Drugs type 2 diabetes Flashcards
Discuss the pathophysiology of hyperglycaemia in terms of the organs involved
- Pancreas: ↓ insulin secretion or inadequate secretion (resistance), ↑
glucagon secretion - Gut: ↓ incretin secretion (glucagon-like peptide 1 (GLP1) and gastrointestinal insulinotropic peptide (GIP) from gut)
- Act on pancreas to ↑ glucose-stimulated insulin secretion and ↓ glucagon under normal conditions
- Fat: ↑ lipolysis (FA production) → FA also ↑ insulin resistance
- Kidney: ↑ glucose reabsorption in diabetics
- Renal threshold for glycosuria higher, which itself contributes to blood glucose remaining elevated
- Muscle: ↓ insulin-stimulated glucose uptake
- Liver: ↑ hepatic glucose production (since not suppressed by insulin)
- Overall system of ↑ energy intake or ↓ energy expenditure (diet and lifestyle critically important)
- T2D is a heterogeneous condition - spectrum of disease affects treatment
- Lean → overweight → obese → morbidly obese
- e.g. morbidly obese individual might benefit most from bariatric surgery to improve condition, whilst a lean person might have inherent poor islet ß
cell function ∴ more likely to need insulin therapy
- e.g. morbidly obese individual might benefit most from bariatric surgery to improve condition, whilst a lean person might have inherent poor islet ß
- Insulin resistance with metabolic syndrome features** (mild to severe)
- ß cell susceptibility to failure (low to high)
As such we cannot take a one treatment fits all approach
What are the long term goals of diabetes therapy?
- Sustained metabolic control (prevent progressive islet failure)
- Low therapy-associated unwanted effects
- Enhanced quality of life
- Reduced diabetes complications
- Reduced diabetes-related mortality and all-cause mortality
Discuss the effects of healthy eating and physical activity on glycaemic management in type 2 diabetes
RE: Look AHEAD study
* Failure to achieve improvement in primary outcome: primary CVD outcomes, CVD death and all cause mortality
- aim to reduce body weight and waist circumference and increase fitness and produce leaner body mass
* Trends mostly in right direction underpowered because of low rates of events
* Multiple risk factor improvements- BP, HDL Chol, triglyceride, weight, waist circumference, sleep apnoea
score
* Improved fitness and quality of life
* Very intensive lifestyle management works to lower body weight but is not sustainable
* It has modest effect on HbA1c
Discuss the natural history of diabetes
- Three main stages: NGT, IGT, and T2D
- From NGT -> T2D: insulin sensitivity remains low
- From IGT, beta-cell function progressively worsens
List some glucose lowering medications
- Alpha-glucosidase inhibitors (e.g. acarbose): ‘others’
- Biguanides (metformin): insulin sensitisers
- Sulphonyureas (e.g. gliclazide,
glibenclamide, glimepiride): insulin secretagogues - Thiazolidinediones (e.g. rosiglitazone, pioglitatazone): also insulin sensitisers
Describe the action, side effects, types and contraindications of metformin
Metformin enhances liver sensitivity to insulin
* Impairs appetite
* Side effects: gastrointestinal disturbance (nausea, indigestion, diarrhoea - about 10% of patients don’t tolerate)
* Rarely: lactic acidosis due to renal impairment
* Contraindications: impaired renal function, severe cardiovascular and hepatic dysfunction, elderly
* Withdraw prior to contrast material, severe systemic illness and major surgery
* These can cause AKI ∴ stop medication to prevent lactic acidosis
- Metformin targets the liver, muscle, and fat tissue
- Usual starting dose is 500mg bd, maximum 1 g tds (x3 daily)
- Available in multiple forms: 500, 850, 1000mg
- Extended release preparation available - slowly digestible and acts longer (less side effects)
Describe the action, side effects, types and contraindications of sulphonylureas
(e.g. gliclazide, gibenclamide, glimepiride - long-acting)
* Cheap and been around for ~60 years
* MoA: enhance insulin secretion
- ATP-sensitive K+ channel in ß cells has sulphonylurea component
- Drug binding has same effect as ATP → closes channel and causes membrane
depolarisation ∴ insulin release (aka targets step 4 of insulin secretion pathway, see [[Physiology B3 - Lecture 4]]
- Doesn’t improve the cell, but makes the cell work harder to produce more insulin (may wear out ß cells that are already damaged in T2D)
- Side effects: hypoglycaemia: insulin secretion no longer glucose-dependent ∴ risk of inappropriate insulin
secretion - Varied duration of action - long-acting preparation used with caution in elderly
- No effect on cardiovascular risk
- Gliclazide (Diamicron, Glyade)
– 80 mg tablet, Max dose 320 mg/d
– 60 mg modified release (MR) tablet, Max 120 mg/day - Glibenclamide (Glimel, Daonil)
– 5 mg tablet, Max dose 20 mg/d - Glipizide (Minidiab, Melizide)
– 5 mg tablet, Max dose 20 mg/d - Glimepiride (Amaryl, Dimirel)
– 1,2,3,4 mg tablets, Max dose 4 mg/d
Describe the action, side effects, types and contraindications of glitazones or thiazolinediones
Glitazones are insulin sensitisers.
- Use declining (causes weight gain)
MoA:
* Selective PPARγ transcription factor agonist
* Bind to receptor and activate insulin- responsive genes
* Sensitise peripheral tissues to insulin ∴ ↑ glucose transport into muscle and adipose tissue
* Inhibit hepatic gluconeogenesis
* Promote lipogenesis
Has an effect on liver, muscle, fat (aka like metformin)
Side effects:
* Fluid retention
* Weight gain
* Hepatic dysfunction (rare)
* Increased distal fracture risk in post-menopausal women
- Contraindications: cardiac failure and hepatic dysfunction, question about rosiglitazone and MI and CVD death
- Rosiglitazone (Avandia)
– 4 and 8 mg tablets, Max dose 8 mg/d - Pioglitazone (Actos)
– 15, 30,45 mg tablets, Max dose 45 mg/d
Discuss the ADOPT study
- Sulphonylurea (Gibenclamide) worst at maintaining long-term glucose control
- Best drug at lowering glycaemia during the first 6 months, but this effect was not sustained
- May hasten damage to ß cells and accelerate the slope of the T2D curve
- Associated with some increase in body weight, but this reached a plateau
- Best at reducing congestive heart failure events
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- Best drug at lowering glycaemia during the first 6 months, but this effect was not sustained
- TZD (Rosiglitazone) best at preventing mono-therapy failure (better sustained glucose-lowering drug)
* PPARγ receptor works mostly in fat ∴ this drug caused continual weight gain (often not tolerated if patient already overweight)
* Associated with increased fractures in women
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* Metformin: weak but reproducible weight-loss
* All agents associated with different adverse effects
Describe the action, side effects, types and contraindications of GLP-1
An incretin-related therapy
e.g. eventide, liraglutide (must be injected)
* Given by subcutaneous injection - short and long-acting agents available
MoA:
* Enhances glucose-stimulated insulin secretion (incretin effect)
* Enhances the effect of elevated glucose to suppress glucagon secretion (since glucagon also elevated in T2D)
* Increases satiety
* Upregulates genes essential for ß cell function e.g. GLUT2 and glucokinase → ß cells differentiate into mature, healthy ß cells
* Promotes ß cell proliferation
* Protects against ß cell apoptosis (T2D has loss of ß cell mass through apoptosis)
* Decreases gastric emptying rate ∴ slows rate of glucose absorption from a meal
* Central effect to reduce appetite, food intake and body weight - causes weight loss
* Synthetic GLP1 receptor agonists don’t have same site for DPP4 inactivation so hang around for longer
- Side effects: nausea and vomiting
- Do not cause hypoglycaemia (unless with other agents that cause hypoglycaemia)
- As effective as insulin in lowering HbA1c through incretin effect
- Better CVD outcomes, CVD death and all cause mortality than SGLT2 inhibitors (LEADER study)
Infused glucose (vs oral) produces poorer insulin secretion because of incretin - hormones e.g.GLP1(in gut)enhance glucose-stimulated insulin secretion.
Pancreas and gut.
Describe the action, side effects, types and contraindications of DPP-IV inhibitors
e.g. sitagliptin, vildagliptin, alogliptin
* Good oral bioavailability with long duration of action (1 tab daily)
- incretin enhancers
* MoA:
* Dipeptidyl peptidase IV enzyme breaks down GLP1 in blood, inactivating it very quickly (T1/2 of GLP1 is only ~3 mins)
* Inhibiting this enzyme allows GLP1 to be around longer - protect GLP-1 from degradation
* Lower HbA1c as single agents or as add-on therapies
* Neutral effect on body weight
- Side effects: low - safe in elderly and in patients with other co-morbidities
act on liver, pancreas and gut
Describe the action, side effects, types and contraindications of SGLT2i
e.g. dapagliflozin, empagliflozin, entrugliflozin
* Once daily oral dosing
MoA: independent of insulin ∴ may compliment other anti-diabetic medications
* Potent, selective inhibitors of SGLT2 - expressed only in kidney
* Effectively reduce blood glucose levels and have a low incidence of hypoglycaemia
* Reduce weight and lower blood pressure
* Can be used regardless of duration of diabetes
- SGLT2:
- Low affinity, high capacity - responsible for majority of renal glucose reabsorption
- Inhibition results in ~80-100g/day of glucose lost in urine ∴ ↓ plasma glucose
- Weight loss because of associated caloric loss
- Lower BP through diuretic effect
- SGLT1: bowel and kidney
- High affinity, low capacity - responsible for small portion of renal glucose reabsorption
- Prominent role in intestinal glucose absorption
Side effects:
* Good - very low incidence of hypoglycaemia
* Effectiveness diminishes as renal function ↓
* Reduced intravascular volume-dependent side effects more common in ≥ 75 years, eGFR <60mL/min/1.73m2 or on loop diuretics
* Lower doses to initiate therapy in these patients
* Higher incidence of genital mycotic infections e.g. thrush (relatively higher in females, GMI, uncircumcised males)
* UTIs typically mild to moderate, no occurrence of serious adverse events
kidney
Describe glucose transport in the kidney
- In non-diabetic individuals approx. 180g of glucose filtered by glomeruli daily
- Glucose reabsorbed in tubule by Na+ glucose co-transporter 1 and 2
- ~90% reabsorbed in early PCT via SGLT2
- Remainder reabsorbed late PCT via SGLT1
- No glucose excreted in urine
- In hyperglycaemic individuals, glucose reabsorbed by the kidney effectively doubles
Discuss the key findings of the ACCORD study
- All cause mortality higher in intensive treatment group, though cause was unclear
- Intensive group had increased hypoglycaemia requiring assistance
- Weight gain greater in intensive group
- Higher baseline HbA1c and failure to improve average HbA1c both linked to increased mortality
-
Speculation: cardiomyocytes develop insulin resistance to protect from nutrient-induced toxicity in patients with poorly controlled T2D
- Attempts to override insulin resistance with high doses of insulin causes harm to heart
