Ryden 9 16

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

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Per

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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

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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


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

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Per

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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

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pat

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pat

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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


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.


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.


SulphonylureaSulphonylurea––insulininsulin MetforminMetformin

UKPDS – patient characteristicsUKPDS – patient characteristics



UKPDS – patient characteristicsUKPDS – patient characteristics



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


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

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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

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%)

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PioglitazonePioglitazone(301 events)(301 events)

PlaceboPlacebo(358 events)(358 events)

Time from randomizationTime from randomization

Pro

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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


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

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P

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ants

wit

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%)

even

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%)

Par

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P

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ants

wit

h

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%)

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.


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.


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.


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


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



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


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.


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..


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

Overall mortalityOverall mortalityHeart failureHeart failureMyocardial infarctionMyocardial infarction


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


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



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%

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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

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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

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Standard

Intensive

Standard

Intensive

HR (95% CI) = 0.90 (0.82 – 0.98)

P = 0.01


Norhammar A, et al. Norhammar A, et al. EuroInterventionEuroIntervention. 2010;5:891-897. doi:10.4244/.. 2010;5:891-897. doi:10.4244/.

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Mo

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Mo

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(%)

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

(%)


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


♦♦

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


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!!!!!


Health & Medicine

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