early initiation of insulin:basal bolus versus premixed insulin-dr shahjada selim
TRANSCRIPT
Early Initiation of Insulin:Basal Bolus versus
Premixed
Dr Shahjada SelimAssistant Professor
Department of EndocrinologyBangabandhu Sheikh Mujib Medical University, Dhaka
Email: [email protected]
ADA Diabetes Management Algorithm 2015
Need for Early and aggressive treatment
Legacy effect: early vs late glycemic control and complications risk
Aggressive glycemic control:
‘Modestly reduced macro-
vascular complication risk
while posed additional
complication’
In Early stage T2 DM
Inzucchi et al., 2012; Skyler, Bergenstal, Bonow, et al., 2009, Stratton IM et al. BMJ 2000;321:405–412
Insulin at Diagnosis
AACE and the Canadian Diabetes Association suggest considering insulin treatment at the time of T2DM diagnosis if glycemic control is very poor (HbA1c levels >9%)
ADA/EASD guidelines recommend insulin therapy be considered for patients who present for the first time with T2DM and an HbA1c level >10%.
Handelsman, Y. et al. Endocr. Pract.17 (Suppl. 2), 1–53 (2011). Bhattacharyya, O. K. Can. Fam. Physician. 55, 39–43 (2009).
Early Insulinization is Recommended by the ADA/EASD
to Avoid Clinical Inertia
● If HbA1c targets are not achieved after ~3 months of initial treatment, alternative therapy such as basal insulin should be initiated1,2
Early insulin therapy has the potential to achieve near-normal glucose control & prevent progression of glucose intolerance3
1. Inzucchi SE, et al. Diabetologia 2012;55:1577–96 2. Nathan DM, et al. Diabetes Care 2009;32:193–203
3. ORIGIN Trial Investigators. N Engl J Med 2012;367:319–28
ADA=American Diabetes Association; EASD=European Association for the Study of Diabetes
The legacy of basal insulin
Treat-To-Target Concept has demonstrated the role of basal insulin analogs in facilitating early insulin replacement, lower risk of hypoglycemia and becoming foundation of the therapy.
4T study also showed that, over the longer term (3 years), a premixed insulin regimen was not as effective as basal insulin at attaining glycemic targets.
Diabetes Care in 2012: Current Trends and Future Directions
4-T Study: Insulins Relative Changes over 3 Years and Hypoglycaemia
N Engl J Med 2009; 361: 1736-47
Differential effects of basal vs prandial insulin components of dysglycemia, body weight and
hypoglycemia risk: the 4T study
Biphasic Prandial Basal
Median HbA1c level achieved + + +
HbA1c targets achieved + ++ ++
Mean SMBG level achieved + ++ ++
Fewer hypoglycaemic episodes ++ + +++
Less weight gain + + ++
Less increase in waist circumference
+ + ++
Overview of Main Results
1Riddle M, et al. Diabetes Care 2003;26:3080–6; 2Yki-Järvinen H, et al. Diabetologia 2006;49:442–51; 3Bretzel RG, et al. Lancet 2008;371:1073–84; 4Janka H, et al. Diabetes Care 2005;28:254–9; 5Rosenstock J, et al. Diabetes Care 2006;29:554–9; 6Yki-Jarvinen H, et al. Diabetes 2006;55 Suppl. 1:A30
Hb
A1
c (%
)
APOLLO3 LAPTOP4 Triple Therapy5
LANMET2Treat-To-Target1
INITIATE6
7.147.156.96
7.146.80
8.718.85 8.80
9.58.80
8.61
6.96
Baseline
Study endpoint
58.0Target HbA1c
≤7% (%)49.4 48.057.0NA NA
7
8
9
10
6
The most studied basal insulin With established CV safety, 10 million patients, > 60 million patient-years, >59,000 participants in clinical trials
Consistent achievement of glycaemic targets with basal insulin GLARGINE
0
100
200
300
400
0 4 8 12 16 20 24 hrs
Isoglycemic clamp study
Plas
ma
Insu
lin (p
M)
• Inadequate prandial insulin : Postprandial Hyperglycemia• Excess inter-prandial supply: Increased risk of Hypoglycemia
riskHYPO risk
HYPO
HYPER HYPER HYPER
Luzio S et al, Diabetologia 49:1163-8, 2006
Insulin Profiles: Premixed 30/70 Aspart
pre-mixesare NOT suitable to
Treat-to-target A1C <7.0%
2015 – Basal & “Premix”Fixed ratio.2
Premix :
Less flexible.1
Less studied alternative.1
Less adaptable.2
Less desirable to intensify.3
More Hypos & weight gain
Unable to titrate individually
1. Diab Care 38; 38:140–149 Jan 2015. 2. Owens DR. Diabet. Med. 30, 276–288; 2013. 3. AACE Algorithm 2013
“The fixed-ratio nature of premixed formulations make them less flexible &
adaptable to the individual’s specific needs than a basal-plus strategy”.2
CLINICAL EVIDENCES for
basal/basal-plus/basal-bolus
strategy versus premixed
LAPTOP study: Comparison of insulin glargine added to an OAD regimen versus
switching to premixed insulinRANDOMISATION
Patients with T2DM HbA1c: 7.5% to 10.5%and FBG: ≥6.7 mmol/L
(≥120 mg/dL) and treated with OADs(n = 364)
Insulin glargine + OADs (n = 177)Initial dose: 10 IU once daily in the
morning
Human premixed insulin (70/30) (n = 187)
Initial dose: 10 IU before breakfast and 10 IU before dinner
Treatment phaseScreening
24 weeks
Run-in phase
3–14 weeksSubjects taking sulphonylurea and metformin for at least a month were enrolled. Sulphonylurea was replaced with 3 or 4 mg glimepiride during run-in phase. OHA dose remained the same throughout the study in the insulin glargine arm, while OHAs were discontinued in the premixed insulin arm.
Janka H, et al. Diabetes Care 2005;28:254–9.
15
Significantly greater reduction in FBG and PPBG with insulin
glargine vs premix
4
6
8
10
12
14
16
Endpoint
Fasting Afterbreakfast
Lunch After lunch
Dinner After dinner
Bedtime 03.00
*
**
*
*
Blo
od
gluc
ose
(mm
ol/L
)
BaselineInsulin glargine + OHAsPremixed insulin twice daily
Time of day*p < 0.05 for treatment comparison of changes from baseline to endpoint
Janka H, et al. Diabetes Care 2005;28:254–9.
Insulin glargine provided better glycaemic control and less weight gain than premix
Premixed insulin†
Insulin glargine‡
0
-0.5
-1.0
-1.5
-2.0
-1.31
Premixed insulin†
Insulin glargine‡
Wei
ght
gai
n (k
g)
1.4
2.12.5
2.0
1.5
1.0
0.5
0
-1.64HbA
1c
cha
nge
from
bas
elin
e (
%)
Final daily dose:
Premixed insulin 64.5 IU
Insulin glargine 28.2 IU
p = 0.0003
p = NS
†Twice daily; ‡plus OHAs
Janka H, et al. Diabetes Care 2005;28:254–9.
17
Lower incidence of hypoglycaemia with insulin glargine versus premixed
0.51
0
2
4
6
8
10
12
Eve
nts
per
pa
tient
per
yea
r Premixed insulinInsulin glargine*
All confirmedhypoglycaemia
Confirmedsymptomatic
Confirmednocturnal
p < 0.0001
p = 0.0009
p = 0.0449
Hypoglycaemia confirmed by blood glucose <60 mg/dL (3.3 mmol/L)
Janka H, et al. Diabetes Care 2005;28:254–9.
*Plus ODAs
1,04
2,62
9.87
5.73
4.07
INITIATE (Raskin) study: Comparative study of insulin glargine versus premix added to
an OAD regimenRANDOMISATION
Insulin-naïve patients with T2DM previouslytreated with metformin(>1,000 mg/day) alone
or plus other OADsHbA1c ≥8%(n = 222)
Insulin glargine + OADs (n = 114): Initiated at 10–12 U
once daily at bedtime
Premixed insulin aspart (BIAsp 70/30) + OADs (n = 108)
Initiated at 5–6 U twice daily, before breakfast and dinner
Treatment phaseScreening
28 weeks
Run-in phase
3–14 weeks
During run-in, metformin was optimised to 1,500–2,550 mg/day, secretagogues and -glucosidase inhibitors were discontinued. Pioglitazone was continued (if taken pre-study) and subjects taking rosiglitazone were changed to pioglitazone.
Raskin P, et al. Diabetes Care 2005;28:260–5.
HbA1c was reduced in both groups with a significantly greater
effect with premixed
0
2
4
6
8
10
12
14
16
0
2
4
6
8
10
12
*FPG target of 80–110 mg/dL (4.4–6.1 mmol/L)
p < 0.01
p = NS
Target FPG* achieved by 57%of insulin glargine group and36% of premix group
HbA1c<7% achieved by 40%of insulin glargine group and66% of premix group
PremixInsulin glargine
14,0
7,1
13,5
6,5
Baseline Study end
FP
G (
mm
ol/L
)
9,7
6,9
9,8
7,4
Baseline Study end
Hb
A 1c (
%)
Raskin P, et al. Diabetes Care 2005;28:260–5.
Hypoglycaemia, weight gain and daily dose all lower with insulin
glargine vs premix
0
10
20
30
40
50
0
1
2
3
4
5
6
0
20
40
60
80
100
*Minor hypoglycaemia: <56 mg/dL (<3.1 mmol/L) with or without symptoms
p < 0.05p < 0.01
Raskin P, et al. Diabetes Care 2005;28:260–5.
Hypoglycaemia* Daily insulin doseWeight gain
p < 0.0543
16
Premixedinsulin
Insulinglargine
% p
atie
nts
5,4
3,5
Premixedinsulin
Insulinglargine
kg78,5
51,3
Premixedinsulin
Insulinglargine
IU a
t stu
dy e
nd
GINGER: Basal Bolus provides superior glycemic control vs.
intensified premixed insulin therapySubjects: 310 with inadequately controlled type 2 diabetes (HbA1c 8–11%) Pretreated with premixed insulin (mean of 5 years),with some receiving metformin (continued during study)
Fritsche A, et al. Diabetologia 2008;51 Suppl. 1:S83
Mean baseline values:• HbA1c (%): 8.5
• BMI (kg/m2): 30.1• Diabetes duration (years): 13.0
52 weeksRandomization
Insulin glargine + three daily doses of insulin glulisine +/- metformin (n=153)
Twice-daily premixed insulin +/- metformin (n=157)
Fritsche A, et al. Diabetologia 2008;51 Suppl. 1:S83
p=0.0004
% a
chie
ving
HbA
1c <
7.0
0
10
20
30
40
50
Glargine+ glulisine
Premixedinsulin
47
28
Months
7.0
8.0
9.0
6.0
p=0.0001
0 3 6 9 12
8.5
8.6
7.7
7.3
HbA
1c (%
) Premixed insulinGlargine + glulisine
GINGER: Basal Bolus provides superior glycemic control vs. intensified
premixed insulin therapy
GINGER: Basal Bolus has an acceptable safety
profile in late stage T2D
0
1
2
3
4
Glargine+ glulisine
Premixedinsulin
Mea
n bo
dy w
eigh
t cha
nge
from
bas
elin
e (k
g)
3.6
2.2
p=0.007
Sym
ptom
atic
hyp
o(e
vent
/pat
ient
-yea
r)
0
5
10
15
Glargine+ glulisine
Premixedinsulin
9.9
13.4
p=NS
Sev
ere
hypo
(eve
nt/p
atie
nt-y
ear)
0.00
0.05
0.10
0.15
0.20
0.25
Glargine+ glulisine
Premixedinsulin
0.1
0.2
p=NS
Fritsche A, et al. Diabetologia 2008;51 Suppl. 1:S83
Treatment satisfactionwith insulin glarginevs premixed insulin analogues
LADI – switching from premixed to glargine + glulisine improves treatment
satisfaction in T2DM
Series10
5
10
15
20
25
30
18
29
DTSQ
sco
rep<0.0001
Schreiber S, et al. Diabetologia 2007;50(suppl 1):S410–1.
Baseline 12 weeks
Basal-plus and basal-bolus insulin therapy providedbetter patient treatment satisfaction
Treatment satisfaction is higher with insulin glargine than with
premixed human insulin
p = 0.0012
Bradley C, et al. Diabetes 2005;54(Suppl):Abstract 1246-P.
0
5
10
15
Insulin glargine+ OADs
Premixed humaninsulin 30/70 BID
DT
SQ
c sc
ore
at e
ndpo
int
11.5
14.0
At 24 weeks insulin glargine was associated with a greater increase
in patient treatment satisfaction
High physician satisfaction with switching from premixed insulin to
insulin glargine
Hammer H and Klinge A. Int J Clin Pract 2007;61:2009–18.
Efficacy Safety
Very goodGoodSatisfactoryUnsatisfactoryNo response given
Most physicians rated the efficacy and safety
of insulin glargine as ‘very good’ or ‘good’
46%
41%54%42%
Markers of glycemic variability were better in patients treated
with BB than in those treated with MIX in better control group.
Conclusion: These results suggest that BB therapy achieves
better glucose profiles than MIX therapy.
Subcontinental Data
Addition of insulin aspart with basal insulin is associated with improved glycemic control in Indian patients with uncontrolled type 2 diabetes
mellitus
Banerjee S, Maji D, Baruah M. J Assoc Physicians India. 2013 Jan;61(1 Suppl):24-7.
Recent 2015 ADA Standard of care
Basal insulin alone is the most convenient initial insulin regimen, beginning at 10 U or 0.1–0.2 U/kg, depending on the degree of hyperglycemia.
Basal insulin is usually prescribed in conjunction with metformin and possibly one additional noninsulin agent.
A less studied alternative, transitioning from basal insulin to twice-daily premixed (or biphasic) insulin analog (70/30 aspart mix, 75/25 or 50/50 lispro mix), could also be considered.
Regular human insulin and human NPH-Regular premixed formulations (70/30) are less costly alternatives to rapid-acting insulin analogs and premixed insulin analogs, respectively, but their pharmacodynamic profiles make them suboptimal for the coverage of postprandial glucose excursions.
ADA STANDARDS OF MEDICAL CARE IN DIABETES—2015
Conclusion
Basal Insulin strategy:
• Simple, flexible approach to intensifying a basal insulin regimen.• Easily progressed to a basal-bolus regimen, if required.• Premixed insulin regimens are less flexible & must be switched to a more physiological basal-bolus regimen if further
intensification is required.• Switching from premixed insulin regimens to basal ± boluses improves patient satisfaction.• The basal-bolus regimen offers patients flexible treatment that responds to different needs and lifestyles and reduces
glucose variability
Laptop Study1 Initiate Study2
Hammer & Kingler3 AT-LANTUS Study5
1. Janka H, et al. Diabetes Care 2005;28:254–9. 2. 2. Raskin P, et al. Diabetes Care 2005;28:260–5.3. 3. Davies M, et al. Diabetes Res Clin Pract
2008;79:368–75.4. 4. Hammer H and Klinge A. Int J Clin Pract
2007;61:2009–185. 5. Diabetes Care 34:249–255, 2011.
DURABLE Study5
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