7. Brief Lipid Update Flashcards
A 76-year-old patient with a previous MI (3 years ago) has a blood pressure of 140/80 on atenolol. The LDL is 3.0mmol on atorvastatin (80mg). Is there evidence to lower his BP further? What type of medication do we give if we do want to lower his BP further?
Yes – we should give this patient a thiazide diuretic instead of just leave him alone
There is evidence that patients with a lowered systolic blood pressure are at a reduced risk of cardiovascular events and death (SPRINT study).
prevent two ‘events’. This is good value for money.
Using thiazides in 100 people with CAD will save 2 lives over 5 years. Therefore, we should start this patient on thiazides to bring the blood pressure down to 120/80.
Optimal Medical Therapy in this case
- Intensive lifestyle modification
- Aspirin (all these patients should be on aspirin to prevent death – proven in ISIS-2 trial)
- High dose statin (Atorvastatin 40-80mg od – minimises cholesterol)
- Optimal blood pressure control – to SBP 120 if possible
- Thiazides are almost free
- Assessment for probable T2DM (check HbA1c)
AGGRESSIVE MANAGEMENT OF BLOOD PRESSURE AND LIPIDS IMPROVES SURVIVAL
Back to our 76-year-old patient – shall we give him a PCSK9 inhibitor to lower his lipid levels?
Situation: if they are statin intolerant
Evolocumab (monoclonal antibody against PCSK9)
THIS DRUG DOES NOT PREVENT DEATH. STATINS AND THIAZIDES ARE VERY BENEFICIAL. EVOLOCOMAB HAS GOT A PLACE IN FAMILIAL DISEASE, BUT RCTs HAVE NOT DEMONSTRATED A REDUCTION IN DEATH RATE YET. WE NEED SOME MORE END-POINT DATA BEFORE WE USE THIS DRUG FOR THE AVERAGE PATIENT.
Cons:
- absolute risk reduction is small
- not cheap
- no effect on mortality
→ RESERVE THIS DRUG FOR HIGH RISK PATIENTS
How do PCSK9 inhibitors work?
- PCSK9 regulates the levels of the LDL receptor (recycles the LDL receptor)
- Gain-of-function mutations in PCSK9 reduce LDL receptor levels in the liver
- This results in high levels of plasma LDL cholesterol and increased susceptibility to CHD
- Loss-of-function mutations lead to higher levels of the LDL receptor, lower LDL cholesterol levels, and protection from coronary heart disease
- PCSK9 protein regulates the level of the LDL receptor (recycles it)
- Inhibiting PCSK9 with monoclonal antibodies increases removal of LDL cholesterol from plasma as it stops PCSK9 reducing LDL receptor levels
- The levels of LDL in the plasma drop with use of the drugs to insanely low levels within weeks
- PCSK9 inhibitors are very expensive
Available options for statin intolerant patients
- Niacin NO LONGER AVAILABLE
- Ezetemibe – good lipid lowering agent (not as effective as statins)
- Plasma Exchange where available (if cholesterol is really high)
- Evolocumab (monoclonal antibody against PCSK9)
Until recently none of the above had evidence for prevention of atherosclerotic CVD (ASCVD)…
Does good glucose control prevent complications?
- YES (UKPDS published 1998)
- But only after about 15 years in NEWLY diagnosed type 2 diabetes
- Is it worth it? And what happened after this?
LEGACY EFFECT.
Having good blood glucose control, even for a relatively short period of time, has benefits later on. If you teach a diabetic how to control their glucose very tightly, they will first see the benefits 15 years later, however the legacy of this benefit continues.
LEGACY EFFECT but cons?
he ACCORD study found that suddenly aggressively controlling the blood glucose in 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.
The take home message is that there is such a thing as ‘too late’. When you first get diabetes, you should start with very tight control. As you get older, you need to let up.
Summary of the findings of key studies
- DCCT: type 1 diabetes, good control improves outcome
- UKPDS: New type 2 diabetes put onto good control, low mortality in both groups for 15 years, but then good control improved outcome, LEGACY EFFECT
- ACCORD: take older people who had poor control for a long time, and suddenly massively tighten control (A1c=6%): they already had coronary artery disease, so increased unexpected death
- ADVANCE: (A1c=6.5%, reduced death)
What is an example of an SGLT2 inhibitor?
EMPAGLIFOZIN
SGLT2 inhibitor mechanism
- SGLT2 inhibition reduces renal glucose reabsorption (induces glycosuria)
- This leads to a reduction in blood glucose and blood pressure (due to diuresis)
- This has shown to cause a significant reduction in mortality after just 4 years
- The effect is due to a reduction in the incidence of cardiovascular events
- Empagliflozin: This drug is also effective in heart failure because of its diuretic effect
- In normal diabetic patients, the GFR gets progressively worse over the years
- Initially, empagliflozin causes an immediate reduction in GFR, but this eventually recovers
- After recovery from this initial fall, the drug prevents further GFR reduction
- The drug is associated with a reduction in renal failure
- It is also EXPENSIVE (a lot cheaper than evolocumab)
- Associated risk: increased risk of genital skin infections (mostly mycoses)
This drug reduced HbA1c, weight, waist circumference and systolic BP
- There was a major reduction in risk of adverse cardiovascular events over 4 years
- With this drug, reduction in events were seeing within 6 months
- The drug prevented heart disease significantly
Other studies have shown that T2DM patients may be waiting 15 years to see any benefit of good glucose control. What was different about this drug (SGLT2 inhibitor)?
This drug has an additional, hidden benefit; it is a diuretic. In patients with heart failure, the adverse effects were reduced due to diuretic effects of the drug. This drug:
- Prevents macroalbuminuria
- Prevents renal failure
- Prevents renal replacement therapy
How does the SGLT-2 inhibitor, empagliflozin, exert its cardiovascular benefit?
If we compare SGLT-2 inhibitors, because it is cheaper compared to other diabetes drugs, it is a pretty good value drug.
The SGLT-2 inhibitors have an added benefit in diabetes patient with renal function problems and heart failure.
What are examples of GLP1 Analogues?
Exanatide, Liraglutide (Victoza/Saxenda), Semaglutide
GLP1 Analogues: mechanisms
These drugs work by stimulating insulin release in the gut (from the pancreas). This is an endogenous hormone that is produced by the gut and signals to the pancreas to make more insulin. It is responsible for the incretin effect. It also has a direct effect on appetite and gastric emptying.
Liraglutide and semaglutide benefits and risks
- Studies investigating the use of liraglutide and cardiovascular outcomes in T2DM patients have shown that there is a reduction in events when GLP1 analogues are given to people with poorly controlled diabetes. Semaglutide has shown even better results*
- ADVERSE EFFECTS → trial withdrawal*
Management of hyperglycaemia in T2DM
- Everyone is given metformin (if not contraindicated and if tolerated)
- Then, you can add whatever you want
- Sulphonylureas
- Thiazolidinediones
- DPP-4 inhibitors (gliptins)
- SGLT-2 inhibitors
- GLP-1 receptor agonists
- Insulin (basal)
GLP1 Analogues: mechanisms
These drugs work by stimulating insulin release in the gut (from the pancreas). This is an endogenous hormone that is produced by the gut and signals to the pancreas to make more insulin. It is responsible for the incretin effect. It also has a direct effect on appetite and gastric emptying.
