3. Brief lipid update / effects on cardiovascular health

Question 1

What does the SPRINT study show about the use of thiazide diuretics on top of medications they already take in people with CHD?

Answer 1

Saves 2 lives per 100 people per year

Question 2

What is the optimal medical therapy in people with CHD?

Answer 2

Intensive lifestyle modification, aspirin, high dose statin e.g. atorvastatin 40-80mg OD, optimal BP control, thiazides are very cheap, assessment for probable T2DM (HbA1c). Aggressive management of blood pressure and lipids improves survival

Question 3

What are alternative options for people with statin intolerance?

Answer 3

Niacin (no longer available), ezetimibe, plasma exchange (where available), evolucumab - PCSK9 monoclonal antibody

Question 4

What does PCSK9 do?

Answer 4

Regulates the levels of LDL receptor

Question 5

Gain of function mutations in PCSK9 will…

Answer 5

reduce LDL receptor levels in the liver, resulting in high levels of circulating LDL and increased susceptibility to CHD

Question 6

Loss of function mutations in PCSK9 leads to…

Answer 6

Higher levels of LDL receptor, lower LDL cholesterol levels, and protection from coronary heart disease

Question 7

What happens when you inhibit PCSK9 with monoclonal antibodies?

Answer 7

It can increase the removal of LDL cholesterol from the plasma.

Question 8

What are the benefits of Evoluocumab?

Answer 8

A study on the benefits of Evolucumab in patients with established CVD showed it significantly and safely decreases major CV events when added to statin therapy, however has no effect on mortality. Benefit was achieved with lowering LDL cholesterol well below current targets.

Question 9

Who is PCSK9 inhibitor reserved for?

Answer 9

For high risk patients e.g. familial hypercholesterolaemia, statin-intolerant patients -> high net value patients. It is a very expensive drug.

Question 10

What does the UKPDS study (1977-2007) show about aggressive control of blood glucose?

Answer 10

That it maintains a lower HbA1c through 15 years of follow-up in newly diagnosed T2DM. The effect of intensive treatment on the risk of microvascular events was not apparent until around 9 years after beginning the trial. This shows that, to achieve favourable outcomes later on, blood glucose control must be good from the beginning. In reality it takes about 15 years before the benefits of good blood glucose control become apparent.

Patients who reverted back to poor glucose control quickly reached similar HbA1c values to their counterparts in the conventional management group. However mortality remained low -> legacy effect. So having good blood glucose control, even for a relatively short period of time, has benefits later on.

Question 11

The Accord and Advance studies looked at the benefits of blood glucose control in people who had had some sort of cardiovascular complication of their diabetes. What did it find?

Answer 11

Accord found that suddenly aggressively controlling the blood glucose of people who have had poor control for decades leads to reduced complications but increased mortality.
Sudden aggressive blood glucose control can precipitate tachycardia and kill patients.

Question 12

Summarise the DCCT study

Answer 12

Type 1 diabetes, good control improves outcomes

Question 13

Summarise the UKPDS study

Answer 13

New T2DM put onto good control. 15 years before benefits are seen. Low mortality in both groups (i.e. those who reverted back to poor glucose control vs. those who maintained good glucose control) for 15 years (legacy effect) but the good control group had improved outcomes and lower HbA1c.

Question 14

Summarise the ACCORD study

Answer 14

take older people who had poor control for a long time, and suddenly massively tighten control (HbA1c=6%): they already had coronary artery disease, so increased unexpected death

Question 15

Summarise the ADVANCE study

Answer 15

HbA1c=6.5%, reduced death

Question 16

What are examples of SGLT2 inhibitors?

Answer 16

Empagliflozin, dapagliflozin, canagliflozin

Question 17

How do SGLT2 inhibitors work?

Answer 17

Designed to make you pee out glucose, leads to reduction in blood glucose and blood pressure due to diuresis. Significantly reduces mortality as the effect is due to a reduction in the incidence of cardiovascular events. Also effective in HF because of its diuretic effect.

Question 18

What is the effect of SGLT2 inhibitors on CV events?

Answer 18

Significant reduction in mortality after just 4 years.

Question 19

What happens to GFR after taking SGLT2 inhibitors?

Answer 19

Initially causes a reduction in GFR but this will eventually recover and is associated with a reduction in renal failure and heart failure.

Question 20

How affordable are SGLT2 inhibitors?

Answer 20

Very expensive (NNT = 100, £48000 to prevent one death)

Question 21

How do GLP-1 analogues work?

Answer 21

GLP-1 is secreted from the gut and signals to the pancreas to make more insulin via increatin effect. It also has a direct effect on appetite and gastric emptying.

Question 22

Examples of GLP1 analogues

Answer 22

exenatide, liraglutide, semaglutide

Question 23

What is GLP1 broken down by?

Answer 23

DPP4

Question 24

What does inhibiting DPP4 with gliptins do?

Answer 24

Extends the half life of GLP1

Question 25

What is found in glia monster venom and has a similar structure to GLP1?

Answer 25

Exendin-4

Question 26

What does exendin-4 do?

Answer 26

It lowers blood glucose towards target levels and is associated with weight loss and hypothalamic safety.

Question 27

What is the synthetic version of exendin-4?

Answer 27

Exenatide

Question 28

What does exenatide do?

Answer 28

Mimics endogenous GLP1 activity by stimulating insulin release in response to glucose preventing glucagon which raised blood glucose from being released after meals.

Question 29

What has the use of liraglutide shown?

Answer 29

Shown to cause a significant reduction in events within 4 years

Question 30

Summary of diabetes care (non-insulin)

Answer 30

• Metformin if tolerated/not contraindicated.
• If non-insulin monotherapy at maximum does does not achieve or maintain HbA1c target after 3 months, add a second oral agent e.g. GLP1 receptor agonist or basal insulin.
• In patients with long standing suboptimal T2DM control and established CVD, empagliflozin or liraglutide should be considered as they have been shown to reduce CV and all-cause mortality when added to standard care.

Question 31

Efficacy of the different types of non-insulin treatments for diabetes

Answer 31

Metformin - high, DPP-4 inhibitor - intermediate, SGLT2 inhibitor - intermediate, GLP-1 receptor agonist -high

Question 32

Hypo risk of the different types of non-insulin treatments for diabetes

Answer 32

Metformin, DPP-4 inhibitor, SGLT2 inhibitor, GLP-1 receptor agonist - low for all

Question 33

Effects on weight by the different types of non-insulin treatments for diabetes

Answer 33

Metformin - neutral/loss, DPP-4 inhibitor - neutral, SGLT2 inhibitor - loss, GLP-1 receptor agonist - loss

Question 34

Side effects of the different types of non-insulin treatments for diabetes

Answer 34

Metformin - lactic acidosis, DPP-4 inhibitor - rare, SGLT2 inhibitor - GU, dehydration, GLP-1 receptor agonist - GI

Question 35

Costs of the different types of non-insulin treatments for diabetes

Answer 35

Metformin - low. DPP-4 inhibitor, SGLT2 inhibitor, GLP-1 receptor agonist - high.

Question 36

Which treatments are particularly safe in people with longstanding poorly controlled diabetes?

Answer 36

SGLT2 inhibitors and GLP1 analogues

Question 37

Which treatments are particularly good at managing blood glucose in people with T2DM and heart disease?

Answer 37

DPP-4 inhibitor, SGLT2 inhibitor, GLP-1 receptor agonist