diabetes and nephrology symposium november 19 th,2014 optimizing glycemic control in ckd presented...

Diabetes and Nephrology Symposium November 19th,2014

Optimizing Glycemic control in CKD

Presented by Laila Bishara MD, FRCPC

Disclosure

Financial Disclosure• Grants/research support: None• Speakers bureau/honoraria: Eli Lilly, Sanofi

Aventis, Merck and NovoNordisk• Consulting fees: None

T

Learning objectives

• To identify the role of glycemic control in various stages of CKD

• To individualize patient’s glycemic goals in CKD

• To review the therapeutic options for glucose control and the limitations and risks in patients with CKD

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/mmol2013

Case 1• 56 year old man works as a bank manager• Non-smoker and consumes alcohol occasionally.• Type 2 diagnosed 3 years ago.• No known coronary artery disease• Hypertension controlled on ramipril 10 mg.• On Atorvastatin 10 mg.• Received dietary education at the time of diagnosis • His HbA1C was 6.6 to 7.3% in the first 12 months, then went up gradually• Metformin was added and titrated up to 1000 mg bid.• Over the following year, he was switched to Janumet 50 mg/ 1 gm bid • Recent blood work: HbA1C 7.9 %. LDL 1.8, TC/HDL 3.5.• ACR: < 2 mg/ mmol• eGFR > 60 ml/ minute

Case 1

• What is the HbA1C target for this patient ?• Would glycemic control impact on his risk for

developing nephropathy?• Anti-hyperglycemic agents needed to bring

him in target?

Case 2• 54 year old woman• Type 2 diabetes diagnosed 6 years ago.• Hypertension and dyslipidemia treated• No known coronary artery disease or any macrovascular

disease• Medications: Rosuvastatin 10 mg, Coversyl 8 mg,

Metformin 1 gm bid, Onglyza 5 mg and Glicalzide MR 60 mg• ACR on 2 different occasions 5 mg/ mmol• eGFR: > 60 ml/ minute• LDL 1.7, blood pressure 125/75• HbA1C: 8.7% not changed significantly from 8.9% 3 months

ago

Case 2

• What is the HbA1C target for this patient ?• Would glycemic control impact on the course

of nephropathy?• Agents needed to bring her on target?

Case 2

• What if ACR was 30 mg/ mmol?• What if eGFR was lower?• Glycemic target?• Agents?

Targets Checklist

A1C ≤7.0% for MOST people with diabetes

A1C ≤6.5% for SOME people with T2DM

A1C 7.1-8.5% in people with specific

features

2013

Type 1 Diabetes

DCCTN = 1441 T1DM

Intensive(≥ 3 injections/day or

CSII)

vs. \

Conventional (1-2 injections per

day)

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 microalbuminuriaDashed line = risk of developing macroalbuminuria

DCCT: Reduction in Albuminuria

RRR = relative risk reductionCI = confidence interval

guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.caCopyright © 2013 Canadian Diabetes Association

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 ratioCI = confidence interval


EDIC: Continued Reduction in Albuminuria

EDIC: Early Glycemic Control Reduces Long-term Risk of Impaired GFR

Risk reduction with intensive therapy50%

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

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

Type 2 Diabetes

UKPDS: N = 3867 T2DM

06

8

9

0 3 6 9 12 15

A1C

(%

)

Conventional7.9%

Intensive7.0%

7

UKPDS Study Group. Lancet 1998:352:837-53.

UKPDS 33: relative risk reduction with intensive treatment

Rela

tive r

isk

reduct

ion

for

inte

nsi

ve t

reatm

en

t (%

)

Intensive treatment reduced HbA1c by 0.9% for a median of 10 years in 3,867 patients with type 2 diabetes

* p < 0.05 ** p < 0.01

Any

diab

etes

endp

oint

Micro

vasc

ular

endp

oint

MI

Cata

ract

extrac

tion

Retin

opat

hy

(12

year

s)Al

bum

inur

ia

(12

year

s)

0

10

20

30

*

** *

*

**Lancet 1998;352:837–53

Holman RR et al. N Engl J Med 2008;359.

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”


ADVANCEN = 11,140 T2DM

Intensive (A1C ≤6.5% with gliclazide MR) vs.

Standard glycemic control

ADVANCE: Glucose Control

Follow-up (months)

Mean A1C (%)

Standard control 7.3%

Intensive control 6.5%

10.0

9.0

8.0

7.0

6.0

5.0

0.00 6 12 18 24 30 36 42 48 54 60 66

p < 0.001

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

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

00 6 12 18 24 30 36 42 48 54 60

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

BENEFITHYPO-

GLYCEMIA

Case 1• 56 year old man • Type 2 diagnosed 3 years ago.• No known coronary artery disease• Hypertension controlled on Ramipril 10 mg.• On Atorvastatin 10 mg.• Janumet 50 mg/ 1 gm bid • Recent blood work: HbA1C 7.9 %. LDL 1.8,

TC/HDL 3.5.• ACR: < 2 mg/ mmol• eGFR > 60 ml/ minute

Case 1

• HbA1C target ?• Would glycemic control impact on his risk for

developing nephropathy?• Anti-hyperglycemic agents needed to bring

him in target?

2013 CDA Recommendations• Therapy in most individuals with type 1 or type 2

diabetes should be targeted to achieve an A1C ≤ 7.0% in order to reduce the risk of microvascular [Grade A, Level 1A] and, if implemented early in the course of disease, macrovascular complications [Grade B, Level 3]

• An A1C ≤6.5% may be targeted in some patients with type 2 diabetes to further lower the risk of nephropathy [Grade A, Level 1] and retinopathy [Grade A, Level 1], but this must be balanced against the risk of hypoglycemia [Grade A, Level 1].

After Metformin? Depends …Patient characteristics Agent characteristics

Degree of hyperglycemia BG lowering efficacy & durability

Risk of hypoglycemia Risk of inducing hypoglycemia

Weight Effect on weight

Comorbidities (renal, cardiac, hepatic)

Contraindications & side effects

Access to treatment Cost and coverage

Patient preferences Other

2013

2013


Case 2• 54 year old woman• Type 2 diabetes diagnosed 6 years ago.• Hypertension and dyslipidemia treated• No known coronary artery disease or any macrovascular

disease• Medications: Rosuvastatin 10 mg, Coversyl 8 mg,

Metformin 1 gm bid, Onglyza 5 mg and Glicalzide MR 60 mg• ACR on 2 different occasions 5 mg/ mmol• eGFR: > 60 ml/ minute• LDL 1.7, blood pressure 125/75• HbA1C: 8.7% not changed significantly from 8.9% 3 months

ago

Case 2

• What is the HbA1C target for this patient ?• Would glycemic control impact on the course

of nephropathy?• Agents needed to bring her on target?

2013


Case 2

What if the ACR was 30 mg/mmol ?

Case 2

What if the eGFR was 45?

Issues with low GFR

• Mostly stages 4 and 5 CKD• Most oral agents need to be stopped, few

exceptions.• Insulin is the preferred therapy• Risk of hypoglycemia is higher.

Adapted from: Product Monographs as of March 1, 2013; CDA Guidelines 2008; and Yale JF. J Am Soc Nephrol 2005; 16:S7-S10.

Antihyperglycemic Agents and Renal Function

Not recommended / contraindicated SafeCaution and/or dose reduction

Repaglinide

Metformin 30 60

Saxagliptin

Linagliptin

Glyburide 30 50

Thiazolidinediones 30

GFR (mL/min): < 15 15-29 30-59 60-89 ≥ 90

CKD Stage: 5 4 3 2 1

Gliclazide/Glimepiride 15 30

Liraglutide 50

Exenatide 30 50

Acarbose 25

Sitagliptin 50

5015 2.5 mg

15

30 50 mg25 mg


Progressive deterioration of -cell function

Lifestyle changes

OHA monotherapy and combinations

BasalAdd basal insulin and titrate

Basal PlusAdd bolus insulin at one mealA1C above target

FBG above targetA1C above target

Basal bolusAdditional bolus doses at other meals as needed

FBG at targetA1C above target

OHA=oral hypoglycemic agent

41Raccah D et al. Diabetes Metab Res Rev 2007;23(4):257-264.Nathan DM et al. Diabetologia 2006;49:1711–1721.Woerle H. Arch Intern Med 2004;164:1627–1632.

Types of Insulin

Types of Insulin (continued)

Ser

um

Insu

lin L

evel

Time

Analogue Bolus: Apidra, Humalog, NovoRapid

Human Basal: Humulin-N, Novolin ge NPH

Analogue Basal: Lantus, Levemir

Human Bolus: Humulin-R, Novolin ge Toronto


Time

Ser

um

Insu

lin L

evel

Human Premixed: Humulin 30/70, Novolin ge 30/70

Analogue Premixed: Humalog Mix25, NovoMix 30


How to dose?

“Whatever you pick will be WRONG … and that’s okay!”

• You will inject ______ units of insulin each night (0.1 unit per

kg)

• You will continue to increase by 1 unit every night until your

blood sugar level is _______ mmol/L before breakfast

• If hypoglycemia

Basal insulin

10

4-7

Basal Plus or Basal-Bolus

• If full Basal-Bolus: 0.4 to 0.5 u/kg = TDI• 50% bolus, 50% basal (or 60:40)

OR• Add 10% of basal dose as bolus insulin ac meal (4-

T study)OR

• Add 2 units and self-titrate (START protocol)OR

• Add 4 units and self-titrate (STEP protocol)

Harris, S et al. START study. As presented at the CDA / CSEM conference in Vancouver, BC, October 2012.Meneghini L, Mersebach H, Kumar S, et al. Endocrine Practice 2011;17:727-36.

Premixed

• 0.4 to 0.5 units / kg• Traditionally: 2/3 in the AM + 1/3

in the PM• Practically 50% am and 50%

evening

Case 4• 62 year old man• Type 1 diabetes since age 10• On insulin pump• HbA1C inadequate over the years: 9 to 10%• Main barrier is fear of hypoglycemia yet he suffers

Hypoglycemia unawareness• Retinopathy and Coronary artery disease• Nephropathy for the last 10 years, progressed over the

last 3 years• Last eGFR 15• Discussing dialysis Vs transplant with nephrologist

Case 4

• Target A1C?• Would it impact on that stage of kidney

disease?• Dialysis Vs Transplant

Case 5• 77 year old frail woman• Weight: 145 lbs• Type 2 diabetes for 25 years• Retinopathy, neuropathy and nephropathy• Coronary artery disease. Bypass surgery 10 years ago and

recent angioplasty• On insulin for 15 years• Currently on Metformin 1 gm bid, Lantus 32 units at night

and Humalog 10 to 12 units per meal• HbA1C is 8%• eGFR: 38• ACR : 20 mg/ mmol

Case 5

• A1C target?• Need to modify treatment?

Consider A1C 7.1-8.5% if …• 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 is it difficult to

achieve an A1C ≤ 7%, despite effective doses of multiple antihyperglycemic agents, including intensified basal-bolus insulin therapy

2013

Recommendation Less stringent A1C targets (7.1 to 8.5% in most cases) may be appropriate in patients with type 1 or type 2 diabetes with any of the following [Grade D, Consensus]:

– Limited life expectancy– High level of functional dependency– Extensive coronary artery disease at high risk of

ischemic events– Insulin therapy

2013

diabetes and nephrology symposium november 19 th,2014 optimizing glycemic control in ckd presented...

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