Dilemma of Treating Diabetes in CKD

1. Dilemma of treating
Diabetes in CKD!!!
Dr Sanjay Maitra
MD,DM(PGI,CHD)
Clinical Fellowship,Univ.of Toronto(CANADA)
Senior Consultant Nephrologist
Apollo Health City, Hyderabad

2. Damned if you do
&
Damned if you don’t!!!
Good Glycaemic Control vs Risk of Hypoglycaemia

3. Outline of talk
 Epidemiology –The Diabetes Pandemic
 Diabetes is the leading cause of CKD and ESRD
 CKD –a very frequent and under-recognised
complication of diabetes
 Patients of Type 2 DM and CKD are highest risk for
CAD and mortality
 How to detect diabetic kidney disease and CKD
 Good glycaemic control prevents progression of CKD
 The problems of diabetic control in CKD
 The options available

4. Epidemiology

5. India has around 61 Million diabetics

11. Diabetes as the leading cause of CKD and
ESRD

14. Stages of CKD according to the US National Kidney Foundation and
the Kidney Disease Outcomes Quality Initiative ; Modified by NICE

23. Incidence of CKD in India – 800 per million population
Incidence of ESRD in India- 150-200 per million population

25. Cross sectional study involving 52,273 patients
Mean age 50.1±14.6 yrs
M:F ratio 70:30
Diabetic nephropathy –commonest cause of CKD (31%)
CKD of unknown aetiology (16%)
CGN (14%)
Hypertensive nephrosclerosis (13%)

26. Diabetic Kidney Disease
Very often missed
Type 2 Diabetes is often missed initially in
many as it’s manifestations are non-specific
Early diabetic kidney disease including CKD
are missed in many as the presentation may
be non-specific

27. Diabetics likely to be detected early
Patients of unknown etiology are likely to be younger ,females and to have CKD-5
INDIAN CKD REGISTRY DATA-2012

28. How to detect diabetic kidney disease &
CKD?

36. Type 2 diabetes mellitus (T2DM) drives a network of vascular
risks. CHD = coronary heart disease; ESRD = end-stage renal
disease; LVD = left ventricular dysfunction.
Adapted from: Afghahi H, et al.[21]

44. Good glycaemic control prevents
progression of CKD

45. Carbohydrate and Insulin Metabolism
in CKD
In pts. with ESRD tissue insensitivity to insulin is
of primary importance
Alterations in insulin degradation and insulin
secretion also may contribute.
Dramatic reduction in insulin clearance
Concomitant decline in hepatic insulin metabolism.
Insulin secretion tends to be blunted.
Spontaneous hypoglycaemia may appear

47. Typical progression of diabetic kidney disease
• Exposure to diabetes is
required for diabetic
nephropathy to develop
in susceptible patients.
• The time at which the
complication becomes
clinically apparent and
the rate at which it
progresses is variable and
can be modified by
careful management of
glycemia, hypertension,
and hyperlipidemia.
• ESRD, End-stage kidney
disease.
47
Seaquist ER, Ibrahim HN. J Clin Endocrinol Metab. 2010 Jul;95(7):3103-10

55. Does Therapeutic intervention work?)

59. Problems of Diabetes control in CKD

68. Currently Available Classes of Anti-hypoglycaemic agents
Mech. Of action Classes of drugs
Insulin sensitizers Biguanides
Thiazolidinediones
Stimulators of Insulin secretion Sulphonylureas
Meglitinides
Decrease GI carbohydrate abs Acarbose
Stmulates Insulin
secretion,decreases glucagon
production, increases satiety
GLP-1 agonists
Decreases inactivation of
incretins(GLP-1)
DPP-4 inhibitors
SGLT-2 Inhibitors Prevent glucose re-absorption in
kidneys
Increases glucose utilisation Insulins

70. Biguanides : Metformin
Class Insulin sensitisers
Mech of action Acts on hepatic and muscle AMP activated Protein
Kinase
HbA1c Reduction 1-2%
Status Drug of choice for overweight Type 2 diabetics, Initial
monotherapy for De-novo Pts.
Advantages Weight neutral or promote weight loss
Low risk of hypoglycaemia
Small improvement in abnormal lipid profiles
Improves cardiac end points.
Side-Effects GI side-effects common
Lactic acidosis ,dangerous but rare
<1% incidence ,Mortality approx 30%
Renal failure increases the risk
Megaloblastic anemia rarely

71. Mechanism Of Action Of Metformin

72. Thiazolidinediones: Pioglitazone , Rosiglitazone
Class Insulin Sensitisers
Mech of action Selective agonists of peroxisomal proliferator activated
receptor gamma (PPAR-λ)
Are Prandial glucose regulators
Improve insulin sensitivity in adipose tissue,muscle &
Liver
HbA1c Reduction 0.5-1.0% , control better in long term
Advantages Pioglitazone has better cardiac outcomes in e-GFR <60
ml/min
Side Effects Fluid retention ,GI side effects, fractures in women
Use with caution in e-GFR<30ml/min, CHF
In Dialysis patients Use Pioglitazone with caution, Rosiglitazone not at all
Rosiglitazone Under surveillance for causing increased heart failure
and AMI

73. Sulphonylureas :Glipizide,Gliclazide,Glimepiride
Mech of action Stimulation of insulin secretion from β cells of
Pancreas
HbA1C Reduction 1-2%
Advantage Cheap, easily available
Side effects Weight gain, hypoglycaemia which can be severe at
times
Limitations Significant secondary failure rates
50% needed insulin by 6 yrs in one study
Worse CVS outcomes as compared to metformin
Unsuitable for severe hepatic failure patients also
Renal status Only newer 2nd generation meds like glipizide,
gliclazide and glimeperide are suitable for use
Glipizide(GLYNASE) is the Drug of Choice In CKD
Glimeperide ,Glyburide(DAONIL) with caution

74. K+
140
kDa
65
kDa
 - cell
membrane
K+
KATP channel
Modes of action: Glimepiride
Most Sulphonylureas
Glimepiride
Sulphonylurea
Receptor
65kDa Component absent in Cardiovascular System
Safer to use in patients with a higher cardiovascular risk
So What ??
Glimepiride
GLUT-4

76. Meglitinides : Repaglinide and Nateglinide
Mech of action Stimulation of Insulin secretion from Pancreas
Close ATP dependent K+ channels on cell
membranes of Pancreatic β cell, depolarises
Calcium influx causes insulin release
HbA1c reduction Upto 2.1 % (Repaglinide> Nateglinide)
Side effects Hypoglycaemia, weight gain, GI symptoms rare
Advantages Hepatic clearance
Safe in renal failure(Repaglinide>Nateglinide)
Repaglinde is considered first line drug for renal
transplantation

77. Repaglinide – Exerts direct action on Pancreatic
Beta Cell unlike Sulfonylurea
3. Repaglinide binds to the receptor different from that
SU binding of the ATP-sensitive potassium channel
Am J Cardiovasc Drugs 2007; 7 (5): 319-335
4. Closure of the ATP-dependent
potassium (K+-ATP) channel
1. Glucose is
transported into the
cell
2. Glucose metabolized
leading to formation of ATP
from ADP
5. Opening of
voltage-dependent
Ca2+-channels
6. Insulin exocytosis
Repaglinide unlike SU’s –
Glucose dependent Insulin Release helps reducing Blood Glucose & PPBG levels
77

78. But, Repaglinide is different from the
Nateglinide
Characteristics Repaglinide Nateglinide
Therapeutic dose
(mg/day)
1.5 - 16 90-360
Half-life (h) 0.5-1 1.1-1.5
Active metabolites No Yes
Renal Excretion Low Intermediate
Dose Reduction with
Renal Impairment
No Initiate at Low Dose
Repaglinide - A better therapeutic option for the
management of Diabetes with Chronic Kidney Disease
Abe M, Okada K, Soma M. Curr Drug Metab. 2011 Jan;12(1):57-69
78

79. Alpha glucosidase inhibitors :Acarbose,Miglitol, Voglibose
Mech of Action Inhibit the enzymes that help absorption of
carbohydrates from intestines
HbA1c reduction About 0.8% for Acarbose
Advantage No weight gain, no hypoglycaemia
Side Effects GI side effects like bloating, flatulence, abdominal
pain diarrhoea common
24%-45% drop out rates
Limitations Acarbose not recommended for GFR<25ml/min
Voglibose use with caution in severe renal failure

80. What are the incretins?
• GIP: Glucose-dependent insulinotrophic polypeptide
Small effect in Type 2 diabetes.
• GLP-1(glucagon-like peptide 1)
augmented in the presence of hyperglycaemia.
Action less at euglycaemia and in normal subjects.
• Pituitary Adenylate Cyclase Activating Peptide (PACAP)

81. GLP-1 Modes of Action in Humans
GLP-1 is secreted
from the L-cells
in the intestine
This in turn…
• Stimulates glucose-dependent
insulin secretion
• Suppresses glucagon secretion
• Slows gastric emptying
Long term effects
demonstrated in animals…
• Increases beta-cell mass and
maintains beta-cell efficiency
• Reduces food intake
Upon ingestion of food…

82. GLP -1 Agonists : Exenatide,Liraglutide
Background GLP-1 levels are decreased in Diabetes
Exogenous GLP-1 is rapidly degraded by enzyme DPP-
4,not useful
Mech. of Action Analogue of GLP- 1 resistant to DPP-4 degradation
Stimulates Insulin secretion, decreases glucagon
production, increases satiety
HbA1c reduction 0.5-1%
Advantages No weight gain,Low risk of Hypoglycaemia,lowers BP
Disadvantages Need Injections ,GI side effects ,Risk of
Pancreatitis,Renal impairment, Antibody production
Renal Failure Use with caution in GFR 30-50ml/min
Avoid if GFR<30ml/min

91. Insulin therapy in CKD
No dosage adjustment in GFR>50ml/min
Use 75% of the dose for GFR 10-50ml/min
Use 50% of regular dose for GFR<10min/min
Monitor closely and individualise treatment
SC INSULIN IN DIALYSIS PATIENTS
Dialysis Treatment may decrease insulin
resistance and enhance degradation
No consensensus about the best regime for
dialysis patients and whether only short acting
insulins are to be used

92. Insulin Mechanism of Action

96. Conclusions
The Diabetes Pandemic, getting worse
Diabetes ,the leading cause of CKD and ESRD
CKD ,very frequent un-recognised
Patients of Type 2 DM and CKD are highest risk
for CAD and mortality
How to detect diabetic kidney disease and CKD
Good glycaemic control prevents progression of
CKD
The problems of diabetic control in CKD
The options available

97. Drug GFR 30-45
ml/min
GFR 15-
30ml/min
GFR
<15ml/min
Biguanides Metformin ± x x
Sulphonylureas: Glypizide
Glimiperide,Glyburide
+
±
+
x
+
X
TZD: Pioglitazone + + x
Meglitinide: Repaglide + + +
Alpha glucosidase inhibitors
Acarbose,Voglibose
+ x x
SGLT –Inhibitors
Dapaflozin,Canaflozin
± x x
Conclusions
Options Available in CKD

98. Drug GFR 30-45
ml/min
GFR 15-
30ml/min
GFR
<15ml/min
GLP-1 Agonists :Exenetide,Liraglutide ± x x
DPP-4 Inhibitors : Linagliptin
Sitagliptin
Saxagliptin
+
50%
50%
+
25%
50%
+
25%
50%
Insulin + + +
Conclusions
Options Available in CKD