1. Minding the Kidney in t2dm

2. 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

3. 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)
Markers of kidney damage (one or more)
Albuminuria (AER >30 mg/24 hours; ACR >30 mg/g [>3 mg/mmol])
Urine sediment abnormalities
Electrolyte and other abnormalities due to tubular disorders
Abnormalities detected by histology
Structural abnormalities detected by imaging
History of kidney transplantation
Decreased GFR
GFR <60 ml/min/1.73 m2 (GFR categories G3a–G5)
Kidney International Supplements (2013) 3, 5–14; doi: /kisup

4. Slide 5: What is CKD?
Myth in general is that CKD means renal failure.
Chronic kidney disease (CKD) comprises a spectrum of different pathophysiological processes associated with abnormal kidney function and a progressive decline in glomerular filtration rate (GFR).
CKD includes 5 stages: The term chronic renal failure applies to the process of continuing significant irreversible reduction in nephron number and typically corresponds to CKD stages 3–5.
Early intervention can make a difference.

5. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee

6. 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:

7. Kidney Disease in Diabetes: a silent killer ?
No signs or symptoms until >70% of kidney function is lost1,2
CVD risk equivalent. 3
Serum creatinine rises only if >50% of renal function is already lost4
50% of beta cell function may be lost at diagnoses in T2DM What about renal function at baseline?
PCPs screen only 20% of their diabetic patients for kidney disease
Hypoglycemia worsens in kidney impairment
-- if >50% of kidney function is lost, the risk of dying from a cardiovascular event is similar to that of having had a heart attack
All patients with T2D are at risk of declining renal function (by the nature of the disease)
Diabetes patients are much more likely to experience hypoglycaemic side effects with their medication if they also had chronic kidney disease.
Type 2 diabetes is a major risk factor for cardio-renal dysfunction.
Cardio-renal dysfunction can be generally defined as a pathophysiological disorder of the heart and kidneys whereby acute or chronic dysfunction of one organ may induce acute or chronic dysfunction of the other.
Among patients with both CKD and diabetes, the rate of CV events is more than twice the rate among patients with diabetes alone.
Often, symptoms may not occur until more than 70% of kidney function is lost.
Microalbuminuria (albumin excretion above the normal range but below the level of detection by tests for total protein) is a sensitive indicator
of CKD in people with diabetes, and indicates an increased risk of micro and macro vascular disease that requires aggressive intervention
Microalbuminuria is important for physicians for two reasons:
1- This is the earliest point in time that you can identify declining renal function and
2- CV risk
Early intervention is desirable as it allows us to control the progression of albuminuria.
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,
4. Jemel A et al., CA Cancer J Clin. 2007;57;43–66.

8. Albuminuria and reduced GFR: 2 manifestations of nephropathy in T2DM
Adapted from de Boer. IH, Steffer MW. J Am Soc Nephrol. 2007; 18:

9. 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 ( ml/min)
Normal: >90
Mild RI: 60 – 90,
Moderate: 30-60
Severe: < 30
S. Creatinine
Male:
Female:

10. CKD prevalence-India 5 True burden of CKD is higher by 5 fold
MIND - cross sectional, multi-centre, observational study conducted at 6 sites across India
Patient having raised creatinine (>1.1 mg/dl) = 8.4%
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
Bharti Hospital, Karnal, Haryana; Excel Care Hospitals, Guwahati, Assam; Private Clinic, Hyderabad, Andhra Pradesh; Diabetes, Obesity, and Thyroid center, Gwalior, Madhya Pradesh; Department of Endocrinology, Osmania Medical College, Hyderabad, Andhra Pradesh; Department of Endocrinology, KEM Hospital, Parel, Mumbai, Maharashtra. 5
8.4%
Raised
Ser. Creat. (N=82)
Rasied ser. Creat >1.1 mg/dl
Sahay R et al. Diabetes Research and Clinical Practice-volume106, supplement-1. PO162.

11. DPP4I in Renal Impairment

12. Fold increase in exposure relative to normal renal function
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
(n = 6)
> 80
50 to ≤ 80
30 to ≤ 50
< 30
< 30 on HD
Renal impairment status
Creatinine clearance1 (mL/min)
Fold increase in exposure relative to normal renal function
Linagliptin
ESRD
Severe
Moderate
Mild
Normal
(n = 8)
> 50 to ≤ 80
>30 to ≤50
<30
on HD
Saxagliptin
(5-hydroxy saxagliptin metabolite)2
Sitagliptin
Vildagliptin
(LAY151 metabolite)3
1. Estimated creatinine clearance values were calculated using the Cockcroft-Gault formula % 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. Diabetes Obes Metab. 2011;13:939–946.

13. No dose adjustment in renal disease: is it of clinical relevance?

14. Renally excreted drugs (sitagliptin/metformin) were found to be dosed inappropriately in real world data from the US
Large OPD electronic record survey for T2 DM patients with RI to look at the rates of diagnosis and medication dose adjustment as per the stage of the disease. (USA)
Juliana Meyers et al. Postgraduate Medicine, Vol 123, issue 2, 2011

15. 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

16. 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)
Real world data from US shows that 85% T2DM patients on sitagliptin were on inappropriate dose as per their renal function. Similar data has come from the UK database showing that 20-25% patients were on full dose of sita, vilda and saxagliptin even in patients with moderate renal impairment. We do not have such data from India. But we expect to see a similar scene in our country too. To complicate further, an Indian T2DM patients don’t consider T2DM as a serious disease and don’t F/U with their physicians, and the prevalence is as high as 41%.
Please take an opinion of audience on these 2 issues. Question : Do you think dose adjustment in CKD patients is a challenge and is not as easy as it is perceived?
If asked, remember that in DEDICOM study, no renal impairment patients were included.
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): , Nagpal J et al. Diabetes Care. 2006; 29:2341–2348.

17. Albuminuria as predictor of CV mortality in the general population
Risk of CV mortality (HR)
Albumin concentration (mg/L) 1 2 3 4 5 10
100
1000
N=40.856
The hazard ratio for cardiovascular mortality in the group of 40,856 subjects shows a splay, without a specific cut-off value above which the risk is increased. For every doubling of UAC the risk for dying is increased 1.29fold. From Hillege HL et al. Circulation 2002;106:
Hillege et al; Circulation 2002;106:

18. Albuminuria is a risk factor for kidney disease
Risk of developing sustained eGFR < 60 mL/min/1.73 m2 *
Hazard ratio (95% CI) *
Approval date:
Review date:
Slide objective
To discuss albuminuria as a risk factor for kidney disease
Key points
Analysis on a subgroup of patients from the Epidemiology of Diabetes Interventions and Complications (EDIC) study/Diabetes Control and Complications Trial (DCCT) show that the presence of current micro- and macroalbuminuria (n = 18 and n = 41, respectively) was associated with a significant annual decrease in estimated glomerular filtration rate (eGFR) (microalbuminuria – hazard ratio [HR]: 1.8, confidence interval [CI]: 1.6–1.9, p < ; macroalbuminuria – HR: 5.7, 95% CI: 4.5–6.8, p < ), compared with patients with normal albumin excretion rates (AER; n = 30)
The findings provide support for albuminuria as a risk factor for kidney disease
Slide background
Study objective: To examine the impact of AER on eGFR, and the incidence of sustained eGFR < 60 mL/min/1.73 m2 in patients with Type 1 Diabetes (T1D)
Study design: A multicenter study on 1,439 patients with T1D of up to Year 14 of the EDIC study (mean duration of 19 years in the DCCT/EDIC). Urinary albumin measurements from 4-hour urine collections were obtained from participants annually during the DCCT and the EDIC (half of the cohort each year). Serum creatinine was measured annually in both the DCCT and EDIC study. GFR was estimated from serum creatinine using the abbreviated Modification of Diet in Renal Disease equation
Key findings: A total of 89 participants developed an eGFR < 60 mL/min/1.73 m2 (patients who had stage 3 chronic kidney disease [CKD] on two or more successive occasions [sustained] during the DCCT/ EDIC study; cumulative incidence of 11.4% at 23 years). Of these, 20 patients (24%) had AER < 30 mg/24 h at all prior evaluations, 14 (16%) had developed microalbuminuria (AER 30–300 mg /24 h) before they reached Stage 3 CKD, and 54 (61%) had macroalbuminuria (AER >300 mg/24 h) before they reached stage 3 CKD. Macroalbuminuria is associated with a significant increased rate of eGFR decline (5.7% compared with 1.2% per year with patients with AER < 30 mg/24 h; p < ), and risk of eGFR < 60 mL/min/1.73 m2 (adjusted HR: 15.3; p < ). Microalbuminuria had weaker and less consistent effects on eGFR
Overall study conclusion: Macroalbuminuria was a strong predictor of eGFR loss and risk of developing sustained eGFR < 60 mL/min/1.73 m2
Reference
Molitch ME, Steffes M, Sun W, et al. Development and progression of renal insufficiency with and without albuminuria in adults with Type 1 Diabetes in the diabetes control and complications trial and the epidemiology of diabetes interventions and complications study. Diabetes Care. 2010;33:1536–43.
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 < versus normal.
CI, confidence interval; eGFR, estimated glomerular filtration rate.
Molitch ME, et al. Diabetes Care. 2010;33:1536–43.

19. 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*
N = 10,640
300 30 3
0.25
0.5
1.0
2.0
4.0
8.0
16.0
32.0
p for trend <
Every 10-fold increment in baseline UACR
HR: 3.27 (95% CI: 2.09–5.11)
After correcting regression dilution bias
HR: (95% CI: 4.31–25.49)
Baseline UACR (mg/g)
HR (95% CI)
Approval date:
Review date:
Slide objective
To highlight that albuminuria is a risk factor for renal events
Key points
Patients with a higher baseline urinary albumin creatinine ratio (UACR) level were associated with an increased risk of renal events in a log-linear fashion (n = 10,640; hazard ratio [HR]: 3.27; 95% confidence interval [CI]: 2.09–5.11; probability for trend < ), where every 10-fold increment in baseline UACR corresponds approximately to a change from one clinical stage of albuminuria to the next
This risk increases 10.5-fold following the correction for regression dilution bias (HR: 10.48; 95% CI: 4.31–25.49)
Slide background
Study objective: To explore whether albuminuria and a reduced estimated glomerular filtration rate (eGFR) are separate and independent risk factors for cardiovascular (CV) and renal events in patients with Type 2 Diabetes (T2D). Specifically, the effects of UACR and eGFR on the risk for CV and renal events were examined
Study design: An observational study conducted on 10,640 patients with T2D from the Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE) study, which originally examined the effects of routine blood pressure-lowering on adverse outcomes in these patients. UACR and eGFR on the risk for CV and renal events were evaluated with available data
Key findings: Of the patients, 8.8% (n = 938) experienced a CV event, and 1.0% (n = 107) experienced a renal event during an average 4.3-year follow-up. The multivariable-adjusted HR for CV events was 2.48, with a 95% CI of 1.74–3.52 for every 10-fold increase in baseline UACR, and HR of 2.20 with 95% CI of 1.09–4.43 for every halving of baseline eGFR, following the adjustment for regression dilution. There was no evidence of interaction between the effects of higher UACR and lower eGFR. Patients with both a baseline UACR > 300 mg/g and eGFR < 60 mL/min/1.73 m2 had a 3.2-fold higher risk for CV events, as well as a 22.2-fold higher risk for renal events, compared with patients with neither of these risk factors.
Overall study conclusion: High albuminuria and low eGFR are independent risk factors for CV and renal events among patients with T2D
Reference
Ninomiya T, Perkovic V, de Galan BE, et al. Albuminuria and kidney function independently predict cardiovascular and renal outcomes in diabetes. J Am Soc Nephrol. 2009;20:1813–21.
*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.

20. Evidence for potential renal benefits with DPP4I

21. 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 = )
–20.6 ± 24.6 mg/g
creatinine in patients with normo-, micro-, and macroalbuminuria
Reduce development and progression of microalbuminuria compared with placebo
Slide objective
To provide a summary of evidence of potential renal benefits reported for other dipeptidyl peptidase-4 (DPP-4) inhibitors
Key points
Clinical evidence for potential benefits associated with DPP-4 inhibitors are limited1
A small study conducted on 40 patients with Type 2 Diabetes (T2D) show that treatment with sitagliptin (50 mg/day) for 24 weeks caused a significant reduction in urinary albumin creatinine ratio (UACR; change in UACR from before sitagliptin treatment: –20.6 ± 24.6 mg/g) compared with UACR before sitagliptin treatment (change in UACR from baseline: 2.3 ± 19.9 mg/g; p = )2
Of these patients with significant reduction in UACR with sitagliptin, 13 patients with normoalbuminuria had a reduction in UACR from 11.6 ± 8.4 mg/g to 4.5 ± 5.0 mg/g (p = ), 11 patients with microalbuminuria had a reduction from 98.4 ± 79 mg/g to 24.9 ± 20 mg/g (p = ), while 6 patients with macroalbuminuria had a reduction from 1,263 ± 492 mg/g to 561 ± 89 mg/g (p = )2
In the SAVOR-TIMI 53 trial, treatment with saxagliptin (5 mg/day) reduced the development and progression of microalbuminuria compared with placebo3
Significant proportion of patients had a reduction in the development/progression of UACR following 1 year of treatment with saxagliptin (n = 13,184; p < 0.001): 78.8% (n = 5,244) showed no change in UACR, while 11.8% (n = 782) showed improvement in UACR, compared with placebo (no change: 78.9% [n = 5,155], improvement: 9.6% [n = 628])3
Significant proportion of patients had a reduction in the development/progression of UACR following 2 years of treatment with saxagliptin (n = 6,553; p = ): 76.4% (n = 2,550) showed no change in UACR, while 11.1% (n = 372) showed improvement in UACR, compared with placebo (no change: 76.6% [n = 2,465], improvement: 9.2% [n = 295])3
Significant proportion of patients had a reduction in the development/progression of UACR following saxagliptin at the end of treatment (n = 12,360; p < 0.001): 76.0% (n = 4,762) showed no change in UACR, while 10.7% (n = 670) showed improvement in UACR, compared with placebo (no change: 75.4% [n = 4,594], improvement: 8.7% [n = 532])3
Slide background
Small study on sitagliptin’s effect on albuminuria2
Study objective: To investigate the effects of sitagliptin on albuminuria in patients with T2D
Study design: Forty patients with T2D were enrolled in the study. All patients had a glycosylated hemoglobin (HbA1c) level > 6.5% despite receiving education on diet and exercise, and pharmacological therapy for the management of their disease for at least 6 month prior to entering the study. All patients were treated with sitagliptin (50 mg/day) for 24 weeks
Study measurements: Fasting blood glucose, postprandial blood glucose, HbA1c, glycated albumin, UACR, highly sensitive C-reactive protein (hsCRP), and soluble vascular cell adhesion molecule 1 (sVCAM-1)
Other key findings: Significant reductions in blood pressure, fasting blood glucose, postprandial blood glucose, HbA1c, glycated albumin at the 3- and 6-month mark following treatment with sitagliptin. There were also significant reductions in hsCRP and sVCAM-1 following 6 months of sitagliptin treatment (p < for all measurements mentioned in other key findings)
Conclusion: Findings provide some evidence for sitagliptin in reducing albuminuria without lowering the estimated glomerular filtration rate
SAVOR-TIMI 533
Study objective: To determine whether saxagliptin can reduce the risk of cardiovascular (CV) events when used alone, or added to other diabetes medications
Study design: Randomized, double-blind, placebo-controlled study with a total of 16,492 patients with T2D, a history of CV events, or with CV risk. A total of 8,280 patients were allocated to the saxagliptin arm, while 8,212 patients were in the placebo group. The primary endpoint for this study was time to first occurrence of the primary composite endpoint, which consists of CV death, non-fatal myocardial infarction (MI), or non-fatal stroke. Study was conducted in 26 countries
Key findings: Primary endpoint event occurred in 613 patients in the saxagliptin group and in 609 patients in the placebo group (7.3% and 7.2%, respectively). Results demonstrated non-inferiority of saxagliptin against placebo for the primary endpoint, but did not show superiority of the drug compared with placebo (2-year Kaplan–Meier estimates – hazard ratio [HR]: 1.00; 95% confidence interval [CI]: 0.89–1.12; p = 0.99 for superiority; p < for non-inferiority). The results were similar in the “on-treatment” analysis (HR: 1.03; 95% CI: 0.91–1.17). The major secondary endpoint of a composite of CV death, MI, stroke, hospitalization for unstable angina, coronary revascularization, or heart failure occurred in 1,059 and 1,034 patients with saxagliptin and placebo, respectively (12.8% and 12.4%, respectively, 2-year Kaplan–Meier estimates – HR: 1.02; 95% CI: 0.94–1.11; p = 0.66). A significantly greater number of patients were hospitalized for heart failure (3.5% vs 2.8%; HR: 1.27; 95% CI: 1.07–1.51; p = 0.007) in the saxagliptin group compared with those in the placebo group. Rates of adjudicated cases of acute and chronic pancreatitis were similar in the two groups (acute pancreatitis: 0.3% and 0.2% for the saxagliptin and placebo groups, respectively; chronic pancreatitis: < 0.1% and 0.1% for the saxagliptin and placebo groups, respectively).
Conclusion: Saxagliptin did not increase or decrease the rate of ischemic events, but increased the rate of hospitalization for heart failure. Other approaches are required to reduce CV risk in patients with T2D despite saxagliptin’s ability to improve glycaemic control
References
Schernthaner G, Morgensen CE, Schernthaner G-H. The effects of GLP-1 analogues, DPP-4 inhibitors and SGLT2 inhibitors on the renal system. Diab Vasc Dis Res. 2014;11:306–23.
Hattori S. Sitagliptin reduces albuminuria in patients with Type 2 Diabetes. Endocr J. 2011;58:69–73.
Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with Type 2 Diabetes Mellitus. N Engl J Med. 2013;369:1317–1326.
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– Scirica BM, et al. N Engl J Med. 2013;369:1317–26 (also see supplementary materials).

22. Sitagliptin : Vildagliptin : Saxagliptin :
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),
Mori et al. J Diabetes Invest 2014; 5: 313–319
Watanabe.
Scirica BM et al. NEJM DOI: /NEJMoa

23. Urinary Albumin Creatinine Ratio
The DPP-4 Inhibitor Linagliptin Reduces Albuminuria in Patients with Diabetes on top of stable dose of ACE/ARB
Human study 20
-20
-40
% Change
(95% CI) from Baseline in
Urinary Albumin Creatinine Ratio
12 Weeks Rx
24 Weeks Rx
Linagliptin
(n=157)
Placebo
(n=55)
(n=163)
(n=49)
p=0.0702
p=0.0305
↓ 29%
↓33%
Groop P-H et al: Diabetes 61 (Suppl 1):A243; 2012

24. Albuminuria Lowering by Linagliptin is independent of Glucose and blood pressure reduction
Quartile of HbA1c Reduction from Baseline
Albuminuria-lowering effects of linagliptin are independent of BP reduction
Linagliptin (n=168)
Placebo (n=59)
eGFR (MDRD), mL/min/1.73m2, mean change ± SD
Week 24
Last value on
treatment
–1.50 ± 15.9
–1.24 ± 15.5
–2.29 ± 19.9
–1.38 ± 19.5
SBP, mm Hg, mean change ± SD
–0.59 ± 17.0
–1.82 ± 13.6
DBP, mm Hg, mean change ± SD
0.59 ± 9.5
–1.75 ± 9.9 %
(n=44) %
(n=41)
>1.1%
(n=37)
-25%
-36%
-32%
% Change
(95% CI) from Baseline to Week 24 in
Urinary Albumin Creatinine Ratio * * *
* 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

25. Incidence of renal events 16% Lesser renal events with linagliptin
HR = 0.84
(CI = )
(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
Here is another data with respect to linagliptin where it has been shown that there were lesser new onset micro-albuminuria in linagliptin arm vs placebo. This is a metanalysis of 13 linagliptin studies vs. placebo, were > 50% patients had normal kidney function. We can see that there were 16% lesser renal events in linagliptin arm as compared to placebo. Renal events were defined as New onset of microalbuminuria, new onset of macroalbuminuria,
new onset of CKD, worsening of CKD. Out of these, majority contribution was by reduction in new onset micro-albuminuria.
200
Placebo
Linagliptin
N = 1961
N = 3505
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
Cooper ME et al. Am J Kidney Dis May 7. pii: S (15) doi: /j.ajkd [Epub ahead of print]

26. 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, ; P = 0.03)
Linagliptin may have the potential to slow CKD progression in T2DM1
1. Cooper ME et al. Am J Kidney Dis May 7. pii: S (15) doi: /j.ajkd [Epub ahead of print]

27. CARMELINA™ and MARLINA-T2D™ are ongoing studies that will provide insight into the effects of linagliptin on the renal system 1 2
Trial type
CV and renal microvascular outcome
Efficacy
Comparator
Placebo
Placebo
Population
T2D patients with vascular complications and albuminuria or renal-related end-organ damage
T2D patients with albuminuria on ACE inhibitor or ARB
Endpoint measures
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
Slide objectives
To highlight that most dipeptidyl peptidase-4 (DPP-4) inhibitors had been, or are currently being studied for cardiovascular (CV) safety
To provide an overview of their study designs to distinguish similarities and differences
Key points
CARMELINA and MARLINA-T2D are ongoing large clinical trials that will provide insight into the effect of linagliptin on the renal system1,2 CARMELINA will examine CV and renal microvascular outcomes, while MARLINA-T2D will investigate drug efficacy in a specific group of patients with Type 2 Diabetes (T2D) and renal impairment1,2
CARMELINA comprises patients with vascular complications and albuminuria, or renal-related end-organ damage, while those in MARLINA-T2D have albuminuria and are currently on an angiotensin-converting-enzyme inhibitor or angiotensin receptor blocker1,2
Although not the primary outcome measure in these studies, CARMELINA will examine time to first occurrence of a composite renal endpoint of renal death, end-stage renal disease, or sustained decrease ≥ 50% in estimated glomerular filtration rate following 48 months of linagliptin treatment, while MARLINA-T2D will investigate the time-weighted average of percentage change from baseline in urinary albumin creatinine ratio following 24 weeks of linagliptin treatment1,2
Slide background
CARMELINA1
Study objective: To investigate the long-term impact of linagliptin on CV morbidity, mortality, and renal function in a selected population of patients with T2D, and to compare outcomes against placebo, on a background of standard of care
Study design: Randomized, double-blind, placebo-controlled trial with an estimated enrolment of 8,300 patients
Study status: Ongoing (estimated completion date: January 2018)
MARLINA-T2D2
Study objective: To evaluate the effect of linagliptin on glycaemic control and renal efficacy following 24 weeks of treatment
Study design: Randomized, double-blind, placebo-controlled trial with an estimated enrolment of 404 patients
Study status: Ongoing (estimated completion date: December 2015)
References
ClinicalTrials.gov. NCT Available at:
ClinicalTrials.gov NCT Available at:
*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. NCT Available at: Accessed 1 April 2015; 2. ClinicalTrials.gov NCT Available at: Accessed 1 April 2015.

28. Looking ahead: Potential renal benefits with SGLT2 inhibitors

29. Change in gMean UACR versus placebo at Week 24
Empagliflozin caused a clinically significant reduction of microalbuminuria when added to standard therapy
Change in gMean UACR versus placebo at Week 24
Empagliflozin
Slide objective
To highlight the positive renal effects associated with empagliflozin
Key points
The graph shows the effect of empagliflozin (10 mg [n = 141] and 25 mg [n = 150]) on the change in urinary albumin creatinine ratio (UACR) from baseline compared with placebo (n = 147) at Week 24 in patients with Type 2 Diabetes (T2D) and microalbuminuria
Empagliflozin 10 mg resulted in a significant reduction in UACR from baseline when compared with placebo (percentage difference versus placebo: 30%; p < 0.001)
Empagliflozin 25 mg also caused a significant reduction in UACR from baseline when compared with placebo (percentage difference versus placebo: 25%; p = 0.004)
Results were from a pooled analysis of data from four Phase 3, randomized, controlled trials with empagliflozin
Slide background
A pooled analysis of four randomized Phase 3 trials in patients with T2D aged > 18 years, with a body mass index ≤ 45 kg/m2, and glycosylated hemoglobin level 7–10%
A total of 2,477 patients were analyzed, who were treated with empagliflozin (10 or 25 mg) for 24 weeks as monotherapy or add-on therapy
A post hoc analysis of the efficacy and/or safety of empagliflozin 10 and 25 mg versus placebo in patients with T2D and pre-existing albuminuria:
microalbuminuria (UACR 30–300 mg/g) at baseline (n = 458; treated set)
macroalbuminuria (UACR ≥ 300 mg/g) at baseline (n = 73; treated set)
albuminuria (UACR ≥ 30 mg/g) at baseline (n = 511; treated set)
Reference
Cherney D, von Eynatten M, Lund S, et al. Sodium glucose cotransporter 2 (SGLT2) inhibition with empagliflozin (EMPA) reduces microalbuminuria in patients with Type 2 Diabetes (T2D). Poster number: 1125-P. Presented at the American Diabetes Association (ADA) 74th Scientific Session June 13–17, San Francisco, California.
Note: Data on the pooled analysis for patients with microalbuminuria were presented by Cherney and colleague at the 2014 American Diabetes Association Scientific Sessions. The remaining data are currently unpublished, and remain on Boehringer Ingelheim’s internal files
p = vs placebo
p < vs placebo
Mean baseline
64.6
69.3
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.

30. 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
Slide objective
To provide a summary of evidence of potential renal benefits reported for the three sodium glucose cotransporter 2 (SGLT2) inhibitors currently available in the market
Key points
Clinical evidence for potential benefits associated with SGLT2 inhibitors are limited, but had been shown in patients with Type 2 Diabetes (T2D) treated with canagliflozin, dapagliflozin, and empagliflozin1
A 52-week trial conducted on 269 patients with T2D showed that treatment with canagliflozin caused a reduction in mean percentage change in urinary albumin creatinine ratio (UACR) from baseline (100 mg canagliflozin: 29.9%; 300 mg canagliflozin: 20.9%) compared with placebo (0.7%)2
Another 52-week trial conducted on 1,450 patients with T2D showed that treatment with canagliflozin caused a reduction in mean change in UACR from baseline (100 mg canagliflozin: –0.1 g/mol; 300 mg canagliflozin: –0.9 g/mol). In contrast, the active comparator in this trial, glimepiride, resulted in an increase in mean change in UACR from baseline (0.7 g/mol)3
In a 104-week trial conducted on 252 patients with T2D, treatment with 10 mg dapagliflozin caused a reduction in mean change in UACR from baseline (–11.69 mg/g). In contrast, placebo and 5 mg dapagliflozin resulted in an increase in mean change in UACR (69.7 mg/g and 78.0 mg/g, respectively)3
Slide background
52-week trial with canagliflozin against placebo2
Study objective: To evaluate the efficacy and safety of canagliflozin in patients with T2D and Stage 3 chronic kidney disease
Study design: A randomized, double-blind, placebo-controlled, Phase 3 trial with a total of 269 patients assigned to 100 mg canagliflozin (n = 90), 300 mg canagliflozin (n = 89), and placebo treatment (n = 90), respectively
Primary endpoint: Change from baseline glycosylated hemoglobin (HbA1c) at Week 26
Key findings: Canagliflozin (100 and 300 mg) caused a significant reductions in HbA1c from baseline compared with placebo at Week 26 (–0.33, –0.44, and –0.03%, respectively; p < 0.05). Reductions were also observed in the fasting plasma glucose levels. There was a higher proportion of patients achieving HbA1c < 7.0% with canagliflozin 100 and 300 mg compared with placebo (27.3, 32.6, and 17.2%, respectively). Overall rates of adverse events were similar for canagliflozin (100 and 300 mg) and placebo (78.9, 74.2, and 74.4%, respectively), with slightly higher rates of urinary tract infections. There were transient changes in renal function parameters that trended towards baseline over 26 weeks of canagliflozin treatment
Conclusion: Findings show that canagliflozin improved glycaemic control, and was largely well tolerated in individuals with T2D and Stage 3 chronic kidney disease
52-week trial with canagliflozin against glimepiride3
Study objective: To compare efficacy and safety of canagliflozin compared with glimepiride in patients with T2D uncontrolled with metformin
Study design: A randomized, double-blind, placebo-controlled, Phase 3, non-inferiority trial with a total of 1,450 patients assigned to 100 mg canagliflozin (n = 483), 300 mg canagliflozin (n = 485), and placebo treatment (n = 482) respectively.
Primary endpoint: Change from baseline HbA1c to Week 52 with a non-inferiority margin of 0.3% for comparison of canagliflozin against placebo. Superiority was assessed if non-inferiority was demonstrated
Key findings: Canagliflozin 100 mg was non-inferior compared with glimepiride in lowering of HbA1c at 52 weeks (least-squares mean difference: –0·01%; 95% confidence interval [CI]: –0·11 to 0·09). Canagliflozin 300 mg was superior to glimepiride (least squares mean difference: –0·12%; 95% CI:–0·22 to –0·02). Of the patients, 8% (n = 39) had serious adverse events in the glimepiride group compared with 5% (n = 24) of those in the canagliflozin 100 mg group, and 5% (n = 26) in the 300 mg group. A greater incidence of genital mycotic infections were reported with canagliflozin 100 mg and 300 mg treatment compared with the placebo arm (women: 11% and 15%, respectively, compared with 2%; men: 7% and 8%, respectively, compared with 1%), urinary tract infections (6% for both canagliflozin doses compared with 5%), and osmotic diuresis-related events (pollakiuria: 3% for both doses compared with < 1%; polyuria: < 1% for both doses compared with < 1%)
Conclusion: Canagliflozin provides greater reductions in HbA1c levels compared with glimepiride. It is also well tolerated in patients with T2D receiving metformin
104-week trial with dapagliflozin against placebo4
Study objective: To evaluate the efficacy and safety of dapagliflozin in patients with T2D and moderate renal impairment
Study design: A randomized, double-blind, placebo-controlled, Phase 2/3 trial with a total of 252 patients assigned to 5 mg dapagliflozin (n = 83), 10 mg dapagliflozin (n = 85), and placebo treatment (n = 84), respectively.
Primary endpoint: Mean change from baseline HbA1c after 24 weeks of treatment
Key findings: Mean change in HbA1c levels was not statistically different for both doses of dapagliflozin compared with placebo after 24 weeks (0.41 [p = 0.561], 0.44 [p = 0.435], and 0.32% for 5 and 10 mg doses, and placebo, respectively). Dapagliflozin caused a reduction in weight from baseline (0.34 and 1.10 kg for 5 and 10 mg doses, respectively), while an increase in weight from baseline was reported in patients on placebo (2.63 kg). The mean systolic and diastolic blood pressure measurements decreased in patients following treatment with dapagliflozin compared with placebo. Dapagliflozin was associated with a higher incidence of genital and urinary tract infections compared with placebo. Across the 104 weeks of the study, 7.7% of patients receiving dapagliflozin experienced bone fracture, while none was reported for those receiving placebo. At 1 week of the study, the mean serum creatinine increased with dapagliflozin (0.13 and 0.18 mg/dL for 5 and 10 mg dapagliflozin, respectively), but remained unchanged throughout the rest of the study. Overall, no changes were observed across all groups with regard to mean serum electrolytes; however, there were fewer episodes of hyperkalemia reported with dapagliflozin than with placebo
Conclusion: Findings show that dapagliflozin did not significantly improve glycaemic control, but reduced weight and blood pressure in patients with T2D and moderate renal impairment
References
Schernthaner G, Morgensen CE, Schernthaner G-H. The effects of GLP-1 analogues, DPP-4 inhibitors and SGLT2 inhibitors on the renal system. Diab Vasc Dis Res. 2014;11:306–23.
Yale JF, Bakris G, Cariou B, et al. Efficacy and safety of canagliflozin in subjects with Type 2 Diabetes and chronic kidney disease. Diabetes Obes Metab. 2013;15:463–73.
Cefalu WT, Leiter LA, Yoon K-H, et al. Efficacy and safety of canagliflozin versus glimepiride in patients with Type 2 Diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet. 2013;382:941–50.
Kohan DE, Fioretto P, Tang W, et al. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int. 2014;85:962–71.
–7.5
–29.9
–20.9
–11.69
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.

31. Thank You