ChemPath: Brief Lipid Update

• Intensive lifestyle modification • Aspirin • High-dose statin (atorvastatin 40-80mg OD) • Optimal blood glucose control • Thiazides • Assessment for probable T2DM

Worth it, as 2 in 100 will be prevented from a further MI in the next 5 years 20% relative risk reduction 2% absolute risk reduction Shown by the SPRINT Study

• Ezetemibe • Plasma exchange • PCSK9 inhibitors NOTE: niacin is no longer available

• PCSK9 targets the LDL receptors leading to endocytosis and their degradation • This reduces the ability of the liver to take up cholesterol from the blood

Evolocumab

Patients who are at very high risk (e.g. familial hypercholesterolaemia) Statin-intolerant patients NOTE: PCSK9 inhibitors reduce the incidence of cardiovascular events but has no effect on mortality, and has a high NNT (Fourier study)

15 years to see a reduction in complications Shown by the UKPDS study

A period of good glycaemic control will have a beneficial effect on mortality for up to 10 years even if the patient reverts to poor glycaemic control after a certain period of time. Shown by the UKPDS study

Good control in type 1 diabetes improves outcomes *Legacy effect was shown here too*

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)

• Reduced the incidence of complications • Increased mortality (likely due to precipitating tachycardia and arrhythmias) Really important to consider whether the patient has atheromas to begin with before suddenly tightening glucose control This was found by the ACCORD trial

Increases urinary excretion of glucose causing a reduction in blood glucose and blood pressure. NOTE: this can also be used in heart failure because of its diuretic effect Main side-effects: UTIs due to glycosuria, rarely DKA

Empagliflozin

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*

• Produced by the gut and signals to the pancreas to produce more insulin (incretin effect) • Also has a direct effect on satiety and gastric emptying

DPP4

Gliptins (by inhibiting DPP4 and, thereby, preventing the breakdown of GLP1) Likely to be phased out as GLP-1 analogues work better

• Exanatide (synthetic version of exendin 4) • Liraglutide (saxenda) • Semaglutide All injections at the moment so SGLT2 inhibitors are preferred in combination with metformin

• Metformin • if non-insulin monotherapy at maximum tolerated dose does not achieve or maintain the HbA1c target after 3 months add either: • Second oral agent OR • GLP1 agonist OR • Basal insulin In patients with long-standing suboptimally controlled T2DM and established cardiovascular disease, empagliflozin (SGLT2 inhibitor) or liraglutide (GLP1 analogue) should be considered.

Bile. Dietary.

NPC1L1

ABC G5 ABC G8

Hydrolysed by 7-alpha-hydroxylase into bile acids. Esterification by ACAT and incorporation with ApoB + triglycerides to form VLDL

MTP