How to manage muscle ache in the legs and back in a patient with heart failure with reduced ejection fraction (HFrEF) taking dapagliflozin (Forxiga)?

Managing Muscle Aches from Dapagliflozin in HFrEF

Muscle aches are not a recognized adverse effect of dapagliflozin in major clinical trials, and you should investigate alternative causes before attributing symptoms to this medication. The extensive safety data from DAPA-HF and other trials do not identify myalgia or muscle pain as a significant adverse event associated with dapagliflozin 1, 2, 3.

Verify the Diagnosis

First, confirm that muscle aches are actually related to dapagliflozin rather than other causes:

• Review the temporal relationship: Did muscle aches begin shortly after starting dapagliflozin (within days to weeks), or were they pre-existing? 4

• Assess for volume depletion: Dapagliflozin causes mild natriuresis and diuresis, which can lead to volume depletion in approximately 5.7% of patients, potentially causing muscle cramps or weakness 2, 3. Look for orthostatic hypotension, dizziness, or increased thirst.

• Check electrolyte abnormalities: Obtain serum potassium, magnesium, and calcium levels, as electrolyte disturbances from concurrent diuretic therapy (not dapagliflozin itself) commonly cause muscle symptoms in heart failure patients 1, 3.

• Evaluate statin use: If the patient is on statin therapy for cardiovascular disease (common in HFrEF), this is a far more likely cause of muscle aches than dapagliflozin 1.

• Consider worsening heart failure: Muscle fatigue and discomfort can reflect inadequate cardiac output or worsening heart failure rather than medication side effects 1.

Management Algorithm

If Volume Depletion is Present:

• Reduce loop diuretic dose if the patient is euvolemic or mildly volume depleted, as dapagliflozin enhances diuretic efficacy through complementary mechanisms 5, 3

• Ensure adequate hydration without overloading the patient 3

• Continue dapagliflozin as the benefits (26% reduction in cardiovascular death or HF hospitalization) far outweigh mild volume-related symptoms 1, 2

If Electrolyte Abnormalities are Present:

• Correct hypokalemia with potassium supplementation or dietary modification 1

• Replete magnesium if levels are low, as hypomagnesemia commonly causes muscle cramps and is often overlooked 1

• Do not discontinue dapagliflozin, as it does not cause significant electrolyte disturbances and actually has minimal effects on potassium levels 5, 3

If Statin-Related Myalgia is Suspected:

• Check creatine kinase (CK) levels to rule out statin-induced myopathy 1

• Consider switching to a lower-intensity statin or alternate-day dosing rather than discontinuing cardiovascular protection 1

• Maintain dapagliflozin as it provides critical mortality and morbidity benefits in HFrEF 1, 2

Critical Clinical Considerations

Do not discontinue dapagliflozin without compelling evidence of causation. The drug has demonstrated:

• 31% reduction in all-cause mortality in HFrEF patients 2
• 26% reduction in cardiovascular death or HF hospitalization regardless of diabetes status 1, 2
• Significant improvements in quality of life as measured by Kansas City Cardiomyopathy Questionnaire scores 1, 6

The safety profile of dapagliflozin is exceptionally favorable:

• Symptomatic hypotension occurs in only 0.3% of patients (vs 0.5% with placebo) 3
• No excess kidney adverse events despite use with ACE inhibitors/ARBs and mineralocorticoid receptor antagonists 5, 3
• Minimal blood pressure effects, particularly in patients with lower baseline blood pressure 3
• No significant effect on heart rate or potassium levels 5, 3

Alternative Explanations to Investigate

Before attributing muscle aches to dapagliflozin, systematically evaluate:

• Peripheral arterial disease: Common in HFrEF patients, causing leg pain with exertion 1
• Deconditioning: Heart failure patients often have reduced exercise capacity leading to muscle discomfort with activity 1
• Spinal stenosis or musculoskeletal disorders: Back pain may be unrelated to cardiac medications 1
• Hypothyroidism: Can cause both muscle aches and worsen heart failure 1
• Vitamin D deficiency: Associated with muscle pain and weakness 1

When to Consider Supervised Exercise Training

If muscle symptoms reflect deconditioning rather than medication side effects:

• The American College of Cardiology provides a Class 1 recommendation (Level A evidence) for exercise training in heart failure patients 1
• Supervised exercise training improves exercise capacity, symptoms, and quality of life in HFrEF 1
• This addresses the underlying functional impairment rather than unnecessarily discontinuing life-saving therapy 1

Bottom Line

Muscle aches are not a recognized adverse effect of dapagliflozin in rigorous clinical trials involving thousands of patients 1, 2, 3, 6, 4. The overwhelming evidence supports continuing dapagliflozin while investigating alternative causes of muscle symptoms, including volume status, electrolyte abnormalities, concurrent statin therapy, and underlying musculoskeletal or vascular conditions. Discontinuing dapagliflozin without clear causation deprives the patient of proven mortality and morbidity benefits 1, 2, 3.