Management of Type 2 Diabetes

Question 1

What are the goals of treating type 2 diabetes? [3]

Answer 1

1. Reducing rates of microvascular complications:
2. Cardiovascular safety
   
   • minimum requirement (FDA 2008)
3. Reducing rates of macrovascular complications

Question 2

What are the microvascular complications of type 2 diabetes? [3]

Answer 2

1. retinopathy,
2. nephropathy,
3. foot disease (ulceration)

Question 3

What are the macrovascular complications of type 2 diabetes? [4]

Answer 3

1. myocardial infarction,
2. stroke,
3. heart failure,
4. peripheral vascular disease

Question 4

What are the biomedical targets associated with type 2 diabetes management? [4]

Answer 4

1. HbA1c:
   
   • 7% or individualised
2. BP:
   
   • <130/80
   • (ACEI or ARB, CCB, Thiazide diuretic)
3. Cholesterol:
   
   • Statin if aged >40,
   • <5 once started
4. Normal body weight.

Question 5

What are the important variables that need to be considered in the core diabetes model (CDM) for management of T2DM? [8]

Answer 5

1. Patient socio-cultural context/preferences/motivation
2. Age
3. Duration of diabetes
4. Complications (Macro, Micro. Hypo awareness)
5. Co-morbidity (CVD, Renal, Heart failure, Frailty)
6. HbA1c
7. BMI
8. Current lifestyle

Question 6

What lifestyle measures must be recommended for people with type 2 diabetes? [3]

Answer 6

1. increased activity levels
2. diet quality
3. calorie restriction

Question 7

Describe the drug management of type 2 diabetes under the following headings:

1. first line drugs?
2. second line drugs?
3. third line drugs?
4. fourth line drugs?

Answer 7

1. 1st Line:
   
   • Metformin
   • but sometimes sulphonylureas (SU)
2. 2nd Line:
   
   • two agents (add SU, Flozin, Gliptin, Glitazone)
3. 3rd Line:
   
   • three agents
   • (add any of the above OR start injectable therapy with GLP-1 agonist or Insulin)
4. 4th Line:
   
   • four agents from list above

Question 8

Describe the pharmacology of metformin under the following headings:

1. mechanism of action? [4]
2. benefits? [4]
3. disadvantages? [2]

Answer 8

1. Mechanism of Action:
   
   • Major effect is to suppress hepatic gluconeogenesis, reducing glucose output from liver
   • Also increases peripheral insulin sensitivity
   • Increases glucose uptake and utilisation
   • Increases AMPK activity
2. Benefits:
   
   • Moderate efficacy
   • Weight reduction
   • Low hypo risk
   • CV benefit
3. Side effects:
   
   • GI side effects
   • Small risk of lactic acidosis

Question 9

Describe the pharmacology of sulphonylureas under the following headings:

1. mechanism of action [5]
2. benefits [1]
3. disadvantages [4]

Answer 9

1. Mechanism of Action:
   
   • Sulphonylureas bind to the SUR1 receptor on the cell membrane of pancreatic beta cells, which results in closure of ATP-K+ channels.
     
     • This allows an influx of calcium which results in exocytosis of insulin.
   • Increased cellular glucose uptake & glycogenesis
   • Reduces gluconeogenesis
   • ATP sensitive potassium channels protect the heart during myocardial ischaemia.
     
     • The reduction in voltage-dependent calcium influx reduces myocardial contractility and oxygen demand.
     • By binding to the SUR2A receptor on cardiac myocytes and blocking ATP-K+ channels sulphonylureas may prevent this happening
2. Benefits:
   
   • High efficacy
3. Disadvantages:
   
   • No CV benefit
   • Weight gain
   • High hypo risk
   • Caution in CKD

Question 10

Describe the pharmacology of DPP-4 inhibitors (Gliptins) under the following headings:

1. mechanism of action [3]
2. benefits [3]
3. cautions [2]

Answer 10

1. Mechanism of Action:
   
   • Inhibit DPP-4 and enhance effects of endogenous incretins (e.g. GLP-1)
     
     • Oral glucose stimulates the release of the endogenous incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulin-releasing polypeptide (GIP).
     • These stimulate insulin release and inhibit glucagon release resulting in lower blood glucose.
     • They are rapidly inactivated by dipeptidyl peptidase-4 (DPP-4). The DPP-4 inhibitors prolong the action of endogenous incretins, enhancing the first-phase insulin response.
   • Increase glucose-mediated insulin secretion
   • Suppresses glucagon secretion
2. Benefits:
   
   • Low/moderate efficacy
   • Low hypo risk
   • Few adverse events
3. Cautions:
   
   • No CV benefit
   • Reduce dose in CKD

Question 11

Describe the pharmacology of SGLT2 inhibitors (Flozins) under the following headings:

1. mechanism of action [2]
2. benefits [6]
3. cautions [3]

Answer 11

1. Mechanism of Action:
   
   • Inhibit SGLT2 in the proximal convoluted tubule of the kidney
   • Decreases renal reabsorption of glucose
2. Benefits:
   
   • Moderate efficacy
   • CV benefit (BP + HF)
   • Renal benefit (CANA)
   • Weight loss
   • Low hypo risk
   • Reduced CV events
3. Cautions:
   
   • Risk of GU infections
   • Small risk of hypovolemia/diabetic ketoacidosis (DKA)
   • Do not start if eGFR <60

Question 12

Describe the pharmacology of thiazolidinediones (Glitazones) under the following headings:

1. mechanism of action [2]
2. benefits [4]
3. side effects [3]

Answer 12

1. Mechanism of action:
   
   • PPAR gamma-receptor agonists
   • Increase sensitivity of fat, muscles, and liver to endogenous and exogenous insulin
2. Benefits:
   
   • Moderate efficacy
   • Probably CV protection
   • Low hypo risk
   • Past experience
3. Side effects:
   
   • Weight gain
   • Fluid retention
   • Fractures

Question 13

Describe the pharmacology of GLP-1 receptor agonists under the following headings:

1. mechanism of action [4]
2. benefits [3]
3. disadvantages [4]

Answer 13

1. Mechanism of action:
   
   • Increases glucose mediated insulin secretion
   • Suppresses glucagon secretion
   • Increases satiety
   • Suppresses appetite
2. Benefits:
   
   • High efficacy
   • CV benefit
   • Low hypo risk
3. Disadvantages:
   
   • Injected
   • Weight loss
   • GI side effects
   • Uncertain safety re. pancreas

Question 14

Describe the pharmacology of insulin under the following headings:

1. mechanism of action [5]
2. benefits [1]
3. disadvantages [4]

Answer 14

1. Mechanism of action:
   
   • Increase glucose uptake and utilisation in skeletal muscle
   • Reduce hepatic glucose output
   • Increase glycogenesis
   • Decrease lipolysis
   • Decrease gluconeogenesis
2. Benefits:
   
   • High efficacy
3. Disadvantages:
   
   • Injected
   • No CV benefit
   • Weight gain
   • Highest hypoglycaemia risk

Question 15

What are the considerations that must be taken into account when prescribing T2DM drugs to the elderly? [5]

Answer 15

1. Polypharmacy with risk of drug interactions
2. Increased likelihood of adverse events (AEs) to drugs
3. Decrease in eGFR
4. Increased likelihood of hypoglycaemia
5. Individualise therapy balancing likely benefit with potential risks

Question 16

What are the considerations that must be taken into account when prescribing T2DM drugs to patients with renal disease? [5]

Answer 16

1. Stop metformin when eGFR <30ml/min/1.72m2
2. Caution with sulphonylureas as increased risk of hypoglycaemia
3. Dose-dose reduction required for some tides & gliptins
4. SGLT2 inhibitors less effective at glucose lowering in CKD (eGFR>60)
5. Renal protection with canagliflozin (CANA)

Question 17

What are the considerations that must be taken into account when prescribing T2DM drugs to patients with heart failure? [3]

Answer 17

1. May use metformin in chronic heart failure, withhold during acute episodes of failure
2. Stop or do not initiate glitazone
3. Flozins reduced hospitalisation for heart failure with & without diabetes (EMPA-REG, DAPA-HF)