insulin therapy: art of initiation and titration

Insulin Therapy-the Art Of Initiation and Titration

Insulin is the body’s key to metabolism

Characteristics :

BASAL : 1u/hr between meals,through the night with fasting» To restrict but not eliminate hepatic glucose

production which is necessary for cerebral glucose metabolism

» Correlate highly with FPG

PRANDIAL : 5 to 10 times basal rate, peaks in ½ to 1 hr. returning to base line in 2 to 4 hrs

Intiating insulin therapy

• In type 1 daibetes – All patients – In some patients like LADA who may be initially

responsive to to oral hypoglycemic agents later require insulin

Indications for Insulin Use in Type 2 DiabetesPregnancy (preferably prior to pregnancy)Acute illness requiring hospitalization

Perioperative/intensive care unit setting

Postmyocardial infarction

High-dose glucocorticoid therapy

Inability to tolerate or contraindication to oral antiglycemic agents

Newly diagnosed type 2 diabetes with significantly elevated blood glucose levels (pts with severe symptoms or DKA)

Patient no longer achieving therapeutic goals on combination antiglycemic therapy

Advantages of Insulin Therapy• Oldest of the currently available medications,

has the most clinical experience• Most effective of the diabetes medications in

lowering glycemia– Can decrease any level of elevated HbA1c

– No maximum dose of insulin beyond which a therapeutic effect will not occur

• Beneficial effects on triglyceride and HDL cholesterol levels.

Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

*Lower extremity amputation or fatal PVD†P < 0.0001; ‡P = 0.035Error bars = 95% CIs

Perc

enta

ge re

ducti

on in

rela

tive

risk

corr

espo

ndin

g to

a 1

% fa

ll in

HbA

1c

–50

–45

–40

–35

–30

–25

–20

–15

–10

–5

0

21%

Any diabetes-related endpoint

21%

Diabetes-related death

14%

All cause mortality

14%

Myocardial infarction

12%

Stroke

43%

Peripheral vascular disease*

37%

Microvascular disease

19%

Cataract extraction

Adapted from Stratton IM, et al. UKPDS 35. BMJ 2000;321:405–412.

UKPDS: Observational data for a 1% decrease in HbA1c

–55

†

†

†† ‡

†

†

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metformin

Sus

TZDs

EXENATIDE

INSULIN

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5

9.5%HbA1c 6.5%HbA1c

Fears & concerns

about insulin therapy

Patient Concerns About Insulin

• Fear of injections(Trypanophobia)• Perceived significance of need for insulin• Worries that insulin could worsen diabetes• Concerns about hypoglycemia• Complexity of regimens

21

When to Start Insulin?

• Watch for the following signs– Increasing BG levels– Elevated A1C– Unexplained weight loss– Traces of ketonuria– Poor energy level

When OHAs are not enough to achieve target glycemic status --

…..When Oral Medications Are Not Enough

– Sleep disturbances– Polydipsia

• Next steps– Make a decision to start insulin– Offer patient encouragement, not blame

What we have in our pockets?

• Basal Insulins (NPH,Lantus)• Bolus Insulins(Human Regular)• Premixed (Human 70/30)

Bolous insulins (Mealtime or prandial)Insulin Type Onset of

actionPeak of action

Duration of action

Human regular

Short acting 30-60 minutes 2-4 hours 8-10 hours

Insulin analogs

(Lispro,Aspart,Glulisin)

Rapid acting 5-15 minutes 1-2 hours 4-5 hours

Inhaled insulin Rapid acting 10-20 minutes 2 hours 6 hours

The time course of action of any insulin may vary in different individuals, or at different times in the same individual. Because of this variation, time periods indicated here should be considered general guidelines only.

Basal Insulins

Insulin Type Onset of action

Peak of action

Duration of action

NPH Intermediate acting

1-2 hours 5-7 hours 13-18 hours

Glargine(Lantus)Aventis

Long acting

1-2 hours Relatively flat

Upto 24 hours

Detemir(Levimir)Novo

Long acting

2-4 hours 8-12 hours 16-20 hours

The time course of action of any insulin may vary in different individuals, or at different times in the same individual. Because of this variation, time periods indicated here should be considered general guidelines only.

Pre-mixed Insulins

Insulin Composition ExamplesNPH-Regular 70% NPH

30% RegularHumulin 70/30

Dongsulin 70/30Mixtard 70/30

Insulin Composition Example

Rapid acting aspart

(Free and soluble) +

Intermediate acting aspart(protaminated-crystallized

30% rapid acting aspart +70 % intermediate acting aspart(IAA)

NovoMix 30

Humolog Mix 25

Humolog Mix 50

(25% lispro75%IAA)

(50% lispro 50%IAA)

The ADA Treatment Algorithm for the Initiation and Adjustment of Insulin

Initiating and Adjusting Insulin

Continue regimen; check HbA1c every 3 months

If fasting BG in target range, check BG before lunch, dinner, and bed. Depending on BG results, add second injection

(can usually begin with ~4 units and adjust by 2 units every 3 days until BG in range)

Recheck pre-meal BG levels and if out of range, may need to add another injection; if HbA1c continues to be out of range, check 2-hr postprandial levels and adjust

preprandial rapid-acting insulin

If HbA1c ≤7%...

Bedtime intermediate-acting insulin, or bedtime or morning long-acting insulin

(initiate with 10 units or 0.2 units per kg)

Check FG and increase dose until in target range.

If HbA1c 7%...

Hypoglycemia or FG >3.89 mmol/l (70 mg/dl):

Reduce bedtime dose by ≥4 units(or 10% if dose >60 units)

Pre-lunch BG out of range: add rapid-acting insulin at breakfast

Pre-dinner BG out of range: add NPH insulin at breakfast or rapid-acting insulin at lunch

Pre-bed BG out of range: add rapid-acting insulin at dinner


Target range: 3.89-7.22 mmol/L (70-130 mg/dL)

Nathan DM et al. Diabetes Care. 2006;29(8):1963-72.

If HbA1c ≤7%... If HbA1c 7%...

Step One…






If HbA1c ≤7%...




If HbA1c 7%...

Hypoglycemia

or FG >3.89 mmol/l (70 mg/dl): Reduce bedtime dose by ≥4 units

(or 10% if dose >60 units)








Step One: Initiating Insulin

• Start with either…– Bedtime intermediate-acting insulin or– Bedtime or morning long-acting insulin

Insulin regimens should be designed taking lifestyle and meal schedules into account


Step One: Initiating Insulin, cont’d

• Check fasting glucose and increase dose until in target range– Target range: 3.89-7.22 mmol/l (70-130 mg/dl)– Typical dose increase is 2 units every 3 days, but if

fasting glucose >10 mmol/l (>180 mg/dl), can increase by large increments (e.g., 4 units every 3 days)


• If hypoglycemia occurs or if fasting glucose < 3.89 mmol/l (70 mg/dl)…– Reduce bedtime dose by ≥4 units or 10%

if dose >60 units

Step One: Initiating Insulin, cont’d


Reduction in overnight and fasting glucose levels achieved by adding basal insulin may be sufficient to reduce postprandial elevations in glucose during the day and facilitate the achievement of target A1C concentrations.

While using basal insulin alone,never stop or reduce ongoing oral therapy

• If HbA1c is <7%...

– Continue regimen and check HbA1c every 3 months

• If HbA1c is ≥7%...– Move to Step Two…

After 2-3 Months…


With the addition of basal insulin and titration to target FBG levels, only about 60% of patients with type 2 diabetes are able to achieve A1C goals < 7%.[36] In the remaining patients with A1C levels above goal regardless of adequate fasting glucose levels, postprandial blood glucose levels are likely elevated.






If HbA1c ≤7%...




If HbA1c 7%...









Step Two…


Step Two: Intensifying InsulinIf fasting blood glucose levels are in target range but HbA1c ≥7%, check blood glucose before lunch, dinner, and bed and add a second injection:• If pre-lunch blood glucose is out of range,add rapid-acting insulin at breakfast• If pre-dinner blood glucose is out of range,add NPH insulin at breakfast or rapid-acting insulin at lunch• If pre-bed blood glucose is out of range,add rapid-acting insulin at dinner


Making Adjustments

• Can usually begin with ~4 units and adjust by 2 units every 3 days until blood glucose is in range


When number of insulin Injections increase from 1-2 ………..Stop or taper of insulin secretagogues (sulfonylureas).

• If HbA1c is <7%...

– Continue regimen and check HbA1c every 3 months

• If HbA1c is ≥7%...– Move to Step Three…

After 2-3 Months…








If HbA1c ≤7%...




If HbA1c 7%...









Step Three…

Step Three: Further Intensifying Insulin

• Recheck pre-meal blood glucose and if out of range, may need to add a third injection

• If HbA1c is still ≥ 7% – Check 2-hr postprandial levels – Adjust preprandial rapid-acting insulin


Premixed Insulin • Not recommended during dose adjustment

• Can be used before breakfast and/or dinner if the proportion of rapid- and intermediate-acting insulin is similar to the fixed proportions available


• Choice of an insulin regime for initiation of therapy has always been a matter of debate.

• There is no universal consensus for the optimal method of starting insulin therapy in patients with type 2 diabetes (T2DM) who do not respond to oral anti-diabetic drugs (OADs).

Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas A, Wender R, Matthews DR, American Diabetes Association (ADA), European Association for the Study of Diabetes (EASD) Diabetes Care. 2012 Jun; 35(6):1364-79.

• While the American Diabetes Association (ADA) and European Association for study of Diabetes (EASD) suggest basal insulin as an initial preferred strategy , the International Diabetes Federation (IDF) recommends both premixed and basal insulin

• Many national guidelines, on the other hand, support the use of premixed insulin as a preferred choice for initiation of therapy. Intensive insulin therapy, too, is indicated as initial line of management in a select group of patients

• The value 74 mg% is taken by calculating PPGE for the diagnostic cut offs for diabetes (200 mg% and 126 mg%).

• The value 40 mg% is taken by calculating PPGE for the diagnostic cut offs for prediabetic (impaired glucose tolerance 140 mg%, and impaired fasting glucose 100 mg%).

Kalra and Gupta, Diabetes and Metabolic disorders 2015 vol 14:17

• Prandial: fasting index (PFI) = (PPG‐FPG) /FPG• The value 0.6 is taken by calculating PFI for the diagnostic cut offs of

diabetes (200 mg%, 126 mg%).• The value 0.4 is taken by calculating PFI for the diagnostic cut offs of

prediabetes.


• *The value 1.3 is calculated with the diagnostic cut offs of diabetes using FPG (7.8 mmol/l) and HbA1c (6%).

• **The value 20 is calculated with the diagnostic cut offs for diabetes using FPG (126 mg%) and currently accepted HbA1c (6.3%) levels.


• Use of sulfonylureas with insulin regimens ?

Thank you

insulin therapy: art of initiation and titration

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