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Managing micro- and macrovascular Managing micro- and macrovascular risk in T2DM risk in T2DM
Lars RydénLars Rydén
Photo: Lennart Nilsson SCANPIXPhoto: Lennart Nilsson SCANPIX
Lars Rydén MD, Dr h.c., FESC, FACC, FAHALars Rydén MD, Dr h.c., FESC, FACC, FAHADeclaration of interestDeclaration of interest
Advisory board / speakerAdvisory board / speaker AstraZenecaAstraZeneca BMSBMS RocheRoche SanofiSanofi
Research supportResearch support Swedish Heart–Lung FoundationSwedish Heart–Lung Foundation Karolinska InstitutetKarolinska Institutet Stockholm County CouncilStockholm County Council AFA InsuranceAFA Insurance Swedish Medical AssemblySwedish Medical Assembly AstraZenecaAstraZeneca RocheRoche
Banting FG. Banting FG. Edin Med JEdin Med J. 1929;36:1-18.. 1929;36:1-18.
The first attempt to develop a The first attempt to develop a glucose-lowering drugglucose-lowering drug
Frederic G. BantingFrederic G. Banting(1891 – 1941)(1891 – 1941)
““DiabetusDiabetusLigate pancreatic Ligate pancreatic ducts of dogs. Keepducts of dogs. Keepdogs alive till dogs alive till acini degenerate acini degenerate leaving islets. leaving islets. Try to isolate Try to isolate the internal secretion the internal secretion of these to relieve of these to relieve glycosurea.”glycosurea.”
Best, Banting,Best, Banting,and one of the dogsand one of the dogs
The first patient treated with insulinThe first patient treated with insulin
The Banting & Best The Banting & Best experiment, 1921experiment, 1921 Ligated the pancreatic Ligated the pancreatic
duct inducing digestive duct inducing digestive cell necrosiscell necrosis
Homogenized and Homogenized and filtered the remaining filtered the remaining parts of pancreasparts of pancreas
Kept the Kept the pancreatectomized dog, pancreatectomized dog, Marjorie, alive several Marjorie, alive several months by injections of months by injections of the isolated substance the isolated substance "isletin""isletin"
Banting FG, Best CH, Macleod JJR. Banting FG, Best CH, Macleod JJR. Am J PhysiolAm J Physiol. 1922;59:479.. 1922;59:479.
The first (human) patient treated The first (human) patient treated with insulinwith insulin
Leonard ThompsonLeonard Thompson(1908 – 1935)(1908 – 1935)
Dying from diabetes,Dying from diabetes,he was the first he was the first human to get the human to get the extract in extract in January 1922January 1922
Survived untilSurvived untilthe age of 27.the age of 27.
Banting FG, Best CH, Macleod JJR. Banting FG, Best CH, Macleod JJR. Am J PhysiolAm J Physiol. 1922;59:479.. 1922;59:479.
A much-acknowledged contributionA much-acknowledged contribution
The 1923 Nobel prize in medicine or The 1923 Nobel prize in medicine or physiology was awarded tophysiology was awarded to FREDERICK GRANT BANTINGFREDERICK GRANT BANTINGJOHN JAMES RICKARD MACLEODJOHN JAMES RICKARD MACLEOD
““for the discovery of insulin.”for the discovery of insulin.”
Banting shared his prize money with Banting shared his prize money with Charles Best while Mcleod shared Charles Best while Mcleod shared his with James Colliphis with James Collip
T1DM T1DM –– insulin insulin
Decrease in retinopathy with 2% Decrease in retinopathy with 2% ∆∆ in HbA in HbA1c1c
Impact of insulin on microvascularImpact of insulin on microvascularcomplications in T1DMcomplications in T1DM
DCCT Research Group. DCCT Research Group. N Engl J MedN Engl J Med. 1993;329:977-986.. 1993;329:977-986.
ConventionalConventionaltreatmenttreatment
IntensiveIntensivetreatmenttreatment
Mean reduction 76% Mean reduction 76% (95% CI, 62 – 85%)(95% CI, 62 – 85%)
PP < 0.001 < 0.001
Per
cen
tag
e o
f p
atie
nts
Per
cen
tag
e o
f p
atie
nts
Follow-up (years)Follow-up (years)ConventionalConventional 375375 220220 7979 5252IntensiveIntensive 342342 202202 7878 4949
0 1 2 3 4 5 6 7 8 9
50
60
30
40
10
20
0
Cumulative incidence of predefined cardiovascular events in theDiabetes Control and Complications Trial (DCCT–EDIC)
Years since entryYears since entryAt riskAt riskIntensiveIntensive 705705 686686 640640 118118ConventionalConventional 721721 694694 637637 9696
Impact of insulin on macrovascularImpact of insulin on macrovascularcomplications in T1DMcomplications in T1DM
57% risk reduction in non-fatal MI, stroke or CVD death (intensive vs. conventional; P = 0.02)
Intensivetreatment
Cu
mu
lati
ve i
nci
den
ce
of
no
nfa
tal
MI,
str
oke
or
dea
th f
rom
CV
D
Conventionaltreatment
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Years
0.06
0.04
0.02
0.00
DCCT (intervention period) EDIC (observational follow-up)
DCCT/EDIC Study Research Group. DCCT/EDIC Study Research Group. N Engl J MedN Engl J Med. 2005; 353:2643-2653.. 2005; 353:2643-2653.
Liver
Pancreas
Muscle and adipose tissue
InsulinInsulin
Sulphonylurea
Incretins
Metformin
Thiazolidinedionesα-glucosidaseinhibitors
Incretins
Metformin
Thiazolidinediones
GlucoseGlucose
GI
T2DM – a variety of drugsT2DM – a variety of drugs
Insulin in T2DM Insulin in T2DM –– why? why?
Restores insulin deficit in dysglycemiaRestores insulin deficit in dysglycemia Improved buffering of glucose changes by Improved buffering of glucose changes by
reducing the need for pancreatic insulinreducing the need for pancreatic insulin Reduces toxic pro-oxidant effects Reduces toxic pro-oxidant effects
of hyperglycemia of hyperglycemia Anti-inflammatory, vasodilatory & Anti-inflammatory, vasodilatory &
antithrombotic effectsantithrombotic effects Improves endothelial repair & dysfunctionImproves endothelial repair & dysfunction
Impact of glucose-lowering drugs Impact of glucose-lowering drugs on vascular endpoints in T2DMon vascular endpoints in T2DM
UKPDS.UKPDS. Lancet Lancet. 1998;352:837-853.. 1998;352:837-853.
Randomized tointensive 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)
Impact of glucose-lowering drugs Impact of glucose-lowering drugs on vascular endpoints in T2DMon vascular endpoints in T2DM
UKPDS.UKPDS. Lancet Lancet. 1998;352:837-853.. 1998;352:837-853.
Impact of intensive glucose lowering on Impact of intensive glucose lowering on microvascular complicationsmicrovascular complications
Decrease in retinopathy with Decrease in retinopathy with 2% 2% ∆∆ in HbA in HbA1c1c
Follow-up (years)Follow-up (years)
ConventionalConventional
IntensiveIntensive
Mean reduction 76% Mean reduction 76% (95% CI, 62 – 85%)(95% CI, 62 – 85%)
PP < 0.001 < 0.001
Per
cen
tag
e o
f p
atie
nts
Per
cen
tag
e o
f p
atie
nts
0 1 2 3 4 5 6 7 8 9
50
60
30
40
10
20
0
p=0.0099
0%
10%
20%
30%
0 3 6 9 12 15
% o
f pat
ient
s wi
th a
n ev
ent
Years from randomisation
Intensive
Conventional
Risk reduction 25%(95% CI: 7% to 40%)
Per
cen
tag
e o
f P
erce
nta
ge
of
pat
ien
ts w
ith
eve
nt
pat
ien
ts w
ith
eve
nt
Years from randomizationYears from randomization0 3 6 9
30
10
20
0
12 15
P = 0.0099
ConventionalConventional
IntensiveIntensive
Decrease in microvascular Decrease in microvascular complications with complications with
0.9% 0.9% ∆∆ in HbA in HbA1c1c
DCCT Research Group. DCCT Research Group. N Engl J MedN Engl J Med. 1993;329:977-986.. 1993;329:977-986. UKPDS.UKPDS. Lancet Lancet. 1998;352:837-853.. 1998;352:837-853.
Impact of glucose-lowering drugs on Impact of glucose-lowering drugs on macrovascular endpoints in T2DMmacrovascular endpoints in T2DM
UKPDS.UKPDS. Lancet Lancet. 1998;352:837-853.. 1998;352:837-853.
Glycaemic control and macrovascular disease: Beneficial start
UKPDS – 10-year follow-upUKPDS – 10-year follow-upGlycemic control (HbAGlycemic control (HbA1c1c) during follow up) during follow up
Between group difference in HbABetween group difference in HbA1c1c lost after the first years lost after the first years
Holman RR, et al. Holman RR, et al. N Engl J MedN Engl J Med. 2008;359:1577-1589.. 2008;359:1577-1589.
Impact of glucose-lowering drugs on Impact of glucose-lowering drugs on macrovascular endpoints in T2DMmacrovascular endpoints in T2DM
UKPDS – 10-year follow-upUKPDS – 10-year follow-upAll-cause mortalityAll-cause mortality
Holman RR, et al. Holman RR, et al. N Engl J MedN Engl J Med. 2008;359:1577-1589.. 2008;359:1577-1589.
Impact of glucose-lowering drugs on Impact of glucose-lowering drugs on macrovascular endpoints in T2DMmacrovascular endpoints in T2DM
SulphonylureaSulphonylurea––insulininsulin MetforminMetformin
UKPDS – patient characteristicsUKPDS – patient characteristics
Impact of glucose-lowering drugs on Impact of glucose-lowering drugs on macrovascular endpoints in T2DMmacrovascular endpoints in T2DM
UKPDS.UKPDS. Lancet Lancet. 1998;352:837-853.. 1998;352:837-853.
UKPDS – patient characteristicsUKPDS – patient characteristics
Impact of glucose-lowering drugs on Impact of glucose-lowering drugs on macrovascular endpoints in T2DMmacrovascular endpoints in T2DM
UKPDS.UKPDS. Lancet Lancet. 1998;352:837-853.. 1998;352:837-853.
MedicationMedication %%DiureticDiuretic 1313BP loweringBP lowering 1212ASAASA 1.51.5Lipid-loweringLipid-lowering 0.30.3
The PROACTIVE study: pioglitazone vs. placebo as add-on therapy
11°° endpoint: death, MI/ACS, stroke, leg endpoint: death, MI/ACS, stroke, leg amputation, coronary or leg revascularizationamputation, coronary or leg revascularization 22°° endpoint: death, MI or stroke endpoint: death, MI or stroke
Impact of glucose-lowering drugs on Impact of glucose-lowering drugs on macrovascular endpoints in T2DMmacrovascular endpoints in T2DM
Dormandy JA, et al. Dormandy JA, et al. LancetLancet. 2005;366:1279-1289.. 2005;366:1279-1289.
Number at riskNumber at risk
PioglitazonePioglitazone 2,4882,488 2,3732,373 2,3022,302 2,2182,218 2,1462,146 348348
PlaceboPlacebo 2,5302,530 2,4132,413 2,3172,317 2,2152,215 2,1222,122 345345
55
1010
1515
2525
0066
2020
00 1212 1818 2424 3030 3636
PioglitazonePioglitazone(514 events)(514 events)
10% RRR10% RRRHR (95% CI) = HR (95% CI) =
0.90 (0.80 –1.02)0.90 (0.80 –1.02)P P = 0.095= 0.095 PlaceboPlacebo
(572 events)(572 events)
Time from randomizationTime from randomization
Pro
po
rtio
n o
f ev
ents
(%
)P
rop
ort
ion
of
even
ts (
%)
55
1010
1515
2525
00
66
2020
00 1212 1818 2424 3030 3636
PioglitazonePioglitazone(301 events)(301 events)
PlaceboPlacebo(358 events)(358 events)
Time from randomizationTime from randomization
Pro
po
rtio
n o
f ev
ents
(%
)P
rop
ort
ion
of
even
ts (
%)
16% RRR16% RRRHR (95% CI) = HR (95% CI) =
0.84 (0.72 – 0.98)0.84 (0.72 – 0.98)PP = 0.027 = 0.027
Number at riskNumber at risk
PioglitazonePioglitazone 2,5362,536 2,4872,487 2,4352,435 2,3812,381 2,3362,336 396396
PlaceboPlacebo 2,5662,566 2,5042,504 2,4422,442 2,3712,371 2,3152,315 390390
Glycaemic control and macrovascular disease: Glycaemic control and macrovascular disease: Beneficial start, subsequent doubtsBeneficial start, subsequent doubts
ACCORDACCORD ADVANCEADVANCE
VADTVADT
Impact of glucose-lowering drugs on Impact of glucose-lowering drugs on macrovascular endpoints in T2DMmacrovascular endpoints in T2DM
00 11 22 33 44 55 66 77 88 00 11 22 33 44 55 66 77 88
00 11 22 33 44 55 66 77 88 00 11 22 33 44 55 66 77 88
00
2020
4040
6060
8080
100100
00
2020
4040
6060
8080
100100
00
1010
2020
00
1010
2020
Years since randomizationYears since randomization Years since randomizationYears since randomization
Par
tici
pan
ts w
ith
P
arti
cip
ants
wit
h
even
ts (
%)
even
ts (
%)
Par
tici
pan
ts w
ith
P
arti
cip
ants
wit
h
even
ts (
%)
even
ts (
%)
HR (95% CI) = 1.19 (1.03 – 1.38)HR (95% CI) = 1.19 (1.03 – 1.38)HR (95% CI) = 0.91 (0.81 – 1.03)HR (95% CI) = 0.91 (0.81 – 1.03)
Primary outcome until end of study Death from any cause until end of study
StandardStandard
IntensiveIntensive
IntensiveIntensive
StandardStandard
The ACCORD Study Group. The ACCORD Study Group. N Engl J MedN Engl J Med. 2011;364:818-828. . 2011;364:818-828.
Impact of glucose-lowering drugs on Impact of glucose-lowering drugs on macrovascular endpoints in T2DMmacrovascular endpoints in T2DM
T2DM at high risk (CVD or risk factors); N = 10,251T2DM at high risk (CVD or risk factors); N = 10,251 Glycaemic controlGlycaemic control
Intensive HbAIntensive HbA1c1c < 6.0% vs. conventional HbA < 6.0% vs. conventional HbA1c1c 7.0 7.0 –– 7.9% 7.9% Impact on cardiovascular morbidity and mortalityImpact on cardiovascular morbidity and mortality
The ACCORD Study Group. The ACCORD Study Group. N Engl J MedN Engl J Med. 2011;364:818-828. . 2011;364:818-828.
Impact of glucose-lowering drugs on Impact of glucose-lowering drugs on macrovascular endpoints in T2DMmacrovascular endpoints in T2DM
Nonfatal MINonfatal MIOR (95% CI) = 0.83 (75 – 0.93) OR (95% CI) = 0.83 (75 – 0.93)
All-cause mortality All-cause mortality OR (95% CI) = 1.02 (0.87 – 1.19)OR (95% CI) = 1.02 (0.87 – 1.19)
Meta-analysis of five major trialsMeta-analysis of five major trialsUKPDS, PROACTIVE, ADVANCE, VADT, ACCORD UKPDS, PROACTIVE, ADVANCE, VADT, ACCORD
Mean HbAMean HbA1c1c difference intensive vs. standard = 0.9% difference intensive vs. standard = 0.9%
Impact of intensive glucose-lowering on Impact of intensive glucose-lowering on macrovascular complications in T2DMmacrovascular complications in T2DM
Ray KK, et al. Ray KK, et al. LancetLancet. 2009;373:1765-1772.. 2009;373:1765-1772.
Impact of intensive glucose-lowering on Impact of intensive glucose-lowering on macrovascular complications in T2DMmacrovascular complications in T2DM
Turnbull FM, et al. Turnbull FM, et al. DiabetologiaDiabetologia. 2009;52:2288-2298.. 2009;52:2288-2298.
Meta-analysis of four major trialsMeta-analysis of four major trialsUKPDS, ADVANCE, VADT, ACCORD UKPDS, ADVANCE, VADT, ACCORD
Impact of insulin on macrovascular Impact of insulin on macrovascular complications in T2DM (and IGT)complications in T2DM (and IGT)
In In high-riskhigh-risk people with IFG, IGT or early diabetes, people with IFG, IGT or early diabetes, does insulin replacement therapy does insulin replacement therapy targetingtargeting fasting fasting normoglycemia (normoglycemia (<< 5.3 mM or 95 mg/dL) with insulin 5.3 mM or 95 mg/dL) with insulin glargine, reduce CV outcomes more than standard glargine, reduce CV outcomes more than standard
approaches to dysglycemia?approaches to dysglycemia?
ORIGIN Trial Investigators. ORIGIN Trial Investigators. N Engl J MedN Engl J Med. 2012;367:319-328.. 2012;367:319-328.
Impact of insulin on macrovascular Impact of insulin on macrovascular complications in T2DM (and IGT)complications in T2DM (and IGT)
6.9
5.25 5 5.1 5.1 5.2 5.2 5.3
6.96.6
6.8
4.0
4.5
5.0
5.5
6.0
6.5
7.0
7.5
8.0
0 1 2 3 4 5 6 7 End
Year
FP
G (
mm
ol/
L)
Glargine
Standard
PenultimatePenultimateIQR 4.4 – 5.8IQR 4.4 – 5.8
IQR 5.7 – 7.9IQR 5.7 – 7.9
ORIGIN Trial Investigators. ORIGIN Trial Investigators. N Engl J MedN Engl J Med. 2012;367:319-328.. 2012;367:319-328.
Fasting glucose at study endFasting glucose at study endInsulinInsulin 5.3 mmol/L5.3 mmol/LStandard careStandard care 6.8 mmol/L6.8 mmol/L
Impact of insulin on macrovascular Impact of insulin on macrovascular complications in T2DM (and IGT)complications in T2DM (and IGT)
ORIGIN Trial Investigators. ORIGIN Trial Investigators. N Engl J MedN Engl J Med. 2012;367:319-328.. 2012;367:319-328.
Safety of glucose-lowering Safety of glucose-lowering drugs in T2DMdrugs in T2DM
Potential problemPotential problem Avoid or reconsiderAvoid or reconsider
Weight gainWeight gain SUs, glinides, TZDs, insulinSUs, glinides, TZDs, insulin
GastrointestinalGastrointestinal Biguanides, Biguanides, αα-glucosidase inhibitors-glucosidase inhibitors
HypoglycemiaHypoglycemia SUs, glinides, insulinSUs, glinides, insulin
Kidney dysfunctionKidney dysfunction Biguanides, SUsBiguanides, SUs
Hepatic dysfunctionHepatic dysfunction Glinides, TZDs, biguanides, Glinides, TZDs, biguanides, αα-glucosidase -glucosidase inhibitorsinhibitors
Cardiovascular concernsCardiovascular concerns Biguanides, TZDsBiguanides, TZDs
Rydén L, et al. Rydén L, et al. Eur Heart JEur Heart J. 2007;28:88-136.. 2007;28:88-136.
1 1 2 2 4 4 Favours Favours TZDTZD Placebo Placebo
RosiRosi
PioPio
TotalTotal
Odds ratio (95%CI)Odds ratio (95%CI)
Safety of glucose-lowering drugsSafety of glucose-lowering drugs
Hernandez AV, et al. Hernandez AV, et al. Am J Cardiovasc DrugsAm J Cardiovasc Drugs. 2011;11:115-128.. 2011;11:115-128.
Pio- and rosiglitazone and heart failure Pio- and rosiglitazone and heart failure
Safety of glucose-lowering drugsSafety of glucose-lowering drugs
Rosiglitazone and CVD events Rosiglitazone and CVD events
Nissen SE, Wolski K. Nissen SE, Wolski K. N Engl J MedN Engl J Med. 2007;356:2457-2471.. 2007;356:2457-2471.
Safety of glucose-lowering drugsSafety of glucose-lowering drugs
Rosiglitazone and CVD events Rosiglitazone and CVD events
Nissen SE, Wolski K. Nissen SE, Wolski K. N Engl J MedN Engl J Med. 2007;356:2457-2471.. 2007;356:2457-2471.
U.S. Food and Drug AdministrationU.S. Food and Drug Administration
Strict demands on cardiovascular Strict demands on cardiovascular safety of glucose-lowering drugssafety of glucose-lowering drugs
FDA NewsFDA NewsFOR IMMEDIATE RELEASEFOR IMMEDIATE RELEASEDecember 17, 2008 December 17, 2008 Consumer Inquiries: Consumer Inquiries: 888-INFO-FDA 888-INFO-FDA FDA Announces New Recommendations on Evaluating Cardiovascular FDA Announces New Recommendations on Evaluating Cardiovascular Risk in Drugs Intended to Treat Type 2 Diabetes Risk in Drugs Intended to Treat Type 2 Diabetes
The U.S. Food and Drug Administration recommended today that The U.S. Food and Drug Administration recommended today that Manufacturers developing new drugs and biologics for type 2 diabetes Manufacturers developing new drugs and biologics for type 2 diabetes provide evidence that the therapy will not increase the risk of such provide evidence that the therapy will not increase the risk of such cardiovascular events as a heart attack.cardiovascular events as a heart attack.
The recommendation is part of a new guidance for industry that applies The recommendation is part of a new guidance for industry that applies to all diabetes drugs currently under development. to all diabetes drugs currently under development.
Safety of glucose-lowering drugs:Safety of glucose-lowering drugs:rosi- vs. pioglitazonerosi- vs. pioglitazone
Systematic review and meta-analysis of 16 Systematic review and meta-analysis of 16 observational studies comparing risk of observational studies comparing risk of cardiovascular outcomes forcardiovascular outcomes for Rosiglitazone (N = 429,000) Rosiglitazone (N = 429,000) andand Pioglitazone (N = 381,000) Pioglitazone (N = 381,000)
in patients with T2DM during 105 days – 7 yearsin patients with T2DM during 105 days – 7 years
Loke YK, et al. Loke YK, et al. BMJBMJ. 2011;342:d1309. 2011;342:d1309..
Safety of glucose-lowering drugs:Safety of glucose-lowering drugs:rosi- vs. pioglitazonerosi- vs. pioglitazone
Loke YK, et al. Loke YK, et al. BMJBMJ. 2011;342:d1309. 2011;342:d1309..
Overall mortalityOverall mortalityHeart failureHeart failureMyocardial infarctionMyocardial infarction
Safety of glucose-lowering drugs:Safety of glucose-lowering drugs:rosi- vs. pioglitazonerosi- vs. pioglitazone
The TIDE Trial Investigators. The TIDE Trial Investigators. Diabetologia.Diabetologia. 2012;55:36-45. 2012;55:36-45.
Safety of glucose-lowering drugs:Safety of glucose-lowering drugs:rosi- vs. pioglitazonerosi- vs. pioglitazone
The TIDE Trial Investigators. The TIDE Trial Investigators. Diabetologia.Diabetologia. 2012;55:36-45. 2012;55:36-45.
Insulin – potential drawbacksInsulin – potential drawbacks
Smith U, Gale AM. Smith U, Gale AM. Diabetologia.Diabetologia. 2009;52:1699-1708. 2009;52:1699-1708.
Insulin – potential drawbacksInsulin – potential drawbacks
Hemkens LG, et al. Hemkens LG, et al. Diabetologia.Diabetologia. 2009;52:1732-1744. 2009;52:1732-1744.Jonasson JM, et al. Jonasson JM, et al. DiabetologiaDiabetologia. 2009;52:1745-1754.. 2009;52:1745-1754.
GlargineGlargine StandardStandard HR (95%CI)HR (95%CI) PP n (%)n (%) RateRate n (%)n (%) RateRate
Cancer deathCancer death 0.94 (0.77 – 1.15)0.94 (0.77 – 1.15) 0.520.52 189 (3.0)189 (3.0) 0.510.51 201 (3.2)201 (3.2) 0.540.54
Any cancerAny cancer 1.00 (0.88 – 1.13)1.00 (0.88 – 1.13) 0.970.97 476 (7.6)476 (7.6) 1.321.32 477 (7.6)477 (7.6) 1.321.32
LungLung 1.21 (0.87 – 1.67)1.21 (0.87 – 1.67) 0.270.27 80 (1.3)80 (1.3) 0.220.22 66 (1.1)66 (1.1) 0.180.18
ColonColon 1.09 (0.79 – 1.51)1.09 (0.79 – 1.51) 0.610.61 76 (1.2)76 (1.2) 0.210.21 70 (1.1)70 (1.1) 0.190.19
BreastBreast 1.01 (0.60 – 1.71)1.01 (0.60 – 1.71) 0.950.95 28 (0.4)28 (0.4) 0.080.08 28 (0.4)28 (0.4) 0.080.08
ProstateProstate 0.94 (0.70 – 1.26)0.94 (0.70 – 1.26) 0.700.70 88 (2.1)88 (2.1) 0.360.36 89 (2.2)89 (2.2) 0.380.38
MelanomaMelanoma 0.88 (0.44 – 1.75)0.88 (0.44 – 1.75) 0.710.71 15 (0.2)15 (0.2) 0.040.04 17 (0.3)17 (0.3) 0.050.05
OtherOther 0.95 (0.80 – 1.14)0.95 (0.80 – 1.14) 0.590.59 233 (3.7)233 (3.7) 0.640.64 245 (3.9)245 (3.9) 0.670.67
Any skinAny skin 1.02 (0.78 – 1.33)1.02 (0.78 – 1.33) 0.880.88 110 (1.8)110 (1.8) 0.300.30 108 (1.7)108 (1.7) 0.290.29
Impact of insulin on Impact of insulin on cancer in T2DMcancer in T2DM
1 10
ORIGIN Trial Investigators. ORIGIN Trial Investigators. N Engl J MedN Engl J Med. 2012;367:319-328.. 2012;367:319-328.
Safety of glucose-lowering drugsSafety of glucose-lowering drugs
Pioglitazone and bladder cancer Pioglitazone and bladder cancer
Lewis JD, et al. Lewis JD, et al. Diabetes CareDiabetes Care. 2011;34:916-922. 2011;34:916-922..
Kaiser Permanente diabetes registry Kaiser Permanente diabetes registry 193,099193,099
On pioglitazoneOn pioglitazone 30,17330,173
HR for bladder cancerHR for bladder cancer
OverallOverall 1.2 (95% CI, 0.9 – 1.5)1.2 (95% CI, 0.9 – 1.5)
Treated > 24 monthsTreated > 24 months 1.5 (95% CI, 1.03 – 2.0)1.5 (95% CI, 1.03 – 2.0)
Effects of established glucose-lowering Effects of established glucose-lowering drugs on cardiovascular riskdrugs on cardiovascular risk
Some reflections Some reflections Strict glycaemic control in the presence of multifactorial Strict glycaemic control in the presence of multifactorial
therapy (lipids, blood pressure etc) less rewarding!therapy (lipids, blood pressure etc) less rewarding! The impact of glycaemic control perhaps more apparent if The impact of glycaemic control perhaps more apparent if
instituted in early dysglycaemia?instituted in early dysglycaemia? Are patients without apparent CVD more sensitive to glycaemic Are patients without apparent CVD more sensitive to glycaemic
control?control? Legacy effect may be important – is follow up still too short?Legacy effect may be important – is follow up still too short? Hypoglycaemia and weight gain do not fully explain lack of Hypoglycaemia and weight gain do not fully explain lack of
effect!effect! Some glucose-lowering drugs may cause harm alone Some glucose-lowering drugs may cause harm alone
or when combined!or when combined! Insulin safe at least if given to strict glycaemic targetsInsulin safe at least if given to strict glycaemic targets
2-year mortality 18.4%2-year mortality 18.4%Predicted mortality 22.3%Predicted mortality 22.3%
55
1010
1515
2020
2525
0 200 400 600Follow-up time (days)
♦♦
♦♦
Total study mortality 21.3%Total study mortality 21.3%
800 1,000 1,200
Which patients are we studying?Which patients are we studying?
Malmberg K, Rydén L, et al. Malmberg K, Rydén L, et al. Eur Heart JEur Heart J. 2005;26:650-661.. 2005;26:650-661.
Per
cen
t
00
Mortality in DIGAMI 2Mortality in DIGAMI 2
Which patients are we studying?Which patients are we studying?
ACCORDACCORD F/u median 3.4 yearsF/u median 3.4 years 11°° outcome: MI, stroke, outcome: MI, stroke,
CV deathCV death
ADVANCEADVANCE F/u median 5 yearsF/u median 5 years 11°° outcome: major outcome: major
macro- and macro- and microvascular events microvascular events
ADVANCE Collaborative Group. ADVANCE Collaborative Group. N Engl J. MedN Engl J. Med. 2008;358:2560-2572.. 2008;358:2560-2572.ACCORD Study Group. ACCORD Study Group. N Engl J MedN Engl J Med. 2008;358:2545-2559.. 2008;358:2545-2559.
Events in ACCORD and ADVANCE related to DIGAMI 2Events in ACCORD and ADVANCE related to DIGAMI 2
Years of follow-upYears of follow-up Months of follow-upMonths of follow-up
Pat
ien
ts w
ith
eve
nts
(%
)P
atie
nts
wit
h e
ven
ts (
%)
Cu
mu
lati
ve in
cid
ence
(%
)C
um
ula
tive
inci
den
ce (
%)
Standard
Intensive
Standard
Intensive
HR (95% CI) = 0.90 (0.82 – 0.98)
P = 0.01
Effects of established glucose-lowering Effects of established glucose-lowering drugs on cardiovascular riskdrugs on cardiovascular risk
Norhammar A, et al. Norhammar A, et al. EuroInterventionEuroIntervention. 2010;5:891-897. doi:10.4244/.. 2010;5:891-897. doi:10.4244/.
2020
2525
1515
1010
55
00
Mo
rtal
ity
(%)
Mo
rtal
ity
(%)
00 11 22 33 44 55 66
Years after PCIYears after PCI
STEMI + DMSTEMI + DM
NSTEMI + DMNSTEMI + DM
STEMI STEMI – no– no DM DM
Stable AP + DMStable AP + DM
NSTEMI – no DMNSTEMI – no DM
Stable AP – no DMStable AP – no DM
From the Swedish PCI registryFrom the Swedish PCI registry
One
-yea
r m
orta
lity
(%)
Effects of established glucose-lowering Effects of established glucose-lowering drugs on cardiovascular riskdrugs on cardiovascular risk
DiabetesDiabetes
No diabetesNo diabetes
Norhammar A, et al. Norhammar A, et al. HeartHeart. 2007;93:1577-1583; SWEDEHEART 2011 Annual Report. . 2007;93:1577-1583; SWEDEHEART 2011 Annual Report. www.ucr.uu.se/swedeheart/.../178-swedeheart-annual-report-2011-englishwww.ucr.uu.se/swedeheart/.../178-swedeheart-annual-report-2011-english
One-year mortality following MI: Sweden 1994 – 2010One-year mortality following MI: Sweden 1994 – 2010
Effects of established glucose-lowering Effects of established glucose-lowering drugs on cardiovascular riskdrugs on cardiovascular risk
♦♦
One-year mortality DIGAMI 2One-year mortality DIGAMI 2
DiabetesDiabetes
No diabetesNo diabetes
One
-yea
r m
orta
lity
(%)
One-year mortality following MI: Sweden 1994 – 2010One-year mortality following MI: Sweden 1994 – 2010
Norhammar A, et al. Norhammar A, et al. HeartHeart. 2007;93:1577-1583; SWEDEHEART 2011 Annual Report. . 2007;93:1577-1583; SWEDEHEART 2011 Annual Report. www.ucr.uu.se/swedeheart/.../178-swedeheart-annual-report-2011-englishwww.ucr.uu.se/swedeheart/.../178-swedeheart-annual-report-2011-english
Effects of multifactorial treatment of Effects of multifactorial treatment of T2DM on cardiovascular riskT2DM on cardiovascular risk
Courtesy: P. Gaede.Courtesy: P. Gaede.
SmokingSmoking3%3%
Blood Blood pressurepressure
11%11%
HbAHbA1c1c
13%13% Total cholesterolTotal cholesterol48%48%
LipidsLipids73%73%
HDL-cholesterolHDL-cholesterol25%25%
Proportionate contribution of treatment components applying UKPDS Proportionate contribution of treatment components applying UKPDS risk score in STENO–2 intensive armrisk score in STENO–2 intensive arm
T2DM/CVDT2DM/CVD
InflammationhsCRP
IL–1IL–6
TNF–αMMPs
CD40–ligPAI–1
Adipokines
DyslipidemiaSmall dense LDL
HDLFFAs
TriglyceridesApoB, ApoA–1
HypercoagulabilityPAI–1
FibrinogenAntithrombin activity
GH systemIGF–I
IGFBP–1IBFBP–3
Dysglycaemiaβ-cell dysfunctionInsulin resistance
Oxidative stressAGEsoxLDL
PAF-acetylhydrolase
Endothelial dysfunction
vWFtPA antigen
Adhesion moleculesET–1, NO
T2DM – more than hyperglycaemiaT2DM – more than hyperglycaemia
Inflammation and thrombolysis/ fibrinolysis
↓ hs-CRP 40%
↓ Fibrinogen 10%
↓ PAI–1 6%
Hypertension
↓ Blood pressure 1 – 3 mmHg
Glycemic control
↓ HbA1c 0.85% ↓ FPG 2.16 mmol/L↓ HOMA–IR 35%
Dyslipidemia
↑ HDL 21%↓ Triglycerides 43%
↓ LDL 10%
Shift to fewer and larger particles!
Targets for the balanced PPAR Targets for the balanced PPAR αα//γγ agonist aleglitazaragonist aleglitazar
Henry RR, et al. Henry RR, et al. LancetLancet. 2009;374:126-135.. 2009;374:126-135.
Effects of GLP–1 on Effects of GLP–1 on various tissuesvarious tissues
Baggio LL, Drucker DJ. Baggio LL, Drucker DJ. GastroenterologyGastroenterology. 2007;132:2131-2157.. 2007;132:2131-2157.
OR (95%CI)
Trials with GLP–1 analogs Trials with GLP–1 analogs and DPP–4 inhibitorsand DPP–4 inhibitors
Monami M. et al. Monami M. et al. Curr Med Res OpinCurr Med Res Opin. 2011;27:57-64.. 2011;27:57-64.
OR (95%CI)Ongoing trials with CV endpointsOngoing trials with CV endpointsAcronymAcronym TypeType DrugDrugLeaderLeader GLPGLP––11 LiraglutideLiraglutideExscelExscel GLPGLP––11 ExenatideExenatideELIXAELIXA GLPGLP––11 LixisenatideLixisenatideSAVORSAVOR––TIMI 53TIMI 53 DPPDPP––44 inhibitor inhibitor SaxagliptinSaxagliptinTECOSTECOS DPPDPP––4 inhibitor4 inhibitor SitagliptinSitagliptinCAROLINACAROLINA DPPDPP––4 inhibitor4 inhibitor LinagliptinLinagliptinEXAMINEEXAMINE DPPDPP––4 inhibitor4 inhibitor AlogliptinAlogliptin
Trials with GLP–1 analogs Trials with GLP–1 analogs and DPP–4 inhibitorsand DPP–4 inhibitors
Monami M. et al. Monami M. et al. Curr Med Res OpinCurr Med Res Opin. 2011;27:57-64.. 2011;27:57-64.
ConclusionsConclusions Strict glycaemic control protects from Strict glycaemic control protects from
microvascular complicationsmicrovascular complications Glucose target in established T2DM Glucose target in established T2DM
remains uncertainremains uncertain Available drugs may be less well suited Available drugs may be less well suited
for cardioprotectionfor cardioprotection Individualized multifactorial Individualized multifactorial
management importantmanagement important
Effects of established glucose-lowering Effects of established glucose-lowering drugs on cardiovascular riskdrugs on cardiovascular risk
ConclusionsConclusions Strict glycaemic control protects from Strict glycaemic control protects from
microvascular complicationsmicrovascular complications Glucose target in established T2DM Glucose target in established T2DM
remains uncertainremains uncertain Available drugs may be less well suited Available drugs may be less well suited
for cardioprotectionfor cardioprotection Individualized multifactorial Individualized multifactorial
management importantmanagement important
New tools and strategies
New tools and strategies
for gluco-metabolic control
for gluco-metabolic control
needed!!!!!needed!!!!!
Effects of established glucose-lowering Effects of established glucose-lowering drugs on cardiovascular riskdrugs on cardiovascular risk