Lowered mortality and cardiovascular events with early stages of CKD

• Little or no effects in those on dialysis

• Had uncertain effects in kidney transplant recipients

• Effects on stroke and kidney function remain to be elucidated

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Novel Therapeutic Modalities

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Pleiotropic Renoprotective Effects of Anti-diabetic Drugs Beyond Glycaemic Control

PPAR-γ agonists

Incretin- based Agents

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PPAR-γ Agonists

• TZDs- Pioglitazone and Rosiglitazone

• Varied reports from clinical studies

• Heightened cardiovascular risks and malignancy

• TZDs are unlikely to be a major player in the therapeutic armamentarium for DN

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Incretin- Based Agents

• Incretins secreted into the circulation postprandially• Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like

peptide 1 (GLP-1) • Exert insulinotropic activity

• Impaired incretin regulation is implied in type 2 diabetes

• GLP-1 exerts antidiabetogenic properties by • stimulating insulin secretion, increasing β-cell mass, inhibiting glucagon

secretion, delaying gastric emptying and inducing satiety

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• GLP-1gets rapidly degraded by dipeptidyl peptidase 4 (DPP-4)

• Limitation can be overcome by using • DPP-4 resistant GLP-1 receptor agonists and • DPP-4 inhibitors.

• Other than glycaemic effects reduce-• Blood pressure, • Dyslipidemia, and • Inflammation to a certain degree • Risk of hypoglycaemia

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• Sitagliptin/ Alogliptin/ Saxagliptin

• Experimental models indicated renoprotective benefits

• Lowered albuminuria in patients with type 2 DM• 6 months of sitagliptin or 12 weeks of alogliptin• Data from small, uncontrolled studies

• Findings must be interpreted with caution

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• Four phase III studies, comprising 217 patients with DN on RAS inhibition• 24 weeks of linagliptin significantly reduced albuminuria (32% reduction),

independent of HbA1c

• Advantages of DPP-4 inhibitors• Tolerability, • Weight neutral benefit and • Low risk of hypoglycaemia

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• GLP 1 Agonists- Exenatide, liraglutide, dulaglutide

• Exenatide treatment in Type 2 DM• Reductions in both albuminuria and urinary levels of TGF-β and type IV

collagen

• The anti-fibrotic effect of linagliptin was demonstrated in a type 1 model of DN after 4 weeks of treatment

• Limited clinical evidence of the effect of targeting TGF-β

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Vitamin D Receptor Activators

• Anti-inflammatory and anti-proteinuric effects in animal models of DN

• Phase III VITAL trial in Patients with Type 2 Diabetes• Adjuvant paricalcitol at 2 μg/day lowers residual albuminuria in DN• Drawbacks-

• Poor tolerance- 42% of patients needed a reduced dose of paricalcitol,• High cost of treatment

• Concrete evidence demonstrating the successful use of VDR activators to retard the progression of DN is still awaited

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Sodium-Glucose Co-transporter 2 Inhibition

• Along with aiding glycemic control, SGLT-2 inhibitors appear to promote an attractive cardiovascular portfolio

• EMPA-REG study,Empagliflozin added to standard care• Over 7,000 type 2 diabetics at high cardiovascular risk• Reduced the rates of

• Death from cardiovascular causes (3.7%, vs. 5.9% in the placebo group; 38% RRR),

• Hospitalization for heart failure (2.7% Vs 4.1%, 35% RRR), and • Death from any cause (5.7% Vs 8.3%, 32% RRR)

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• Renoprotective effect of SGLT2 inhibitors attributed to a decrease in high glucose-induced inflammatory and fibrotic markers in human proximal tubular cells

• By blocking glucose entry into the cell empagliflozin attenuated High glucose-induced-• Expression of Toll-like receptor-4, binding of nuclear deoxyribonucleic

acid to nuclear factor κB and activator protein 1, and secretion of collagen IV and interleukin-6

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• Reporting with negligible clinical impact-• Drug dose-dependent hyperkalemia and urogenital infections

• Dapagliflozin in the most recent trial involving diabetic patients with moderately decreased renal function group showed favorable results in terms of reduced albuminuria

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Selective C-C Chemokine Receptor Type 2 Antagonism

• MCP-1 overexpression plays an indispensable role in promoting monocyte and macrophage migration and activation

• CCR2 antagonist- CCX140-B is a small molecule • Inhibits CCR2 and blocks MCP-1-dependent monocyte activation and

chemotaxis• Improved glycaemia and albuminuria in animal models

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• The first evidence that CCR2 inhibition lowers albuminuria in DN came from a recent European study

• Patients with type 2 DM, Age: 18–75 years with UACR 100–3000 mg/g, eGFR ≥25 mL/min/1.73m2, and taking stable antidiabetic treatment and an ACEi or ARB for at least 8 weeks

• Stratified to once a day• Oral placebo, • 5 mg CCX140-B, or • 10 mg CCX140-B

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• UACR changes (during 52 weeks)• -2% for placebo (95% CI -11% to 9%), • -18% for 5 mg CCX140-B (-26% to -8%), and • -11% for 10 mg CCX140-B (-20% to -1%)

• No significant difference in adverse events or renal events during the study.

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5’ Adenosine Monophosphate-activated Protein Kinase Activators

• AMPK is a metabolic master switch that regulates downstream signals based on shifts in surrounding energy reservoirs

• Evidence of dysregulation of AMPK in relevant tissues is implicated in the development of metabolic syndrome and diabetes

• Insulin-resistant animal models• AMPK activation proven to improve glucose and lipid homeostasis

coordinating anabolic processes

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• Metabolic stress –• Adenosine triphosphate (ATP) consumption -increase in the adenosine

monophosphate (AMP)/ATP ratio

• Several upstream kinases or compound molecule that consists of three proteins: • STE-related adaptor (STRAD), mouse protein 25 (MO25), and the tumor-

suppressor liver kinase B1 (LKB1)

• Upstream enzymes • Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ) and • TGF β-activated kinase (TAK1) 1/25/2017

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• Response to oxidative stress- Activated AMPK phosphorylates its main downstream targets of lipid homeostasis• ACETYL-COA carboxylase and hydroxymethylglutaryl CoA reductase.

These are primarily involved in the rate-limiting steps• Promote fatty acid oxidation

• Adaptive responses for cell survival• Fortify cellular autophagy, antioxidant defense and mitochondrial bio-

genesis

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• Sirtuin 1 (Sirt1) protein• founding member of a family of NAD+-dependent deacetylases and is

linked to longevity associated with calorie reduction• Expression and activity significantly reduced in type 2 diabetic animal

models and human kidneys the

• Mechanism of Sirt1 reduction in the diabetic condition has not been clarified, • Recent publications showed - AMPK activation by resveratrol and

theobromine leads to Sirt1 activation, which protects the diabetic kidney

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• Conventional activators of AMPK providing additional renoprotective effects in addition to their intrinsic activities –• 5-aminoimidazole-4-carboxamide ribonucleoside, • Metformin, • Adiponectin, and • Resveratrol

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Some of the Newer Drugs andTerminated RCTs

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Endothelin Receptor Antagonist

• Avosentan on Time to Doubling of Serum Creatinine, End Stage Renal Disease or Death in Patients With Type 2 Diabetes Mel-litus and Diabetic Nephropathy (ASCEND) trial• Favorable effect of reducing albuminuria when added to standard

treatment

• Terminated due to-• An increased risk of fluid overload and consequent congestive heart

failure resulting from proximal tubular sodium reabsorption

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Endothelin Receptor Antagonist

• Ongoing Study of Diabetic Nephropathy With Atrasentan(SONAR) phase III trial • Approaching its closing date, though some safety issues concerning

edema and heart disease are constantly being raised

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Antioxidative and Anti-inflammatory Agent

• Bardoxolone• Powerful antioxidative and anti-inflammatory effects through the

activation of the nuclear 1 factor-related factor 2 transcription factor• Failed to produce promising results

• Dropped from BEAM and BEACON trials, • Trivial muscle cramps to serious issues including heart failure, • Non-fatal myocardial infarction, stroke, and cardiovascular mortality• Also increased urine albumin excretion and blood pressure

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Glycosaminoglycans

• Sulodexide

• Potentiates the antiprotease activities of both antithrombin III and heparin cofactor II, shown • Beneficial effects in diabetic animal models• Failed to prove efficacious in the sulodexide macroalbuminuria (Sun-

MACRO) trial

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Others

• Xanthine oxidase inhibitors• Proven efficacy in terms of delaying the decline in the rate of eGFR in a

relatively small sample of CKD patients • Need to be validated in a larger population

• Anti-transforming growth factor β (TGF-β) antibody (LY2382770),• Effect demonstrated in an animal model, has not yet been translated into

human data

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Others

• Pentoxifylline- methylxanthine derivative and nonspecific PDI• Effects anti-inflammatory, antiproliferative, and ant-fibrotic actions

• Pentoxifylline for Renoprotection in Diabetic Nephropathy (PREDIAN) trial, • Rate of eGFR decline and the change in urinary albumin excretion were

significantly lower

• Stem cell therapy in experimental DN models has not yet shown efficacy in either diabetic mice or rat models

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Points to Remember

• Diabetes is the leading cause of chronic kidney disease (CKD)

• Screened regularly for kidney disease• key markers- glomerular filtration rate (eGFR) and urine albumin

• Intensive management of blood glucose has shown great promise for people with diabetes, especially for those in the early stages of CKD.

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Points to Remember

• Agents proven blood pressure lowering and slowing the progression of kidney disease • Angiotensin-converting enzyme (ACE) inhibitors and • Angiotensin receptor blockers (ARBs)

• ACEi and ARBs dual blockade is not recommended

• In people with diabetes, excessive consumption of protein may be harmful.

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Any Questions?

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Health & Medicine

Recent advancement in managing diabetic nephropathy