Chemical Pathology 19 - Lipid Update

Question 1

What is the statistical mortality benefit of adding a thiazide diuretic to outstanding BP medications, following an MI?

Answer 1

Worth it, as 2 in 100 will be prevented from a further MI in the next 5 years

*SPRINT Study*

Question 2

What is the statistical mortality benefit of adding a PCSK9 inhibitor to outstanding BP medications, following an MI?

Answer 2

Decreases incidence of non-fatal MI and major CV events, but does not reduce death

NNT is high (£600,000 to prevent one event)

*Fourier study*

Question 3

Give an example of a PCSK9 inhibitor medication, and how it works

Answer 3

Evolocumab

Regulates LDL-receptor recycling to reduce cholesterol

Question 4

When should PCSK9 inhibitors be used in clinical practice?

Answer 4

Reserve them for HIGH RISK patients:

Statin-intolerant

Uncontrolled lipids (I.e. FH)

High net-value patients (doesn’t make much sense)

Question 5

What did the UKPDS study show?

Answer 5

That it takes 15 years for good glucose control to show a benefit

Question 6

What is the “legacy effect” shown after the UKPDS study?

Answer 6

Reverting back to poor glucose control on completion of the study meant that HbA1c became bad again BUT MORTALITY + OTHER OUTCOMES REMAINED LOWER in the previous intense group

Benefits were sustained for up to 10 years after the cessation of randomised interventions

Question 7

What did the Advance study show?

Answer 7

Targeting HbA1c of less than 6.5% reduces microvascular events

Intensive glucose control was associated with an increased risk of severe hypoglycaemia and hospitalisation BUT no increased risk of mortality (unlike Accord study)

Question 8

What did the Accord study show?

Answer 8

If you take someone who already has knackered coronary arteries with atheromas and suddenly tighten glucose control, mortality actually increases (even though complications are reduced)

*Deaths were unexplained - likely to be arrhythmias*

Question 9

What did the DCCT show?

Answer 9

Good control in type 1 diabetes improves outcome

*Legacy effect was shown here too*

Question 10

What makes SGLT2 inhibitors such a fabulous drug class according to Meeran?

Answer 10

Reduce HbA1c, BP, weight, type 2 diabetes incidence and cardiovascular disease, with immediate effect!

Question 11

What were the key finding of the EMPA-REG study?

Answer 11

Significant reduction in mortality after just 4 years

Reduces HbA1c

Treats heart failure due to diuresis

Prevents nephropathy as it reduces albuminuria by letting glucose pass into the tubules instead - protects the kidneys (initial sharp reduction in GFR but then recovers)

*Albumin is poisonous to the kidneys so these SGLT2 inhibitors are renal-protective*

Question 12

What are the side-effects of SGLT-2 inhibitors?

Answer 12

UTIs

Rarely DKAs

Question 13

What is the broad mechanism of action of SGLT2 inhibitors?

Answer 13

They cause glycosuria

Question 14

Give an example of a GLP-1 analogue drug

Answer 14

Exanatide

Liraglutide (Victoza or Saxenda)

Semaglutide

*All injections at the moment so SGLT2 inhibitors are preferred in combination with metformin*

Question 15

What is the mechanism of action of the ‘gliptin’ drugs?

Answer 15

DPP4 inhibitors

*Likely to be phased out as GLP-1 analogues work better*

Question 16

Summary of T2DM treatment

Answer 16

Start with metformin to improve insulin sensitivity

Tight glucose control for 15-20 years IF atheromas aren’t present to begin with

SGLT2 inhibitors particularly useful if there is heart failure

Alternative drugs can be used in dual/triple therapy with metformin including GLP-1 analogues (good for weight loss) and sulfonylureas (risk of hypos)