Long-term Benefits of Intensive Glucose

Control for Kidney Protection

Overview
DM and progression to DKD
UKPDS and Legacy Effect
Asian Diabetic Patients Profile
The Role of SU in Maintaining Good Glycemic
Control in DKD
ADVANCE ON Study
DM and progression to DKD
DM And Progression To Kidney Failure
Importance of reduction of renal events in T2D
Natural History of Diabetic Nephropathy
Assessing Patients with T2DM and Renal Impairment:
Is it Diabetic Nephropathy ?
Risk Factors For Development & Progression
of Diabetic Nephropathy

Modifiable Non Modifiable

BP DM Duration

Glycemic Control Genetic

Proteinuria Gender

Smoking Ethnicity
UKPDS and Legacy Effect
 Meta-analysis:
Effect of Intensive Glucose control on Macrovascular Outcomes

n = 27,049
4 Trials (ACCORD, ADVANCE, UKPDS, VADT); Average duration 4.4 yrs
2370 Vascular events

Confidence
For every 1% HbA1c HR
Interval
Major CV events 0.91 0.84 0.99

Myocardial infarction 0.85 0.76 0.94

CV mortality 1.10 0.84 1.42

Stroke 0.96 0.83 1.10

FM Turnbull et al. Diabetologia 2009; 52:2288-98

UKPDS legacy effect: Reductions in relative risk
at 10-year post-study follow-up
Any diabetes-related endpoint 0.91
0.83 0.99 p = 0.04

Diabetes-related death 0.83

0.73 0.96 p = 0.01

Death from any cause 0.87

0.79 0.96 p = 0.007

Myocardial Infarction 0.85

0.74 0.97 p = 0.01

Stroke 0.91
p = 0.39
0.73 1.13
0.82
Peripheral vascular disease 1.19 p = 0.29
0.56
0.76
Microvascular disease 0.64 0.89 p = 0.001

-
-

-
Data represent point estimate and 95% CI 0.1 0.5 1 5 10
Intensive better Conventional better
Intensive = SU or insulin in 5-year UKPDS. Median
HbA1c at end of UKPDS 7.9%
Conventional = diet only in 5-year UKPDS. Median Holman RR, et al. 10-year follow-up of intensive glucose control in
type 2 diabetes. N Engl J Med. 2008; 359: 1577-89.
HbA1c at end of UKPDS 8.5%
Asian Diabetic Patients Profile
 Asian Phenotypes T2DM Patients
Younger Onset
Of Diabetes

Lower Rates Of
Higher Rate Of Type 1 Diabetes
Renal Complications
and Stroke compare to
CV Death &
Major Coronary Event Lower BMI But
High Visceral Fat

Long Disease Low Level of

Duration -Cell Function

Adapted from Chan JCN, Yeung R, Luk A. Diabetes Voice 2014. March 14, Volume 59
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

High Incidence of ESRD due to Diabetes in South East Asia

USRDS 2010 Annual Data Report

Singapore: http://www/nrdo.gov.sg
Number of Dialysis in Indonesia is Growing Significantly

TRIVIA
QUIZ

Indonesia Renal Registry 2014

 BURDEN DISEASE
RS Soetomo : Diabetes Patient with CKD, Total BPJS Cost

Mohon dapat ditambahkan bila dr sonny memiliki data

ini, terimakasih

Indonesia Renal Registry 2014

The Role of SU in Maintaining Good
Glycemic Control in Diabetic Kidney
Diseases
 Sulfonylureas Revisited BAD Press

Have high rates of Hypoglycaemia & Weight Gain

Exhaust cells leading to early Oral agent failure
Have adverse Cardiac effects
 Despite The Controversy,
SUs Were The Most Common Drug Prescribed in Asia

Japan Diabetes Clinical Data Management OAD Prescription in Indonesia

Study Group (JDDM)
Diabetes Management Variable n (%)*
Type of OAD Therapy
Biguanides 1085 (59.26)
Sulphonylureas 1036 (56.58)
Meglinitides 8 (0.44)
Alpha glucosidase inhibitors 461 (25.18)
TZDs 51 (2.79)
Other OADs 48 (2.62)
Traditional herbal medicines 5 (0.27)
SUs were the most
prescribed OAD Double drug fixed dose combination 88 (4.81)

1. Kobayashi M, et al. Diabetes Res. Clin. Pract. 73: 198204

2. Soewondo P. Med J Indones 2010;19(4):235-244
Summary of glucose-lowering interventions
HbA1c efficacy

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

ADVANCE ON STUDY
 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.

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
EasyDIA Powerful Efficacy For Early Control In Real Life
In Early Patients

Reaching up to -3.76%
HbA1c Reduction

Weight Reduction in The

Overweight and Obese
Diamicron MR 60 Delays The Need For Insulin Injections

Satoh study
Retrospective study (1981-2000) conducted in Japan.
Aim: to evaluate a possible difference in time until
start of insulin treatment between
T2DM treated with gliclazide and glibenclamide.
Patients: 274 type 2 diabetic patients

Moreover, the mean HbA1c during treatment was significantly lower with
gliclazide compared with glibenclamide (6.8% vs 7.4%)

Satoh J et al. Diabetes Res Clin Pract. 2005;70:291-297

Diamicron MR 60 Does Not Exhaust The Pancreas
After Long-Term Prescription up to 120 mg

Similar use of Insulin

after 10 yrs

Table 1. Treatments used at the end of ADVANCE-ON

(10 years after entry of patients in the ADVANCE trial)

ADVANCE-ON Collaborative Group. N Engl J Med. 2014;371:1392-1406.

 ADVANCE Goes Beyond UKPDS

HbA1c target of 6.5% vs 7.0% in UKPDS

Significant reduction in renal events:
21% reduction in nephropathy (p=0.006)
INTENSIVE CONVENTIONAL
No reduction in UKPDS
30% reduction in macroalbuminuria (p<0.001)
Non significant 10% reduction in UKPDS

ADVANCE Collaborative Group. N Engl J Med 2008; 358:2560-72

ADVANCE :
The Only One Demonstrate Significant Reduction in
ESRD/Dialysis

Coca SG et al. Arch Intern Med. 2012;172(10):761-769.

 Long-term Benefits of Intensive
Glucose Control for Preventing
End-Stage Kidney Disease:
ADVANCE-ON

Diabetes Care DOI: 10.2337/dc15-2322

Muh Geot Wong,1 Vlado Perkovic,1
John Chalmers,1 Mark Woodward,1,2,3
Qiang Li,1 Mark E. Cooper,4 Pavel Hamet,5
Stephen Harrap,6 Simon Heller,7
Stephen MacMahon,1,2
Giuseppe Mancia,8 Michel Marre,9
David Matthews,10 Bruce Neal,1,11
Prof V. Perkovic Neil Poulter,11 Anthony Rodgers,1
Bryan Williams,12 and Sophia Zoungas,1,13
Australia for the ADVANCE-ON Collaborative Group

Renal-data Diabetes Care, published online March 23, 2016

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

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.

Unique Renal Protection Beyond Glycemic Control

Dialysis or renal transplant

in patients with HbA1c<7%

Gliclazide MR

Figure 1. Reduction of risk of end-stage renal disease (ESRD) in patients achieving glycemic control

Lee YH et al. Diabetes Metab. 2015;41(3):208-215.

Diamicron MR 60: Kidney Protection at All Stages
Diamicron MR 60 Guarantees Less Hypoglycemia
Than Glimepiride Whatever Renal Function

GUIDE study. Schernthaner G et al. Eur J Clin Invest. 2004;34:535-542.

GUIDE Study
 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
 Conclusions
Renal disease is a major complication

High incidence in SE Asia & costly RRT

ADVANCE + ADVANCE-ON confirms:

Benefits of intensive glucose control

Most benefit in those with preserved kidney function

Strongest evidence to date on Renal Protection

THANK YOU