ADVANCE in Glycemic Control:

Which Benefits for Diabetic Patients

in terms of Cardiovascular Outcomes

Sony Wibisono M
Diabetes and Nutrition Centre Surabaya – Division of
Endocrinology and Metabolism - Department of Internal
medicine – Faculty of Medicine Airlangga University Surabaya
Banjarmasin, 10 May 2014
 Overview of presentation

Global burden of diabetes in 2013 (6th Ed IDF

Diabetes Atlas)

Perspectives on recent morbi-mortality trials:

Anything gained?

Comparison of the results of the various trials

Conclusion
2013 IDF Diabetes Atlas - Sixth edition
 A huge and growing problem

2013 IDF Diabetes Atlas - Sixth edition

 Top 10 countries

2013 IDF Diabetes Atlas

- Sixth edition
Global cardiometabolic risk
 Risks associated with diabetes

Cause of death Hazard ratio 95% CI

Stroke 2.8 2.0–3.7

Coronary heart disease 3.2 2.9–3.5
Other Cardiovascular Disease 2.3 1.8–2.9
All Cardiovascular Disease 3.0 2.8–3.3

All causes 2.5 2.4–2.7

Stamler et al, MRFIT Group. Diabetes Care 1993;16:434-443

Perspectives on recent morbi-mortality
trials: Anything gained?
 Blood glucose and vascular risk in diabetes
Evidence in 2000

UK Prospective Diabetes Study Lancet 1998

 UKPDS: HbA1c and vascular disease

Recommended Guidelines : reduction of HbA1c < 7.0%

Stratton et al. BMJ 2000.

 Blood glucose and vascular risk in diabetes
Evidence in 2000

Guidelines UKPDS

Stratton et al. BMJ 2000.

 Blood glucose lowering in diabetes
Unresolved issues 2000

Among patients with diabetes…

Does blood glucose-lowering therapy:

Produce additional micro-vascular benefits when

haemoglobin A1c is reduced to 6.5% or lower?

Produce macro-vascular benefits when haemoglobin

A1c is reduced to 6.5% or lower?
Clinical trials to prevent cardiovascular
disease in patients with T2D
 Reduction of CV disease risk in type 2 diabetes:
lessons learned from ACCORD and VADT trials

ACCORD1 VADT2

Number 10,251 1,791

Primary CVD
 10% (p=0.16)  13% (p=0.12)
endpoint
Mortality
 22% (p=0.04)  6.5% (p=NS)
(overall)

CV mortality  39% (p=0.02)  25% (p=NS)

1. N Engl J Med. 358(2008)2545-59

2. N Engl J Med. 360(2009)129-39
 Lessons from ACCORD1 and VADT2

Intensive glucose control :

 Does not reduce cardiovascular disease

mortality in type 2 diabetes

 May increase risk of coronary heart disease,

especially in patients with pre-existing
coronary heart disease

1. ACCORD Study Group. N Engl J Med. 358(2008)2545-2559.

2. VADT Investigators. N Engl J Med. 360(2009)129-139.
 Food and Drug Administration Guidance

As a result of concerns regarding the association of

antidiabetic agents with adverse CV outcomes;

The FDA released a guidance in December 2008 titled,

“Diabetes Mellitus – Evaluating Cardiovascular Risk in New
Antidiabetic Therapies to Treat Type 2 Diabetes.”

This guidance outlines requirements for CV safety

assessment before and after approval of all new antidiabetic
therapies. Specifically, sponsors must rule out an upper 95% CI
of the hazard ratio (HR) of 1.8 before approval and 1.3 after
approval. In most cases, these upper CI boundaries would be
associated with HRs of 1.0 or less.
Adapted from White et al. (2011) American Heat journal Vol. 162, No 4
Morbi-mortality trials
 DPP4i and CVD : meta-analysis “hints”

MACE HR 0.71 [0.59 – 0.86]

Perception of “protective” effects
Monami et al. Diabetes, Obesity Metab 15(2013)112-20
 Study protocol

Worldwide Orientation Plan 2013-2014

 Baseline patient characteristics

SAVOR EXAMINE
Median age (yr) 65 61
Duration of diabetes (yr) 10.3 7.3
HbA1c 8.0% 8.0%
Established CVD
Hypertension 81% 83%
Prior MI 38% 88%
Prior HF 13% 28%

eGFR (ml/min) 72 71

Worldwide Orientation Plan 2013-2014

 Composite of cardiovascular death,
myocardial infarction, or ischemic stroke

Scirica et al. NEJM 369(2013)1317-26

 Composite of cardiovascular death,
myocardial infarction, or ischemic stroke

White et al. NEJM 369(2013)1327-35

 Significantly more patients in saxagliptin group than placebo
were hospitalized for heart failure

2-year KM rate (%)

Placebo Saxagliptin P-value for

HR
(N=8,212) (N=8,280) superiority

CV Death 2.9 3.2 1.03 (0.87-1.22) 0.72

MI 3.4 3.2 0.95 (0.80-1.12) 0.52

Ischemic Stroke 1.7 1.9 1.11 (0.88-1.39) 0.38

Hosp for Cor. Revasc 5.6 5.2 0.91 (0.80-1.04) 0.18

Hosp for Unstab Angina 1.0 1.2 1.19 (0.89-1.60) 0.24

Hosp for Heart Failure 2.8 3.5 1.27 (1.07-1.51) 0.007

All-Cause Mortality 4.2 4.9 1.11 (0.96-1.27) 0.15

Individual Endpoints
Scirica et al. NEJM 369(2013)1317-26
 Hospitalization for Heart Failure

Need to consider that increase in heart

failure hospitalization is a real signal

Physicians should be reluctant to give to patients with heart failure

Sattar EASD Barcelona 26-Sept 2013

 Glycemic Indices Over Time

Mean HbA1c (%) HbA1c <7.0%

* *
* * * *

*p<0.001
Scirica et al. NEJM 369(2013)1317-26
 Glycemic Indices Over Time

Worldwide
White Orientation
et al. NEJM Plan 2013-2014
369(2013)1327-35
 Hypoglycemia
Significantly more patients in saxagliptin group than placebo
reported at least one Hypoglycemia

p<0.001
p=0.002

15

10
(%)
p=0.047
5 p=0.33

Major – required assistance to actively intervene

Minor – symptoms, but recovered by themselves w/in 30 min, or glucose level <54 mg/dl
 No cardiovascular protection
observed with DPP4 inhibitors

Should we be surprised that only

non-inferiority was achieved ?

Limited efficacy on glycemic control (-0.30% /-0.36%)

Short duration (1.5 to 2.1 yrs)

Not designed to assess impact on micro-vascular events

Very minimal effects on hypertension or dyslipidemia

 Lessons learned from trials

Big trials get closer to truth – provide robust evidence on

speculated matters, good or bad – trials helpful
Mechanistic or observational studies can only ever be
hypothesis generating

Results reaffirm understanding that lowering glucose in short

term yields more micro than macro gain:
Better ways to  CVD: statins to lower cholesterol ?
Blood pressure and smoking reduction
CVD mortality rates : battle being won
• Ferguson & Sattar (2013) DOM
 DPP-4 inhibitors: Conclusion

 No cardiovascular protection
 hospitalization for heart failure

 Limited glycemic efficacy

 Increased risk of hypoglycemia

 ADVANCE study: Action in Diabetes and Vascular disease
preterAx and diamicroN mr Controlled Evaluation

What about ADVANCE ?

Differently…

Rationale and design of the ADVANCE study. J Hypertens. 2001;19(suppl 4):S21-S28.

ADVANCE-baseline characteristics. Diabet Med. 2005;22:1-7.
 ADVANCE study: Action in Diabetes and Vascular disease
preterAx and diamicroN mr Controlled Evaluation

2x2 factorial randomized trial (2 arms, 4 subgroups)

– Blood pressure-lowering arm: Perindopril-Indapamide or
placebo on top of current therapy, including other BP-lowering drugs.
– Glucose-lowering arm: Gliclazide MR-based intensive therapy
targeting an HbA1c ≤6.5% versus standard glucose control.

11 140 patients

Intensive BP-control Standard BP-control

Perindopril-Indapamide PLACEBO
Intensive HbA1c Standard HbA1c Intensive HbA1c Standard HbA1c
control with Gliclazide control control with Gliclazide control
(same glycemic control)

Rationale and design of the ADVANCE study. J Hypertens. 2001;19(suppl 4):S21-S28.

ADVANCE-baseline characteristics. Diabet Med. 2005;22:1-7.
 ADVANCE: positive trend for reducing cardiovascular death

CONTROL Group; Turnbull FM, Abraira C, Anderson RJ, et al. Diabetologia. 2009;52:2288-2298.
 Renal Protection

ESRD
 65%
Intensive glucose control based on
gliclazide MR improves kidney outcomes

Perkovic et al. Kidney Int 83(2013) 517–24

 ADVANCE: Summary Renal Protection

ADVANCE results for different stages of renal disease in the intensive arm based on gliclazide MR.

Perkovic V et al; ADVANCE Collaborative Group. Kidney Int. 2013;83(3):517-523.

 ADVANCE versus ACCORD and VADT

VADT

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

VADT Group. N Engl J Med 2009;360:129-39
ACCORD Study Group. N Engl J Med 2008;358:2545-59
 Concomitant treatment at
end of the study

SAVOR ADVANCE

Antidiabetic agents:
Metformin 69% 74%
Sulfonylureas 40% 93%
DPP-4 inh. 99% 0%
TZDs 5% 17%
Insulin 44% 40%
Cardiovascular agents:
Statin 81% 46%
RAS blocking 82% 89%
-blockers 63% any BP lowering drug
Aspirin 78%

Worldwide
Scirica Orientation
et al. NEJM Plan 2013-2014
369(2013)1317-26
 Hypoglycemia

SAVOR ADVANCE

Major hypoglycemia* 2.1% (177 patients) 2.7% (150 patients)

*required assistance - active intervention
 Summary of glucose-lowering interventions
HbA1c efficacy

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

 Conclusions from ADVANCE and SAVOR trials
Reduction of CV disease risk in type 2 diabetes:

SAVOR1 ADVANCE2

Number 16,492 11,140

Primary CVD endpoint 0% (p=0.99)  6% (p=0.12)

Myocardial infarction  5% (p=0.52)  2% (p=0.28)

Stroke  11% (p=0.15)  2% (p=0.78)

CV mortality  3% (p=0.72)  12% (p=0.12)

Mortality (all cause)  11% (p=0.15)  7% (p=0.28)

Hospitalization for
 27% (p=0.007)  5% (p=0.45)
heart failure

1-Scirica et al. NEJM 369(2013)1317-26

2-Patel et al, NEJM 358(2008)260-72
The population meeting criteria for our study (37,501 individuals) were age
of at least 40 years, diagnosis with type 2 diabetes between 1995 and 2010,
prescription for their first noninsulin glucose-lowering medication at least 6
months after enrollment, and at least 5 years of continuous enrollment with
at least two HbA1c records and complete pharmacy claim data

Zhang Y. Diabetes Care 2014 vol. 37 no. 5 1338-1345

LYs, QALY Metformin, SU, DPP-IV, GLP-1 agonist similar,
cost SU lower and longer dependence insulin

Zhang Y. Diabetes Care 2014 vol. 37 no. 5 1338-1345

ADVANCE-ON results: 2014

Evidence of CV
protection
Thank You