Early Initiation of Insulin:Basal Bolus versus

Premixed

Dr Shahjada SelimAssistant Professor

Department of EndocrinologyBangabandhu Sheikh Mujib Medical University, Dhaka

Email: selimshahjada@gmail.com

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

Thank you