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Diabetes and CKD

Andrew Steele MD, FRCPC

Chief and Medical Director Nephrology

and Diabetes, Lakeridge

Lead Nephrologist, Central East LHIN

May 29, 2013

Overview

Diabetes epidemiology

CKD in Diabetes

Diabetic Kidney Disease and CV Risk

CDA Guidelines and Recommendations

Issues with glycemic control in CKD

Safety Issues and Hypoglycemia

Emerging therapies for glycemic control

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http://www.google.ca/url?sa=i&rct=j&q=kidney+disease&source=images&cd=&cad=rja&docid=w2gttOPye5p3tM&tbnid=urFnch4MFSzX4M:&ved=0CAUQjRw&url=http://www.life123.com/health/medical-conditions/kidney-problems/kidney-disease-symptoms.shtml&ei=JVsxUevsKoHWygHNy4H4Cw&bvm=bv.43148975,d.aWc&psig=AFQjCNFew5Z_24nGTiQjGpi6WpFPgm78uw&ust=1362275462252871

Proportion of Adult Ontarians with Diabetes 2003 to 2009: ICES

1,044,622 people with Diabetes have been identified in Ontario by 2009

Adapted from IDF Diabetes Atlas, 4th ed. International Diabetes

Federation, 2009.

Diabetes, a growing global epidemic likely to

affect ~500 million people by 2030

>90% of diabetic patients have type 2 diabetes1

EU: 10.1%

+17% North America: 13.6%

+16%

China: 14.1%

+45%

*All cases of diabetes, including type 1 and type 2 diabetes, and impaired glucose tolerance (IGT), in patients aged 20-79 years.

aAbsolute number of cases and national prevalence 1International Diabetes Federation. IDF Diabetes Atlas, 4th ed. Brussels, Belgium: International Diabetes Federation, 2009. http://www.idf.org/diabetesatlas accessed July 6th 2011.

Prevalence (%) estimates of diabetes* (age 20-79 years, 2030)1a

5

73

2H

Q1

1N

P0

68

Public Health Agency of Canada. Diabetes in Canada: Facts and figures from a public health perspective. Ottawa, 2011.

Prevalence of diagnosed diabetes among individuals aged ≥ 1 year, by age group

and sex, 2008/09

Diabetes in Canada: Prevalence of Diagnosed

Diabetes by age and sex

Prevalence increased with age. The sharpest increase occurred after age 40 years. The highest prevalence was in the 75-79 year age group.

Pre

va

len

ce

(%

)

0

10

15

25

30

1-19

5

20

20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 ≥85 Canada Age group (years)

Females

Males

Total

Overall Prevalence

6.4%

7.2%

6.8%

Patients with DM are more likely to be hospitalized

for many conditions

Public Health Agency of Canada (August 2011); using 2008/09 data from the Canadian Chronic Disease Surveillance System (Public Health Agency of Canada).

Diabetic Nephropathy

“ Progressive increase in proteinuria in people with

longstanding diabetes, followed by declining function

which can eventually lead to End-Stage Renal Disease

(ESRD)”

Importance of the Problem

Diabetic Nephropathy From the perspective of diabetes – One of the most frequent vascular

complications

Type 1 diabetes 30%

Type 2 diabetes 40%

From the perspective of kidney disease – The most common cause of end-stage renal disease (ESRD)

Incident patients 45%

Prevalent patients 55%

From the perspective of cardiovascular disease (CVD) - Progressive risk amplifier

Much of the excess CVD risk in diabetes occurs in the subset of those with diabetic kidney disease (DKD)

lla

illi

lla

illi

Incidence of Diabetic ESRD: Whites,

1992

USRDS 2004

lla

illi

lla

illi

Incidence of Diabetic ESRD: Whites,

2002

USRDS 2004

Diabetes is #1 Cause of New Cases of ESRD

Public Health Agency of Canada (August 2011); using 2008/09 data from the Canadian Chronic Disease Surveillance System (Public Health Agency of Canada).

CKD

in Diabetes

ACR ≥2.0 mg/mmol

and / or

eGFR <60 mL/min

2013

Stages of Diabetic Nephropathy

Note: change in definition of microalbuminuria

ACR ≥2.0 mg/mmol

2013

Chronic Kidney Disease (CKD)

Checklist

SCREEN regularly with random urine albumin creatinine ratio

(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 Angiotensin Receptor Blocker (ARB)

PREVENT complications with “sick day management” counselling

and referral when appropriate

2013

Hemmelgarn, JAMA 2010

CV Risk Factors in Diabetes and CKD

CV risk factors should be treated as aggressively in patients with T2DM as in those with a prior myocardial infarction (MI)

Increased CV Risk in CKD and Proteinuria!

11

Approach to CV Risk Reduction:

CDA 2013 Guidelines

All individuals with diabetes (T1D or T2D) should follow a comprehensive,

multifaceted approach to CV risk including:

*Statins, ACEIs/ARBs, and/or ASA as indicated.

CDA: Canadian Diabetes Association.

CDA 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes 2013;37(suppl 1):S1-S212.

Healthy weight Healthy Diet Physical activity Smoking cessation

Glycemic control BP control Additional vascular

protective medications*

Control of lipids

19

Optimal glycemic control in type 1 and type 2 diabetes has

been shown to reduce the development and progression of

nephropathy

Glucose Control and Diabetic

Nephropathy

Reducing Progression of Diabetic

Nephropathy

Optimal glycemic control

Optimal blood pressure control (< 130/80)

ACE-inhibitor (ACEi) or Angiotensin Receptor Blocker (ARB)

Optimize Cardiovascular Risk Factors

Safety concerns – K+, ARF, hypoglycemia....

guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca

Copyright © 2013 Canadian Diabetes Association

The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977-986.

34% RRR (p<0.04)

43% RRR (p=0.001)

56% RRR (p=0.01)

Primary Prevention Secondary Intervention

Solid line = risk of developing microalbuminuria Dashed line = risk of developing macroalbuminuria

DCCT: Reduction in Albuminuria

RRR = relative risk reduction CI = confidence interval



deBoer IH et al. Arch Intern Med 2011;171(5):412-420.

HR 1.92 (p<0.05)

HR 0.64 (95% CI 0.40-1.02)

Return to normoalbuminuria Macroalbuminuria

HR = hazard ratio CI = confidence interval



EDIC: Continued Reduction in

Albuminuria

EDIC: Early Glycemic Control Reduces

Long-term Risk of Impaired GFR

Risk reduction with intensive therapy

50% (95% CI 18-69; p=0.006)

DCCT/EDIC Research Group. N Engl J Med 2011;365:2366-76.

After median 8.5 years post-trial follow-up

Aggregate Endpoint 1997 2007

Any diabetes related endpoint RRR: 12% 9%

P: 0.029 0.040

Microvascular disease RRR: 25% 24%

P: 0.0099 0.001

Myocardial infarction RRR: 16% 15%

P: 0.052 0.014

All-cause mortality RRR: 6% 13%

P: 0.44 0.007

Holman R, et al. N Engl J Med 2008;359.

UKPDS: Post-trial Monitoring “Legacy Effect”



New/worsening nephropathy, retinopathy

66

Cumulative

incidence (%)

Follow-up (months)

HR 0.86 (0.77-0.97)

p = 0.01 Standard

control

Intensive

control

25

20

15

10

5

0 0 6 12 18 24 30 36 42 48 54 60

Intensive Standard HR p

Nephropathy/retinopathy (%) 9.4 10.9 0.86 0.01

Nephropathy (%) 4.1 5.2 0.79 0.006

Retinopathy (%) 6.0 6.3 0.95 NS

Adapted from:

ADVANCE Collaborative Group. N Engl J Med 2008;358:2560-72. ADVANCE Collaborative Group. N Engl J Med 2008;358:24.

ADVANCE: Primary Microvascular

Outcomes

Leon

70 year old hypertensive for 10 years with type

2 diabetes for 8 years

Presents to emergency with acute

hypoglycemia

His blood sugar is 2.8

http://www.google.ca/url?sa=i&rct=j&q=70+year+old+man&source=images&cd=&cad=rja&docid=jIfxkgkMmF_tRM&tbnid=fIsxs3MAmX2mRM:&ved=0CAUQjRw&url=http://www.kval.com/news/local/96390759.html&ei=eJB0UZ7VLua-2AWpmYDgBg&bvm=bv.45512109,d.aWM&psig=AFQjCNFs7G_jk4UoXqYiF3mRiVoJugOIpg&ust=1366680036891144

What we know…..

eGFR 40 ml/min

Blood Pressure 132/82 mmHg

Waist Circumference 104 cm

ACR 44 mg/mmol

A1c 0.080

Lipids Optimal

Leon’s Medications

Metformin 1000 mg BID

Glyburide 10 mg BID

Ramipril 10 mg OD

Atorvastatin 10 mg OD

Etiology of hypoglycemic events in ESRD

patients hospitalized due to hypoglycemia

46%

39%

7%2% 2% 2% Hypoglycemic agents

SepsisSevere MalnutritionLiver FailureAlcohol

Renal Failure, 22(2), 219-223 (2000)

Hypoglycemia often caused by drugs in CKD patients

Summary hypoglycemia in CKD patients:

1. Loss of renal cortical gluconeogenesis

2. Malnutrition

3. Decreased insulin clearance

4. Failure to adjust dose of AHA

Reducing Progression of Diabetic

Nephropathy

Optimal glycemic control

Optimal blood pressure control (< 130/80)

ACE-inhibitor (ACEi) or Angiotensin Receptor Blocker (ARB)

Optimize Cardiovascular Risk Factors

Safety concerns – K+, ARF, hypoglycemia....



Counsel all

Patients

About

Sick Day

Medication

List

2013

When to Refer…..

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)



What we know…..Leon

eGFR 40 ml/min

Blood Pressure 132/82 mmHg

Waist Circumference 104 cm

ACR 44 mg/mmol

A1c 0.080 Lipids Optimal

Metformin 1000 mg BID

Glyburide 10 mg BID

Ramipril 10 mg OD

Atorvastatin 10 mg OD


Glycemic Targets: CDA

2013 Clinical Practice Guidelines

*Examples are shown on next slide.



≤ 7.0% Most people with T1DM or T2DM

≤ 6.5%

May be considered to further reduce the risk of nephropathy or retinopathy, but must be balanced against the risk of hypoglycemia

7.1 - 8.5% May be considered in select situations*

A1C Target

23

Glycemic Targets: CDA

2013 Clinical Practice Guidelines



A less stringent A1C target (7.1% - 8.5)

may be appropriate in people with:

Limited life expectancy

High level of functional dependency

Extensive CAD at high risk of ischemic events

Multiple comorbidities

Recurrent severe hypoglycemia

Hypoglycemia unawareness

Longstanding diabetes for whom it is difficult to achieve A1C

≤ 7.0% despite effective doses of multiple antihyperglycemic

agents, including intensified basal-bolus insulin regimen

24

aRosiglitazone vs. other treatments.

Kahn SE et al. N Engl J Med 2006; 355:2427-43.

Time (years)

A1

C (

%)

0

Rosiglitazone, 0.07 (0.06 to 0.09)

Metformin, 0.14 (0.13 to 0.16)a

Glyburide, 0.24 (0.23 to 0.26)a

No. of patients

Treatment difference

(95% CI)

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

Annual curve (95% CI)

6.0

6.4

6.8

7.2

7.6

8.0

0 1 2 3 4 5

4012 3308 2991 2583 2197 822

ADOPT

It is Hard to Treat T2DM Adequately…

Because T2DM is a Progressive Disease

33

Increased

glucagon

secretion

Islet-α cell

Increased

lipolysis

Decreased

incretin effect

Neurotransmitter

dysfunction

DeFronzo R. Diabetes 2009; 58:773-85.

Hyperglycemia

Decreased

insulin secretion

Increased

glucose

reabsorption

Increased

hepatic glucose

production

Decreased

glucose

uptake

It is Hard to Treat T2DM Adequately…

Because T2DM has Multiple Pathophysiologic

Abnormalities

34

Lack of Improvement in A1C

in Canada Over Time

1. Harris SB, et al. Diabetes Res Clin Pract 2005; 70(1):90-7.

2. Braga M, et al. Can J Cardiol 2010; 26(6):297-302.

Pro

po

rtio

n w

ith

A1C

< 7

.0%

100

0

60

20

80

40

DICE Study (2005)1 DRIVE Survey (2010)2

Proportion of Subjects with T2DM and A1C Control

53% 51%

31

QUESTION

Which currently available classes of

glucose-lowering medications have been shown to

definitively reduce the risk for CVD in patients with

T2DM?

1. Alpha-glucosidase inhibitor (Acarbose)

2. Biguanides (Metformin)

3. Dipeptidyl peptidase-4 (DPP-4) inhibitors

4. Glucagon-like peptide 1 (GLP-1) receptor agonists

5. Sulfonylureas (SUs)

6. Thiazolidinedione (TZD; pioglitazone)

7. None of the above

41

Conflicting Evidence: Glycemic Control and

Reductions in Risk for CVD

Long-term follow-up of the

UKPDS study

benefit of metformin

> SU / insulin

Meta-analyses of individual

studies

CVD = cardiovascular disease.

1. UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:837-53. 2. The ACCORD Study Group. N Engl J Med 2011; 364:818-28.

3. The ADVANCE Collaborative Group. N Engl J Med 2008; 358:2560-72. 4. Duckworth W, et al. N Engl J Med 2009; 360:129-39.

5. Holman RR, et al. N Engl J Med 2008; 359:1577-89. 6. Boussageon R, et al. BMJ 2011; 343:d4169. 7. Hemmingsen B, et al. BMJ 2011; 343:d6898.

• Original UKPDS study

• ACCORD

• ADVANCE

• VADT

Evidence

of Benefit

No Evidence

of Benefit

42

UKPDS:

Metformin in Overweight Patients

Compared with conventional policy:

*p < 0.02

UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:837-53.

BUT: N = just 342

risk reduction

in MI*

42%

32%

39%

36% risk reduction

in all cause

mortality*

risk reduction in any

diabetes-related

endpoints*

risk reduction in

diabetes-related

deaths*

43

Controversies: Glucose Control for

Prevention of CV Events

If you start treating too late,

do you lose CV benefit?

UKPDS vs. ACCORD, ADVANCE, VADT

Do some treatments produce side-effects

that counteract CV benefit?

? certain SUs1,2

? thiazolidinediones (TZDs)3-6

Do we need longer follow-up to see benefit?

1. Tzoulaki I, et al. BMJ 2009; 339:b4731. 2. Schramm TK, et al. Circulation 2008; 117:1945-54.

3. Nissen SE, et al. N Engl J Med 2007; 356:2457-71. 4. Home PD, et al. Lancet 2009; 373:2125-35.

5. Dormandy JA, et al. Lancet 2005; 366:1279-89. 6. Wilcox R, et al. Am Heart J 2008; 155:712-7.

44

QUESTION

Assuming you consider Leon's hypoglycemia is AHA

related –What would you do?

Stop SU and add Acarbose

Stop SU and add bedtime insulin

Stop DU and add dipeptidyl peptidase (DPP-4) inhibitor

Stop DU and add glucagon-like peptide 1 (GLP-1) agonist

Continue the Sulfonylurea (SU) at lower dose

Stop SU and add thiazolidinedione (TZD; pioglitazone)

None of the above

45

Glycemic

control

Drug

toxicity

Hypoglycemia

Hyperglycemia

Individualizing Pharmacologic Therapy in

T2DM: CDA 2013 Clinical Practice Guidelines



Patient-related

Factors

Hyperglycemia

Hypoglycemia

Weight

Comorbidities

Preferences

Access to treatment

Other

Agent-related

Factors

Glucose-lowering efficacy/durability

Hypoglycemia

Effect on weight

Contraindications and side effects

Cost and coverage

Other

25


CPG

- therapeutic

considerations for

renal impairment

2013

T2DM Treatment Options (1 of 4)

*In alphabetical order.


Class* Drug

(brand name)

Expected

decrease in

A1C with

monotherapy

Hypoglycemia Other therapeutic

considerations

Alpha-

glucosidase

inhibitor

acarbose Rare

• Improved postprandial control

• GI side effects

• Weight: neutral to

• Cost: $$

DPP-4

inhibitors

linagliptin

saxagliptin

sitagliptin

Rare • Weight: neutral to

• Cost: $$$

GLP-1

agonists

exenatide

liraglutide

to

Rare

• GI side effects

• Weight:

• Cost: $$$$

46


Class* Drug (brand name)

Expected

decrease in

A1C with

monotherapy


considerations

Insulin

Rapid-acting analogues

- aspart

- glulisine

- lispro

Short-acting

- regular

Intermediate-acting

- NPH

Long-acting basal

analogues

- detemir

- glargine

Premixed

- premixed regular-NPH

(30/70 40/60, 50/50)

- biphasic insulin aspart

- insulin lispro/lispro

protamine

Yes

• No dose ceiling

• Flexible regimens

• Weight:

• Cost: $ to $$$$

*In alphabetical order, continued from previous slide.


47


*In alphabetical order, continued from previous slides.


Class* Drug (brand name)

Expected

decrease in

A1C with

monotherapy


considerations

Insulin

secretagogues

Sulfonylureas

- gliclazide

Yes

• Meglitinide associated with

less hypoglycemia in the

context of missed meals,

but usually requires TID to

QID dosing

• Gliclazide and glimepiride

associated with less

hypoglycemia than

glyburide

• Weight:

• Cost: $ to $$

- glimepiride Yes

- glyburide Yes

(note: chlorpropamide

and tolbutamide still

available in Canada

but rarely used)

Meglitinides

- nateglinide Yes

- repaglinide Yes

48


Class* Drug

(brand name)

Expected

decrease in

A1C with

monotherapy


considerations

Biguanides metformin Rare

• Improved CV outcomes in overweight

subjects

• Contraindicated if CrCl/eGFR

< 30 mL/min or hepatic failure

• Caution if CrCl/eGFR < 60 mL/min

• Weight: neutral as monotherapy;

promotes less weight gain when

combined with other antihyperglycemic

agents including insulin

• B12 deficiency

• GI side effects

TZDs pioglitazone

rosiglitazone Rare

• CHF, edema, fractures, rare bladder

cancer (pioglitazone), CV controversy

(rosiglitazone),

• 6-12 weeks required for maximal effect

• Weight:

• Cost: $$

*In alphabetical order, continued from previous slides.


49

Glucose Control in CKD/ESRD Intensive Glycemic Control and End-Stage Renal Disease

in Type 2 Diabetes : ADVANCE

N = 11,140 T2DM 5 Yrs

A1c 7.35% vs 6.6%

ESRD 20 vs 7

Nephropathy 4.1% vs. 5.2%

HR =0.79; 95% CI ( 0.66 to 0.93, P=0.006)

NNT = 430 to prevent one ESRD

Not felt to be worth it

Kidney Int 2013 Mar; 83:517.

Glucose Control in ESRD: Excellent glycemic control has not been emphasized as much in

diabetic dialysis patients than in those without renal failure.

Some possible reasons for this practice include the following [21]:

Lack of macrovascular or survival benefit

precipitation of severe hypoglycemia

lack of symptoms with hyperglycemia

The perceived inability to significantly alter progressive damage in

organs other than the kidney.

The perceived lack of accuracy of the glycated hemoglobin level

http://www.uptodate.com/contents/management-of-hyperglycemia-in-diabetics-with-end-stage-renal-disease/abstract/21

Glucose Control in ESRD:

Asia N= 150 diabetic subjects

with ESRD starting HD

treatment.

60.5 ± 10.2 years

2.8 years, 76% of the

patients died;

HbA1c < 7.5%), mortality

was lower than in those

with poor glycaemic

control (HbA1c ≥ 7.5%).

Morioka et al. Diabetes Care. Vol. 24. 2001.


Asia 7-year observational study

N = 114 diabetic HD patients

Good: HbA1c <6.5%

Fair: HbA1c > 6.5% < 8.0%

Poor: HbA1c > 8.0%

Mortality was significantly higher

(HR 2.89; P = 0.01) in those

with poor glycaemic control/

Oomichi et al. Diabetes Care. Vol. 29. 2006


USA

A. N = 24 875 US diabetic dialysis patients HgbA1c <5.0 % 11.3%

HgbA1c 5.1 – 7.0% 40.7%

HgbA1c > 7.0% 35%

HgbA1c > 8.5% 14%.

No correlation between HbA1c and survival was found at 12 months in

B. N = 23 618 US diabetic HD patients

HbA1c values were incrementally associated with higher mortality.

HbA1c in the range of 5–6% vs. HbA1c >10% Adjusted all-cause HR = 1.41 (P < 0.001)

CV death HR = 1.73 (P < 0.001)

Kidney Int 2006;70:1503-1509.

Diabetes Care. Vol. 30. 2007

Glucose Control in ESRD: However since diabetes-related damage is likely to present in varying degrees among

different organs, good glycemic control should be a significant treatment goal for diabetic patients with end-stage renal disease.

1. A1c is probably less informative

2. Aim for A1c < 7% if possible

3. A1c < 8.5% for long standing DM, elderly, frail, established CVD

4. Difficult to achieve in PD

5. Avoid Hypoglycemia is paramount

6. Avoid symptomatic hyperglycemia

7. Choosing safe drugs

In conclusion, there is an urgent need for large prospective RCTs in diabetic patients with CKD / ESRD with the following goals:

different approaches of antidiabetic treatment

efficacy and safety of different levels of glycaemic control

Glucose Control in CKD and ESRD:

LH KCC

<.07 = 65.5%

<0.084 =23.9% (89.4%)

Home HD

<0.07% =60.6%

<0.084 =21.2% (81.8%)

PD

<0.07 = 38.1%

<0.084= 34.9% (73 %)

ICHD

<0.07=44.2%

<0.084=18.4% (62.6%)

Possible Benefits of Newer Classes

of AHA

Incretin Therapy

ADVANCE:

Severe Hypoglycemia Associated with Adverse Clinical

Endpoints and Death

Numbers above sets of bars are HR (95% CI). aAdjusted for multiple baseline covariates. bPrimary endpoints. Major macrovascular event = CV death, nonfatal myocardial infarction,

or nonfatal stroke; major microvascular event = new or worsening nephropathy or retinopathy.

Zoungas S, et al. N Engl J Med 2010; 363:1410–8.

b b

25

0

15

5

20

10

Severe Hypoglycemia

(n = 231)

No Severe Hypoglycemia

(n = 10,909)

3.53

(2.41–5.17)a

Major

macrovascular

eventb

15.9

10.2

2.19

(1.40–3.45)a

Major

microvascular

eventb

11.5

10.1

3.27

(2.29–4.65)a

Death from

any cause

19.5

9.0

3.79

(2.36–6.08)a

CV disease

9.5

4.8

2.80

(1.64–4.79)a

Non-CV disease

10.0

4.3

Pa

tie

nts

wit

h ≥

1

hyp

og

lyc

em

ic e

ve

nts

(%

)

54

Some Antihyperglycemic Therapies

May Have Adverse CV Effects

Data suggest an increase in CV risk with certain oral antihyperglycemic agents

Certain sulfonylureas1,2 — possibly mediated by:

increased CV risks associated with hypoglycemia

effects on cardiac potassium ATP channels (loss of beneficial ischemic pre-conditioning)

Thiazolidinediones3-6

increased risk of edema, CHF

1. Tzoulaki I, et al. BMJ 2009; 339:b4731. 2. Schramm TK, et al. Circulation 2008; 117:1945-54.

3. Nissen SE, Wolski K. N Engl J Med 2007; 356:2457-71. 4. Home PD, et al. Lancet 2009; 373:2125-35.

5. Dormandy JA, et al. Lancet 2005; 366:1279-89. 6. Wilcox R, et al. Am Heart J 2008; 155:712-17.

52

Effects of Incretin Agents on CV Events

in T2DM: Risk Reduction for MACE in

Meta-analyses

MACE = CV death, MI, stroke, hospitalization for ACS or HF.

Monami M, et al. Exp Diab Res 2011; doi:10.1155/2011/215764.

Lamanna C, et al. EASD Annual Meeting, September 2011.

-60

-45

-30

-15

0

Ris

k r

ed

ucti

on

fo

r M

AC

E (

%)

-31%

p = 0.006

-26%

p = 0.121

GLP-1R agonists vs.

all comparators

(20 trials)1

-54%

p = 0.009

GLP-1R agonists

vs. placebo

(13 trials)1

DPP-4 inhibitors vs.

all comparators

(43 trials)2

DPP-4 inhibitors

vs. placebo

(25 trials)2

-29%

p = 0.045

68

Ongoing CV Outcome Trials:

DPP-4 Inhibitors

CVD = cardiovascular.

Adapted from:

1. Golden SH. Am J Cardiol 2011; 108(Suppl):59B-67B.

2. Fonseca V. Am J Cardiol 2011; 108(Supp):52B–58B.

3. www.clinicaltrials.gov

Trial Therapies # Population Primary endpoint End Date

CAROLINA Linagliptin/

Glimepiride

6000 CVD or ≥ 2 RF Non-inferiority: time to

first occurrence of any

component of MACE

composite outcome

Sept 2018

EXAMINE Alogliptin/

Placebo

5400 ACS 15-90 days

before

Non-inferiority: time to

occurrence of MACE

Dec 2014

SAVOR-TIMI 53 Saxagliptin/

Placebo

16,500 CVD or ≥ 2 RF Superiority efficacy,

non-inferiority safety:

composite CV death, NF

MI, NF stroke

July 2013

TECOS Sitagliptin/

Placebo

14,000 Established CVD Non-inferiority: time to

first occurrence of

composite CV outcome

Dec 2014

72

Ongoing CV Outcome Trials:

GLP-1 Agonists

CVD = cardiovascular.

Adapted from:

1. Golden SH. Am J Cardiol 2011; 108(Suppl):59B-67B.

2. Fonseca V. Am J Cardiol 2011; 108(Supp):52B–58B.

3. www.clinicaltrials.gov

Trial Therapies # Population Primary endpoint End Date

ELIXA Lixisenatide/

Placebo

6000 ACS leading to

hosp ≤ 180 days

before

Non-inferiority:

CV death, NF MI,

NF stroke, UA

hospitalization.

Oct 2013

EXSCEL Exenatide

LAR/

Placebo

9500 T2DM, A1C of

7.0-10.0%

Non-inferiority:

Time to primary

composite CV endpoint

Mar 2017

LEADER Liraglutide/

Placebo

8754 CVD, PAD, CKD,

CHF or RF if age

> 60 years

Superiority:

Time to composite CV

death, NF MI, NF stroke

Jan 2016

REWIND Dulaglutide/

Placebo

9622 CVD or ≥ 2 RF if

age ≥ 60 years

Superiority:

Time to composite CV

death, NF MI, NF stroke

Apr 2019

73

Leon

Goals:

1. Optimal glycemic control

2. Optimal blood pressure control (< 130/80)

3. ACE-i or ARB

4. Optimize Cardiovascular Risk Factors

5. Safety concerns – K+, ARF, hypoglycemia....

70 y.o.

HT 15 years

T2DM 10 years

CKD Stage 3

ER: Severe Hypoglycemia


Overall Conclusions

T2DM is over 10% of population and growing

DM Nephropathy is # 1 cause of ESRD

CDA recommends vascular protection in T2DM patients

Multi-risk factor intervention is necessary, including glycemic control

No prospective evidence yet of CV benefit with any antihyperglycemic therapy

Individualized goals of therapy are now the recommended, beware safety issues including hypoglycemia and increased morbidity and mortality

Newer agents may offer some benefit over traditional agents, especially in CKD and high risk patients

Large prospective RCTs are ongoing and needed to answer the question of targets, safety and optimal agents in CKD/ESRD

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