diabetes and nephrology symposium november 19 th,2014 optimizing glycemic control in ckd presented...
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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
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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”
guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.caCopyright © 2013 Canadian Diabetes Association
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
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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.caCopyright © 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.
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
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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
guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.caCopyright © 2013 Canadian Diabetes Association
Time
Ser
um
Insu
lin L
evel
Human Premixed: Humulin 30/70, Novolin ge 30/70
Analogue Premixed: Humalog Mix25, NovoMix 30
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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