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
2013
ACR ≥2.0 mg/mmol
CKD
in Diabetes
and / or
eGFR <60 mL/min
Stages of Diabetic Nephropathy
Note: change in definition of microalbuminuria
ACR ≥2.0 mg/mmol
2013
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?
Targets2013Checklist
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
Type 1 Diabetes
DCCT
N = 1441 T1DM
Intensive
(≥ 3 injections/day or
CSII)
vs.
\
Conventional
(1-2 injections per
day)
DCCT: Reduction in Albuminuria
Primary Prevention
Secondary Intervention
34% RRR
43% RRR
(p<0.04)
(p=0.001)
56% RRR
(p=0.01)
RRR = relative risk reduction
Solid line = risk of developing microalbuminuria
Dashed line = risk of developing macroalbuminuria CI = confidence interval
The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977-986.
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Copyright © 2013 Canadian Diabetes Association
EDIC: Continued Reduction in
Albuminuria
Return to normoalbuminuria
Macroalbuminuria
HR 1.92
HR 0.64
(p<0.05)
(95% CI 0.40-1.02)
HR = hazard ratio
CI = confidence interval
deBoer IH et al. Arch Intern Med 2011;171(5):412-420.
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Copyright © 2013 Canadian Diabetes Association
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.
Type 2 Diabetes
UKPDS: N = 3867 T2DM
9
Conventional
7.9%
A1C (%)
8
Intensive
7.0%
7
6
0 0
3
UKPDS Study Group. Lancet 1998:352:837-53.
6
9
12
15
Relative risk reduction for
intensive treatment (%)
UKPDS 33: relative risk reduction with intensive
treatment
0
Intensive treatment
reduced HbA1c by 0.9%
for a median of 10
years in 3,867 patients
with type 2 diabetes
10
*
* p < 0.05 ** p < 0.01
20
*
**
*
30
**
Lancet 1998;352:837–53
Holman RR et al. N Engl J Med 2008;359.
UKPDS: Post-trial Monitoring “Legacy
Effect”
After median 8.5 years post-trial follow-up
Aggregate Endpoint
Any diabetes related endpoint
RRR:
P:
1997
12%
0.029
2007
9%
0.040
Microvascular disease
RRR:
25%
P: 0.0099
Myocardial infarction
RRR:
P:
16%
0.052
15%
0.014
All-cause mortality
RRR:
P:
6%
0.44
13%
0.007
Holman R, et al. N Engl J Med 2008;359.
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24%
0.001
ADVANCE
N = 11,140 T2DM
Intensive (A1C ≤6.5% with gliclazide MR)
vs.
Standard glycemic control
ADVANCE: Glucose Control
10.0
9.0
Standard control
7.3%
8.0
Mean
A1C (%)
7.0
p < 0.001
6.0
Intensive control
6.5%
5.0
0.0
0
6
12
18
24
30
36
42
Follow-up (months)
ADVANCE Collaborative Group. N Engl J Med 2008;358:24.
48
54
60
66
ADVANCE: Primary Microvascular
Outcomes
New/worsening nephropathy, retinopathy
25
20
HR 0.86 (0.77-0.97)
p = 0.01
15
Cumulative
incidence (%)
Standard
control
10
Intensive
control
5
0
0
6
12
18
24
30
36
42
48
54
60
66
Follow-up (months)
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
ADVANCE
Collaborative
Group. N Engl
J Med 2008;358:2560-72.
2008;358:24.
BENEFIT
HYPOGLYCEMIA
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 … 2013
Patient characteristics
Agent characteristics
Degree of hyperglycemia
Risk of hypoglycemia
BG lowering efficacy &
durability
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
guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca
Copyright © 2013 Canadian Diabetes Association
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
guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca
Copyright © 2013 Canadian Diabetes Association
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.
Antihyperglycemic Agents and Renal Function
CKD Stage:
GFR (mL/min):
5
< 15
4
15-29
3
30-59
30
Metformin
Linagliptin
15
Saxagliptin
15
Sitagliptin
25 mg
Exenatide
2.5 mg
≥ 90
60
50
30 50 mg
50
30
50
50
Liraglutide
Glyburide
1
25
Acarbose
Gliclazide/Glimepiride
2
60-89
15
30
30
50
Repaglinide
Thiazolidinediones
30
Not recommended / contraindicated
Caution and/or dose reduction
Safe
Adapted from: Product Monographs as of March 1, 2013; CDA Guidelines 2008; and Yale JF. J Am Soc Nephrol 2005; 16:S7-S10.
guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca
Copyright © 2013 Canadian Diabetes Association
Intensification of Therapy in T2D
FBG at target
A1C above target
Basal bolus
Additional bolus doses at
other meals as needed
FBG above target
A1C above target
Basal Plus
Add bolus insulin at one meal
A1C above target
Basal
Add basal insulin and titrate
OHA monotherapy and combinations
Lifestyle changes
OHA=oral hypoglycemic agent
Progressive deterioration of -cell function
Raccah 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.
41
Types of Insulin
Insulin Type (trade name)
Onset
Peak
Duration
10 - 15 min
10 - 15 min
10 - 15 min
1 - 1.5 h
1 - 1.5 h
1-2h
3-5h
3-5h
3.5 - 4.75 h
30 min
2-3h
6.5 h
1-3h
5-8h
Up to 18 h
90 min
Not
applicable
Up to 24 h
(glargine 24 h,
detemir 16 - 24 h)
Bolus (prandial) Insulins
Rapid-acting insulin analogues (clear):
• Insulin aspart (NovoRapid®)
• Insulin glulisine (Apidra™)
• Insulin lispro (Humalog®)
Short-acting insulins (clear):
• Insulin regular (Humulin®-R)
• Insulin regular (Novolin®geToronto)
Basal Insulins
Intermediate-acting insulins (cloudy):
• Insulin NPH (Humulin®-N)
• Insulin NPH (Novolin®ge NPH)
Long-acting basal insulin analogues
(clear)
• Insulin detemir (Levemir®)
• Insulin glargine (Lantus®)
Types of Insulin (continued)
Insulin Type (trade name)
Time action profile
Premixed Insulins
Premixed regular insulin – NPH (cloudy):
• 30% insulin regular/ 70% insulin NPH
(Humulin® 30/70)
• 30% insulin regular/ 70% insulin NPH
(Novolin®ge 30/70)
• 40% insulin regular/ 60% insulin NPH
(Novolin®ge 40/60)
• 50% insulin regular/ 50% insulin NPH
(Novolin®ge 50/50)
Premixed insulin analogues (cloudy):
• 30% Insulin aspart/70% insulin aspart protamine
crystals (NovoMix® 30)
• 25% insulin lispro / 75% insulin lispro protamine
(Humalog® Mix25®)
• 50% insulin lispro / 50% insulin lispro protamine
(Humalog® Mix50®)
A single vial or cartridge contains a
fixed ratio of insulin
(% of rapid-acting or short-acting
insulin to % of intermediate-acting
insulin)
Serum Insulin Level
Time
Human Basal: Humulin-N, Novolin ge NPH
Analogue Basal: Lantus, Levemir
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Copyright © 2013 Canadian Diabetes Association
Human Bolus: Humulin-R, Novolin ge Toronto
Analogue Bolus: Apidra, Humalog, NovoRapid
Serum Insulin Level
Time
Human Premixed: Humulin 30/70, Novolin ge 30/70
Analogue Premixed: Humalog Mix25, NovoMix 30
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Copyright © 2013 Canadian Diabetes Association
How to dose?
“Whatever you pick will be
WRONG … and that’s okay!”
Basal insulin
10 units of insulin each night (0.1 unit per
• You will inject ______
kg)
• You will continue to increase by 1 unit every night until your
blood sugar level is _______
4-7 mmol/L before breakfast
• If hypoglycemia
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 (4T 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
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•
•
•
•
•
•
•
•
•
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?
2013
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