minding the kidney in t2dm n.
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Our aim is to reduce morbidity and mortality related to Non communicable diseases such as hypertension, diabetes, cardiovascular disease, stroke, Obesity, Cancer and lifestyle diseases among those least able to withstand the burden of the disease.

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some important definitions
Some important definitions
  • Azotemia - elevated blood urea nitrogen (BUN >28mg/dL) and creatinine (Cr>1.5mg/dL)
  • Uremia - azotemia with symptoms or signs of renal failure
  • End Stage Renal Disease (ESRD) – GFR <15 ml/min + uremia requiring transplantation or dialysis
  • Chronic Renal Failure (CRF) - irreversible kidney dysfunction with azotemia >3 months
  • Creatinine Clearance (CCr) - the rate of filtration of creatinine by the kidney (GFR marker)
  • Glomerular Filtration Rate (GFR) - the total rate of filtration of blood by the kidney
ckd definition kdoqi guidelines
CKD Definition - KDOQI GUIDELINES

CKD is defined as abnormalities of kidney structure or function, present for > 3 months,

with implications for health. (Not Graded)

Criteria for CKD (either of the following present for > 3 months)

Kidney International Supplements (2013) 3, 5–14; doi:10.1038/kisup.2012.77

faster progression in asians
Faster progression in Asians

Asians are more susceptible than Caucasians to diabetic nephropathy.

Exhibit faster progression from microalbuminuria to macroalbuminuria and renal failure.

Chandie Shaw PK, South-Asian type 2 diabetic patients have higher incidence and faster progression of renal disease compared with Dutch-European diabetic patients. Diabetes Care, 2006;29:1383-1385.

kidney disease in diabetes a silent killer
Kidney Disease in Diabetes: a silent killer ?

1. Keen and Viberti, J Clin Pathol. 1981;34:1261–6.

2. McLaughlin NG et al., Northeast Florida Medicine, 2005.

3. United States Renal Data System. Annual data reportt, 2009. http://www.usrds.org/atlas.htm

4. Jemel A et al., CA Cancer J Clin. 2007;57;43–66.

albuminuria and reduced gfr 2 manifestations of nephropathy in t2dm
Albuminuria and reduced GFR: 2 manifestations of nephropathy in T2DM

Adapted from de Boer. IH, Steffer MW. J Am Soc Nephrol. 2007; 18:1036-1037

misleading serum creatinine
Misleading serum creatinine
  • 65-year-old,
  • 75-kg active gentleman
  • Needing wound care
  • Serum creatinine is 1.0 mg per dL
  • 85-year-old
  • 50-kg homebound woman
  • Needing wound care
  • Serum creatinine of 1.0 mg per dL

Both patients have identical creatinine within the normal range

Cockcroft-Gault Equation:

Creatinine Clearance (ml/min) = 140-Age (yrs) X Weight (Kg)/ 72 X Sr. Creatinine (mg/dl)

For women, multiply by 0.85

creatinine clearance : 78 mL per minute 

creatinine clearance of 32 mL per minute

Creatinine Clearance (100-125 ml/min)

Normal: >90

Mild RI: 60 – 90,

Moderate: 30-60

Severe: < 30

S. Creatinine

Male: 0.6-1.2

Female: 0.5-0.9

ckd prevalence india
CKD prevalence-India

MIND - cross sectional, multi-centre, observational study conducted at 6 sites across India

T2DM study population

(N=977)

  • Prevalence of CKD (based on eGFR and UACR) = 39.3%

39.3%

CKD Prevalence

(based on eGFR + UACR)

(N=384)

True burden of CKD is

higher by 5 fold

5

8.4%

Raised

Ser. Creat. (N=82)

Rasied ser. Creat>1.1 mg/dl

  • Patient having raised creatinine (>1.1 mg/dl) = 8.4%

Sahay R et al. Diabetes Research and Clinical Practice-volume106, supplement-1. PO162.

slide12
Linagliptin is the only DPP-4 inhibitor with no need for dose adjustment even in patients with renal impairment (RI)

2-fold increase in exposure

Linagliptin

Sitagliptin

Fold increase in exposure relative to normal renal function

Fold increase in exposure relative to normal renal function

Normal

Mild

Moderate

Severe

ESRD

Normal

Mild

Moderate

Severe

ESRD

(n = 6)

(n = 6)

(n = 6)

(n = 6)

(n = 6)

(n = 6)

(n = 6)

(n = 6)

(n = 6)

(n = 6)

Creatinine clearance1(mL/min)

Creatinine clearance1(mL/min)

> 80

50 to ≤ 80

30 to ≤ 50

< 30

< 30 on HD

> 80

50 to ≤ 80

30 to ≤ 50

< 30

on HD

Renal impairment status

Renal impairment status

Saxagliptin

(5-hydroxy saxagliptin metabolite)2

Vildagliptin

(LAY151 metabolite)3

Fold increase in exposure relative to normal renal function

Fold increase in exposure relative to normal renal function

Normal

Mild

Moderate

Severe

ESRD

Normal

Mild

Moderate

Severe

ESRD

(n = 8)

(n = 8)

(n = 8)

(n = 8)

(n = 8)

Creatinine clearance1(mL/min)

Renal impairment status

> 80

> 50 to ≤ 80

>30 to ≤50

<30

on HD

Renal impairment status

1. Estimated creatinine clearance values were calculated using the Cockcroft-Gault formula.2. 90% confidence intervals not available. 3. n numbers, 90% confidence intervals and definitions of RI according to creatinine clearance not available for vildagliptin.Source: Graefe-Mody U, et al. DiabetesObesMetab. 2011;13:939–946.

slide14
Renally excreted drugs (sitagliptin/metformin) were found to be dosed inappropriately in real world data from the US

Juliana Meyers et al. Postgraduate Medicine, Vol 123, issue 2, 2011

slide15
Renally excreted drugs (sitagliptin/metformin) were found to be dosed inappropriately in real world data from the US
  • Renal Impairment is common but often undetected in patients with T2DM
  • Further analysis is needed to understand the clinical and economic consequences of these findings

Juliana Meyers et al. Postgraduate Medicine, Vol 123, issue 2, 2011

real world data on dose adjustment based on kidney function
Real world data on dose adjustment based on kidney function

US Database:

85% and 99% patients with RI were not dose adjusted for sitagliptin & metformin, respectively

UK Database:

20-25% patients on full dose of sitagliptin, saxagliptin & vildagliptin had renal impairment (eGFR<60ml/min)

41% T2DM patients in DELHI did not follow up with their physicians

for 1 year

Middleton R et al. Nephrol Dial Transplant (2014) 21:88-92., Meyers JL et al. Postgraduate medicine. 2011;123(3):133-143., Nagpal J et al. Diabetes Care. 2006; 29:2341–2348.

slide17

5

N=40.856

4

3

Risk of CV mortality (HR)

2

1

2

10

100

1000

Albumin concentration (mg/L)

Albuminuria as predictor of CV mortality in the general population

Hillege et al; Circulation 2002;106:1777-1782

albuminuria is a risk factor for kidney disease
Albuminuria is a risk factor for kidney disease

Risk of developing sustained eGFR < 60 mL/min/1.73 m2

*

Hazard ratio (95% CI)

*

Annual % decrease in eGFR (95% CI)

1.2 (1.2–1.3)

1.8*(1.6–1.9)

5.7*(4.5–6.8)

*p < 0.0001 versus normal.

CI, confidence interval; eGFR, estimated glomerular filtration rate.

Molitch ME, et al. Diabetes Care. 2010;33:1536–43.

albuminuria is a risk factor for renal events
Albuminuria is a risk factor for renal events

In ADVANCE, higher UACR levels at baseline were log-linearly associated

with an increased risk of renal events*

Every 10-fold increment in baseline UACR

HR: 3.27 (95% CI: 2.09–5.11)

After correcting regression dilution bias

HR: 10.48 (95% CI: 4.31–25.49)

32.0

16.0

8.0

4.0

HR (95% CI)

p for trend < 0.0001

2.0

N = 10,640

1.0

0.5

0.25

3

30

300

Baseline UACR (mg/g)

*Death as a result of kidney disease, requirement for dialysis or transplantation, or doubling of serum creatinine to 200 mol/L.

CI, confidence interval; HR, hazard ratio; UACR, urinary albumin creatinine ratio.

Ninomiya T, et al. J Am Soc Nephrol. 2009;20:1813–21.

effect of dpp4i on albuminuria
Effect of DPP4I on albuminuria

Sitagliptin, 50 mg/day

(after 24 weeks; n = 40)1

Saxagliptin, 5 mg/day* (median follow-up: 2.1 years; n = 12,360)2

Significant reduction in UACR (p = 0.0014)

–20.6 ± 24.6 mg/g

creatinine in patients with normo-, micro-, and macroalbuminuria

Reduce development and progression of microalbuminuria compared with placebo

Effect of Blood Pressure reduction & Glycemic control in this?

*2.5 mg daily in patients with an estimated glomerular filtration rate ≤ 50 mL/min/1.73 m2.

DPP-4, dipeptidyl peptidase-4; UACR, urinary albumin creatinine ratio.

Source: Hattori S. Endocr J. 2011;58:69–73. 2. Scirica BM, et al. N Engl J Med. 2013;369:1317–26 (also see supplementary materials).

sitagliptin hattori et al single centre

Sitagliptin:

  • Hattori et al - single centre observational data (n = 40) with significant changes in the blood pressure at the end of study.
  • Mori et al - changes related to reduction in DBP (n=41) 1
  • Thus reductions are not independent of glucose and BP control 2

Vildagliptin :

    • MA reduction was not studied to be independent of glucose and BP3 (n=37)

Saxagliptin :

  • SAVOR-TIMI showed microalbuminuria reduction, however there was no analysis done to prove the effect is independent of BP and glucose control 4
  • Hattori S. Endocrine Journal 2011, 58 (1), 69-73.
  • Mori et al. J Diabetes Invest 2014; 5: 313–319
  • Watanabe. http://www.endocrine-abstracts.org/ea/0029/ea0029p687.htm
  • SciricaBM et al. NEJM 2013. DOI: 10.1056/NEJMoa1307684
slide23
The DPP-4 Inhibitor Linagliptin Reduces Albuminuria in Patients with Diabetes on top of stable dose of ACE/ARB

Human study

12 Weeks Rx

24 Weeks Rx

p=0.0702

p=0.0305

20

20

% Change

(95% CI) from Baseline in

Urinary Albumin Creatinine Ratio

↓33%

↓ 29%

0

0

-20

-20

-40

-40

Linagliptin

(n=157)

Placebo

(n=49)

Linagliptin

(n=163)

Placebo

(n=55)

Groop P-H et al: Diabetes 61 (Suppl 1):A243; 2012

albuminuria lowering by linagliptin is independent of glucose and blood pressure reduction
Albuminuria Lowering by Linagliptin is independent of Glucose and blood pressure reduction

Albuminuria-lowering effects of linagliptin are independent of BP reduction

Quartile of HbA1c Reduction from Baseline

>1.1%

(n=37)

0.1 - 0.63%

(n=44)

0.63 - 1.1%

(n=41)

% Change

(95% CI) from Baseline to Week 24 in

Urinary Albumin Creatinine Ratio

-25%

-32%

-36%

*

*

*

* Significant change versus baseline after 24 weeks of Rx

  • The renoprotective effects of linagliptin may be due to the
    • Inhibition of podocyte damage
    • Inhibition of myofibroblast transformation
    • Increased GLP-1 receptor expression in the kidney

Groop P-H et al: Diabetes 61 (Suppl 1):A243; 2012

composite of 6 predefined renal endpoints

Composite of 6 predefined renal endpoints: New Onset Micro-albuminuria, New Onset Macro-albuminuria, Increase in Serum Creatinine(increase to 2.8 mg/dl), Loss of baseline eGFR >50%, Acute renal failure, Death from any cause

HR = 0.84

(CI = 0.72-0.97)

(P = 0.02)

Incidence of renal events

Analysis of 13 studies

350

16% Lesser renal events with linagliptin

311

300

Incidence rate per 1000 patient-years

268

250

200

Placebo

Linagliptin

N = 1961

N = 3505

Cooper ME et al. Am J Kidney Dis. 2015 May 7. pii: S0272-6386(15)00604-6. doi: 10.1053/j.ajkd.2015.03.024. [Epub ahead of print]

linagliptin majority were reduction in new onset m icro albuminuria
Linagliptin: Majority were Reduction in New Onset micro-albuminuria

Linagliptin treatment significantly reduced the hazard of new onset of Micro-albuminuria by 18%

(HR=0.82; 95% CI, 0.69-0.98; P = 0.03)

Linagliptin may have the potential to slow CKD progression in T2DM1

1. Cooper ME et al. Am J Kidney Dis. 2015 May 7. pii: S0272-6386(15)00604-6. doi: 10.1053/j.ajkd.2015.03.024. [Epub ahead of print]

slide27
CARMELINA™and MARLINA-T2D™are ongoing studies that will provide insight into the effects of linagliptin on the renal system

1

2

Efficacy

CV and renal microvascular outcome

Trial type

Comparator

Placebo

Placebo

T2D patients with vascular complications and albuminuria or renal-related end-organ damage

Population

T2D patients with albuminuria on ACE inhibitor or ARB

  • Time to first occurrence of primary CV composite endpoint*
  • Time to first occurrence of renal composite endpoint**

1. Change from baseline in HbA1c at Week 24

2. Time-weighted average of percentage change from baseline in UACR at Week 24

Endpoint measures

*Cardiovascular (CV) composite endpoint: CV death (including fatal stroke and fatal myocardial infarction [MI]); non-fatal MI; non-fatal stroke; hospitalization for unstable angina pectoris.

**Renal composite endpoint: renal death; sustained end-stage renal disease; sustained decrease of ≥ 50% estimated glomerular filtration rate.

ACE, angiotensin-converting-enzyme; ARB, angiotensin receptor blocker; HbA1c, glycosylated hemoglobin; T2D Type 2 Diabetes; UACR, urine albumin creatinine ratio.

Source: 1. ClinicalTrials.gov. NCT01897532. Available at: https://clinicaltrials.gov/ct2/show/NCT01897532?term=CARMELINA&rank=1. Accessed 1 April 2015; 2. ClinicalTrials.gov NCT01792518. Available at: https://clinicaltrials.gov/ct2/show/NCT01792518?term=MARLINA&rank=1. Accessed 1 April 2015.

slide29
Empagliflozin caused a clinically significant reduction of microalbuminuria when added to standard therapy

Change in gMean UACR versus placebo at Week 24

Empagliflozin

p = 0.004 vs placebo

p < 0.001 vs placebo

CI, confidence interval; gMean, geometric mean; UACR, urine albumin creatinine ratio (median).

Adjusted mean based on analysis of covariance with last observation carried forward imputation in patients who received ≥ 1 dose of study drug, who had a baseline and on-treatment UACR measurement. Source: Cherney D, et al. ADA 2014, Poster 1125-P.

a reduction in albuminuria has been observed across the sglt2 inhibitor class
A reduction in albuminuria has been observed across the SGLT2 inhibitor class

Canagliflozin

(52 weeks; n = 269)

Median percentage change in UACR from baseline (%)1

Dapagliflozin

(104 weeks; n = 252)

Mean change in UACR from baseline (mg/g)3

Canagliflozin

Dapagliflozin

Placebo

(n = 90)

100 mg

(n = 90)

300 mg

(n = 89)

Placebo

(n = 84)

5 mg

(n = 83)

10 mg

(n = 85)

69.7

78.0

–11.69

–29.9

–20.9

–7.5

SGLT2, sodium glucose cotransporter 2; UACR, urinary albumin creatinine ratio.

Source: 1. Yale JF, et al. Diabetes Obes Metab. 2013;15:463–73; 2. Cefalu WT, et al. Lancet. 2013;382:941–50; 3. Kohan DE, et al. Kidney Int. 2014;85:962–71.