Lipid Lowering Drugs - Cardiovascular

Snapshot
- A 40-year-old man presents to his primary care physician for high cholesterol levels. Six months ago, at his last clinic visit, he was found to have high levels of LDL cholesterol. Since then, he has tried to change his diet and exercise more frequently but admits that this has been difficult for him. He reports recently starting a “natural” treatment for high cholesterol and that it is “a healthy vitamin.” Since starting this treatment, however, he reports having a flushed face. (Niacin)

                        Introduction
                    
                        Key enzymes in lipid physiology
                    
                        lipoprotein lipase (LPL) 
                    
                        degrades triglycerides (TG) that are circulating around the bloodstream in chylomicrons and very low-density lipoproteins (VLDL)
                    
                        hormone-sensitive lipase 
                    
                        degrades TG stored in adipose tissues
                    
                        HMG-CoA reductase 
                    
                        converts HMG-CoA into mevalonate, a precursor of cholesterol
                    
                        peroxisome proliferator-activated receptor-α (PPAR-α) 
                    
                        activated during starvation and catabolizes fatty acids
                    
                        increases synthesis of LPL, causing a reduction in TG
                    
                        raises high-density lipoprotein (HDL)
                    
                        Lipid-lowering agents
                    
                        acts on the liver
                    
                        HMG-CoA reductase inhibitors
                    
                        PCSK9 inhibitors
                    
                        acts peripherally
                    
                        fibrates
                    
                        niacin
                    
                        acts on intestinal absorption
                    
                        bile acid resins
                    
                        ezetimibe
                    
                        Relative Effects of Lipid-Lowering Agents on LDL, HDL, and TG
                    
                        Drug
                    
                        LDL
                    
                        HDL
                    
                        TG
                    
                        HMG-CoA reductase inhibitors
                    
                        ↓↓↓*
                    
                        ↑
                    
                        ↓
                    
                        PCSK9 inhibitors
                    
                        ↓↓↓
                    
                        ↑
                    
                        ↓
                    
                        Fibrates
                    
                        ↓
                    
                        ↑
                    
                        ↓↓↓*
                    
                        Niacin
                    
                        ↓↓
                    
                        ↑↑*
                    
                        ↓
                    
                        Bile acid resins
                    
                        ↓↓
                    
                        ↑
                    
                        ↑
                    
                        Ezetimibe
                    
                        ↓
                    
                        ↑/-
                    
                        ↓/-
                    
                        * = best therapy

HMG-CoA Reductase Inhibitors
- Drugs
  - lovastatin, pravastatin, simvastatin, rosuvastatin, and atorvastatin
- Mechanism
  - prevents synthesis of mevalonate, a cholesterol precursor, by inhibiting HMG-CoA reductase
    
    this is the rate-limiting step of cholesterol synthesis
    
    increases LDL receptors
- Clinical use
  - ↓ mortality in patients with coronary artery disease
  - primarily lowers low-density lipoproteins (LDL)
    
    most effective drug for lowering LDL
- Toxicity
  - hepatotoxicity
  - myopathy
    
    especially when used in combination with fibrates and niacin
  - inhibitors of P450 can ↑ serum concentration

PCSK9 Inhibitors
- Drugs
  - alirocumab and evolocumab
- Mechanism
  - monoclonal antibodies that bind to proprotein convertase subtilisin/kexin type 9 (PCSK9)
    
    PCSK9 destroys LDL-receptor on hepatocytes, which results in decreases clearance of LDL
  - inhibition of PCSK9 improves clearance of LDL
- Clinical use
  - primarily decreases LDL
- Toxicity
  - myopathy
  - neurocognitive effects
    
    delirium
    
    dementia

Fibrates
- Drugs
  - gemfibrozil, bezafibrate, and fenofibrate
- Mechanism
  - activates PPAR-α and upregulates lipoprotein lipase
    
    reduces levels of triglycerides
  - induces HDL synthesis
- Clinical use
  - primarily decreases TG
    
    most effective drug for lowering TG
- Toxicity
  - myopathy
  - cholesterol gallstones
  - can ↑ LDL so, so fibrates are not often used as monotherapy

Niacin (Vitamin B3)
- Mechanism
  - inhibits hormone-sensitive lipase
  - inhibits hepatic VLDL synthesis
- Clinical use
  - primarily increases HDL
    
    most effective drug for increasing HDL levels
- Toxicity
  - red and flushed face/upper body
    
    thought to be due to a release of prostaglandins and histamine
    
    treat with non-steroidal anti-inflammatory drugs (NSAIDs)
  - ↑ glucose
  - ↑ uric acid
  - acanthosis nigricans
  - pruritus

Bile Acid Resins
- Drug
  - cholestyramine, colestipol, and colesevelam
- Mechanism
  - binds to bile acids and prevents reabsorption of bile acids in the distal ileum
    
    this forces the liver to make more bile acids by using the available cholesterol in the body
- Clinical use
  - primarily decreases LDL
- Toxicity
  - gastrointestinal upset
  - malabsorption, especially of fat-soluble vitamins

Ezetimibe
- Mechanism
  - inhibits sterol transporter at the small intestine brush border, preventing the absorption of cholesterol
    
    this decreases the hepatic stores of cholesterol
- Clinical use
  - primarily decreases LDL
  - primarily used in combination with a statin
- Toxicity
  - rare hepatotoxicity
    
    when used in combination with statins
  - gastrointestinal upset

Action	Numeric Key	Letter Key	Function Key
Show Bullets		S	Enter (frontside only)
20%	1	N
40%	2	H
60%	3	F	Enter (backside only)
80%	4	E
100%	5	M
Toss	0	T

Relative Effects of Lipid-Lowering Agents on LDL, HDL, and TG
Drug	LDL	HDL	TG
HMG-CoA reductase inhibitors	↓↓↓*	↑	↓
PCSK9 inhibitors	↓↓↓	↑	↓
Fibrates	↓	↑	↓↓↓*
Niacin	↓↓	↑↑*	↓
Bile acid resins	↓↓	↑	↑
Ezetimibe	↓	↑/-	↓/-
* = best therapy