Insulin And Oral Hypoglycaemic Agents

Front 1

Therapies for diabetes

Back 1

Type 1
-Insulin
-Lifestyle (diet/exercise)
Type 2
-Lifestyle
-Oral hypoglycemic agents
-Insulin
-Treat associated problems (HT, lipids and albuminuria)

Front 2

Insulin (therapy)

Back 2

different human recombinant analogues (onset/peak/duration)

subcutaneously

1) fixed proportion mixtures (70/30, 75/25, 50/50)
(bedtime intermediate insulin optional)
2) Basal-Bolus regimen

Front 3

Side effects of Insulin Therapy

Back 3

1) Hypoglycaemia
2) Weight gain - modest
3) Problems at injection site (lipo-hypertrophy and atrophy - decr absorption)
4) Allergic reactions & insulin resistance

Front 4

Oral Hypoglycaemic agents

Back 4

1) Biguanides - Metformin
2) Sulphonylureas
3) Thiazolidinediones
4) a-glucosidase inhibitors (Acarbose)
5) Incretin-based therapies

Front 5

Biguanides (Metformin)

Back 5

first drug of choice in most Type 2 diabetics

molecular mechanisms not fully known (increase glucose uptake and utilisation in skeletal muscle, decr gluconeogenesis)

additional benefits - no hypo, no incr in appetite, lower LDL

Side effects
- GIT 30%) anorexia, diarrhoea, nausea (mild)
- lactic acidosis - rare
- C/l in pregnancy

Front 6

Sulphonylureas

Back 6

Mechanism - insulin secretagogues - increase endogenous insulin release via the sulphonylurea receptor on b-cells (need functional b-cells)

Glibencalmide, glipizide (2nd gen)

variable t1/2s

CYP2C9!

Unwanted effects:
- hypoglycaemia
- weight gain (stimulate appetite)
- uncommon S/E - skin rash, haemolytic anaemia, GI upset
- avoid during & after AMI

Front 7

Sulphonylureas - drug interaction

Back 7

ADRs can result in severe hypoglycaemia

1. compete with salicylates & sulfonamides for albumin

2. compete for CYP2C9 with:
- NSAIDs
- warfain
- alcohol
- MAOIs
- antibiotics (sulfonamides, trimethoprim, chloramphenicol)

3. also b-blockers may mask Sx of hypoglycemia - avoid prescribing in poorly controlled diabetics

Front 8

Thiazolidinediones (TZD) - Glitazones

Back 8

Mechanism
- PPARy agonists - activate PPARy in fat & liver - transcription of target genes
- slow onset (1-2 months)
- incr insulin sensitivity of liver/muscle/fat indirectly

Rosiglitazone & pioglitazone

Benefits - decr requirement for exogenous insulin by 30%, reduce circulating FFAs and maybe TGs

Unwanted effects
- idiosyncratic hepatotoxicity (troglitazone)
- weight gain of 3-4 kgs (incr. adipogenesis) - PROBLEM
- fluid retention/hemodilution - avoid in HF
- increase in cardiac events - MI (rosiglitazone)

Hence, probably should look for other treatment

Front 9

a-Glucosidase inhibitors

Back 9

a-glucosidase = maltase
breaks down maltose to glucose

Acarbose & Miglitol
- inhibits breakdown of sugars in the gut
- decrease in postprandial glucose but not basal plasma glucose

Benefits
- does not affect weight
- regularly co-administered with metformin

Major side effects
- related to action (v. common) - flatulence, diarrhoea & abdo pain

Front 10

Incretin-Based Therapies
1. GLP-1 Receptor Agonists

Back 10

Exenatide (gila monster saliva)
Liraglutide (fatty acid -GLP-1)

Stable analogues of GLP-1 (t1/2 over 10h)

peptides - SC (not oral)

used in conjunction with others

Actions
- incr. insulin and decr. glucagon release after meals
- decr gastric emptying - satiety - wt loss
- decr TGs
- do not cause hypoglycaemia (unless + sulphonylurea)

Side-effects - related to action - N&V, diarrhoea, bloating, abdo pain - decr with time, pancreatitis

Front 11

Incretin-Based Therapies
2. Dipeptidyl peptidase-4 (DPP-4) Inhibitors

Back 11

Sitagliptin & Saxagliptin

- endogenous GLP-1 rapidly degraded by DPP-4
- DPP-4 inhibitors limit GLP-1 breakdown

oral

Actions - inhibit DPP-4 to increase GLP-1 activity - this incr post prandial insulin, lowers TGs
- no effect on gastric emptying (weight neutral)
- no effect on glucagon

Side-effects (generally well tolerated)
- N&V, diarrhoea, bloating, abdo pain