Chemical Pathology 19 - Lipid Update

Question 1

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

Answer 1

prevented from a further MI in the next 5 years

KEY POINT: aggressive management of blood pressure and lipids improves survival (CV death, MI, ACS, HF)

Question 2

What were the results of the SPRINT study?

Answer 2

reducing BP further (140/80→120/80) greatly reduced deaths

Question 3

When would you use a PCSK9 mAb?

Answer 3

high-risk patients:

Statin-intolerant

Uncontrolled lipids (i.e. Familial Hypercholesterolaemia)

High net value patients

Question 4

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

Answer 4

Decreases incidence of non-fatal MI, but does not reduce death

FOURIER “PCSK9” Study

Question 5

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

Answer 5

Evolocumab
Regulates LDL-receptor recycling to reduce cholesterol

Question 6

What are some options for statin intolerant patients?

Answer 6

Niacin (no longer available)

Ezetemibe (reduced absorption – block NPC1L1)

Plasma exchange (where available)

Evolocumab (PCSK9 monoclonal antibody)

Question 7

What did the UKPDS study show?

Answer 7

Effect of intensive treatment on risk of microvascular events was not apparent until ~9 years after trial start

In reality - takes 15 years for good glucose control to show a benefit

Question 8

What is the Legacy effect of UKPDS?

Answer 8

patients who reverted to poor glucose control quickly reached similar HbA1c values to conventional group

HOWEVER, mortality remained low in intensive group despite their blood glucose control deteriorating

I.E. having good blood glucose control, even for a short while, can improve later mortality up to 10yrs

Question 9

What did the Advance study show?

Answer 9

no significant difference

Question 10

What did the Accord study show?

Answer 10

Pre existing vascular disease + diabetes -> sudden aggressive blood glucose control

reduced complications but increased mortality

Sudden aggressive blood glucose control → arrythmias → death

I.E. do NOT suddenly control blood glucose → as patient ages, control needs to be less tight

need tight control when coronary arteries are normal

Question 11

What did the DCCT show?

Answer 11

Good control in type 1 diabetes improves outcome

Question 12

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

Answer 12

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

Also used in HR (diuresis) and nephropathy!

Question 13

What is the broad mechanism of action of SGLT2 inhibitors?

Answer 13

They cause glycosuria

reduce glucose re-uptake in kidneys → osmotic diuresis (reduced blood glucose and low BP)

Question 14

What did the EMPA REG study show?

Answer 14

adults w/ T2DM and established CVD

significant ↓mortality (incidence of cardiovascular events) after just 4 years if SGLT2 inhibitors

Question 15

Give an example of a GLP-1 analogue drug

Answer 15

Semaglutide

Exenatide (Exendin 4) - increased hypothalamic satiety

Liraglutide (Saxenda) - LEADER study: ↓ significant CVD and MI events

Question 16

What is the mechanism of action of GLP1 analogues?

Answer 16

DPP4 inhibitors

• GLP-1 secreted from gut L-cells → signals pancreas to make insulin
• Direct effect on appetite and gastric emptying
• Responsible for incretin effect
• GLP-1 broken down by DPP4 (i.e. inhibiting DPP4 using Gliptinsmakes GLP-1 last longer; i.e. sitagliptin)

Question 17

What is the best drug combo in diabetes?

Answer 17

Metformin + DPP4 inhibitor

Metformin + SGLT2 inhibitor

Metformin + GLP-1-R agonist

The bottom 2 are associated with better outcomes than DPP4 inhibitors