What is the cause of hot sensations, fatigue, and generalized weakness in a 40-year-old female with hypertension, diabetes, and non-alcoholic fatty liver disease (NAFLD) on dapagliflozin, sitagliptin, metformin, saroglitazar, chlordiazepoxide, telmisartan, and atorvastatin?

Evaluation of Hot Sensations, Fatigue, and Generalized Weakness in a 40-Year-Old Female with Metabolic Comorbidities

Most Likely Diagnosis

This clinical presentation most likely represents medication-induced heat intolerance and fatigue, specifically from chlordiazepoxide, with possible contribution from hyperinsulinemia related to her diabetes medications. 1, 2

Immediate Medication Review Required

Discontinue chlordiazepoxide immediately, as benzodiazepines with anticholinergic properties can impair thermoregulation and cause heat-related symptoms, particularly hot sensations and excessive sweating. 1

• Anticholinergic drugs inhibit sweating and reduce heat elimination, leading to heat intolerance even without environmental heat exposure 1
• The combination of lying in bed all day with generalized weakness suggests drug-induced sedation and impaired thermoregulation 1
• Consider alternative anxiolytic if needed, such as SSRIs without anticholinergic effects 1

Secondary Contributing Factor: Hyperinsulinemia

Evaluate for hyperinsulinemia as a cause of hot flashes and fatigue, even with normal glucose levels. 2

• Obtain fasting insulin level and consider 75-gram oral glucose tolerance test with insulin measurements 2
• Hyperinsulinemia without hypoglycemia produces sympathoexcitatory responses manifesting as hot flashes and increased sweating 2
• If hyperinsulinemia confirmed, metformin (which she is already taking) has sympathoinhibitory actions that should help, but dose optimization may be needed 2

Cardiovascular Risk Assessment

Screen for cardiovascular disease urgently, as cardiovascular disease is the leading cause of death in NAFLD patients and can present with fatigue and weakness. 3

• Calculate QRISK-3 score to assess 10-year cardiovascular risk 3
• Obtain ECG to exclude arrhythmias or ischemic changes 3
• Check troponin if any chest discomfort or dyspnea present 3
• Ensure blood pressure is controlled (<130/85 mmHg) 3

NAFLD-Specific Evaluation

Assess liver fibrosis stage using FIB-4 score followed by transient elastography, as advanced fibrosis increases cardiovascular mortality risk and may contribute to fatigue. 4

• Patients with F2-F3 fibrosis require intensified cardiovascular risk management 4
• Fatigue is a common non-specific complaint in NAFLD but does not correlate with disease severity 3
• Continue saroglitazar for NAFLD management 4

Metabolic Screening

Screen annually for diabetes complications and metabolic deterioration given her NAFLD diagnosis. 3

• Check HbA1c to ensure diabetes control (target <48 mmol/mol or 6.5%) 3
• Measure fasting lipid panel for dyslipidemia 3
• Assess thyroid function (TSH) as hypothyroidism increases NAFLD prevalence to 30.2% and causes fatigue 3

Medication Optimization for NAFLD

Consider adding GLP-1 receptor agonist (semaglutide or tirzepatide) for her diabetes and NAFLD, which would address multiple issues simultaneously. 4

• GLP-1 agonists improve liver histology, reduce weight, and improve glycemic control 4, 5
• Liraglutide specifically improves liver fat, resolves NASH, and reduces weight 5
• Current regimen of dapagliflozin, sitagliptin, and metformin is compatible with GLP-1 addition 6, 7

Verify adequate dosing of current diabetes medications:

• Dapagliflozin reduces steatosis by 20% but effect on liver histology unknown 4
• Combination of dapagliflozin with sitagliptin and metformin is safe and effective 7
• No dose adjustments needed when these agents are combined 6

Lifestyle Intervention (Critical Component)

Prescribe specific exercise regimen: 150-300 minutes per week of moderate-intensity aerobic exercise over minimum 3 days per week, plus resistance training on at least 2 days. 3

• Resistance exercise has lower cardiorespiratory demand and may be preferable given her current deconditioning 3
• Exercise reduces liver fat independent of weight loss 3
• Target 7-10% body weight loss to improve liver inflammation and fibrosis 4

Implement Mediterranean diet immediately:

• Eliminate sugar-sweetened beverages and ultra-processed foods 4
• Increase fruits, vegetables, whole grains, legumes, nuts, and olive oil 4
• This dietary pattern improves NAFLD independent of weight loss 4

Smoking cessation if applicable, as smoking increases cardiovascular and liver disease progression risk. 3

Critical Pitfalls to Avoid

• Do not attribute symptoms to menopause without excluding medication effects and metabolic causes, as her menstrual cycle is normal 1, 2
• Do not continue chlordiazepoxide assuming symptoms are unrelated, as anticholinergic effects directly cause heat intolerance 1
• Do not overlook cardiovascular disease, which accounts for over one-third of deaths in NAFLD patients 3
• Do not delay fibrosis assessment, as advanced fibrosis significantly increases mortality risk 4

Monitoring Plan

• Reassess symptoms 2 weeks after chlordiazepoxide discontinuation 1
• Repeat cardiovascular risk assessment annually using QRISK-3 3
• Monitor HbA1c, blood pressure, and lipids every 3-6 months 3
• Repeat FIB-4 and transient elastography annually to assess fibrosis progression 4
• Screen for hepatocellular carcinoma if cirrhosis develops 4