Diabetes Mellitus :

Oral Anti-diabetic Agents and Insulin

Therapy

Presented by
Kok Ying Sean
Pegawai Farmasi U44
 Target for control

At least 90 mins after meal

Overt CVD: < 1.8 mmol/L

Why Hyperglycaemia?
Why Hyperglycaemia?
 Oral Anti-diabetic agents
6 classes:
• Biguanides
• Sulphonylureas / Meglitinides
• Alpha –glucosidase inhibitor
• Thiazolidinediones (TZD)
• Dipeptidyl Peptidase (DPP4) Inhibitor
• Sodium-glucose cotransporter 2
(SGLT2) Inhibitor
 Biguanides : Metformin
• ↓ Hepatic glucose production
↑ Insulin sensitivity in muscle
X stimulate insulin secretion, so usually will not cause hypo
• Lowers blood glucose especially fasting blood glucose
• ↓ HbA1c by about 1.5%
• =) Weight stability/ mild weight loss

=( Nausea, Anorexia, Diarrhea, Lactic acidosis ( Rare)

•CAUTION ! Not to use:

Taken with or after meal
or
 Srcl > 150 umol/L Start with
CrCL single
< 30 daily( dose
mL/min ,
MTF eliminated via kidney, and may
weekly
accumulate in body, titration
cause lactic acidosis )
 Liver cirhosis
 Chronic heart failure
 Myocardial infarction
 Resipratory failure
 Biguanides : Metformin
Drugs Formulation Min dose Max dose

Metformin 500mg Initial dose 500mg oD 1000mg TDS

Usual dose 1500mg OD

Metformin SR 850mg Usual dose 850mg OD 850mg TDS

Metformin XR 500mg / 750mg Initial dose 500mg OD 2000mg OD

Usual dose 2000mg OD
 Sulphonylureas (SU)
• ↑ Insulin secretion
• ↓ HbA1c by about 0.4-1.6 %
• =( Hypoglycaemia ( higher risk in renal impairment, liver cirrhosis
and elderly )
Weight gain (1.5-2.5 kg)

•CAUTION ! Not to use:

 CrCL < 30 mL/min ( for glibenclamide : < 59 mL/min)
Glibenclamide ‘s metabolites are active and excreted by kidney
 Glibenclamide not to use in those > 60 years old as significant risk of hypo

• Formulation and dose

Drugs Formulation Min dose Max dose
Glibenclamide 5mg 2.5mg OD 10mg BD
Dose conversion
Gliclazide 80mg
Gliclazide 40mg
: Gliclazide MR OM 160mg BD
Gliclazide MR 80mg OD : 30mg OD
30 / 60mg 30mg OM 120mg OM
 Alpha- Glucosidase Inhibitors
• ↓ rate of absorption of polysaccharides in small intestine
• ↓ postprandial glucose, without causing hypoglycaemia
• To be taken after first mouthful of food, taking it > 15 mins of a
meal will render its useless as being degraded by bacteria in gut
• ↓ HbA1c by about 0.5-0.8 %
• =)  Low risk of hypo
 Weight neutral
=( Bloating, abdominal discomfort, diarrhoea and flatulence
•CAUTION ! Not to use:
 CrCL < 25mL/min

•Formulation and dose

Drugs Formulation Min dose Max dose
Acarbose 50mg/100mg Initial dose 50mg OD 100mg TDS
Usual dose 50-100mg during
main meal
 Dipeptidyl Peptidase (DPP4) Inhibitor
• Incretin Enhancer ( glucose dependant manner):
 Reducing hepatic glucose output by suppressing glucagon
 Insulin secretion
 Reduce gastric motility ( slow glucose absorption)
 Increase satiety

• ↓ HbA1c by about 0.5-0.8 %

•
=)  Low risk of hypo
 Weight neutral

•CAUTION !
 CrCL < 50 mL/min , saxa : 2.5mg OD

•Formulation and dose

Drugs Formulation Min dose Max dose

Saxagliptin 2.5mg/5mg 2.5mg OD 5mg OD
Treatment Algorithm for Newly Diagnosed T2DM
Treatment Recommendations for Follow up
General Notes for Oral Anti-diabetic Agents
• Metformin is the preferred choice as first line
therapy. Other OAD agents are acceptable
alternatives.
• Agents that improve fasting hyperglycaemia include
MTF and TZDs while others reduce postprandial
hyperglycaemia.
• If glycaemia target are not achieved, intensification
of treatment should be made every 3 months.
• If monotherapy failed, combination of other agents
is recommended.
• Compliance can be improved with daily dosing OAD.
 Insulin therapy
Insulin types:
• Prandial insulin
 Administered pre meal as short or rapid onset of action
 Control postprandial glucose

• Basal Insulin
 Administered once or twice daily
 Cover in between meal and night time

• Premixed Insulin
 Biphasic insulin
 Cover for both postprandial glucose excursion and basal
insulin needs
Pharmacokinetic profile
Insulin Regimen
SMBG
 SMBG
OADs + Intermediate acting insulin

Pre
Breakfast !
OADs + Long acting insulin
 SMBG
Basal Bolus Insulin Regimen

Pre meal &

Premixed Insulin Regimen pre bed !
• Modification of an insulin regimen to Intensification
achieve glucaemic control
• Dose titration/ adjustment
• Adjusted at least weekly according to
Optimization
SMBG
• Starting insulin
Initiation
Insulin Therapy – 3 stages process
 Insulin Initiation and Optimisation

Metformin should be continued Sulphonylureas should be

while on insulin therapy unless is withdrawn once prandial insulin
contraindicated or intolerant is used

3Fs :
Fix the
Fasting
First
 Insulin Initiation and Optimisation : BASAL insulin
Initiation
 10 units / 0.2 U/kg at bedtime
 0.1 U/kg if risk of hypo

Optimization ( Monitor PRE breakfast )

 Adjust insulin according to 3 consecutive BG values
(obtained every 3-7 days )
< 4mmol/L ( >1 value) : ↓ 2 units Nocturnal
4.4 – 7 mmol/L ( all value) : maintain hypo !
>7 mmol/L (>1 value, no hypo): ↑ 2 units

Optimal dose
 Lean patient : 0.2-0.3 units/kg
Most patient : 0.4-0.5 units/kg
Obese patient : up to 0.7 units/kg
Insulin Initiation and Optimisation : PREMIXED insulin
Initiation
 10 units / 0.2 U/kg at pre-dinner / pre-breakfast + pre dinner
 0.1 U/kg if risk of hypo

Optimization ( Monitor PRE meals and Pre bed)

 Adjust insulin according to 3 consecutive BG values
(obtained every 3-7 days )
Between
< 4mmol/L ( >1 value) : ↓ 2 units meal
4.4 – 7 mmol/L ( all value) : maintain hypo !
>7 mmol/L (>1 value, no hypo): ↑ 2 units

Optimal dose
 Most patient : 0.5-1 units/kg
Obese patient : more than 1 units/kg
Insulin Initiation and Optimisation : PRANDIAL insulin
Initiation
 6 units / 0.1 U/kg for each meal

Optimization ( Monitor PRE meals and Pre bed )

 Adjust insulin according to 3 consecutive BG values
(obtained every 3-7 days )
Between
< 4mmol/L ( >1 value) : ↓ 2 units meal
4.4 – 7 mmol/L ( all value) : maintain hypo !
>7 mmol/L (>1 value, no hypo): ↑ 2 units

Optimal dose
 Ideally not exceed 0.5 U/kg/dose
 Insulin Intensification: BASAL insulin
Fix FBG using basal insulin
Consider adding bolus insulin :
HbA1c > 7% and FBG at goal or basal insulin > 0.5 U/kg

Add prandial insulin at largest meal

Discontinue SU, continue metformin
Basal Plus
If A1c > 6.5-7% after 3 months/
prandial dose > 30 U per meal, to add
second or third prandial insulin
Basal
Add prandial insulin at each meal
Discontinue SU, continue metformin
Basal Bolus If A1c > 6.5-7% after 3 months/
prandial dose > 30 U per meal, titrate
basal insulin up to 0.7 U/kg
 Insulin Intensification: BASAL insulin
Fix FBG using basal insulin
Consider switch to premixed insulin:
HbA1c > 7% and FBG at goal / post prandial hyperglycaemia

 Starting with 0.7 U/kg/day or total dose

transfer
Premixed
Basal Spilt dose 50:50 Pre breakfast: Pre dinner
BD
Discontinue SU, contimue metformin
Continue titrate the dose once/twice per
week
 Insulin Intensification: PREMIXED insulin
FBG / Pre dinner at goal
HbA1c > 6.5-8%

Premixed
BD
 Starting dose 0.3 U/kg/day or total dose
transfer
 Spilt 50:50 Pre breakfast : Pre dinner
Premixed OD
(pre-dinner)

FPG at goal
Premixed Pre lunch and pre dinner > 7mmol/L
plus
Add prandial insulin at morning and
midday meal
 Insulin Intensification: PREMIXED insulin
FBG / Pre dinner > 7 mmol/L

Premixed Add 6 units or 10 % total daily dose at

plus lunch
Down titrate morning dose may be
needed
Premixed BD FPG / Pre meal > 7 mmol/L
HbA1c > 6.5 -7%
 TDD > 1 U/kg/day
Basal Bolus 
Starting dose 0.7 U/kg/day or total dose
transfer
Spilt dose to 60: 40 Basal : Prandial
Divide prandial dose into 3 main meals
 General Notes for long term use of insulin
• Basal intermediate acting insulin should be administered ore
bed ( preferably not earlier than 10pm) due to risk of
hypoglycaemia in the early hours of morning if given earlier.
• It is not necessary to take extra snacks after intermediate or
long acting insulin.
• High dose of insulin (>1.5 U/kg/day) should consider
secondary cause:
 Non compliance
 Incorrect dosing or timing of injection
 Hypertrophy of injection sites
 Inter meal hypoglycaemia
 Expired insulin or strips
• No maximun dose of insulin
Case Study
 Case Study
Intervention / Suggestion:
1) To start s/c insugen N 10U ON
2) Suggest to add statin
3) Suggest to add ACE / ARB

 All patient without overt CVD over the age of 40 should

be treated with statin regardless of baseline LDL
cholesterol level

 The presence of microalbuminuria or proteinuria

should be treated with ACE or ARB even if the BP is <
135/75mmHg
 References
1. Clinical Practice Guidelines: Management of type 2
diabetes mellitus. 5th ed. Malaysia: Ministry of
Health; March 2016.
2. Practical guide to insulin therapy in type 2 diabetes
mellitus. Malaysia: Ministry of Health; 2010.