What causes low High-Density Lipoprotein (HDL) levels?

Causes of Low HDL Cholesterol

Low HDL cholesterol results primarily from modifiable lifestyle factors—obesity, physical inactivity, and smoking—along with metabolic conditions like diabetes and hypertriglyceridemia, though genetic disorders can also play a role. 1

Primary Modifiable Causes

Lifestyle and behavioral factors are the most common contributors to low HDL:

• Increased adiposity (obesity) is strongly associated with reduced HDL cholesterol levels and represents a major modifiable risk factor 1, 2
• Sedentary lifestyle and lack of physical activity directly contribute to low HDL levels 1, 2
• Cigarette smoking is strongly associated with low HDL cholesterol 2
• Excess body weight, particularly abdominal obesity, is a major cause of low HDL 1, 3

Dietary Factors

Specific dietary patterns can lower HDL cholesterol:

• Low-fat, high-carbohydrate diets can result in reductions in HDL cholesterol levels in certain individuals 1
• Diets high in sugars may cause more evident HDL reduction than diets where carbohydrate is derived from unprocessed grains 1
• Increased intake of sugar and refined carbohydrates, particularly in the setting of insulin resistance and glucose intolerance, contributes to low HDL 1

Metabolic and Endocrine Causes

Metabolic disorders are major nongenetic determinants of low HDL:

• Hyperglycemia and diabetes mellitus (particularly type 2 diabetes) are major causes of low HDL 2, 4, 3
• Hypertriglyceridemia has a moderate inverse relationship with HDL cholesterol concentrations, meaning elevated triglycerides typically accompany low HDL 1, 2
• Insulin resistance and glucose intolerance contribute to reduced HDL levels 1
• Hypothyroidism can cause low HDL as part of secondary dyslipidemia 1

Medication-Induced Causes

Several medications can lower HDL cholesterol:

• Beta-blockers (such as atenolol) can reduce HDL levels; carvedilol is preferred in diabetic patients and those with hypertriglyceridemia 1, 5
• Progestational agents lower HDL 5
• Thiazide diuretics may reduce HDL 1
• Atypical antipsychotics can lower HDL 1
• Protease inhibitors used in HIV treatment 1
• Anabolic steroids 1

Genetic Causes

Familial disorders can cause isolated low HDL:

• Familial isolated decreases in HDL cholesterol increase risk of premature coronary artery disease, demonstrating a genetic component 2
• Familial combined hyperlipidemia (FCHL) is a genetically complex disorder (1-2% prevalence in white populations) that can present with low HDL alongside elevated triglycerides 1
• Familial hypertriglyceridemia (5-10% prevalence, likely polygenic) often presents with low HDL due to the reciprocal relationship between triglycerides and HDL 1

Clinical Context and Pitfalls

Important considerations when evaluating low HDL:

• The reciprocal metabolic relationship between plasma HDL cholesterol and triglyceride levels means that factors reducing HDL are often associated with relative increases in plasma triglycerides 1
• In patients with metabolic syndrome, low HDL is typically accompanied by hypertriglyceridemia, abdominal obesity, and insulin resistance 6
• Very low-fat diets are listed as a major nongenetic determinant of low HDL, creating a clinical dilemma when managing patients who need both LDL reduction and HDL optimization 2
• In patients with coronary artery disease or type 2 diabetes, HDL often loses its protective properties and may become dysfunctional despite normal or even elevated levels 6

The most actionable causes to address are obesity, sedentary lifestyle, smoking, and poorly controlled diabetes, as these represent modifiable risk factors where intervention can improve both HDL levels and overall cardiovascular outcomes 1, 2, 3