The incidence of Chronic KidneyDisease[ CKD ] has reached epidemic proportions. Diabetes tops the list of causes of CKD.Both hypo and hyperglycemia can complicate advanced renal disease. The topic is discussed in this presentation
3. AALLLL ppaattiieennttss wwiitthh DDiiaabbeetteess aanndd
PPrrootteeiinnuurriiaa//RReennaall ffaaiilluurree hhaavvee
ddiiaabbeettiicc rreennaall ddiisseeaassee ..
You may be wrong 50% of the
times !
3
Common Pitfall
28. MMAALLAA-- MMeettffoorrmmiinn AAssssoocciiaatteedd
LLaaccttiicc AAcciiddoossiiss
• Decreased Utilisation vs hepatic dysfn
ANAEROBIC
GLYCOLYSIS
SHOCK STATES
LIVER DYSFN
TYPE B
METFORMIN
Balance
•2-10 per 100,000 patients receiving metformin /year
•MALA accounts for 0.1-1% total patients admitted to ICU
•Mortality is high – 30-50%
30. HHyyppootteennssiioonn rraatthheerr tthhaann
mmeettffoorrmmiinn lleevveell wwhhiicchh
ddeetteerrmmiinneedd LLaaccttaattee aaccccuummuullaattiioonn
30
Conclusion from this
study
38. Drug exposure(AUC) in renal impairment ccoommppaarreedd ttoo ppaattiieennttss
wwiitthh nnoorrmmaall rreennaall ffuunnccttiioonn
Drug Mild RI Moderate RI Severe RI Hemodialysis
Metformin NA NA NA NA
Glibenclamide
NA NA -45% NA
M1+M2
Glimepiride
M2
NA -55%
+100%
-55%
+400%
NA
Repaglinide NA +19% +32% +32%
Pioglitazone NA -17% to -43% 17% to -43% NA
Sitagliptin +61% +126% +277% +350%
Vildagliptin +40% +71% +100% NA
Saxagliptin
+16%
+41%
+108%
NA
(Active
+67%
+192%
+347%
NA
metabolite)
Alogliptin +70% +110% +220% +280%
Linagliptin +29% +56% +41% +54%
Exenatide -19% -3% NA +227%
A.J Scheen. Expert Opinion on Drug Metabolism and Toxicology: 2013
39. Linagliptin in a recent study lowered aallbbuummiinnuurriiaa oonn ttoopp ooff
ssttaannddaarrdd AACCEEii//AARRBB tthheerraappyy iinn ppaattiieennttss wwiitthh TT22DDMM
Albuminuria Lowering by Linagliptin is independent of the Improvement in Glucose
Linagliptin significantly lowers albuminuria on top of recommended
standard treatment for diabetic nephropathy
24 weeks’ treatment
Effect of linagliptin on albuminuria in humans*
Adjusted mean change in albuminuria
(24 weeks)1
Placebo Linagliptin
24 weeks’ treatment
Effect of linagliptin on albuminuria in humans*
Adjusted mean change in albuminuria
(24 weeks)1
Placebo Linagliptin
-29% in albuminuria vs placebo
after 24 weeks’ treatment**
potential for additional kidney benefit
Proven renal safety with potential for additional kidney benefit
1. Inclusion criteria: Stable ACE/ARB background; albuminuria 30-3000 mg/g creatinine; GFR > 30.
*Albuminuria-lowering evidence for linagliptinwill emerge from MARLINA 1218.89.
**ADA 2012, 953-P
39
n
95% CI
59
-20%, +23%
168
-42%, -22%
-4%
-33%
-29%
p < 0.05
Albuminuria:
Early marker for renal damage
Marker for endothelial dysfunction
Cardiovascular risk factor
Lowering of albuminuria is associated with
kidney & CV protection
Definitions
Microalbuminuria
UACR ≥ 30 mg/g creatinine < 300 mg/g
creatinine
Macroalbuminuria
UACR ≥ 300 mg/g creatinine
-29% in albuminuria vs placebo
after 24 weeks’ treatment**
– Mean GFR remains unchanged after treatment initiation with linagliptin up
to 24 weeks
-29% in albuminuria vs placebo
after 24 weeks’ treatment**
lowers albuminuria on top of recommended
diabetic nephropathy
ACE/ARB background; albuminuria 30-3000 mg/g creatinine; GFR > 30.
lowering evidence for linagliptinwill emerge from MARLINA 1218.89.
**ADA 2012, 953-P
n
95% CI
59
-20%, +23%
168
-42%, -22%
-4%
-33%
-29%
p < 0.05
-29% in albuminuria vs placebo
after 24 weeks’ treatment**
unchanged after treatment initiation with linagliptin up
Possible mechanism: The reno-protective
effect of linagliptin as
studies in preclinical model
Inhibition of podocyte damage and
Inhibition of myofibroblast
transformation
Increased GLP-1 receptor
expression
43. CCaassee HHiissttoorryy
• 67 yrs old male in altered sensorium
• Type 2 Diabetes, CAD
• On OHA for the past 5 y
• Fever,Dysuria – 7 d
• Pain abdoment -1 d
• Altered sensorium – 12 h
• On Glimepride, Metformin ,Metoprolol,
Losartan, eplerenone,Asprin,atorvastatin
55. HHeemmooddiiaallyyssiiss ffoorr sseevveerree
hhyyppeerrggllyycceemmiiaa iinn CCKKDD
55
Extreme hyperglycemia with ketoacidosis and hyperkalemia
in a patient on chronic hemodialysis.Hemodial Int. 2008 Oct ;
12 Suppl 2:S43-7.
57. CCAAPPDD ppaattiieenntt
• Dialysate contains
• Glucose in high
• Concentration
• Hyperglycemia
severe and common
57
58. IIccooddeexxttrriinn uussee iinn ddiiaabbeettiicc ppaattiieenntt
• Icodextrin is
Polymer of Glucose
• False high reading of
Blood Glucose if
• GDH/PQQ strips
are used
• Risk of iatrogenic
hypoglycemia due to
misdiagnosis and
over reaction
58
Slide 44, 45: Drug exposure (AUC) in renal impairment compared to patients with normal renal function
The table summarizes the risk of supratheurapeutic levels of different oAD in different levels CKD. And thus requiring dose modification based on creatinine clearence.
In retrospective pooled analysis of type 2 DM patients with evidence of albuminuria, 80% being microalbuminuria. Linagliptin showed 29% RRR in albuminuria compared to placebo on top of the recommended ACE I/ARB therapy at the end of 24 weeks, this indicate potential for additional kidney benefit with renal safety.
Slide 41: Linagliptin in a recent study lowered albuminuria on top of standard ACEi/ARB therapy in patients with T2DM
This reduction in MA was rapid compared to the structural changes that can be appreciated. The reduction was independent of Blood pressure and blood glucose control.