Transcript - Caribbean Institute of Nephrology

MEASURES TO PREVENT
DIABETIC NEPHROPATHY AND
END-STAGE RENAL DISEASE
AND IMPLICATIONS FOR INSULIN
THERAPY
R Wright-Pascoe DM, FACP, FACE,
FRCP (Edin)
The University of the West Indies
Mona
Outline of Presentation
• Epidemiology of Diabetes mellitus in
Jamaica
• Epidemiology of end-stage renal disease
in diabetic subjects
• Define diabetic nephropathy and the
stages of chronic kidney disease (CKD)
• Review the evidence for the role of
hyperglycaemia in diabetic nephropathy
Outline of Presentation
• Discuss the targets of glycaemic control
• Discuss the legacy effect
• Control of glycaemia in Jamaicans with diabetes
mellitus
• Discuss bolus insulin
• Outline the contribution of fasting
hyperglycaemia to HbA1c
• Introduce to ADA ?EASD algorithm
• Review how to use bolus insulin in Type 2
diabetes mellitus
Outline of Presentation
• Discuss the premixed insulins
• Discuss the biphasic insulin
• Outline the use of algorithms to use
biphasic insulins
• Discuss insulin therapy in Type 1 diabetes
mellitus and starting regimes
Prevalence of Diabetes Mellitus in
Jamaica
%
17.9
20
13.4
15
8.1
10
5
1.3
0
1959-60
1969-70
1995
1999
Sargeant et al, 2002
WHO estimates that there will be
155,000 diabetics in Jamaica in
2025
No. of people with
diabetes (000)
120
101
100
80
40
60
40
15
20
0
20-44
45-64
Age (years)
>= 65
King et al, 1998
Age Distribution of Diabetics Attending the DAJ
Clinics in Kingston and St Ann’s Bay Hospital
%
34.4
35
30
25
19.7
17.2
20
19.0
15
10
6.1
6.1
< 29
30-39
5
0
40-49
50-59
Age (years)
Wright-Pascoe R et al, Diabetes Rev 2000
60-69
>70
Number of people with Diabetes by
age-group in developing countries
120
100
80
1995
2025
60
40
20
0
20 - 44
45-64
King H et al. Diabetes Care,1998,21;1414-1431
65+
At the Primary Care Clinics in
Jamaica
Diabetes account for 4-7 % of
patient attendees and 2 % of all
admissions to all general hospitals in
the island
Richard-George
One complication associated
with diabetes mellitus
• End-Stage Renal Disease
• Diabetes mellitus is one of the leading
cause of End-Stage Renal Disease
requiring dialysis in the Caribbean
Diabetic nephropathy is one of the
commonest causes of end-stage
renal disease in the world
29TH January 2011
NHANES II: Annual incidence of
diabetes-associated complications
among USA patients
Complication
Cases per year
Risk % *
Ischemic Herat disease
101,000
1.58
Amputation
47,000
0.73
Cerebrovascular accident
27,000
0.42
Blindness
6,900
0.11
Renal insufficiency
5,900
0.09
* Anual risk of development of complications, calculation based on 6.4
million diabetic patients
Adaptado de: McMillan D.E. Vasc Med 2 (2):132- 42, 1997.
Hyperglycaemia increases risk for
diabetes –related complications
20
Retinopathy
Nephropathy
Neuropathy
Microalbuminuria
15
Relative Risk
13
11
9
7
5
3
1
6
7
8
9
10
11
12
A1C (%)
DCCT, Diabetes Control and Complications Trial.
1. Adapted from Skyler JS. Endocrinol Metab Clin North Am. 1996;25:243-254.
2. DCCT. N Engl J Med. 1993;329:977-986.
3. DCCT. Diabetes. 1995;44:968-983.
Glycaemic control is associated with a
reduction in diabetes –related
complications : UKPDS
Risk Reduction (%)
Risk reduction in complications per
each 1% reduction in mean A1C
50
40
Type 2 DM
43
37
30
21
21
20
14
10
0
Microvascular
Any Endpoint Death Related
Related to Diabetes to Diabetes
Fatal and
Nonfatal MI
UKPDS, United Kingdom Prospective Diabetes Study; MI, myocardial infarction;
PVD, peripheral vascular disease.
Stratton IM et al. Br Med J. 2000;321:405-412.
Amputation or
Death From PVD
The Evidence for Hyperglycaemia
and Diabetic Nephropathy
•
•
•
•
DCCT
UKPDS
Kumamoto
ADVANCE
DCCT: Results after sustained
glycaemic separation for 4-9 years
Intensively treated
group
Conventionally
treated group
• Mean HBA1c 7.2
• Mean HBA1c 9.1%
%
• Mean blood glucose
155mg/dl
(8.6 mmol/l)
• Mean blood glucose
230 mg/dl
• (12.8 mmol/l)
Those with a HBa1c of 7.2%
•
Microalbuminuria
–
•
60%
Clinical grade nephropathy
–
54%
Skyler JS. Microvascular Complications : Retinopathy and Nephropathy
In Endocrn and Metab Clinics of North Am 2001;30:833-856
Those with a HBa1c of 7.2%
•
Microalbuminuria
–
•
39%
Advanced
microalbuminuria
–
51%
• (Albumin excretion
rate >28 ug/min or 40
mg/24 hr)
• (Albumin excretion
rate >70 ug/min or
100mg/ 24 hr)
Skyler JS. Microvascular Complications : Retinopathy and Nephropathy
In Endocrn and Metab Clinics of North Am 2001;30:833-856
Those with a HBa1c of 7.2%
–
Renal damage
•
54%
– AER > 208 ug/min
or 300mg/24hr
Skyler JS. Microvascular Complications : Retinopathy and Nephropathy
In Endocrn and Metab Clinics of North Am 2001;30:833-856
Those with a HBa1c of 7.2% and
previous Diabetic Nephropathy
•
Microalbuminuria
–
43%
• Severe advanced microalbuminuria
–
56%
Skyler JS. Microvascular Complications : Retinopathy and Nephropathy
In Endocrn and Metab Clinics of North Am 2001;30:833-856
Those with a HBa1c of 7.2% and
previous Diabetic Nephropathy
• Clinical grade albuminuria
–
56%
Advanced nephropathy
6.5 % per year increase in the
conventional group vs. the intensive group
Skyler JS. Microvascular Complications : Retinopathy and Nephropathy
In Endocrn and Metab Clinics of North Am 2001;30:833-856
Epidemiology of Diabetes
Interventions and Complications
(EDIC) Study
• Patients in the DCCT
• Seen now by their own physicians
• Enrolled in this observational study
AIM
• To compare the long-term effects of
intensive or conventional glycaemic
control on the development of retinal and
renal complications 6 years later
Steffes MW, Molitch ME, Chavers BM et al, and the DCCT/EDIC
Study Group: Sustained reduction in albuminuria six years after the
Diabetes Control and Complications Trial (Abstract). Diabetes 2001: 50: 254
Results in EDIC
Intensively treated
group
Conventionally
treated group
• Mean HBA1c 7.9 %
• Mean HBA1c 8.2%
Steffes MW, Molitch ME, Chavers BM et al, and the DCCT/EDIC
Study Group: Sustained reduction in albuminuria six years after the
Diabetes Control and Complications Trial (Abstract). Diabetes 2001: 50: 254
Incidence of:
• Microalbuminuria and albuminuria
significantly lower in the intensive-therapy
group compared to the conventionaltherapy group despite the similar HBA1c
(p<0.001)
Steffes MW, Molitch ME, Chavers BM et al, and the DCCT/EDIC
Study Group: Sustained reduction in albuminuria six years after the
Diabetes Control and Complications Trial (Abstract). Diabetes 2001: 50: 254
The United Kingdom Prospective
Diabetes Study (UKPDS)
•
•
•
•
•
•
Type 2 diabetes
Newly diagnosed
N=5102
Aged 25-63 years
Median age 53 years
Duration of follow-up 10 years
UK Prospective Diabetes Study Group: Effect of intensive blood-glucose control with
metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).
Lancet 1998: 352: 854-865
UK Prospective Diabetes Study Group: Intensive blood-glucose control with
sulphonylureas or insulin compared with conventional treatment and risk of complications
In patients with type 2 diabetes (UKPDS 33). Lancet 1998: 352: 837-853
The United Kingdom Prospective
Diabetes Study (UKPDS)
• Half intensive therapy
– Sulphonylureas, insulin, metformin
• Half conventional therapy
– Diet and exercise
Results of UKPDS
Intensively treated
group
Conventionally
treated group
• Mean HBA1c 7.0 %
• Mean HBA1c 7.9 %
• (P<0.001)
Results : Intensive vs. the
Conventional group
• Risk reduction in the appearance of
microalbuminuria
•
At 9 years
–
•
by 24%
At 12 years
–
•
by 33%
At 15 years
–
by 34%
Skyler JS. Microvascular Complications : Retinopathy and Nephropathy
In Endocrn and Metab Clinics of North Am 2001;30:833-856
Results : Intensive vs. the
Conventional group
• Risk reduction in the doubling of the serum
creatinine
•
At 9 years
–
•
by 60%
At 12 years
–
by 74%
Skyler JS. Microvascular Complications : Retinopathy and Nephropathy
In Endocrn and Metab Clinics of North Am 2001;30:833-856
31
UKPDS: legacy effect of earlier glucose control
End of randomised
intervention1
1997
Any diabetes related endpoint
RRR
pvalue
Microvascular disease
RRR
pvalue
Myocardial infarction
RRR
pvalue
All-cause mortality
RRR
pvalue
End of 10-year
observational
follow-up2
2007
12%
0.029
9%
0.040
25%
0.0099
24%
0.001
16%
0.052
15%
0.014
6%
0.44
13%
0.007
RRR = relative risk reduction associated with intensive glucose control
1UKPDS
2Holman
Group. Lancet 1998;352:837–853.
R, et al. N Engl J Med 2008;359:1577–1589.
Conclusions
Clear and unequivocal evidence that
meticulous glycaemic control has a
profound and beneficial effect on the:
1. development of diabetic nephropathy
2. progression of diabetic nephropathy
Intensive glycaemic control in diabetes is
important
ADVANCE: intensive glucose control significantly
reduced nephropathy but not retinopathy
Hazard ratio
Definitions
New or worsening nephropathy:
macroalbuminuria, renal replacement,
or death due to renal disease
New or worsening retinopathy:
proliferative retinopathy, macular
oedema, diabetes-related blindness or
retinal photocoagulation therapy
33
ADVANCE Collaborative Group. N Engl J Med 2008;358:2560–2572.
Does intensive glucose control reduce microvascular
complications in type 2 diabetes?
UKPDS1
ADVANCE2
VADT3
ACCORD
(n=3867)
(n=11,140)
(n=1791)
(n=10,251)
HbA1c (%)*
7.0 vs 7.9
6.5 vs 7.3
6.9 vs 8.4
6.4 vs 7.5
Combined
microvascular
25% RRR
14% RRR
Not available
(p=0.0099)
(p=0.01)
Nephropathy
No difference:
death from renal
disease or renal
failure
21% RRR
Retinopathy
Retinal
photocoagulation
(p=0.0031) &
cataract extraction
(p=0.046)
No difference: new
or worsening
retinopathy
Neuropathy
No difference:
absent ankle/knee
reflexes
No difference: new
or worsening
neuropathy
34 achieved HbA1c, intensive vs standard
* Mean
RRR: relative risk reduction
New or worsening
nephropathy
(p=0.006) & newonset
microalbuminuria
(p=0.02)
Any worsening
albuminuria
(p=0.05)
No difference:
kidney function,
advanced/end stage Not yet
reported
renal disease,
proteinuria
No difference: hard
eye endpoints/
retinopathy
No difference: new
neuropathy
1UKPDS
2ADVANCE
Group. Lancet 1998;352:837–853.
Collaborative Group. N Engl J Med 2008;358:2560–2572.
3Duckworth W, et al. N Engl J Med 2009;360:129–139.
• The beneficial effect of tight glycaemic
control itself on diabetic nephropathy
in CKD stages 3 -5 has not yet been
established unequivally
• If blood pressure is controlled however,
glycaemic control has been shown to
decrease the rate of decrease in GFR1
Alaveras AE, Thomas SM, Sagariotis A et al.
Promoters of progression of diabetic nephropathy: the relative role
of blood glucose and blood pressure control. Nephrol Dial
Transplant 1997; 12(Suppl 2):71-74
Additional Years of
Derived Benefits
Benefits of Improved Glycaemic
Control
2.0
1.5
1.0
0.5
0
Life
Sight
ESRD-free LEA-free
QALYs
Benefit Parameter
ESRD, end-stage renal disease; LEA, lower-extremity amputation; QALYs, quality-adjusted life-years.
Adapted from Klonoff DC et al. Diabetes Care. 2000;23:390-404.
Target HbA1c to prevent Diabetic
Nephropathy
• HbA1c
• <7%
• <6.5%
How Well Controlled Are They
GlyHb (N=66)
Normal or < normal
> 1% above normal
> 2% but < 3%
>3% but < 5%
>5% but <10%
> = 10%
%
27.3
16.7
10.6
13.6
24.2
5.0
53.4%
Wright-Pascoe et al , 1999
What are the messages we must
take back to our practices?
Chronic renal failure in diabetes mellitus is
associated with hyperglycaemia
What are the messages we must
take back to our practices?
• Treating hyperglycaemia aggressively will
decrease appearance of each component
of diabetic nephropathy in persons without
established diabetic nephropathy
What are the messages we must
take back to our practices?
• Treating hyperglycaemia aggressively will
result in delay in the progression of
diabetic nephropathy in persons with
established diabetic nephropathy
What are the messages we must
take back to our practices?
• The time to treat to goal is NOW
• This as there is “memory” in euglycaemia
• Protection against “ Diabetic
Nephropathy” will be seen 10 years after
even if the persons becomes
hyperglycaemic later in life
• THE LEGACY EFFECT
Jamaican diabetics are poorly
controlled and are therefore at risk
for diabetic nephropathy
What are the messages we must
take back to our practices?
The goal for metabolic control
and prevention of disease is a
HbA1C
< 7%
< 6.5%
• Insufficient data and trials regarding the ideal
glucose target in patients with CKD stage 3 or
worse.
• A1c levels >9 % and < 6.5 % were associated
with increased mortality in the presence of nondialysis dependent CKD stage 3 or worse
• ESRD patients with diabetes benefit from
maintaining their A1c between 7–8 %, as A1c
levels above 8 % or below 7 % carry increased
risks of all-cause and cardiovascular death
• Accuracy of HbA1C in CKD
Hyperglycaemia drives diabetic kidney
disease
Three mechanisms have been postulated that explain how hyperglycaemia
causes tissue damage in the kidney:1-3
1. Activation of protein kinase C1
2. Acceleration of the reninHyperglycaemia
angiotensin-aldosterone
Protein kinase C and
Advanced glycation
system (RAAS)1
growth factors
end products (AGEs)
Acceleration
3. Non-enzymatic glycation
of RAAS
that generates advanced
glycation end products1
Tubulointerstitial
Overproduction of
– Circulating levels are
Hypertension
injury
mesangial cell matrix
raised in people with
diabetes, particularly those
with renal insufficiency,
Glomerular
damage
since they are normally
excreted in the urine1
• Oxidative stress seems to be a
Nephron loss
Proteinuria
theme common to all three
pathways3
Reference:
1.Cade WT. Diabetes-Related Microvascular and macrovascular diseases in the physical therapy setting. Phys Ther. 2008;88(11):1322–1335. 2.Wolf G et al. (2005) From the
periphery of the glomerular capillary wall toward the center of disease: podocyte injury comes of age in diabetic nephropathy. Diabetes 54: 1626-1634. 3.Dronavalli S, Duka I
and Bakris GL. Nat Clin Pract Endocrinol Metab. 2008;4(8):444-52.
46
Stages of Diabetic Nephropathy
• Normoalbuminuria
• Microalbuminuria
• Incipient diabetic
nephropathy
• Albumin Excretion Rate
(AER) <20 ug/min
• Increased albumin
excretion rate (AER 20200ug/min
• Persistent
microalbuminuria (2 out
of 3 over 6 months, +/hyperfiltration
• BP elevation
Stages of Diabetic Nephropathy
contd
•
Early overt diabetic nephropathy
Clinical- grade proteinuria
(AER >200 ug/min in 2 of 3 within 6
months or dipstick +proteinuria
Hypertension
•
Advanced diabetic nephropathy
•
•
•
Progressive proteinuria
Hypertension
Declining glomerular filtration rate
(decreased CrCl, Increased BUN
and creatinine)
•
•
•
Uremia
Nephrotic syndrome
Need for renal replacement
therapy
•
End-stage Renal disease
Staging of Chronic Kidney Disease
Persistent albuminuria categories
Description and range
GFR categories (mL/min/1.73
m2)
Description and range
Previous
NKF
CKD
stage
Guide to frequency of monitoring
(number of times per year) by GFR
and albuminuria category
A1
A2
A3
Normal to
mildly
increased
Moderately
increased
Severely
increased
<30 mg/g
<3 mg/mmol
30-300 mg/g
3-30 mg/mmol
>300 mg/g
>30 mg/mmol
1
G1
Normal or high
≥90
1 if CKD
1
2
2
G2
Mildly decreased
60-89
1 if CKD
1
2
G3a
Mild to moderately
decreased
45-59
1
2
3
G3b
Moderately to
severely decreased
30-44
2
3
3
4
G4
Severely decreased
15-29
3
3
4+
5
G5
Kidney failure
<15
4+
4+
4+
3
CKD = chronic kidney disease; GFR = glomerular filtration rate; NKF = National Kidney Foundation.
Levey AS, et al. Kidney Int. 2011;80:17-28.
Approach to the Management
• Inhibition of the renin-angiotensin
aldosterone system (RAS)
– ACE inhibitors
– ARB’s
• Protein restriction
• Blood pressure control
• Optimal glycaemic control
SGLT-2 Inhibitors are not recommended in patients with GFR < 60ml/min
How to achieve this-the role
of insulin therapy
The Insulin molecule
Insulin
• stimulates glucose
uptake from the systemic
circulation
• suppresses hepatic
gluconeogenesis
• primary role in glucose
homeostasis
Current and new antidiabetic medications: benefits
and risks
Intervention
Advantages
Disadvantages
Metformin1
• Weight neutral
• May improve lipid profile
• GI side effects
• Lactic acidosis (rare)
Sulphonylureas1
• Well established
• Weight gain
• Hypoglycaemia
Thiazolidinediones1
• Durable glycaemic control
• Fluid retention, congestive heart failure
• Weight gain, bone fractures
Meglitinides1
• Short duration
• Weight gain
• Frequent dosing
Insulin2
• No dose limit
• Improves lipid profile
• Injections
• Weight gain
• Hypoglycaemia
-Glucosidase inhibitors1
• Weight neutral
• Do not cause hypoglycaemia
• Frequent GI side effects
• Dosing 3 times/day
Amylin analogues3
• Weight loss
• Injections, frequent GI side effects
• Limited experience
DPP-4 inhibitors4
• Weight neutral
• Limited experience
GLP-1 agonists4
• Weight loss
• Injections, frequent GI side effects
• Limited experience
54
A and Bailey C. Drugs 2005;65:385–411. 2Carver C. Diabetes Educ 2006;32:910–917.
4
A, et al. Drugs 2008;68:2131–2162. Bosi E, et al. Diabetes Res Clin Pract 2008;82:S102–S107.
1Krentz
3Krentz
BASAL INSULIN
• Insulin which regulates glucose betweenmeals and during the night and which also
suppresses hepatic glucose production
Insulin PharmacodynamicsBasal insulin
Insulin
NPH
Insulin Detemir
Levemir
Insulin Glargine
Lantus
Onset (hr)
Peak (hr)
Duration (hr)
Appearance
1-2
4-10
14+
Cloudy
3-4
6-8
6-23
Clear
1.5
flat
24
Clear
Insulin Glargine and Detemir
Insulin analogues produced using recombinant
DNA technology.
http://www.endotext.org/diabetes/diabetes14/diabetesframe14.html
Insulin PharmacodynamicsBasal insulin
Insulin
NPH
Insulin Detemir
Levemir
Insulin Glargine
Lantus
Onset (hr)
Peak (hr)
Duration (hr)
Appearance
1-2
4-10
14+
Cloudy
3-4
6-8
6-23
Clear
1.5
flat
24
Clear
How to Use Basal Insulin in Type 2
Diabetes mellitus
Contribution of fasting hyperglycaemia to overall
glycaemia increases with worsening diabetes
•
•
290 patients with T2DM treated with diet or OHAs
Baseline (normal) PG defined as 6.1 mmol/l (110 mg/dl) ― threshold
defined by ADA as the upper limit of normal PG at fasting or
preprandial times
Relative contribution (%)
100
70%
50
Fasting
30%
0
<7.3
7.3―8.4
8.5―9.2 9.3―10.2
HbA1c (%) quintiles
ADA=American Diabetes Association; OHA=oral hypoglycaemic agent; PG=plasma glucose.
Adapted from Monnier L, et al. Diabetes Care 2003;26:881―5.
>10.2
Treat Fasting Hyperglycaemia First
ADA/EASD consensus algorithm
Call to action if HbA1c is 7%
Tier 1:
well-validated therapies
Lifestyle + Metformin
+ Basal insulin
At diagnosis:
Lifestyle +
Metformin
STEP 1
Lifestyle + Metformin
+ Intensive insulin
Lifestyle + Metformin
+ Sulfonylurea
STEP 2
STEP 3
Tier 2:
Less well validated
therapies
Lifestyle + Metformin
+ Pioglitazone
No hypoglycaemia
Oedema/CHF
Bone loss
Lifestyle + metformin
+ GLP-1 agonist
No hypoglycaemia
Weight loss
Nausea/vomiting
Nathan DM, et al. Diabetes Care 2009;32 193-203.
Lifestyle + Metformin
+ Pioglitazone
+ Sulfonylurea
Lifestyle + metformin
+ Basal insulin
63
ADA/EASD Consensus
Algorithm: Step 2
 If step 1 fails to achieve or sustain HbA1c
<7%, another medication should be
added within 2-3 months
 Basal insulin if HbA1c >8.5% or
symptoms of hyperglycemia
* Sulfonylureas other than glybenclamide (glyburide) or chlorpropamide
Nathan DM, et al. Diabetes Care 2009;32:193-203.
Initiation and titration of insulin
glargine: practical advice
In insulin-naïve patients:
• Titrate using an algorithm
• Decide on a target e.g. FBG <5.6 mmol/l (<100
mg/dl)
**
• Make no increase
in insulin dosage if blood glucose
<4 mmol/l (<72 mg/dl)
• Monitor the blood glucose regularly
• Teach self-adjustment of insulin dose using
algorithm
• Follow the patient carefully
1. Davies M, et al. Diabetes Care 2005;28:1282―8.
2. Riddle M, et al. Diabetes Care 2003;26:3080―6.
3. Yki-Jarvinen H, et al. Diabetes 2004;53(suppl 2). Abstract 2181-PO.
*Individualise
Initiation and titration of insulin
glargine: practical advice
• Either start with an insulin dose of 10 U nocte or
in the morning
• Or start with an insulin dose numerically
equivalent to the highest plasma glucose in
mmol/l over the previous 7 days
• The fasting glucose is done daily for 3 days
• The average plasma fasting glucose over 3
consecutive days is calculated
Initiation and titration of insulin
glargine: practical advice
• The dose of the long-acting insulin
analogue is changed or kept as per the
algorithm
• Do this every week
• Or do this every three days
Initiation and titration of insulin
glargine: practical advice
Mean FBG mmol/l (mg/dl)
for previous consecutive 3
days
Titrate weekly**
Titrate every 3 days**
(AT.LANTUS,1 Treat-toTarget2 studies)
Start dose 10 units daily
(AT.LANTUS,1 LANMET3 studies)
Start dose numerically equivalent to the
highest FBG value in mmol/l over the
previous 7 days
≥5.6 (≥100) ― <6.7 (<120)
0–2
0–2
≥6.7 (≥120) ― <7.8 (<140)
2
2
≥7.8 (≥140) ― <10 (<180)
4
2
6–8
2
≥10 (≥180)
1. Davies M, et al. Diabetes Care 2005;28:1282―8.
2. Riddle M, et al. Diabetes Care 2003;26:3080―6.
3. Yki-Jarvinen H, et al. Diabetes 2004;53(suppl 2). Abstract 2181-PO.
*Individualise
Insulin initiation can be easy with
the use of an insulin pen
Easy to teach: simple & quick
Easy to use: dial & dose
Easier to inject: smooth & gentle
Mean final daily insulin glargine doses in studies
using forced-titration algorithms in type 2 diabetics
on OHAs
Mean daily insulin dose
(units)
80
Treat-to-Target1 (insulin glargine ± OHAs)
60
LANMET2 (insulin glargine + metformin)
AT.LANTUS3 (insulin glargine ± OHAs)
Clinic-driven algorithm
40
AT.LANTUS3 (insulin glargine ± OHAs)
Patient-driven algorithm
20
0
48U
68U
44U
46U
1. Riddle M, et al. Diabetes Care 2003;26:3080―6.
2. Yki-Jarvinen H, et al. Diabetes 2004;53(suppl 2). Abstract 2181-PO.
3. Davies M, et al. Diabetes Care 2005;28:1282―8.
Bolus Insulin
Addresses postprandial hyperglycaemia
Insulin Pharmacodynamics- Bolus Insulin
Insulin Type
Insulin Lispro
Onset (hr)
Peak (hr)
Duration (hr)
Appearance
within 15 min
½-1½
3-5
Clear
within 15 min
1-3
3-5
Clear
Apidra
0.25-.5 hr
0.5-1
4
Clear
Regular
½-1 hr
2-4
5-8
Clear
Humalog
Insulin Aspart
Novorapid
Insulin Glulisine
Ultra-short-acting Insulin Analogues vs
Human Insulin
•
•
•
•
Less hexamers
Dissociate quickly when injected
Absorbed rapidly
Peak values <1 hour
Ultra-short-acting
Insulin analogues
Insulin aspart vs Soluble Insulin
• Twice as fast an absorption rate
• Achieves twice as high a peak
• Provides a gentle return to baseline
• Improves HBA1c
• Maintains lower HbA1c
• 72% lower risk of nocturnal hypoglycaemia
Heller SR et al Diabetes Med 2004
http://www.endotext.org/diabetes/diabetes14/diabetesframe14.html
Insulin Pharmacodynamics- Bolus Insulin
Insulin Type
Insulin Lispro
Onset (hr)
Peak (hr)
Duration (hr)
Appearance
within 15 min
½-1½
3-5
Clear
within 15 min
1-3
3-5
Clear
Apidra
0.25-.5 hr
0.5-1
4
Clear
Regular
½-1 hr
2-4
5-8
Clear
Humalog
Insulin Aspart
Novorapid
Insulin Glulisine
Insulin Pharmacodynamics- Premixed Insulins
Insulin
preparations
Onset of
Action
Peak
Action
Maximal
Duration
(h or min)
(h)
(h)
0.5–1 h
0.5–1 h
4 – 12
5 – 10
18–24
18–24
0.5–1 h
5 – 10
18–24
0.5–1 h
0.5–1 h
5– 9
1– 3
18–24
18–24
Intermediate-acting
•
•
•
•
•
Premixed insulin 10/90
Premixed insulin 20/80
Premixed insulin
30/70
Premixed insulin 40/60
Premixed insulin 50/50
How to Start PreMixed Insulin in
Type 2 Diabetes mellitus
Insulin PharmacodynamicsBiphasic Insulin
Insulin
Onset (hr)
Peak (hr)
Duration (hr)
Appearance
Lispro Mix 50/50
.25-.5
.5-3
14-24
Cloudy
Lispro Mix 75/25
.25-5
.5-2.5
14-24
Cloudy
Cloudy
Aspart Mix 70/30
.1-.2
1-4
18-24
When to Administer
• NovoLog® Mix® 70/30 [NovoMix 30] :
• once daily (QD) before supper
• twice (BID), daily before breakfast and supper
• three times (TID), daily before breakfast, lunch
and supper
Jain et al, ADA 2005
Treat-to-target: Phase 1- OD at
suppertime
• Dose of insulin at inclusion:
-Insulin naïve:
12 U
-Insulin on <30 U:
previous dose (ratio 1:1)
-Insulin on 31-60 U:
dose
Jain et al, ADA 2005
same dose as
70% of previous
Treat-to-target: Phase 1
The dose was titrated using the average fasting plasma glucose values
from 3 previous days
Blood glucose
(mg/dl)
<80
80110
111140
141180
>180
< 4.4
4.4-6.1
6.2-7.7
7.8-10.0
>10.0
Dose change
(U)
-3
No
change
+3
+6
Jain et al, ADA 2005
+9
Treat-to-target: Phase 2 ProtocolBreakfast and Supper Insulin
– Patients with FBG ≤ 110 mg/dl (6.1 mmol/l) add 3 units before breakfast
– Patients with FBG > 110 mg/dl (6.1 mmol/l) add 6 units before breakfast
FBG, or predinner SMBG
(mg/dl)
(mmol/l)
Dose change
(U)
Jain et al, ADA 2005
<80
80110
111140
141180
>180
<4.4
4.4- 6.1
6.16-7.7
7.8-10.0
>10.
-3
No
change
+3
+6
+9
Treat-to-target:
titration schedule in Phase 3 –Breakfast,
Lunch and Supper Insulin
•
•
•
•
Dose adjustments
Average post-lunch SMBG values for the preceding 3 days
TID therapy only one dose per day was titrated.
The choice was based on SMBG levels, anticipated diet and activity
Post-lunch
<100
SMBG (mg/dl) <4.4
100140
141180
>180
4.4- 6.1
6.16-7.7
>10.
Dose change
(U)
No
change
+3
+6
Jain et al, ADA 2005
-3
Investigating NovoLog Mix® 70/30 QD, BID and
TID
Withdrawals
1. Novo Log
Mix®70/30 QD (12U)
Completers
(reaching
HbA1c≤6.5%)
100 patients
11
15
68
21
2. NovoLogMix® 70/
30 BID
25
28
3. NovoLogMix® 70/30
TID
0
Jain et al, ADA 2005
17
8
58%
The Insulin doses needed to achieve target
3
Insulin Dose U/Kg
2.5
2
1.5
A1C<6.5%
All patients
1
0.5
0
Phase
Phase
Phase
1QD
2BID
3TID
0.5 U/Kg OD. 1.0 U/Kg BID. 1.5 U/Kg TID
Insulin Therapy in Type 1 Diabetes
 Total Daily Dose
 Average dose
 0.5-1.0 units per kg of body weight per day of insulin
 Starting dose
 0.5-0.75 units/kg/day





Early in the diabetic course
0.1-0.6 units per kg per day
50% basal insulin
50% bolus insulin
1-2 units of insulin will lower the blood glucose by
1.66-2.77 mmol/l.
Hirsch IB 1999 Type 1 diabetes mellitus and the use of flexible insulin regimens. Am Fam Physician 60:2343-52, 2355-6
Hirsch IB 1999 Type 1 diabetes mellitus and the use of flexible insulin regimens. Am Fam Physician 60:2343-52, 2355-6
ADA 1998 Medical Management of Insulin-Dependent (Type I) Diabetes Mellitus, 3rd edition ed. American Diabetes Association, Alexandria, VA
2002 Practical insulin: A handbook for prescribing providers. American Diabetes Association, Alexandria, VA
Insulin Regimes in Type 1 diabetes
A Twice Daily Injection Regime
NPH, Soluble
Breakfast + Dinner
B Three-times Daily Injection Regime
NPH, Soluble
Soluble

Soluble

NPH

Breakfast
Lunch
Dinner
Bedtime
C Multiple Injection Regime
Soluble
NPH (30-40%)
Breakfast + Lunch +
Dinner
Bedtime
Regime B
Normal
Normal
Normal
Normal
Normal
Insulin Regimes in Type 1 diabetes
A Twice Daily Injection Regime
NPH, Soluble
Breakfast + Dinner
B Three-times Daily Injection Regime
NPH, USAI
USAI
USAI
NPH



Breakfast
Lunch
Dinner
Bedtime
C Multiple Injection Regime
Soluble
NPH (30-40%)
Breakfast + Lunch +
Dinner
Bedtime
Regime B
Insulin Regimes in Type 1 diabetes
A Twice Daily Injection Regime
Glargine /Detemir +
Breakfast + Dinner
B Three-times Daily Injection Regime
Glargine/ Detemir +,
Soluble/USAI
Breakfast
Soluble/USAI

Lunch
Soluble/USAI

Dinner
C Multiple Injection Regime
Soluble/USAI
Breakfast +
Lunch + Dinner
NPH (30-40%)
Bedtime
Insulin Regimes in Type 1
Diabetes
A Twice Daily Injection Regime
Detemir/ Glargine
/Bedtime
Ultra-rapid insulin
Breakfast
Breakfast + dinner
B Three-times Daily Injection Regime
Detemir/ Glargine
+/Bedtime
Ultra-rapid insulin
Ultra-rapid insulin
Ultra-rapid insulin
Breakfast



Breakfast
Lunch
Dinner
C Multiple Injection Regime
Ultra -rapid insulin
+
Detemir / Glargine (50%)
Breakfast + Lunch
Dinner
Bedtime
Regime B
Normal
Normal
Normal
Normal
Normal
AACE / ACE diabetes algorithm for
glycaemic control
HbA1c 7.6-9.0 %
Call to action if HbA1c is 6.5%
DPP- 4 / GLP-1
or TZD
Dual Therapy
Metformin
and
Insulin therapy
+/Other agents
SU / Glinide
Triple Therapy
Metformin
and
GLP-1 / DPP4
and TZD or SU
TZD
and SU
Glycemic Control Algorith, Endocr Pract. 2009; 15(No. 6)
AACE / ACE diabetes algorithm for
glycaemic control
HbA1c>9.0%
Call to action if HbA1c is 6.5%
TRIPLE THERAPY
Symptoms
Drug Naive
Insulin and / other
agents
No symptoms
Metformin +GLP-1 /
DPP- 4 + TZD
+ / - SU
Metformin +GLP-1
/DPP4 + SU
+ / - TZD
Glycemic Control Algorith, Endocr Pract. 2009; 15(No. 6)
Insulin
+ or - other agents
Type 2 Diabetic subjects with CKD
Stages 3 -5
Chronic Kidney Disease Stage 3
• eGFR of 30-59 mL/min/1.73 m2
Chronic Kidney Disease Stage 4
• eGFR of 15-29 mL/min/1.73 m2
Chronic Kidney Disease Stage 5
• eGFR of <15 mL/min/1.73 m2
National Kidney Foundation. K/DOQ1 clinical practice guidelines for chronic kidney disease: evaluation,
classification, and stratification. Part 4. Definition and classification of stages of chronic kidney disease.
Am J Kidney Dis 2002; 39 (Suppl 1): S46-S75
Strategies for the Use of Insulin in
CKD 3-5
• Where the GFR less than 50ml but greater than
10 ml/min i.e. Stage 4
• Decrease insulin starting dose by 25%
• Where the GFR less than 10 ml/min i.e. Stage
5
• Decrease insulin starting dose by 50 %
• Use SMBG to aid in achieving control without
hypoglycaemia
Aronoff GR et al. Dosing Guidelines for Adults. 4th edn.
Philadelphia: American College of Physicians; 1999.
Drug prescribing in renal failure;p. p 84
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