Early Glycemic Control for

Long Term Kidney Protection

dr. Hendry Halim, Sp.PD

 DIABETES MELLITUS
Heterogenous, complex metabolis disorder characterized by elevated blood
glucose concentration secondary to either resistance to the action of
insulin, insufficient insulin secretion, or both
The egregious eleven – PERKENI 2019
Factors to Consider when Choosing
an Anti-hyperglycemic Agent

Effectiveness in lowering glucose

Extraglycaemic effects that may reduce long-term complications

Safety profile

Tolerability

Cost

Effect on body weight

Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

Overview
• High and Increasing Prevalence of T2DM and DKD
• The Role of SU in Maintaining Good Glycemic Control in DKD
• ADVANCE ON Study
• Unique Antioxidant Properties of GLICLAZIDE MR
Diabetes is one of the major healthcare burden in
Indonesia

65%
IN JUST 22 YEARS

IDF Diabetes Atlas 6th edition. @International Diabetes Federation

 Global Prevalence
of DKD
Approximately 40% of all
adults with T2D have DKD
globally.1,2

31.6% have signs of CKD

before diagnosis of
diabetes mellitus.3
1. Bailey RA et al. BMC Res Notes. 2014;7:415.
2. Thomas MC et al. Nat Rev Nephrol. 2016;12(2):73-81.
3. Gatwood J et al. PLoS ONE. 2018;13(2):e0192712.
Abbreviations: CKD, chronic kidney disease; DKD, diabetic kidney disease; T2D, type 2 diabetes.
 An Alarmingly High Prevalence of Diabetic
Nephropathy in Asian T2DM :
The Micro Albuminuria Prevalence

Microalbuminuria
Macroalbuminuria
Normoalbuminuria

Prevalence of microalbuminuria and macroalbuminuria (and 95% CI) by country in the per-protocol population
The dotted line represents the average prevalence of microalbuminuria (39.8%)
Wu AYT, et al. Diabetologia 2005;48:17-26
Overview
• High and Increasing Prevalence of DKD
• The Role of SU in Maintaining Good Glycemic Control in DKD
• ADVANCE ON Study
• Unique Antioxidant Properties of GLICLAZIDE MR
The egregious eleven – PERKENI 2019
 Glycemic Control Remains the Most
Important Factor
Design Cohort study
N=271,174 T2D vs 1,355,870 controls
Follow-up: 5.7 years
Country Sweden (Swedish National Diabetes
Register)
Primary To evaluate the association between
Objective the excess risks of death and CV
outcomes in patients with T2D
Key Results “…a glycated hemoglobin level
outside the target range was the
strongest predictor of stroke and
acute myocardial infarction…”

The estimated explained relative risk (i.e., relative importance) shows the strength of the association for various risk-
Rawshani A et al. N Engl J Med. 2018;379:633-644. factor variables (with values outside the target ranges) for predicting acute myocardial infarction and stroke.
Summary of glucose-lowering
interventions HbA1c efficacy

ADA/EASD Guidelines. Diabetes Care 32(2009)193-203

 GUIDE TRIAL
GlUcose control in type 2 dIabetes :
Diamicron MR versus glimEpiride

HYPOGLYCEMIA?

• International, multi-center, randomised, double-blind, parallel group design

• Diamicron MR vs glimepiride (30-120mg) (1-6mg)
• 845 subjects, 6 month duration

G. Schernthaner, U. Di Mario, A. Grimaldi. Diabetologia.2003;46:A281

 Hypoglycaemia* in GUIDE study
(Gliclazide vs Glimepiride)
with blood glucose < 3.0 mmol/L

HbA1c (%) % Patients with hypoglycaemia

10 P=0.003
8.5
8.4 8
8 8.2 8.9%
6
7.5
4
7 7.2 7.2
2 3.7%
6.5
0
Gliclazide MR glimepiride
6
Diamicron MR glimepiride n=403 n=439
G. Schernthaner, U. Di Mario, A. Grimaldi. Diabetologia.2003;46:A281
Hypoglycemia with Different
Sulfonylureas
30

25
Relative risk (%)

20

15

10

Gliclazide Glipizide Glimepiride Glibenclamide

Hypoglycaemia RPG < 2.8 mmol/L (50 mg/dL) Tayek J. Diab Obes Metab 2008; 10:1128-1130
Gribble FM et al. Diabetologia. 2003;46:875-891.

Winkler M, Stephan D, Bieger S, Kuhner P, Wolff F, Quast U. Testing the bipartite model of the sulfonylurea receptor binding site: binding of A-, B-, and A + B-site ligands. J Pharmacol Exp Ther. 2007;322(2):701-708.
 Risk of Symptomatic Hypoglycemia
Sitagliptin vs SU
APaT Population
RRR (95% CI) = 0.52 (0.29, 0.94); P=0.027

Nearly
50% Risk
Reduction
OAD Hypoglycemia (%)
Glimepiride 9.1
Glibenclamide 5.2
Sitagliptin 2.1
Gliclazide MR 1.8
N=421 N=427
Adapted from Aravind et al. 2012
• 63 symptomatic hypoglycemic events were reported by 31 patients in the SU group compared with 22 events
in 16 patients for the sitagliptin group
• In the overall study population, switching to sitagliptin was associated with a nearly 50% reduction of risk
APaT=all patients as treated; CI=confidence interval; RRR=relative risk ratio; SU=sulfonylurea.
1. Aravind SR et al. Curr Med Res Opin. 2012;28(8):1–8.
Overview
• High and Increasing Prevalence of DKD
• The Role of SU in Maintaining Good Glycemic Control in DKD
• ADVANCE ON Study
• Unique Antioxidant Properties of GLICLAZIDE MR
ADVANCE Study : Optimal Efficacy of Gliclazide
MR in Asian Patients
40% of the ADVANCE study subjects
were from Asia

HbA1c reduction after 5 years of treatment with

Gliclazide MR up to 120 mg daily in the ADVANCE
trial, with regards to the initial level of HbA1c

Zoungas S et al. Diabetes Res Clin Pract. 2010;89:126-133.

ADVANCE-ON : Kidney Protection Over The Long Term

End Stage Renal Disease (renal transplant or dialysis)

-65%

Lowering HbA1c to 6.5% for 5 years, using regimen including

gliclazide MR, leads to further renal protection over 10 years
Wong MG et al. Diabetes Care. 2016; doi:10.2337/dc15-2322/-/DC1.
 Renal Benefits Are Even Greater
When Is Prescribed Early

Prof V. Perkovic
Australia

Wong MG et al. Diabetes Care. 2016; doi:10.2337/dc15-2322/-/DC1.

Diamicron MR 60: Kidney Protection at All Stages
Intensive Glycemic Control Increase The Risk of Severe Hipoglycemia?
25

% patients experiencing at least one

VADT1 Intensive Control
Standard Control

severe hypoglycemic event

20 21.2%
ACCORD2

15 16.2%

10
9.9%
ADVANCE3
5
5.1%
2.7% 1.5%
0
P <0.001 P <0.001 HR = 1.86
(95% CI 1.40-2.40)
% HbA1c at study end 6.9 8.4 6.4 7.5 6.5 7.3

% change from baseline -2.5 -1.0 -1.7 -0.6 -1.0 -0.2

VADT: severe change in consciousness including loss of consciousness
ACCORD: requiring assistance of another person and plasma glucose < 2.8 mmol/l or symptoms that promptly resolved with oral CHO,
IV glucose, or glucagon.
ADVANCE: requiring assistance of another person and plasma glucose <2.8 mmol/l
1. Duckworth W et al NEJM 2009;360:129-39
2. Riddle MC. Circulation 2010;122:844-46
3. ADVANCE Study group. NEJM 2008; 358:2560-72
Overview
• High and Increasing Prevalence of DKD
• The Role of SU in Maintaining Good Glycemic Control in DKD
• ADVANCE ON Study
• Unique Antioxidant Properties of GLICLAZIDE MR
Unique Antioxidant Properties of
GLICLAZIDE MR
How to explain Gliclazide MR 60 mg
specific cardiovascular, renal and pancreatic protection
Complication of T2DM
Oxydative stress is leading to macrovascular &
microvascular complications
and pancreas dysfunction
Gliclazide MR : Unique antioxidant properties

Gribble FM et al. Diabetologia. 2003;46:875-891.

Gliclazide MR : Unique antioxidant properties

*
Gribble FM et al. Diabetologia. 2003;46:875-891.
GLICLAZIDE: No Limitation When Renal Function
Declines
Antidiabetic Drug
Dose Reduction
Metformin
Dose Reduction
Glimepiride
Gliclazide
Glibenclamide
Dose Reduction
Sitagliptin
Saxagliptin
Vildagliptin
Linagliptin
Pioglitazone
Acarbose
Dapagliflozin
Liraglutide
Dose Reduction
Exenatide
Exenatide LAR
Dose Reduction
Insulin

GFR >60 <60->30 <30 Hemodialysis

1. Schernthaner G et al. Nephrol Dialysis & Transplant 2010;25:2044-2047
2. KDOQI Diabetes-CKD Update 2012
 Summary

• High and growing burden of DKD; up to 40% of patients with T2D have
DKD.

• DKD is thought to result from uncontrolled blood glucose and oxidative

stress due to hyperglycemia (and is a marker of overall endothelial
dysfunction)

• ADVANCE + ADVANCE-ON confirms Gliclazide MR:

• Benefits of intensive glucose control

• Most benefit in those with preserved kidney function

Nephrol Dial Transplant (2013) 0: 1–18