Participant Guide Female with CKD 2optimalplus.ca/en/documents_cas2/participant_guide.pdf · 2013. 11. 29. · This program has been reviewed by The College of Family Physicians of

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OPTImizing the clinical MAnagement of type 2 diabetes:a knowLedge transfer experience + MORE

Participant Guide FemalewithCKD Cas2se

Cas3se

Cas3se

3

OPTImizing the clinical MAnagement of type 2 diabetes:a knowLedge transfer experience + MORE

Program Overview

OPTIMAL+ is a unique, case-based continuing health education program that was developed based on challenges and gaps in the management of patients with type 2 diabetes identified via the OPTIMAL+ multi-phase in-practice needs assessment initiative.

The OPTIMAL+ needs assessment was conducted with 157 primary care practitioners from across the country who assessed their practice with patients with type 2 diabetes. The results provided insights into actual type 2 diabetes practice based on real cases.

This program contains a series of cases taken directly from the OPTIMAL+ database of 977 patients. The selected cases and “what if” scenarios represent the most common challenges and areas of uncertainties faced by participants in the needs assessment when managing patients with type 2 diabetes. Each case contains its own initial scenario followed by interactive questions to stimulate discussion and “what if” scenarios to enable exploration of different therapeutic avenues.

Learning Objectives

At the conclusion of this case, the participant should be able to:

– Have a clear understanding of the concept of Global Vascular Protection– Determine appropriate and individualized therapeutic targets for A1C, lipids (LDL-cholesterol, ApoB, non-HDL cholesterol) and blood pressure based on the 2012-2013 Canadian clinical practice guidelines– Appropriately select and adjust pharmacotherapy for the patient with type 2 diabetes mellitus who also presents with dyslipidemia, hypertension and impaired kidney function

Accreditation

This program has been reviewed by The College of Family Physicians of Canada and is awaiting final accreditation by the College’s provincial chapters for up to 3 Mainpro-M1 credits.

Keith Bowering, MD, FRCPCDiabetologist, Edmonton, AB

Stewart Harris, MDFamily Physician, London, ON

Lawrence Leiter, MD, FRCPCEndocrinologist, Toronto, ON

Vincent Woo, MD, FRCPCEndocrinologist, Winnipeg, MB

Jean-François Yale, MD, FRCPCEndocrinologist, Montreal, QC

Dr. Jean-Pierre Beauchemin, Quebec City, QC

Dr. Yves Boily, Saguenay, QC

Dr. Alice Cheng, Mississauga, ON

Dr. Marie-Andrée Corbeil, St-Jean-sur-Richelieu, QC

Dr. Keith Dawson, Vancouver, BC

Dr. Chantal Godin, Sherbrooke, QC

Dr. Amir Hanna, Toronto, ON

Dr. Phyllis Hierlihy, Ottawa, ON

Dr. Irene Hramiak, London, ON

Dr. David Lau, Calgary, AB

Dr. Jean Palardy, Laval, QC

Dr. Barna Tugwell, Halifax, NS

Dr. Boji Varghese, Sudbury, ON

Dr. Johanne Blais, Quebec City, QC

Dr. Robin Bustin, Berwick, NS

Dr. Maureen Clement, Vancouver, BC

Dr. Ernest Snyman, Camrose, AB

Executive Committee

SteeringCommittee

Educational Committee

4

•Timesincediabetesdiagnosis:8years •Mildnonproliferativeretinopathy •Hasprivatedruginsuranceplan

Physical ExaminationBMI:32.3kg/m2 Edema:1+BP:138/84mmHg HeartRate:72bpm

MedicationsMetformin1,500mgdaily Ramipril5mgqd Atorvastatin10mgqd

Laboratory ResultsBlood Sugar Levels Lipid Levels Renal FunctionA1C:7.9% Totalcholesterol:4.4mmol/L eGFR:34mL/minFPG:7-9mmol/L LDL-C:2.0mmol/L ACR:92mg/mmolPPG:10-12mmol/L HDL-C:0.9mmol/L K+:5.0mEq/L TG:3.3mmol/L

Discussion Questions

Whataretheclinicalissuesthatyouneedtoaddresswiththispatient?

A1C=glycosylatedhemoglobin;ASA=acetylsalicylicacid;BMI=bodymassindex;BP=bloodpressure;eGFR=estimatedglomerularfiltrationrate;FPG=fastingplasmaglucose;HDL-C=high-densitylipoproteincholesterol;LDL-C=low-densitylipoproteincholesterol;MI=myocardialinfarction;PPG=postprandialplasmaglucose;TG=triglycerides

Female with CKD (62-Year-Old Retired Teacher)

Discussion

• Glycemic Targets and Control• Blood Pressure Targets and Control• Lipid Targets and Control• Global Vascular Protection• Weight Management in diabetes • Implications of Impaired kidney function

5

Consider A1C 7.1-8.5% if …

A1C = glycosylated hemoglobinCanadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes 2013;37(Suppl 1):S1-S212.

• Limited life expectancy• High level of functional dependency

• Extensive coronary artery disease at high risk of ischemic events

• Multiple co-morbidities

• History of recurrent severe hypoglycemia• Hypoglycemia unawareness

• Longstanding diabetes for whom it is difficult to achieve an A1C ≤ 7%, despite effective doses of multiple antihyperglycemic agents, including intensified basal-bolus insulin therapy

A1C = glycosylated hemoglobinAdapted from Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes 2013;37(Suppl 1):S1-S212.

Add an agent best suited to the individual (agents listed in alphabetical order):

Class RelativeA1C

Lowering

Hypo-glycemia

Weight Other therapeutic considerations Cost

-glucosidaseinhibitor (acarbose) Rare Neutral

to Improved postprandial control, GI side-effects $$

Incretin agents:DPP-4 InhibitorsGLP-1 receptor agonists

to

RareRare

neutral GI side-effects

$$$$$$$

Insulin Yes No dose ceiling, flexible regimens $-$$$$

Insulin secretagogue:

MeglitinideSulfonylurea

Yes*Yes

*Less hypoglycemia in context of missed meals but usually requires TID to QID dosingGliclazide and glimepiride associated with less hypoglycemia than glyburide

$$$

Thiazolidinediones Rare

CHF, edema, fractures, rare bladder cancer (pioglitazone), cardiovascular controversy (rosiglitazone), 6-12 weeks required for maximal effect

$$

Weight loss agent (orlistat) None GI side effects $$$

• CAUTION in the elderly• Initial doses = HALF of usual dose• Avoid glyburide• Use gliclazide, gliclazide MR, glimepiride,

nateglinide or repaglinide instead

• CAUTION in the elderly • Increased risk of fractures• Increased risk of heart failure

• May use detemir or glargine instead of NPH or human 30/70 for less hypos

• Premixed insulins and prefilled insulin pens instead of mixing insulin to reduce dosing errors

Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes 2013;37(Suppl 1):S1-S212.

Blood Pressure Targets and Control

2013 CHEP Recommendations:Management of Hypertension in Patients

with Diabetes

More than 3 drugs may be needed to reach target values for diabetic patients.

If creatinine is >150 µmol/L or creatinine clearance is <30 mL/min ( 0.5 mL/sec), a loop diuretic should be substituted for a thiazide diuretic if control of volume is desired.

Diabetes

Withnephropathy

>2-drug combinations

ACE inhibitoror ARB

Withoutnephropathy

1. ACE inhibitor or ARB

or2. DHP-CCB or

thiazide diuretic

Monitor serum potassium and creatinine carefully in patients with CKD prescribed an ACE inhibitor or ARB.Combinations of an ACE inhibitor with an ARB are specifically not recommended in the absence of proteinuria.

A combination of 2 first-line drugs may be considered as initial therapy if the blood pressure is >20 mmHg systolic or >10 mmHg diastolic above target. Combining an ACE inhibitor and a DHP-CCB is recommended.

ACE = angiotensin-converting enzyme; ARB = angiotensin II receptor blocker; CHEP = Canadian Hypertension Education Program; CKD = chronic kidney disease; DHP-CCB = dihydropyridine calcium channel blocker Adapted from the 2013 CHEP Recommendations. Available at http://www.hypertension.ca/chep-recommendations

Threshold equal or over 130/80 mmHg and TARGET below 130/80 mmHg

Glycemic Targets and Control

2013 CDA CPG RecommendedTargets for Glycemic Control

Glycemic targets must be individualized.

A1C = glycosylated hemoglobin; CDA = Canadian Diabetes Association; CPG = clinical practice guidelinesAdapted from Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes 2013; 37(suppl 1):S1-212.

≤7% >7%

7%6.0% 8.5%

Most patients with type 1 and type 2 diabetes

A target A1C ≤6.5%may be considered in some patients with type 2 diabetesto further lower the risk of nephropathyand retinopathy.

Consider if:• Limited life expectancy• High level of functional dependency• Extensive vascular disease• Multiple comorbidities• Recurrent severe hypoglycemia• Hypoglycemia unawareness• Long-standing diabetes for whom

It is difficult to achieve A1C ≤7.0%• Despite effective doses of multiple s

antihyperglycemic agents including intensified basal-bolus insulin therapy

6

Global Vascular Protection

Who should receive Statins?

• ≥40 years old or • Macrovascular disease or• Microvascular disease or• DM >15 yrs duration and age >30 years or• Warrants therapy based on the 2012 Canadian

Cardiovascular Society lipid guidelines

Adapted from Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes 2013;37(Suppl 1):S1-S212.

Among women with childbearing potential, statins should only be used in the presence of proper preconception counseling & reliable contraception.

Stop statins prior to conception.

Jamerson K et al N Engl J Med 2008; 359(23):2417-28.

ACCOMPLISH: Kaplan-Meier Curves forTime to First Primary Composite End Point

p <0.001

20% risk reduction

No. at riskBenazepril plus amlodipine 5512 5317 5141 4959 4739 2826 1447

Benazepril plus hydrochlorothiazide 5483 5274 5082 4892 4655 2749 1390

0

16

14

12

10

8

6

4

2

6 12 18 24 30 36 42

Benazepril plus hydrocholorthiazide

Benazepril plus amlodipine

Patie

nts

with

prim

ary

even

ts (%

)

Months

Adapted from Anderson TJ. Can J Cardiol 2013;29(2):151-167.

2012 CCS Lipid Guidelines for Treatment Thresholds and Targets

Risk Level(Framingham)

Initiate therapy if Primary Target LDL-C

Alternate Target

High Consider Treatment in all ≤ 2 mmol/L or 50%decrease in LDL-C

Apo B ≤ 0.8 g/L

Non HDL-C ≤ 2.6mmol/L

Intermediate LDL-C ≥ 3.5 mmol/L(Strong, Moderate)

Consider ifApo B ≥ 1.2 g/L orNon-HDL-C ≥ 4.3 mmol/L

≤ 2 mmol/L or 50%decrease in LDL-C

Apo B ≤ 0.8 mg/LNon-HDL-C ≤ 2.6mmol/L

Low * LDL-C ≥ 5.0 mmol/L

FamilialHypercholesterolemia

50% reduction inLDL-C

* For those in the 6-9% group, consider yearly calculation of Framingham Risk Score and discussion about risk-benefit of pharmacotherapy at lower levels of LDL-C

Lipid Targets and control

Jamerson K et al. N Engl J Med. 2008;359(23):2417-28

ACCOMPLISH: Blood Pressure Over Time

Mean difference =0.9 mmHg (p <0.001)

Mean difference = 1.1 mmHg (p <0.001)

0 3 6 12 18 24 30 36 4260

70

80

90

100

110

120

130

140

150

160B

lood

pre

ssur

e (m

m H

g)

Months

Benazepril plusamlodipine

Benazepril plus hydrochlorothiazide

Systolic

Diastolic

No. at riskBenazepril plus amlodipine 5740 5517 5404 5178 5010 4866 4298 2804 1074

Benazepril plus hydrochlorothiazide 5757 5537 5408 5222 5033 4825 4299 2529 1042

7

ASA Therapy

• ASA should not be routinely used for the primary prevention of cardiovascular disease in people with diabetes

• ASA may be used in the presence of additional cardiovascular risk factors

Adapted from Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes 2013;37(Suppl 1):S1-S212.ASA = acetylsalicylic acid







2013 CHEP Recommendations:Management of Hypertension in Patients

with Diabetes



Diabetes

Withnephropathy


ACE inhibitoror ARB

Withoutnephropathy


or2. DHP-CCB or

thiazide diuretic





Adapted from Anderson TJ et al. Can J Cardiol 2013;29(2):151-167.

2012 CCS Lipid Guidelines for Treatment Thresholds and Targets

Risk Level(Framingham)

Initiate therapy if Primary Target LDL-C

Alternate Target

High Consider Treatment in all

≤ 2 mmol/L or 50%decrease in LDL-C

Apo B ≤ 0.8 g/L

Non HDL-C ≤ 2.6mmol/L

Weber MA et al J Am Coll Cardiol. 2010;29;56(1):77-85.

ACCOMPLISH: Kaplan-Meier curves for time to the first primary composite end point

0.24

0.18

0.12

0.06

0

0.24

0.18

0.12

0.06

0

0.24

0.18

0.12

0.06

00 6 4212 18 24 30 36 0 6 4212 18 24 30 36 0 6 4212 18 24 30 36

Non-Diabetes All Diabetes High Risk Diabetes

B + A (events = 245)B + H (events = 296)

HR = 0.82 (0.69-0.97); p = .020


HR = 0.79 (0.68-0.92); p = .003


HR = 0.77 (0.64-0.93); p = .007

Time to 1st CV Event (months) Time to 1st CV Event (months) Time to 1st CV Event (months)

Pro

porti

on o

f Pat

ient

s

Pro

porti

on o

f Pat

ient

s

Pro

porti

on o

f Pat

ient

s

Number at RiskB + AB + H

22662293

21802172

22002087

20402012

19651937

18851839

11491102

594534


33473468

33323310

32173186

31013069

29942954

28542815

16771647

853856


14321410

13581333

12991263

12351197

11871145

11291058

683628

340310

CV = cardiovascular; HR = hazard ratio.B + A = benazepril + amlodipine; B + H = benazepril + hydrochlorothiazide.

Vascular Protection Checklist

A1C = glycosylated hemoglobinAdapted from Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes 2013;37(Suppl 1):S1-S212; from Anderson TJ, Grégoire J, et al. Can J Cardiol 2013;29:151-167.

A. A1C: optimal glycemic control (usually ≤7%)B. BP: optimal blood pressure control (<130/80 mmHg)C. Cholesterol: LDL ≤2.0 mmol/L (or Apo B ≤ 0.8 g/L or

Non HDL-C ≤ 2.6 mmol/L) if decided to treat D. Drugs to protect the heart

– ACEi or ARB │ S – Statin │ A – ASA if indicated E. Exercise: regular physical activity, healthy diet,

achieve and maintain healthy body weightS. Smoking cessation

8

Modest weight loss CAN make a difference

• Goal is to prevent weight gain, promote weight loss and prevent weight re-gain

• Weight loss of only 5-10% improves:– Insulin sensitivity – Glycemic control – Blood pressure– Lipid levels


Benefits of Physical ActivityImmediate Benefits• Lowers blood glucose• Decreases insulin resistance

Long-Term Benefits• Improves glycemic control• Decreases insulin resistance• Improves lipid profile• Reduces blood pressure• Produces and maintains weight

loss• Increased cardiorespiratory

fitness• Prevents sarcopenia and

osteoporosis• Slows development of peripheral

neuropathy• Reduces morbidity

and mortality


Look AHEAD: Study Design

Usual medical care+ lifestyle intervention* for 4 years, with maintenance

counselling thereafter



Primary endpoints:cardiovascular death, non-fatal MI, non-fatal stroke


n = 5,14545–74 years with T2DM, BMI ≥25 kg/m2 (≥27 kg/m2 if taking insulin)

Usual medical care + diabetes support and education for 4 years


Total follow-up 11.5 years

*Lifestyle intervention: • ≥7% mean weight loss with hypocaloric diet ± pharmacologic therapy + ≥175 min/week moderate physical activity• Diet = 1,200–1,500 kcal/day (<250 lbs) or 1,500–1,800 kcal/day (≥250 lbs)

AHEAD = Action for Health in Diabetes; BMI = body mass index; MI = myocardial infarction; T2DM = type 2 diabetes mellitusRyan DH et al; Look AHEAD Research Group. Control Clin Trials 2003; 24(5):610-28.

Weight Management in diabetes

Look AHEAD: Results – Changes in Weight, Physical Fitness, Waist

Circumference and A1C

090

92

94

96

98

100

0 1 2 3 4 5 6 7 8 9 10Year

Est

imat

edM

ean

(kg)

Weight

Main effect, −4 (95% CI, −5 to −3)p<0.001

Intervention

Control

* * * * ** *

**

*

0106

108

110

112

114

0 1 2 3 4 5 6 7 8 9 10Year

Est

imat

edM

ean

(cm

)

Waist Circumference

Main effect, −3.2 (95% CI, −3.9 to −2.4)p<0.001

Intervention

Control* * * *

**

** *

*

0.06.6

6.8

7.0

7.2

7.4

0 1 2 3 4 5 6 7 8 9 10Year

Est

imat

edM

ean

(%)

Main effect, −0.22 (95% CI, −0.28 to −0.16)p<0.001

Intervention

Control

* * * **

*

0.05.0

5.5

6.0

0 1 2 3 4 5 6 7 8 9 10Year

Est

imat

edM

ean

(ME

T)

Physical Fitness

Main effect, 0.6 (95% CI, 0.5 to 0.8)p<0.001

Intervention

Control

*

*

*

A1C

Wing RR et al. N Engl J Med 2013;369:145-154

Modest weight loss CAN make a difference

• Goal is to prevent weight gain, promote weight loss and prevent weight re-gain

• Weight loss of only 5-10% improves:– Insulin sensitivity – Glycemic control – Blood pressure– Lipid levels


9

Physical Activity Checklist

DO a minimum of 150 minutes of moderate-to

vigorous-intensity aerobic exercise per week

INCLUDE resistance exercise ≥ 2 times a week

SET physical activity goals and INVOLVE a

multi-disciplinary team

ASSESS patient’s health before prescribing an

exercise regimen


Your patient who was sedentary wishes to initiate vigorous exercise

Look AHEAD: Study Design







n = 5,14545–74 years with T2DM, BMI ≥25 kg/m2 (≥27 kg/m2 if taking insulin)



Total follow-up 11.5 years

*Lifestyle intervention: • ≥7% mean weight loss with hypocaloric diet ± pharmacologic therapy + ≥175 min/week moderate physical activity• Diet = 1,200–1,500 kcal/day (<250 lbs) or 1,500–1,800 kcal/day (≥250 lbs)

AHEAD = Action for Health in Diabetes; BMI = body mass index; MI = myocardial infarction; T2DM = type 2 diabetes mellitusRyan DH et al; Look AHEAD Research Group. Control Clin Trials 2003; 24(5):610-28.

Who Should have Stress Testing and/or Functional Imaging to Screen

for CAD?

ECG = electrocardiography; PAD = peripheral artery disease; TIA = transient Ischemic attackCanadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes 2013;37(Suppl 1):S1-S212.

Exercise ECG stress testing

If cannot exercise or resting ECG abnormality present:– Pharmacologic stress echo– Pharmacologic stress nuclear

imaging

Typical or atypical cardiac symptoms

Associated diseases:– PAD– Carotid bruits– TIA– Stroke

Resting ECG abnormalities (e.g. Q waves)

Who should be screenedwith ECG

Age >40 years

Duration of DM >15years +

Age >30 years

End organ damage– Microvascular– Macrovascular

Cardiac risk factors

ECG = electrocardiographyCanadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes 2013;37(Suppl 1):S1-S212.

Baseline resting ECG

Repeat every 2 years

Physical Activity

Aerobic Exercise Resistance Exercise*Definition andrecommended frequency

Intensity ExamplesDefinition andrecommended frequency

Recommended frequency Examples

Rhythmic, repeated andcontinuous movementsof the same large muscle groups for at least 10 minutes at a time

Recommended for a minimum of 150 minutes per week (moderateintensity)

Moderate:50–70% of person’smaximum heart rate

• Biking• Brisk walking• Continuous

swimming• Dancing• Raking leaves• Water

aerobics

Activities of brief duration involving the use of weights, weight machines or resistance bands to increase muscle strength and endurance

3 times per week• Start with 1 set of

10–15 repetitions while maintaining proper form

• Progress to 2 sets of 10–15 repetitions while increasing the weight slightly

• Progress to 3 sets of 8 repetitions using an increased weight, ensuring proper form is maintained

• Exercise with weight machines

• Exercise with free weights

Vigorous:>70% of person’smaximum heart rate

• Brisk walking up an incline

• Jogging• Aerobics• Hockey• Basketball• Fast

swimming• Fast dancing

*Initial instruction and periodic supervision are recommendedCDA = Canadian Diabetes Association; CPG = Clinical Practice GuidelinesAdapted from Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes 2013;37(Suppl 1):S1-S212.

The 2013 CDA CPGs recommend150 minutes of aerobic exercise and 3 sessions

of resistance exercise per week.

Most people living with diabetes currentlydo not meet these targets.

The 2013 CDA CPGs recommend150 minutes of aerobic exercise and 3 sessions

of resistance exercise per week.

Most people living with diabetes currentlydo not meet these targets.

10

Fox CS et al. Lancet. 2012;380(9854):1662-73.

Meta-analysis including 1,024,977 male and female participants (128,505 with diabetes) from 30 general population and high-risk cardiovascular cohorts and 13 chronic kidney disease cohorts

Impaired kidney function (↑ACR) is a risk factor for cardiovascular and

all-cause mortality

8

2.5

Adju

sted

haz

ard

ratio 4

2

1.5

0

5 10 30 300 1000

Adju

sted

haz

ard

ratio

1

8

4

2

1.5

0

1

ACR (mg/g) ACR (mg/g)2.5

5 10 30 300 1000

No diabetes, 95% CI

Diabetes, 95% CI

All-cause mortality

Cardio-vascular mortality

1. Middleton RJ et al. Nephrol Dial Transplant 2006;21:88–92. 2. 2. Centers for Disease Control and Prevention. National Chronic Kidney Disease Fact Sheet 2010.3. Plantinga LC et al. Clin J Am Soc Nephrol. 2010;5:673-82.

Kidney Disease and Diabetes

• Moderate to severe kidney disease presents in >28% of patients with diabetes1,2,3

• Prevalence of chronic kidney disease (CKD) in patients with prediabetes is 17.7%3

Look AHEAD Trial

AHEAD = Action for Health in Diabetes; BMI = body mass index; MI = myocardial infarction; T2DM = type 2 diabetes mellitusLook AHEAD Research Group. N Engl J Med. 2013;369(2):145-54

100

0Year

Patie

nts

with

End

Poi

nt (%

)

80

60

40

20

02 64 8 10

0 2 64 8 10

20

16

12

8

4

0

Control

Intervention

Hazard ratio, 0.95 (95% CI, 0.80- 1.09)P=0.51

No. at RiskControl 2575 2425 2296 2156 2019 688Intervention 2570 2447 2326 2192 2049 505

Fox CS et al. Lancet. 2012;380(9854):1662-73.

Impaired kidney function (↓eGFR) is a risk factor for all-cause and

cardiovascular mortality

8

15

Adju

sted

haz

ard

ratio 4

2

1.5

0

30 45 60 75 90 105 120 15 30 45 60 75 90 105 120

Adju

sted

haz

ard

ratio

All-cause mortality

Cardio-vascular mortality

1

8

4

2

1.5

0

1

eGFR (mL/min per 1.73m2) eGFR (mL/min per 1.73m2)

No diabetes, 95% CI

Diabetes, 95% CI

Meta-analysis including 1,024,977 male and female participants (128,505 with diabetes) from 30 general population and high-risk cardiovascular cohorts and 13 chronic kidney disease cohorts

Implications of Impaired Kidney Function

Look AHEAD Trial

AHEAD = Action for Health in Diabetes; BMI = body mass index; MI = myocardial infarction; T2DM = type 2 diabetes mellitusLook AHEAD Research Group. N Engl J Med. 2013;369(2):145-54

100

0

Year

98

96

94

92

900

7.4

7.2

7.0

6.8

6.6

0.0

Estim

ated

Mea

n (%

)

1 2 5 643 7 8 9 10 0

Year

1 2 5 643 7 8 9 10

Weight Glycated Hemoglobin

Control

InterventionControl

Intervention

** * * *

* ** *

**

* * **

*

*

Main effect, -0.22 (95% CI, -0.28 to -0.16)P<0.001

Main effect, -4 (95% CI, -5 to 3)P<0.001

Estim

ated

Mea

n (k

g)

11

CKD = chronic kidney diseaseAdapted from Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes 2013;37(Suppl 1):S1-S212.

CKD Checklist

• SCREEN regularly with random urine albumin creatinineratio (ACR) and serum creatinine for estimated glomerular filtration rate (eGFR)

• DIAGNOSE with repeat confirmed – ACR ≥2.0 mg/mmol and/or eGFR <60 mL/min

• DELAY onset and/or progression with glycemic and blood pressure control and ACE-inhibitor or AngiotensinReceptor Blocker (ARB)

• PREVENT complications with “sick day management” counselling and referral when appropriate

CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; ESRD = end-stage renal disease; GFR = glomerular filtration rateAdapted from Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes 2013;37(Suppl 1):S1-S212.

Stages of CKD: eGFR

Stage Qualitative description eGFR (mL/min)1 Kidney damage,

normal GFR90

2 Kidney damage, mildly decreased GFR

60-89

3 Moderately decreased GFR 30-594 Severely decreased GFR 15-295 ESRD <15 (or dialysis)

Adapted from Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes 2013;37(Suppl 1):S1-S212. ACR = albumin-creatinine ratio

When to Refer to a Nephrologist

• Chronic, progressive loss of kidney function• ACR persistently >60 mg/mmol• eGFR <30 mL/min• Unable to remain on renal-protective

therapies due to adverse effects such as hyperkalemia or a >30% increase in serum Cr within 3 months of starting ACEi or ARB

• Unable to achieve target BP (could be referred to any specialist in hypertension)

Adapted from Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes 2013;37(Suppl 1):S1-S212. ACR = albumin-creatinine ratio

Stage of Diabetic Nephropathy byLevel of Urinary Albumin via Various

Test Methods

Urine dipstick NormalMicroalbumin

NegativeOvert Nephropathy

Positive

24 HourACR

30 mg/day2.0 mg/mmol



0 Urinary Albumin Level

CKD = chronic kidney disease; eGFR = estimated glomerular filtration rateAdapted from Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes 2013;37(Suppl 1):S1-S212.

When to ConsiderOther Causes of CKD

Factors Favoring Classical Diabetic Nephropathy vs. Alternate DiagnosesFavours Diabetic Nephropathy Favours Alternate Renal Diagnosis

Persistent albuminuria Extreme proteinuria (>6 g/d)

Bland urine sediment Persistent hematuria (micro- or macroscopic) or active urinary sediment

Slow progression of disease Rapidly falling eGFR

Low eGFR associated with overt proteinuria Low eGFR with little or no proteinuria

Other complications of diabetes present Other complications of diabetes not present or relatively not as severe

Known duration of DM >5 years Known duration of diabetes <5 years

Family history or nondiabetic renal disease (e.g. polycystic kidney disease)

Signs or symptoms of systemic disease

30

25

15

10

5

0

75

60

45

30

15

0

Tonelli M, et al. Lancet. 2012;380(9844):807-14.

Chronic Kidney Disease is a risk factor for myocardial infarction and

all-cause mortalityR

ates

(per

100

0 pe

rson

-yea

rs)

20

Rat

es (p

er 1

000

pers

on-y

ears

)

Myocardial Infarction

All-cause mortality

Previous myocardialinfarction*

Diabetes and CKD CKD (eGFR<60mL/min per 1.73 m2

Diabetes No diabetes or CKD

12

Adapated from Palmer BF N Engl J Med. 2004;351(6):585-92.

Algorithm to Manage Hyperkalemia

• Estimate GFR to assess specific risk of hyperkalemia• Discontinue drugs that interfere with kidney potassium

secretion (inquire about herbal preparations); discontinue NSAIDS

• Prescribe low-potassium diet; inquire about use of salt substitutes that contain potassium

• Prescribe thiazide or loop diuretics• Prescribe NaHCO3 to correct metabolic acidosis in CKD

patients• Initiate low-dose ACE inhibitor or ARB• If potassium >5.5 mmol/L, discontinue ACE inhibitor, ARB and

aldosterone-receptor blocker

13

Weber MA et al J Am Coll Cardiol. 2010;29;56(1):77-85

ACCOMPLISH: Kaplan-Meier curves for time to the first primary composite end point

0.24

0.18

0.12

0.06

0

0.24

0.18

0.12

0.06

0

0.24

0.18

0.12

0.06

00 6 4212 18 24 30 36 0 6 4212 18 24 30 36 0 6 4212 18 24 30 36

Non-Diabetes All Diabetes High Risk Diabetes


HR = 0.82 (0.69-0.97); p = .20


HR = 0.79 (0.68-0.92); p = .003


HR = 0.77 (0.64-0.93); p = .007

Time to 1st CV Event (months) Time to 1st CV Event (months) Time to 1st CV Event (months)

Pro

porti

on o

f Pat

ient

s

Pro

porti

on o

f Pat

ient

s

Pro

porti

on o

f Pat

ient

s


22662293

21802172

22002087

20402012

19651937

18851839

11491102

594534


33473468

33323310

32173186

31013069

29942954

28542815

16771647

853856


14321410

13581333

12991263

12351197

11871145

11291058

683628

340310

CV = cardiovascular; HR = hazard ratio.B + A = benazepril + amoldipine; B + H = benazepril + hydrochlorothiazide.

2013 CDA CPG RecommendedTargets for Glycemic Control

Glycemic targets must be individualized.


≤7% >7%

7%6.0% 8.5%

Most patients with type 1 and type 2 diabetes

A target A1C ≤6.5%may be considered in some patients with type 2 diabetesto further lower the risk of nephropathyand retinopathy.

Consider if:• Limited life expectancy• High level of functional dependency• Extensive vascular disease• Multiple comorbidities• Recurrent severe hypoglycemia• Hypoglycemia unawareness• Long-standing diabetes for whom• It is difficult to achieve A1C ≤7.0%• Despite effective doses of multiple s

antihyperglycemic agents including intensified basal-bolus insulin therapy

2013 CDA CPG RecommendedAdd-On Antihyperglycemic Therapy (1 of 2)

Add an agent best suited to the individual (alphabetical order)

ClassRelative

A1C lowering

Hypo-glycemia Weight

Other therapeutic

considerationsCost

-glucosidase inhibitor (acarbose) Rare Neutral to

• Improved postprandial control

• GI side effects

$$

Incretin agents:DPP-4 inhibitorsGLP-1 receptor agonists

to

RareRare

Neutral to • GI side effects

$$$$$$$

Insulin Yes • No dose ceiling• Flexible regimens $-$$$$

A1C = glycosylated hemoglobin; CDA = Canadian Diabetes Association; CPG = clinical practice guidelines; DPP-4 = dipeptidyl peptidase inhibitor; GI = gastrointestinal; GLP-1 = glucagon-like peptide 1Adapted from Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes 2013; 37(suppl 1):S1-212.

2013 CHEP Recommendations:Management of Hypertension in

Patients with Diabetes



Diabetes

Withnephropathy


ACE inhibitoror ARB

Withoutnephropathy


or2. DHP-CCB or

thiazide diuretic







ClassRelative

A1C lowering

Hypo-glycemia Weight Other therapeutic

considerations Cost

Insulin secretagogues:Meglitinides

Sulfonylureas

Yes

Yes

• Less hypoglycemia with missed meals but usually needs tid to qid dosing

• Gliclazide and glimepiride associated with less hypoglycemia than glyburide

$$

$


• CHF, edema, fractures, rare bladder cancer (pioglitazone), cardiovascular controversy (rosiglitazone)

• 6–12 weeks required for maximal effect

$$

Weight loss agent (orlistat) None • GI side effects $$$

A1C = glycosylated hemoglobin; CDA = Canadian Diabetes Association; CPG = clinical practice guidelines; GI = gastrointestinalAdapted from Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes 2013; 37(suppl 1):S1-212.

2013 CDA CPG RecommendedAlgorithm for Managing Type 2 Diabetes

A1C ≥8.5%

Symptomatic hyperglycemia with metabolicdecompensation

• Start metformin immediately• Consider initial combination with another antihyperglycemic agent

A1C <8.5%

If not at glycemic targets, add an agent best suited to the Individual based on:

Patient characteristics• Degree of hyperglycemia• Risk of hypoglycemia• Overweight or obesity• Comorbidities (renal, cardiac, hepatic)• Preferences and access to treatment• Other

Agent characteristics• Blood glucose-lowering efficacy

and durability• Risk of inducing hypoglycemia• Effect on weight• Contraindications and side effects• Cost and coverage• Other

Initiate lifestyle intervention (physical activity and nutrition therapy) ± metformin.

Make timely adjustments to attain target A1C within 3–6 months.

If not atglycemic target:• Add another

agent from a different class

• Add/intensifyinsulin regimen


• If not at glycemic target after 2–3 months, start/increase metformin

• Initiate insulin ± metformin


Whatareyourtherapeuticgoalsforgainingglycemic,lipidandBPcontrol?

14







15

Incretin-Based Therapies In Kidney Insufficiency: Information from Canadian

Product MonographsExenatide4 Linagliptin2 Liraglutide5 Saxagliptin3 Sitagliptin1

Stage of kidney insufficiency

MildCreatinine clearance >50 mL/min

Yes YesYes

Limited clinical experience

Yes Yes

ModerateCreatinine clearance 30–50 mL/min

Caution YesNot

indicated

YesDose reduction

to 2.5 mg qd

Yes Dose reduction

to 50 mg/day

SevereCreatinine clearance <30 mL/min

No Yes Not indicated

CautionDose reduction

to 2.5 mg qd

Yes Dose reduction

to 25 mg/day

ESRD/dialysisCreatinine clearance <15 mL/min

No Caution* Not indicated

Not indicated

Yes Dose reduction

to 25 mg/day

*Clinical study experience with linagliptin in patients with ESRD and those on dialysis is limited. Linagliptin should be used with caution in these patients.ESRD = end-stage renal disease1. Byetta® (Exenatide) Product Monograph. Scarborough, ON: Eli Lilly Canada; 2012.2. TrajentaTM (Linagliptin) Product Monograph. Burlington, ON: Boehringer Ingelheim (Canada) Ltd.; 2012. 3. Victoza® (Liraglutide) Product Monograph. Scarborough, ON: Novo Nordisk Canada; 2011.4. OnglyzaTM (Saxagliptin) Product Monograph. Mississauga, ON: AstraZeneca Canada Inc., 2012. 5. Januvia® (Sitagliptin) Product Monograph. Kirkland, QC: Merck Frosst Canada Ltd.; 2012.

Insulin

Thiazolidinediones

Glyburide

Gliclazide/Glimepiride

Metformin

Repaglinide

Liraglutide

Exenatide

Sitagliptin

Saxagliptin

Linagliptin

Acarbose

Not Recommended Caution / Reduced Dose Safe

Antihyperglycemic Agents in Kidney Disease

0 25 50 75 100GFR (ml/min)

CKD Stages (GFR) 5 ESKD* (<15)

25

5015

50

30 50

50

30 60

15

30 50

30

Adapted from product monographs, CDA Guidelines, 2008 and Yale JF. December 2011Based on Canadian product monographs as of Sept 10, 2012

CKD = Chronic Kidney Disease GFR = Glomerular Filtration Rate* ESKD – End Stage Kidney Disease

Inhi

bite

urs

de la

D

PP

-4A

goni

stes

des

ré

cept

eurs

du

GLP

-1S

ulfo

nylu

rées

4Severe (15-29) 3 Moderate (30-59) 2 Mild (60-89) 1 (> 90)

15

30

5 mg OD

2.5 mg OD 5 mg OD

25 mg OD 100 mg OD50 mg OD

30

Not Recommended Caution Safe

Who Should Receive ACEi or ARB Therapy?

• ≥55 years of age or • Macrovascular disease or • Microvascular disease

At doses that have shown vascular protection (ramipril 10 mg daily, perindopril 8 mg daily, telmisartan 80 mg daily)

ACEi: angiotensin converting enzyme inhibitor; ARB: angiotensin receptor blockerAdapted from Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes 2013; 37(suppl 1):S1-212.



ClassRelative

A1C lowering

Hypo-glycemia Weight Other therapeutic

considerations Cost

Insulin secretagogues:Meglitinides

Sulfonylureas

Yes

Yes

• Less hypoglycemia with missed meals but usually needs tid to qid dosing

• Gliclazide and glimepiride associated with less hypoglycemia than glyburide

$$

$


• CHF, edema, fractures, rare bladder cancer (pioglitazone), cardiovascular controversy (rosiglitazone)

• 6–12 weeks required for maximal effect

$$

Weight loss agent (orlistat) None • GI side effects $$$

A1C = glycosylated hemoglobin; CDA = Canadian Diabetes Association; CPG = clinical practice guidelines; GI = gastrointestinalAdapted from Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes 2013; 37(suppl 1):S1-212.



ClassRelative

A1C lowering

Hypo-glycemia Weight

Other therapeutic

considerationsCost

-glucosidase inhibitor (acarbose) Rare Neutral to

• Improved postprandial control

• GI side effects

$$

Incretin agents:DPP-4 inhibitorsGLP-1 receptor agonists

to

RareRare

Neutral to • GI side effects

$$$$$$$

Insulin Yes • No dose ceiling• Flexible regimens $-$$$$

A1C = glycosylated hemoglobin; CDA = Canadian Diabetes Association; CPG = clinical practice guidelines; DPP-4 = dipeptidyl peptidase inhibitor; GI = gastrointestinal; GLP-1 = glucagon-like peptide 1Adapted from Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes 2013; 37(suppl 1):S1-212.

2013 CDA CPG RecommendedAlgorithm for Managing Type 2 Diabetes

A1C ≥8.5%

Symptomatic hyperglycemia with metabolicdecompensation

• Start metformin immediately• Consider initial combination with another antihyperglycemic agent

A1C <8.5%

If not at glycemic targets, add an agent best suited to the Individual based on:

Patient characteristics• Degree of hyperglycemia• Risk of hypoglycemia• Overweight or obesity• Comorbidities (renal, cardiac, hepatic)• Preferences and access to treatment• Other

Agent characteristics• Blood glucose-lowering efficacy

and durability• Risk of inducing hypoglycemia• Effect on weight• Contraindications and side effects• Cost and coverage• Other

Initiate lifestyle intervention (physical activity and nutrition therapy) ± metformin.

Make timely adjustments to attain target A1C within 3–6 months.

If not atglycemic target:• Add another

agent from a different class

• Add/intensifyinsulin regimen


• If not at glycemic target after 2–3 months, start/increase metformin

• Initiate insulin ± metformin


Areyouconcernedwiththecurrentpharmacotherapybeingused?Ifso,whatwouldyouaddorchange?

16

White WB et al N Engl J Med 2013; DOI: 10.1056/NEJMoa1305889

EXAMINE: Adverse Events

** Hypoglycemia was reporte d by site investigators

Placebo (n=2679)

Alogliptin(n=2701) P value *

Hypoglycemia ** 173 (6.5) 181 (6.7) 0.74

Pancrea s † AcuteChronic

8 (0.3)4 (0.1)

12 (0.4)5 (0.2)

0.501.00

Angioedema 13 (0.5) 17 (0.6) 0.58

Malignancy 51 (1.9) 55 (2.0) 0.77

Renal dialysis 22 (0.8) 24 (0.9) 0.88


EXAMINE:Kaplan–Meier Estimates of Time to Primary

End-Point Event

Primary end-point: composite of death from cardiovascular causes, nonfatal myocardial infarction or nonfatal stroke

24

0

Months

Cum

ulat

ive

Inci

denc

e of

Prim

ary

End-

Poin

t Eve

nts

(%)

18

12

6

0

6 12 302418

Hazard ratio, 0.96 (upper boundary of the one-sided repeated CI, 1.16) average age starting A1C

Placebo

Alogliptin


EXAMINE:Baseline Characteristics

Placebo(N=2679)

Alogliptin(N=2701)

Median age – years 61.0 61.0Male – % 68.0 67.7Median duration of diabetes –years 7.3 7.1Median body mass index – kg/m2 28.7 28.7Mean A1C - % 8.0 8.0Current smoker – % 14.3 13.0Median glomerular filtration rate* -ml/min/1.73m2

71.2 71.1

Insulin – % 30.3 29.4Statins – % 90.3 90.6Aspirin – % 90.8 90.6

MI or hosp. UA within 15–90 daysAge 61A1C 8.0%97% on antiplatelets91% on statins82% on beta-blockers83% on RAS blockers30% on insulin47% on SU

Study Design• Randomized double-blind, placebo-controlled study of

alogliptin with diabetes standard of care vs. placebo with diabetes and cardiovascular standard of care

aAt randomization, patients were assigned to receive 25, 12.5, or 6.25 mg QD based on renal function. After randomization, dose adjustments were allowed on basis of changes in renal functionWhite WB et al. Am Heart J 2011; 162(4):620-6

Treatment period (4.5 years)

Month 1Day 1Days –14to –1

Month 12 End ofstudy

2-weekfollow-up

Baseline/randomization

Screeningvisit

Visits at months 3, 6 and 9 Visits every 4 months

Placebo QD + standard of care (n = 2679)

Alogliptina QD + standard of care (n = 2701)

Data represent overall mean changes from baseline at the highest maintenance dosesAroda VR et al. Clin Ther 2012; 34(6):1247-58

80 Studies of ≥12 Weeks Duration ExaminingDPP-4 Inhibitor- and GLP-1RA-Based Therapies

Efficacy of Incretins: A Meta-analysis of Randomized Clinical Trials

Exenatide BIDExenatide QW

LiraglutideAlogliptin

Linagliptin

SaxagliptinSitagliptin

Vildagliptin

-1.16 [-1.35 to -0.97]-2.12 [-2.28 to -1.96]

-1.82 [-2.07 to -1.57]-0.97 [-1.27 to -0.67]-1.04 [-1.59 to -0.49]

-0.73 [-0.95 to -0.50]-0.87 [-0.98 to -0.77]-1.57 [-2.23 to -0.90]

Mean FPG difference (95% CI)

-2.5 -2.0 -1.5 -1.0 -0.5FPG change (mmol/L)

Dosage

8.08.18.1 8.1

Linagliptin1 Linagliptin2* Saxagliptin3 Sitagliptin4

5 mg qd 5 mg qd 5 mg qd 100 mg qd

-0.8%-0.7%

-0.8%

-0.6%

513n = 209 453 186

<0.0001 <0.0001 <0.0001<0.0001

Placebo-Corrected, Adjusted Mean Change from Baseline A1C

BaselineA1C (%)

p value

*12-week treatment duration; **24-week treatment durationA1C = glycosylated hemoglobin; DPP-4 = dipeptidyl peptidase 41. Tradjenta (Linagliptin) Package Insert. Ridgefield, CT: Boehringer Ingelheim; 2011. 2. Boehringer Ingelheim. Data on file. 3. Onglyza (Saxagliptin) Package Insert. Princeton, NJ: Bristol-Myers Squibb; 2011. 4. Januvia (Sitagliptin), Package Insert. Whitehouse Station, NJ: Merck; 2011.

Efficacy of DPP-4 Inhibitors in Add-On to Metformin Trials

17

Monami, M et al. Curr Med Res Opin. 2011;27 Suppl 3:57-64.

53 trials enrolling 20,312 and 13,569 patients for DPP4i and comparators, respectively

Safety of DPP-4 inhibitors: a meta-analysis of randomized clinical trials

OutcomeDPP-4i cases

(N)

Comparatorcases (N)

Odds ratio 95% CI P-

value

Cancer 107 69 1.020 0.742-1.402 0.90

Pancreatic cancer NA NA 0.586 0.212-1.616 0.30

Pancreatitis 11 12 0.786 0.357-1.734 0.55

MACE 137 120 0.689 0.528-0.899 0.006

MACE = cardiovascular death, nonfatal MI, nonfatal stroke, hospitalizations for acute coronary syndromes and/or heart failure

SAVOR-TIMI 53†: Adverse Events

Hypoglycemia was defined as any recorded blood glucose <3.0 mmol/L.Scirica BM et al N Engl J Med 2013; DOI: 10.1056/NEJMoa1307684

End Point Saxagliptin(n=8280)

Placebo (n=8212) P Value

Severe infection 590 (7.1) 576 (7.0) 0.78

Opportunistic infection 21 (0.3) 35 (0.4) 0.06

Bone fracture 241 (2.9) 240 (2.9) 1.00

Skin reaction 228 (2.8) 232 (2.8) 0.81

Renal abnormality 483 (5.8) 418 (5.1) 0.04

Hypoglycemia 1264 (15.3) 1104 (13.4) <0.001

Cancer 327 (3.9) 362 (4.4) 0.15

Acute: definite or possible 22 (0.3) 16 (0.2) 0.42

Acute: definite 17 (0.2) 9 (0.1) 0.17

Acute: possible 6 (0.1) 7 (0.1) 0.79

Chronic 2 (<0.1) 6 (0.1) 0.18

Scirica BM et al N Engl J Med 2013; DOI: 10.1056/NEJMoa1307684

SAVOR-TIMI 53:Baseline Characteristics

Placebo(N=8212)

Saxagliptin(N=8280)

Median age – years 65.0 65.1Female – % 32.7 33.4Median duration of diabetes –years 10.3 10.3Mean body mass index – kg/m2 31.2 31.1Mean A1C - % 8.0 8.0Current smoker – % 7.7 9.3Mean estimated glomerular filtration rate – ml/min

72.7 72.5

Established atherosclerotic disease - % 78.7 78.4Insulin – % 41.2 41.6Statins – % 7.6 7.7Aspirin – % 7.3 7.9

Trial Vs n Duration Population Outcome End

Acarbose ACE Placebo 904e 4 yrs pre-diabetics, CV+ * 2014

Canagliflozin CANVAS Placebo 4332 4 yrs All agents, CV+ or RF * 2013

Dapagliflozin DECLARE Placebo 17150 6 yrs High risk CVD * 2019

Dulaglutide REWIND Placebo 9600 6.5 yrs≤2OHA ± basal ins or GLP1, or

basal ins50yo CVD,55 yo CVDsc, 60 yo

RF

* 2019

Exenatide EXSCEL Placebo 9500 5.5 yrs ≤3 agents including insulin * 2017

Linagliptin CARMELINA Placebo 8300 4-5 yrs CV+ or CKD *+unstable angina 2018

Linagliptin CAROLINA Glimepiride 6000 8 yrs +OHA, CV+ or RF *+unstable angina 2018

Liraglutide LEADER Placebo 9000 5 yrs 50 yo CVD 60 yo RF, OHA, or basal * 2016

Lixisenatide ELIXA Placebo 6000 4 yrs ACS 5-90 days pre-rando*+hosp

unstable angina

2014

Semaglutide SUSTAIN-6 Placebo 3260 3 yrs 50yo CVD+ or >60yo and risk factors * 2016

Sitagliptin TECOS Placebo 14000 4-5 yrs CV+, OHA *+unstable angina 2014

Cardiovascular Trials

No. at RiskPlacebo 8212 7983 7761 7267 4855 851Saxagliptin 8280 8071 7836 7313 4920 847

Scirica BM et al N Engl J Med 2013; DOI: 10.1056/NEJMoa1307684

SAVOR-TIMI 53:Kaplan–Meier Rates of Primary End-Point

Primary end-point: composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal ischemic stroke

14

0Days

Patie

nts

with

End

Poi

nt (%

)

12

10

8

6

4

2

0180 360 540 900720

Saxagliptin

Placebo

Hazard ratio, 1.00 (95% CI, 0.89-1.12)P<0.001 for noninferiorityP=0.99 for superiority

2-yr Kalan-Meier rate:Saxagliptin, 7.3%Placebo, 7.2%

Age 65, A1C 8.0%

Saxagliptin Assessment of Vascular Outcomes Recorded in

Patients with DM – TIMI 53Documented type 2 diabetes

Saxagliptin5 mg/d Placebo

Follow-up visitsQ6 months

Final visit

Randomized 1:1 Double-Blind

All other DM Rx per treating MD

2.5 mg/d if eGFR 50 mL/min

DurationEvent driven (n = 1040)Median duration 2.1 y

LTFU 0.2%W/C 2.4%

Primary endpointCV death, MI,

ischemic stroke

Major secondary endpoint: CV death, MI, ischemic stroke, or hosp. for heart failure, unstable angina, or coronary revascularization

Scirica BM et al. N Engl J Med 2013; www.NEJM.org. 13

Established CV Disease or Multiple Risk Factorsn = 16,492

18

0 2 4 6 8 10 12

Skin

Bleeding

Heart failure

Musculoskeletal

Gastrointestinal

Infection

New onset diabetes

Diabetic complication

Active

Placebo

Effect of ERN/LRPT on SERIOUS adverse events(median follow-up 3.9 years)

Percentage of patients

Excess p value3.7% <0.0001

1.8% <0.0001

1.4% <0.0001

1.0% <0.0001

0.7% 0.0008

0.4% 0.05

0.7% 0.0002

0.3% 0.0026

ERN/LRPT

Placebo

HPS2-THRIVE. Adapted from http://www.thrivestudy.org/. Accessed September 17, 2013.The AIM-HIGH Investigators. N Engl J Med 2011;365:2255-67.

AIM-HIGH: Kaplan–Meier Curve for Primary Outcome

No. at RiskPlacebo plus statin 1696 1581 1381 910 436Niacin plus statin 1718 1606 1366 903 428

14

0Years

Cum

ulat

ive

Perc

enta

ge o

f Pa

tient

s w

ith P

rimar

y O

utco

me

10

8

6

4

01 2 3 4

Niacin plus statin

Placebo plus statin

P=0.79 by log-rank test

The AIM-HIGH Investigators. N Engl J Med 2011;365:2255-67.

AIM-HIGH: Primary Outcome

End PointPlacebo

plus Statin (N=1696)

Extended-ReleaseNiacin plus Statin

(N=1718)

Hazard Ratio with Niacin

(95%)P Value *

Number of patients (percent)Primary end point: death from coronary heart disease,

nonfatal myocardial infarction, ischemic stroke, hospitalization for acute coronary syndrome, or symptom-driven coronary or cerebral revascularization

274 (16.2) 282 (16.4) 1.02 (0.87-1.21) 0.80

Individual primary-end-point events

Death from coronary heart disease 26 (1.5) 20 (1.2)

Nonfatal myocardial infarction 80 (4.7) 92 (5.4)

Ischemic stroke 15 (0.9) 27 (1.6)

Hospitalization for acute coronary syndrome 67 (4.0) 80 (4.7)

Symptom-driven coronary or cerebral revascularization 86 (5.1) 80 (4.7)

The ACCORD Study Group. N Engl J Med 2010;362:1563-74.

ACCORD Lipid: Kaplan–Meier Analyses of All-cause and Cardiovascular Death

No. at RiskFenofibrate 2765 2737 2704 2646 2147 1271 469 285 157Placebo 2753 2723 2680 2615 2164 1293 450 274 157

100

Years

80

60

40

20

0

P=0.33

2 3 4 5 6 7 8

Prop

ortio

n w

ith E

vent

(%)

20

10

00 2 4 5 6 7 8

Placebo

Fenofibrate

Death from Any Cause

10

31

Placebo

Fenofibrate

40

20

00 1 2 3 4 5 6 8

Years0 1 2 3 4 5 6 7 8

100

80

60

40

20

Prop

ortio

n w

ith E

vent

(%)

Death from Cardiovascular Causes

P=0.26


0

The ACCORD Study Group. N Engl J Med 2010;362:1563-74.

ACCORD Lipid:Kaplan–Meier Analyses of Primary Outcome and Expanded

Macrovascular Outcome


100

Years

80

60

40

20

0

P=0.32

2 3 4 5 6 7 8

Prop

ortio

n w

ith E

vent

(%)

20

10

00 1 2 3 4 5 6 7 8

Placebo Fenofibrate Placebo Fenofibrate

40

20

00 1 2 3 4 5 6 7 8

Years0 1 2 3 4 5 6 7 8

100

80

60

40

20

Prop

ortio

n w

ith E

vent

(%)

Primary Outcome Expanded Macrovascular Outcome

P=0.30

1


0 0

Effect of Kidney Impairment on the Pharmacokinetics of DPP-4 Inhibitors

ESRD, end-stage renal disease; HD, haemodialysisAdapted from Graefe-Mody U et al. Diabetes Obes Metab. 2011;13:939-46.

7

6

5

4

3

2

1

7

6

5

4

3

2

1

7

6

5

4

3

2

1

Linagliptin(5 mg)

Sitagliptin(50 mg)

Saxagliptin(5-hydroxy saxagliptin metabolite)‡

(10 mg)

Normal(n=6)>80

Mild(n=6)

>50 to 80

Moderate(n=6)

>30 to 50

Severe(n=6)30

ESRD(n=6)

30 on HD

Normal†(n=6)>80

Mild(n=6)

50 to 80

Moderate(n=6)

30 to 50

Severe(n=6)<30

ESRD(n=6)on HD

Normal(n=8)>80

Mild(n=8)

>50 to 80

Moderate(n=8)

>30 to 50

Severe(n=7)<30

ESRD(n=8)on HD

Creatinineclearance*(ml/min)



For i

ncre

ase

in e

xpos

ure

rela

tive

to n

orm

al re

nal f

unct

ion

For i

ncre

ase

in e

xpos

ure

rela

tive

to n

orm

al re

nal f

unct

ion

Renal impairment status



19

ORIGIN: Hazard Ratios for the Co-primary and Other Outcomes

The ORIGIN Trial Investigators. N Engl J Med 2012; 367:319-28.

Outcome Insuline glargine(n = 6264)

Standard care(n = 6273)

Hazard ratio (95% CI) p value

no./100 no./100patient -yr patient -yrno. (%)no. (%)

First co-primary outcomeSecond co-primary outcome

1041 (16.6) 2.941792 (28.6) 5.52

Microvascular outcomes 1323 (21.1) 3.87Total mortality 951 (15.2) 2.57

Total myocardial infarctions 336 (5.4) 0.93Total strokes 331 (5.3) 0.91Death from cardiovascular causes 580 (9.3) 1.57Hospitalization for congestive heart failure 310 (4.9) 0.85

908 (14.5) 2.69Angina 709 (11.3) 2.07

Unstable 238 (3.8) 0.66New 100 (1.6) 0.27Worsening 455 (7.3) 1.29

1013 (16.1) 2.851727 (27.5) 5.28

1363 (21.7) 3.99965 (15.4) 2.60

326 (5.2) 0.90319 (5.1) 0.88576 (9.2) 1.55343 (5.5) 0.95860 (13.7) 2.52743 (11.8) 2.17261 (4.2) 0.72138 (2.2) 0.38446 (7.1) 1.26

Limb or digit amputation 47 (0.8) 0.13 53 (0.8) 0.14Cardiovascular hospitalization 2081 (33.2) 6.98 2071 (33.0) 6.91Non-cardiovascular hospitalization 2339 (37.3) 7.90 2349 (27.4) 7.93

Any cancer 476 (7.6) 1.32 477 (7.6) 1.32Death from cancer 189 (3.0) 0.51 201 (3.2) 0.54

1.02 (0.94–1.11) 0.631.04 (0.97–1.11) 0.27

0.97 (0.90–1.05) 0.430.98 (0.90–1.08) 0.70

1.02 (0.88–1.19) 0.751.03 (0.89–1.21) 0.691.00 (0.89–1.13) 0.980.90 (0.77–1.05) 0.161.06 (0.96–1.16) 0.240.95 (0.85–1.05) 0.290.91 (0.76–1.08) 0.280.72 (0.56–0.93) 0.011.02 (0.89–1.16) 0.800.89 (0.60–1.31) 0.551.00 (0.94–1.07) 0.900.99 (0.94–1.05) 0.85

1.00 (0.88–1.13) 0.970.94 (0.77–1.15) 0.52

0.5 1.0 2.0

Insulin glarginebetter

Standard carebetter

Boussageon R et al. BMJ 2011; 343:d4169.

13 Trials Enrolling 18,315 and 16,218 Individuals Receiving Intensive and Standard Therapy, Respectively

Intensive Glucose-Lowering Treatment and Mortality:A Meta-analysis of Randomized Clinical Trials

No of events/no in groupStudy Intensive

treatmentStandardtreatment

Risk ratio Mantel-Haenszel, random

(99% CI)

Weight(%)

Risk ratio Mantel-Haenszel, random

(99% CI)All cause mortalityUGDP22, 23 64/408 21/205 401 1.53 (0.83 to 2.82)

13.0 1.00 (0.75 to 1.32)UGDP24 91/204 94/21019.2 0.94 (0.78 to 1.13)UKPDS27 539/3071 213/1138

PROactive28 177/2605 186/2633 14.2 0.96 (0.74 to 1.25)0.8 1.66 (0.40 to 6.91)Dargie et al29 8/110 5/114

ACCORD7 257/5128 203/5123 15.7 1.26 (1.00 to 1.60)22.1 0.93 (0.80 to 1.09)ADVANCE6 498/5571 533/5569

HOME30 9/196 6/194 1.0 1.48 (0.39 to 5.63)10.0 1.08 (0.77 to 1.53)VADT8 102/892 95/899

Total (99% CI) 1745/18 185 1356/16 085 100.0 1.04 (0.91 to 1.19)Test for heterogeneity: 2 =0.01, 2 = 13.76,df = 8, p = 0.09, I2 = 42%Test for overall effects: z = 0.72, p = 0.47

Cardiovascular death

UGDP22, 23

31/204 32/210UGDP24

53/408 10/205

UKPDS273/75 3/78

PROactive28301/3070 126/1138

Dargie et al29127/2605 136/2633

ACCORD75/110 4/114

ADVANCE6135/5128 94/5123

HOME30253/5571 289/5569

VADT84/196 1/194

38/892 29/899

Veterans Affairs26

Total (99% CI) 9580/18 260 724/16 163Test for heterogeneity: 2 = 0.04, 2 = 23.29,df = 9, p = 0.006, I2 = 61%Test for overall effects: z = 1.05, p = 0.29

10.0 1.00 (0.55 to 1.81)6.3 2.66 (1.13 to 6.29)1.4 1.04 (0.13 to 8.17)

18.1 0.89 (0.68 to 1.15)16.7 0.94 (0.69 to 1.29)2.1 1.30 (0.24 to 7.04)

15.9 1.43 (1.02 to 2.02)19.2 0.88 (0.70 to 1.09)0./8 3.96 (0.22 to 69.69)9.6 1.32 (0.71 to 2.46)

100.0 1.11 (0.86 to 1.43)

0.2 0.5 1 2 5Favoursintensivetreatment

Favoursstandard

treatment

HPS2-THRIVE. Adapted from http://www.thrivestudy.org/. Accessed March 25, 2013.

HPS2-THRIVE: Effects of ER niacin/laropipranton major vascular eventsRandomized allocation

Risk ratio & 95% CIEvent pPlaceboERN/LRPT(12835)(12838)

Non-fatal MI 402 (3.1%) 431 (3.4%) 0.93 (0.82-1.07) 0.33 Coronary death 302 (2.4%) 291 (2.3%) 1.04 (0.89-1.22) 0.63

Major coronary event 668 (5.2%) 694 (5.4%) 0.96 (0.87-1.07) 0.51

Ischaemic stroke 389 (3.0%) 415 (3.2%) 0.94 (0.82-1.08) 0.37 Haemorrhagic stroke 114 (0.9%) 89 (0.7%) 1.28 (0.97-1.69) 0.08

Any stroke 498 (3.9%) 499 (3.9%) 1.00 (0.88-1.13) 0.56

Coronary revasc 591 (4.6%) 664 (5.2%) 0.89 (0.80-0.99) 0.04 Non-coronary revasc 236 (1.8%) 258 (2.0%) 0.92 (0.77-1.09) 0.33

Any revascularization 807 (6.3%) 897 (7.0%) 0.90 (0.82-0.99) 0.03

Major vascular event 1696 (13.2%) 1758 (13.7%) 0.96 (0.90-1.03) 0.29

1.0 1.2 0.8 ERN/LRPT better Placebo better

20

What if Scenarios

Whatifthepatient…wasonpublicinsuranceplaninsteadofaprivateinsuranceplan?

Whatifthepatient…hadaneGFRof22mL/minbutwascontinuingtodeclineovertime?– Whenwouldyoureferthispatienttoanephrologist?

Whatifthepatient…was84yearsoldwithcognitiveimpairment?

Whatifthepatient…hadaBPof164/84mmHgandwasonramipril10mgqdandamlodipine10mgqd?

As a group, which of these scenarios do you wish to discuss?

“What if the patient…”

• Wasonpublicinsuranceplaninsteadofaprivateinsuranceplan?

• HadaneGFRof22mL/minbutwascontinuingtodeclineovertime?– Whenwouldyoureferthispatienttoanephrologist?

• Was84yearsoldwithcognitiveimpairment?

• HadaBPof164/84mmHgandwasonramipril10mgqd andamlodipine10mgqd?

21

Notes

22

Notes

t

DIAB-1100679-PM-E-11/14

This program was supported in part by an educational grant from Merck Canada Inc.

Documents

Participant Guide Female with CKD 2optimalplus.ca/en/documents_cas2/participant_guide.pdf · 2013. 11. 29. · This program has been reviewed by The College of Family Physicians of