Do Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitors cause orthostatic hypotension?

From the Guidelines

SGLT2 inhibitors are associated with an increased risk of orthostatic hypotension, particularly when used in combination with diuretics and/or ACE inhibitors and angiotensin receptor blockers, as reported in the 2018 consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) 1.

Key Considerations

• The risk of orthostatic hypotension is higher in patients with kidney dysfunction, elderly patients, and those taking diuretics or blood pressure medications.
• SGLT2 inhibitors work by increasing glucose excretion through the kidneys, leading to osmotic diuresis and volume depletion, which can result in a drop in blood pressure when standing up.
• To minimize this risk, patients should be advised to stay adequately hydrated, rise slowly from sitting or lying positions, and monitor for symptoms of hypotension.

Management Strategies

• Healthcare providers may consider starting with lower doses in at-risk patients and gradually titrating up as tolerated.
• Blood pressure should be monitored regularly, especially during the first few weeks of treatment.
• If orthostatic hypotension becomes problematic, dose adjustment of the SGLT2 inhibitor or concurrent antihypertensive medications may be necessary.

Important Safety Information

• The 2018 ADA and EASD consensus report notes that SGLT2 inhibitors have been associated with an increased risk of acute kidney injury, dehydration, and orthostatic hypotension 1.
• Canagliflozin has been associated with an increased risk of lower-limb amputation and fracture, although it is uncertain whether these are class effects 1.

From the FDA Drug Label

INVOKANA results in an osmotic diuresis, which may lead to reductions in intravascular volume. In clinical trials for glycemic control, treatment with INVOKANA was associated with a dose-dependent increase in the incidence of volume depletion-related adverse reactions (e.g., hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration).

Table 5: Proportion of Adult Patients with at Least One Volume Depletion-Related Adverse Reaction (Pooled Results from 8 Clinical Trials for Glycemic Control) ... Overall population 1.5% 2.3% 3.4% ... Volume depletion-related adverse reactions include: hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration.

SGLT2 inhibitors, such as canagliflozin, may cause orthostatic hypotension due to their mechanism of action, which leads to reductions in intravascular volume. The incidence of orthostatic hypotension and other volume depletion-related adverse reactions was dose-dependent and increased with the use of loop diuretics, moderate renal impairment, and age 75 years and older 2.

From the Research

SGLT2 Inhibitors and Orthostatic Hypotension

• The relationship between Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitors and orthostatic hypotension has been investigated in several studies 3, 4, 5, 6.
• A systematic review and meta-analysis of 27 randomized controlled trials found that SGLT2 inhibitors had no significant effect on the incidence of orthostatic hypotension (P > 0.05) 3.
• Another study found that SGLT2 inhibitors are generally well-tolerated, but caution is recommended in the elderly population due to a higher risk of renal impairment, orthostatic hypotension, and dehydration 4.
• A meta-analysis of 16 studies found that SGLT2 inhibitors did not increase the risk of orthostatic hypotension in patients with type 2 diabetes mellitus, with a pooled risk ratio of 1.17 (95% CI: 0.65-2.09) 6.
• The blood pressure lowering effect of SGLT2 inhibitors appears to be a dose-independent class-effect, with a magnitude of effect comparable to that seen with a low dose hydrochlorothiazide 5.

Clinical Evidence and Mechanisms

• The mechanisms of action of SGLT2 inhibitors on blood pressure are not fully understood, but may involve the reduction of renal sodium and glucose reabsorption, leading to increased urinary glucose excretion and a decrease in blood pressure 3, 5.
• SGLT2 inhibitors have been shown to reduce blood pressure in patients with type 2 diabetes mellitus, chronic kidney disease, and resistant hypertension 5.
• The risk of orthostatic hypotension should be considered on an individual basis, especially in patients with a history of orthostatic hypotension, long duration of type 2 diabetes mellitus, or comorbidities 6.

Comparison with Other Studies

• A study on antidepressant drugs found that some medications, such as serotonin-norepinephrine reuptake inhibitors and tricyclic antidepressants, can increase the risk of orthostatic hypotension, but this is not directly related to SGLT2 inhibitors 7.