Multifactorial Intervention in DM ! Beyond a Glucose-centric Approach The ABCDE of Diabetes Maeve C....
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Multifactorial Intervention in DM !Beyond a Glucose-centric Approach
The ABCDE of DiabetesMaeve C. Durkan MBBS, FACP, Mmed.Ed
Consultant in Diabetes, Endocrinology & Metabolism
Steno-2 Study:Composite End Point
Gaede P et al. N Engl J Med. 2003;348:383-393.
*In accordance with national guidelines†Multifactorial intervention
No. at RiskConventional tx* 80 72 70 63 59 50 44 41 13Intensive tx† 80 78 74 71 66 63 61 59 19
Months0 12 24 36 48 60 72 84 96
60
50
40
30
20
10
0
Conventional therapy
Intensive therapy
P=0.007
Primarycomposite end point
(% )
53%
© 2005 Thomson Professional Postgraduate Services®
A Multifactorial ApproachLessons from Steno 2 1,2
HR• Cardiovascular Death 0.43• Cardiovascular Events 0.41• Photocoagulation 0.48
• Not a GLUCOSE-CENTRIC strategy• But tight METABOLIC CONTROL
Multifactorial Approach
• Not a GLUCOSE-CENTRIC strategy• But tight METABOLIC CONTROL
• The EARLIER the better ….Imprinting
• Additional effect with BP & Cholesterol
DM shortens Lives
• Diabetes (-)……………….Live forever !
• DM …………………………..Minus 6 years
• DM & MI ………………….Minus 12 years
2/3 DM patients die from a CV event
• Modifiable Risks
– A ( A1c), B ( BP), C ( Chol)
• Non Modifiable Risks
– Age, gender, ethnic group
50 year old • DM2 x 5 years• Coexistent hypertension ( on CoDiovan )• Stable Angina . No CHF .• O/e : BMI 31, BP 145/90• Cardiac & Respiratory exam normal• On Glucophage 1gm BD
• HbA1c 7.8% ( 62 mmolar) , LFTs ALT 75,AST 45 • GFR 60 , Urine A/c ratio 3.5,
ADOPT 10
HbA1c Over Time
0 1 2 3 4 5
Time (years)
%
0
6.0
8.0
7.0
6.5
7.5
Rosiglitazone
Glyburide
Metformin
Rosiglitazone vs Metformin
0.13 ( 0.22 to 0.05), P=0.002
Rosiglitazone vs Glyburide 0.42 ( 0.50 to 0.33), P<0.001
What Next after Metformin
GRADE study : Worldwide Trial
•Post metformin•Randomization to any one of each class•Except SGLT2•Not powered as a CV trial
What did we get ?What so we want ?
Past Options Now • Limited choice• Weight gain• Hypoglycemia• risk approaching
target• Β cell fatigue• Loss durability• Complications
• More choice • Weight loss / neutrality• Less hypoglycemia• risk approaching
targets• Β cell preservation !• Durability• Complications *
What Next ?
• Sulphonylurea • Incretin
– GLP 1 analogue ( daily/ weekly)– DPP IV
• SGLT2• TZD• Insulin
HbA1c targets
• Individualized
• < 7.0% : For all ?
• < 6.5% : For Newly diagnosed ?
• What about the newly diagnosed 75year old ?
A1c Targets & Effect in DM2
ACCORD 3
10251
ADVANCE 4
11150
UKPDS 5
5102
A1c < 6.0%
A1c > 7.0%
A1c < 6.5% A1c < 7.0%
Glucophage*
Mortality & A1c Targets
• ACCORD 10250 , High risk, Diabetes Duration 8-10years
• VADT 1791, High risk, Diabetes Duration 11.5 years
• ADVANCE 11,140 Moderate risk*, Diabetes Duration 8 yrs.
• STENO 160, Low risk, Short Duration
• UKPDS 3867, Low risk*, Newly diagnosed
• DCCT 1441, Low risk, Diabetes Duration (1-15 years)
Impact of Glucose RCT Lowering Trials in DM
Study Microvasc Extension CVD Extension Mortality Extension
UKPDS 33 ↓ ↓ ↔ ↓ ↔ ↓
DCCT/EDIC ↓ ↓ ↔ ↓ ↔ ↓
ACCORD ↓ ↓ ↔ ↔ ↑
ADVANCE ↓ ↓ ↔ ↔ ↔ ↔
VADT ↓ ↓ ↔ ↓ ↔ ↔
-2
-1
0
1
Ch
ang
e in
Hb
A1c
(%
)
TIME (years)0 1 2 3 4 5 6 10
Hanefeld (n=250)
Charbonnel (n=313)
Chicago (n=230)
ADOPT (n=1,441)
UKPDS (n=1,573)
GliclazideGliclazide
PERISCOPE (n=181)
GLY
GlimepirideGlyburide Glyburide
Glyburide
Glyburide
SU
SU
Alvarsson (n=39)
Alvarsson (n=48)RECORD (n=272)
Tan (n=297)
Gliclazide
DURABILITY OF GLYCEMIC CONTROL DURABILITY OF GLYCEMIC CONTROL WITH SULFONYLUREASWITH SULFONYLUREAS
Sulphonylureas
• Pros
• Effective• Work & work quickly• Work well• 100% responders• HbA1c ↓ 1-2 %• Around for years
• Cons
• Hypoglycaemia• Weight gain• Beta cell fatigue• Durability • CV risk *
Driving Guidelines
New European, UK & Irish Guidelines > 2 hypos / year ( On sulphonylureas ) Glucose records required on SU’s Insulin
-2
-1
0
1
Ch
ang
e in
Hb
A1c
(%
)
TIME (years)0 1 2 3 4 5 6
PIOPIO
PIO
RosiglitazoneRosiglitazone
DURABILITY OF GLYCEMIC CONTROL DURABILITY OF GLYCEMIC CONTROL WITH THIAZOLIDINEDIONESWITH THIAZOLIDINEDIONES
Hanefeld (n=250)
Charbonnel (n=317)
Chicago (n=232) ADOPT (n=1,456)
PIO
PERISCOPE (n=178)
PIO
RECORD (n=301)
Rosenstock (n=115)
ROSI
Tan (n=249)
PIO
TZDs: Pioglitazone (Actos)
• Pros • Effective , more slowly• No hypoglycemia• HbA1c ↓ 1-2 %• Improved Lipids ( LDL*, Tg)• Target IR • Durability• CV benefit proven• NAFLD target ?
• Cons • Weight gain (fluid)• Heart failure (NYC 111&IV)• Bone thinning/ Fractures• C/I with Dapagliflozin*
DPP IV Inhibitors Pros Cons
• Easily added to all, and/or insulin in & DM 2
• Safe & effective in CKD
• Weight neutral
• HbA1c ↓(0.6-1%)
• No hypoglycemia
•Heart Failure•TECOS rr 1.0
•Pancreatitis ?
•Cancer ? NO EVIDENCE
1o Composite Cardiovascular Outcome*
PP Analysis for Non-inferiority
* CV death, nonfatal MI, nonfatal stroke, hospitalization for unstable angina
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
GLP1 Inhibitors Pros Cons
• Easily added to anything, and/or insulin in DM1* & 2
• Safe & effective in CKD
• Concomitant weight loss
• SBP & DBP reduction
• HbA1c reduction
• No hypoglycemia
• 1/3 don’t respond
• Nausea
• Pancreatitis ? NO EVIDENCE
• No CV signal yet– Lixizenatide
• Cancer ? NO EVIDENCE
• Needle
SGLT2 Inhibitors Pros Cons
• Easily added to anything, and/or insulin in DM1 & 2
• Simple & dose response
• Concomitant weight loss
• SBP & DBP reduction
• HbA1c reduction
• No hypoglycemia
• UTI & Genital tract infections
• LDL (unclear mechanism)
• HDL (unclear mechanism)
• No CV signal yet– Canvas
• Limited to CKD ( eGFR>45)
• Reversible shift in GFR
EMPA – REGEmpagliflozin ( NEJM Sept 16,2015)
•Clear Findings•High risk Group•↓Hospitalization for Heart failure•↓Cardiac mortality
Comparability
Admin HbA1c Weight Tolerability
Exenatide
LAR
Inj BD
Inj week
Broadly comparable
Approx. 1-2%
↓↓ Nausea
Liraglutide* Inj QD ↓↓ Nausea
DPP IVs POBroadly comparable
Approx. 0.5 – 1%
←→ -
-
SGLT2s PO ↓ -
65 year old Man• DM2 BMI 27• Glucophage 850mg tds, diamicron 60• HbA1c 7.5%• Spends 4/7 working on farm 200 km away• Stable CKD, eGFR 45• Significant low one night ( requiring 3rd party help)• Driving license due for renewal• What next ?
What’s his priority in treatment?• Safety & Independence• Free of hypoglycemia• Can drive• Can tend to his farm• Personalized HbA1c targets• Comorbidities…eGFR 45
What did I do ?
•Stopped gliclazide / Increase gliclazide
•Add pioglitazone Combination ( Competact )
•Add Incretin ( DPPIV or GLP1 analogue)
•Add SGLT2
BP
• 50 year old man
• DM2 : Diet controlled x 4 years
• Obese, Hypertensive
• No other co-morbidities
• What is his target BP ?
56 year old DM2
• What is his ULTIMATE best target BP ?
• A. Is it ‘ The lower the better, as tolerated ‘
• B. Is there a J curve ?
INVEST Trial
SBP<120 SBP 130-140 SBP > 140
Tight Usual* Not controlled
HR 1.15
CI (1.1-1.36)
Risk Major Events Highest
56 year old DM2 (+) microalbuminuria
• What is his target BP ?
• A. < 130/80• B. < 120/80• C. The lower the better, as tolerated
• Is there a J curve ?
ACCORD : 4733 patients
• SBP < 120• Intensive Arm• RR Stroke :41%
– NTT 89
• A/c 12.4• Macro 6.4%• eGFR 74.9*• Creat 1.1mg/dl*
• SBB < 140* (133.9)• Conventional Arm
• A/C 18.6 ( p < 0.0001)• Macro 7.0% (p < 0.0001)• eGFR 80.6 (p<0.0001)• Creat 1.0 ( p<0.0001)
Cholesterol• 52 year old man ,DM2 x 5 years• HbA1c 6.5%• No co-morbidities / or CAD+
• LDL 4, Tg 1.5, HDL 1 ( Total Cholesterol 4.3 *)
• Will you treat?• What will you treat ?• What is target ?
Treatment Guidelines• EASD / BHS
• Target driven
• LDL < 2 ( 2.5)
• AHA / ACC
• Not target driven
• 50% reduction in LDL
• High intensity vs Low Intensity statins
• ASCVD risk calculator 7.5%
LDL
Atorvastatin
Lipitor
80mg
Simvastatin
Zocor
40mg
Rosuvastatin
Crestor
40mg
LDL @ max
60% 41% 63%
Tg’s 29%
(40mg)
18% (40mg)
28%
(40mg)
Patient returns c/o muscle aches
Do you ?
A. Stop medicationB. Switch to another statinC. Change to fibrate
D. Add ezetrol
LDL 1.3, Tg 1.5, HDL 1
• 52 year old man
• DM2 x 5 years
• HbA1c 6.5%
• STEMI last year / Stent x 1
How Low to GO ?