Ryden 9 16

Managing micro- and macrovascular
risk in T2DM
Lars Rydén

Photo: Lennart Nilsson SCANPIX

Lars Rydén MD, Dr h.c., FESC, FACC, FAHA
Declaration of interest
 Advisory board / speaker





AstraZeneca
BMS
Roche
Sanofi

 Research support








Swedish Heart–Lung Foundation
Karolinska Institutet
Stockholm County Council
AFA Insurance
Swedish Medical Assembly
AstraZeneca
Roche

The first attempt to develop a
glucose-lowering drug
Frederic G. Banting
(1891 – 1941)
“Diabetus
Ligate pancreatic
ducts of dogs. Keep
dogs alive till
acini degenerate
leaving islets.
Try to isolate
the internal secretion
of these to relieve
glycosurea.”
Banting FG. Edin Med J. 1929;36:1-18.

The first patient treated with insulin
 The Banting & Best
experiment, 1921
 Ligated the pancreatic
duct inducing digestive
cell necrosis
 Homogenized and
filtered the remaining
parts of pancreas
 Kept the
pancreatectomized dog,
Marjorie, alive several
months by injections of
the isolated substance
"isletin"
Banting FG, Best CH, Macleod JJR. Am J Physiol. 1922;59:479.

Best, Banting,
and one of the dogs

The first (human) patient treated
with insulin
Leonard Thompson
(1908 – 1935)
Dying from diabetes,
he was the first
human to get the
extract in
January 1922
Survived until
the age of 27.
Banting FG, Best CH, Macleod JJR. Am J Physiol. 1922;59:479.

A much-acknowledged contribution
The 1923 Nobel prize in medicine or
physiology was awarded to
FREDERICK GRANT BANTING
JOHN JAMES RICKARD MACLEOD
“for the discovery of insulin.”

Banting shared his prize money with
Charles Best while Mcleod shared
his with James Collip

Impact of insulin on microvascular
complications in T1DM
Decrease in retinopathy with 2% ∆ in HbA1c

Percentage of patients

60

Conventional
treatment

Mean reduction 76%
(95% CI, 62 – 85%)
P < 0.001

50
40
30
20

Intensive
treatment

10
0
0

1

2

3

4

5

6

7

8

9

Follow-up (years)
Conventional
Intensive

375
342

220
202

DCCT Research Group. N Engl J Med. 1993;329:977-986.

79
78

52
49

Impact of insulin on macrovascular
complications in T1DM
Cumulative incidence of predefined cardiovascular events in the
Diabetes Control and Complications Trial (DCCT–EDIC)
Cumulative incidence
of
nonfatal MI, stroke or
death from CVD

0.06

57% risk reduction in non-fatal MI, stroke or CVD death
(intensive vs. conventional; P = 0.02)

Conventional
treatment

0.04
Intensive
treatment

0.02

0.00

0

1

2 3 4 5 6 7 8 9
DCCT (intervention period)
Years since entry
At risk
Intensive
705
Conventional
721

10 11 12 13 14 15 16 17 18 19 20 21
EDIC (observational follow-up)
686
694

640
637

DCCT/EDIC Study Research Group. N Engl J Med. 2005; 353:2643-2653.

118
96

Years

T2DM – a variety of drugs
GI
Pancreas

Sulphonylurea
Incretins

Incretins
α-glucosidase
inhibitors

Liver

Metformin

Insulin

Insulin

Glucose
Metformin
Thiazolidinediones

Thiazolidinediones

Muscle and
adipose tissue

Insulin in T2DM – why?
 Restores insulin deficit in dysglycemia
 Improved buffering of glucose changes by
reducing the need for pancreatic insulin
 Reduces toxic pro-oxidant effects
of hyperglycemia
 Anti-inflammatory, vasodilatory &
antithrombotic effects
 Improves endothelial repair & dysfunction

Impact of glucose-lowering drugs
on vascular endpoints in T2DM

UKPDS. Lancet. 1998;352:837-853.

Impact of glucose-lowering drugs
on vascular endpoints in T2DM
Randomized to
intensive or conventional
therapy
(N = 4,209)

SU or insulin
(n = 2,729)

Conventional
(primarily diet)
(n = 1,138)

Metformin
(n = 342)

Available follow-up
(n = 2,118)

Available follow up
(n = 880)

Available follow up
(n = 239)

UKPDS. Lancet. 1998;352:837-853.

Impact of intensive glucose lowering on
microvascular complications
Decrease in microvascular
complications with
0.9% ∆ in HbA1c

50

Mean reduction 76%
(95% CI, 62 – 85%)
P < 0.001

40
30
20
10
0

30%
30

Conventional

60

Intensive
0

1

2

3

4

5

6

7

Follow-up (years)

8

Percentage of
patients with event
% of patients with an event

Percentage of patients

Decrease in retinopathy with
2% ∆ in HbA1c

Conventional
Intensive
p=0.0099

20%
20

P = 0.0099

Conventional
10%
10
RiskIntensive
reduction 25%
(95% CI: 7% to 40%)

0%
0

9

DCCT Research Group. N Engl J Med. 1993;329:977-986.

0
0

3
6
9
12
3
6
9
12
Years from randomisation

15
15

Years from randomization
UKPDS. Lancet. 1998;352:837-853.

Impact of glucose-lowering drugs on
macrovascular endpoints in T2DM
Glycaemic control and macrovascular disease: Beneficial start

UKPDS. Lancet. 1998;352:837-853.

UKPDS – 10-year follow-up
Glycemic control (HbA1c) during follow up

Between group difference in HbA1c lost after the first years
Holman RR, et al. N Engl J Med. 2008;359:1577-1589.

UKPDS – 10-year follow-up
All-cause mortality
Sulphonylurea–insulin

Holman RR, et al. N Engl J Med. 2008;359:1577-1589.

Metformin

UKPDS – patient characteristics

UKPDS. Lancet. 1998;352:837-853.

UKPDS – patient characteristics

Medication
Diuretic
BP lowering
ASA
Lipid-lowering

UKPDS. Lancet. 1998;352:837-853.

%
13
12
1.5
0.3

The PROACTIVE study: pioglitazone vs. placebo as add-on therapy
1° endpoint: death, MI/ACS, stroke, leg
amputation, coronary or leg revascularization

20

Pioglitazone
(514 events)

15
10
5

Proportion of events (%)

Proportion of events (%)

25

10% RRR
HR (95% CI) =
0.90 (0.80 –1.02)
Placebo
P = 0.095
(572 events)

25

2° endpoint: death, MI or stroke

20
Placebo
(358 events)

16% RRR
HR (95% CI) =
0.84 (0.72 – 0.98)
P = 0.027

15
10

Pioglitazone
(301 events)

5
0

0
0

6

12

18

24

30

36

0

12

18

24

30

36

Time from randomization

Time from randomization
Number at risk

Number at risk
Pioglitazone
Placebo

6

2,488
2,530

2,373
2,413

2,302
2,317

2,218
2,215

2,146
2,122

348
345

Dormandy JA, et al. Lancet. 2005;366:1279-1289.

Pioglitazone
Placebo

2,536
2,566

2,487
2,504

2,435
2,442

2,381
2,371

2,336
2,315

396
390

Glycaemic control and macrovascular disease:
Beneficial start, subsequent doubts
ACCORD

ADVANCE

VADT

 T2DM at high risk (CVD or risk factors); N = 10,251
 Glycaemic control
 Intensive HbA1c < 6.0% vs. conventional HbA1c 7.0 – 7.9%

 Impact on cardiovascular morbidity and mortality
Primary outcome until end of study

Death from any cause until end of study

HR (95% CI) = 0.91 (0.81 – 1.03)
Standard

80

10

60

Intensive
0

40

0 1 2 3 4 5 6 7 8

20
0

100

20

0

Participants with
events (%)

Participants with
events (%)

100

HR (95% CI) = 1.19 (1.03 – 1.38)
20
Intensive

80

10
Standard

60
40

0
0 1 2 3 4 5 6 7 8

20
0

1 2 3 4 5 6 7 8
0 1 2 3 4 5 6 7 8
Years since randomization
Years since randomization
The ACCORD Study Group. N Engl J Med. 2011;364:818-828.


The ACCORD Study Group. N Engl J Med. 2011;364:818-828.

Impact of intensive glucose-lowering on
macrovascular complications in T2DM
Meta-analysis of five major trials
UKPDS, PROACTIVE, ADVANCE, VADT, ACCORD
Nonfatal MI
OR (95% CI) = 0.83 (75 – 0.93)

All-cause mortality
OR (95% CI) = 1.02 (0.87 – 1.19)

Mean HbA1c difference intensive vs. standard = 0.9%

Ray KK, et al. Lancet. 2009;373:1765-1772.

Impact of intensive glucose-lowering on
macrovascular complications in T2DM
Meta-analysis of four major trials
UKPDS, ADVANCE, VADT, ACCORD

Turnbull FM, et al. Diabetologia. 2009;52:2288-2298.

complications in T2DM (and IGT)

In high-risk people with IFG, IGT or early diabetes,
does insulin replacement therapy targeting fasting
normoglycemia (< 5.3 mM or 95 mg/dL) with insulin
glargine, reduce CV outcomes more than standard
approaches to dysglycemia?
ORIGIN Trial Investigators. N Engl J Med. 2012;367:319-328.

8.0

FPG (mmol/L)

7.5

6.9

7.0
6.5

Glargine

IQR 5.7 – 7.9

Standard

6.6

6.8

6.9

6.0
5.5
5.0

5.2

4.5

5

4.0
0

1

2

5.1

5
IQR 4.4 – 5.8
3

4

5.1

5.2

5.2

5.3

Penultimate
5

6

Year

7

End


Fasting glucose at study end
Insulin
5.3 mmol/L
Standard care 6.8 mmol/L


Safety of glucose-lowering
drugs in T2DM
Potential problem

Avoid or reconsider

Weight gain

SUs, glinides, TZDs, insulin

Gastrointestinal

Biguanides, α-glucosidase inhibitors

Hypoglycemia

SUs, glinides, insulin

Kidney dysfunction

Biguanides, SUs

Hepatic dysfunction

Glinides, TZDs, biguanides, α-glucosidase
inhibitors

Cardiovascular concerns

Biguanides, TZDs

Rydén L, et al. Eur Heart J. 2007;28:88-136.

Safety of glucose-lowering drugs
Pio- and rosiglitazone and heart failure

Odds ratio (95%CI)
Rosi
Pio
Total

Favours

1
TZD

Hernandez AV, et al. Am J Cardiovasc Drugs. 2011;11:115-128.

2
Placebo

4

Rosiglitazone and CVD events

Nissen SE, Wolski K. N Engl J Med. 2007;356:2457-2471.

Strict demands on cardiovascular
safety of glucose-lowering drugs
U.S. Food and Drug Administration
FDA News
FOR IMMEDIATE RELEASE
December 17, 2008
Consumer Inquiries:
888-INFO-FDA
FDA Announces New Recommendations on Evaluating Cardiovascular
Risk in Drugs Intended to Treat Type 2 Diabetes
The U.S. Food and Drug Administration recommended today that
Manufacturers developing new drugs and biologics for type 2 diabetes
provide evidence that the therapy will not increase the risk of such
cardiovascular events as a heart attack.
The recommendation is part of a new guidance for industry that applies
to all diabetes drugs currently under development.

Safety of glucose-lowering drugs:
rosi- vs. pioglitazone

 Systematic review and meta-analysis of 16
observational studies comparing risk of
cardiovascular outcomes for
 Rosiglitazone (N = 429,000) and
 Pioglitazone (N = 381,000)

in patients with T2DM during 105 days – 7 years
Loke YK, et al. BMJ. 2011;342:d1309.

Myocardial infarction

Loke YK, et al. BMJ. 2011;342:d1309.

Heart failure

Overall mortality


The TIDE Trial Investigators. Diabetologia. 2012;55:36-45.

Insulin – potential drawbacks

Smith U, Gale AM. Diabetologia. 2009;52:1699-1708.

Insulin – potential drawbacks

Hemkens LG, et al. Diabetologia. 2009;52:1732-1744.
Jonasson JM, et al. Diabetologia. 2009;52:1745-1754.

Impact of insulin on
cancer in T2DM

Glargine
n (%)
Rate

Standard
n (%)
Rate

HR (95%CI)

P

Cancer death

0.94 (0.77 – 1.15)

0.52

189 (3.0)

0.51

201 (3.2) 0.54

Any cancer

1.00 (0.88 – 1.13)

0.97

476 (7.6)

1.32

477 (7.6) 1.32

Lung

1.21 (0.87 – 1.67)

0.27

80 (1.3)

0.22

66 (1.1)

0.18

Colon

1.09 (0.79 – 1.51)

0.61

76 (1.2)

0.21

70 (1.1)

0.19

Breast

1.01 (0.60 – 1.71)

0.95

28 (0.4)

0.08

28 (0.4)

0.08

Prostate

0.94 (0.70 – 1.26)

0.70

88 (2.1)

0.36

89 (2.2)

0.38

Melanoma

0.88 (0.44 – 1.75)

0.71

15 (0.2)

0.04

17 (0.3)

0.05

Other

0.95 (0.80 – 1.14)

0.59

233 (3.7)

0.64

245 (3.9) 0.67

Any skin

1.02 (0.78 – 1.33)

0.88

110 (1.8)

0.30

108 (1.7) 0.29

1


10

Pioglitazone and bladder cancer

Kaiser Permanente diabetes registry
On pioglitazone

193,099
30,173

HR for bladder cancer
Overall
Treated > 24 months
Lewis JD, et al. Diabetes Care. 2011;34:916-922.

1.2 (95% CI, 0.9 – 1.5)
1.5 (95% CI, 1.03 – 2.0)

Effects of established glucose-lowering
drugs on cardiovascular risk
Some reflections
 Strict glycaemic control in the presence of multifactorial
therapy (lipids, blood pressure etc) less rewarding!
 The impact of glycaemic control perhaps more apparent if
instituted in early dysglycaemia?
 Are patients without apparent CVD more sensitive to glycaemic
control?
 Legacy effect may be important – is follow up still too short?
 Hypoglycaemia and weight gain do not fully explain lack of
effect!
 Some glucose-lowering drugs may cause harm alone
or when combined!
 Insulin safe at least if given to strict glycaemic targets

Which patients are we studying?
Mortality in DIGAMI 2
25

♦
♦

Percent

20

2-year mortality 18.4%
Predicted mortality 22.3%

♦
♦

15
Total study mortality 21.3%

10
5
0

0

200

400
600
800
Follow-up time (days)

Malmberg K, Rydén L, et al. Eur Heart J. 2005;26:650-661.

1,000

1,200

Which patients are we studying?
Events in ACCORD and ADVANCE related to DIGAMI 2

ACCORD

ADVANCE

Standard

Intensive

Years of follow-up

Cumulative incidence (%)

Patients with events (%)

 F/u median 3.4 years
 1° outcome: MI, stroke,
CV death

 F/u median 5 years
 1° outcome: major
macro- and
microvascular events
Standard

Intensive
HR (95% CI) = 0.90 (0.82 – 0.98)
P = 0.01

Months of follow-up

ADVANCE Collaborative Group. N Engl J. Med. 2008;358:2560-2572.
ACCORD Study Group. N Engl J Med. 2008;358:2545-2559.

From the Swedish PCI registry
STEMI + DM

Mortality (%)

25

NSTEMI + DM

20

STEMI – no DM
Stable AP + DM

15

NSTEMI – no DM

10

Stable AP – no DM

5
0
0

1

2

3

4

5

6

Years after PCI
Norhammar A, et al. EuroIntervention. 2010;5:891-897. doi:10.4244/.


One-year mortality (%)

One-year mortality following MI: Sweden 1994 – 2010

Diabetes

No diabetes

Norhammar A, et al. Heart. 2007;93:1577-1583; SWEDEHEART 2011 Annual Report.
www.ucr.uu.se/swedeheart/.../178-swedeheart-annual-report-2011-english


One-year mortality (%)

One-year mortality following MI: Sweden 1994 – 2010

One-year mortality DIGAMI 2

♦

Diabetes

No diabetes

Norhammar A, et al. Heart. 2007;93:1577-1583; SWEDEHEART 2011 Annual Report.
www.ucr.uu.se/swedeheart/.../178-swedeheart-annual-report-2011-english

Effects of multifactorial treatment of
T2DM on cardiovascular risk
Proportionate contribution of treatment components applying UKPDS
risk score in STENO–2 intensive arm

HbA1c
13%

Blood
pressure
11%

Smoking
3%
Courtesy: P. Gaede.

Lipids
73%

Total cholesterol
48%

HDL-cholesterol
25%

T2DM – more than hyperglycaemia
Dysglycaemia
Oxidative stress
AGEs
oxLDL
PAF-acetylhydrolase

Endothelial
dysfunction
vWF
tPA antigen
Adhesion molecules
ET–1, NO

β-cell dysfunction
Insulin resistance

T2DM/CVD

GH system

Hypercoagulability

IGF–I
IGFBP–1
IBFBP–3

PAI–1
Fibrinogen
Antithrombin activity

Inflammation
hsCRP
IL–1
IL–6
TNF–α
MMPs
CD40–lig
PAI–1
Adipokines

Dyslipidemia
Small dense LDL
HDL
FFAs
Triglycerides
ApoB, ApoA–1

Targets for the balanced PPAR α/γ
agonist aleglitazar
Dyslipidemia
↑ HDL 21%
↓ Triglycerides 43%
↓ LDL 10%
Shift to fewer and
larger particles!

Glycemic control
↓ HbA1c 0.85%
↓ FPG 2.16 mmol/L
↓ HOMA–IR 35%

Henry RR, et al. Lancet. 2009;374:126-135.

Inflammation and
thrombolysis/
fibrinolysis
↓ hs-CRP 40%
↓ Fibrinogen 10%
↓ PAI–1 6%

Hypertension
↓ Blood pressure
1 – 3 mmHg

Effects of GLP–1 on
various tissues

Baggio LL, Drucker DJ. Gastroenterology. 2007;132:2131-2157.

Trials with GLP–1 analogs
and DPP–4 inhibitors
OR (95%CI)

Monami M. et al. Curr Med Res Opin. 2011;27:57-64.

Trials with GLP–1 analogs
and DPP–4 inhibitors
Ongoing trials with CV endpoints
Acronym

Type

Drug

Leader
Exscel
ELIXA
SAVOR–TIMI 53
TECOS
CAROLINA
EXAMINE

GLP–1
GLP–1
GLP–1
DPP–4 inhibitor
DPP–4 inhibitor
DPP–4 inhibitor
DPP–4 inhibitor

Liraglutide
Exenatide
Lixisenatide
Saxagliptin
Sitagliptin
Linagliptin
Alogliptin

Monami M. et al. Curr Med Res Opin. 2011;27:57-64.

OR (95%CI)

Conclusions
 Strict glycaemic control protects from
 Glucose target in established T2DM
remains uncertain
 Available drugs may be less well suited
for cardioprotection
 Individualized multifactorial
management important

 Conclusions
 Strict glycaemic control protects from
ies
t eg
stra ntrol
 Glucose target and
co
ls in established T2DM
t oo
olic
remains uncertain ab
New o-met
 Available drugs may d!!!less well suited
c
be !!
glu
ede
or
f
for cardioprotection
ne
 Individualized multifactorial
management important

Ryden 9 16

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