Clinical Context
SGLT2 inhibitors like canagliflozin are cornerstone medications for type 2 diabetes, providing glycemic control alongside cardiovascular and renal protection. However, their mechanism—promoting glucose excretion in urine with obligate water loss—leads to volume contraction and hemoconcentration. This can increase hematocrit, potentially exacerbating pre-existing erythrocytosis and raising blood viscosity.
Erythrocytosis (elevated red blood cell mass, manifesting as high hemoglobin and hematocrit) is associated with increased blood viscosity and thrombotic risk. Causes include polycythemia vera, secondary erythrocytosis from chronic hypoxia (OSA, COPD, altitude), testosterone therapy, and other conditions. In men, testosterone-related erythrocytosis is particularly common, as androgen therapy increases erythropoietin-mediated red cell production.
The CANVAS program established canagliflozin’s cardiovascular benefit in high-risk diabetics. However, subgroup analyses may reveal differential effects in specific populations. This post-hoc analysis examined whether men with baseline erythrocytosis—already at elevated thrombotic risk due to high blood viscosity—experience increased thromboembolic events with canagliflozin’s hemoconcentrating effect.
Study Summary (PICO Framework)
Summary:
In males with erythrocytosis in the CANVAS program, canagliflozin significantly increased thromboembolic events compared to placebo, though no increased risk was observed in females.
| PICO | Description |
|---|---|
| Population | Males with erythrocytosis and CV risk from CANVAS program. |
| Intervention | Canagliflozin (SGLT2 inhibitor). |
| Comparison | Placebo. |
| Outcome | Increased thromboembolic events in males with erythrocytosis. No increase in females. |
Canagliflozin, erythrocytosis & thrombotic risk
Post-hoc analysis · CANVAS + CREDENCE · T2D
In males with erythrocytosis, baseline hematocrit modified canagliflozin's effect on the MI/stroke/thromboembolism composite (P interaction < 0.05), with harm driven by myocardial infarction. No such signal was seen in females, and the overall program risk was unchanged.
Clinical Pearls
1. SGLT2 inhibitor hemoconcentration can compound erythrocytosis-related thrombotic risk. SGLT2 inhibitors increase hematocrit by 2-4% through volume contraction. In patients already at the upper limits of normal hematocrit (or frankly polycythemic), this additional increase may push viscosity into ranges that promote thrombosis. The mechanism is biologically plausible and consistent with the observed signal.
2. Sex difference suggests testosterone-related erythrocytosis may be the vulnerable subgroup. Males have higher baseline hematocrit than females, and testosterone-driven erythrocytosis is male-specific (whether endogenous or from testosterone replacement therapy). The absence of signal in females supports that the risk relates to higher baseline erythrocytosis rather than a general drug effect on coagulation.
3. This doesn’t mean canagliflozin is contraindicated in all men—risk stratification is key. The CANVAS program overall showed cardiovascular benefit with canagliflozin. This subgroup analysis identifies a specific population (men with erythrocytosis) that may not share the favorable risk-benefit profile. Most diabetic men have normal hematocrit and should continue benefiting from SGLT2 inhibitors.
4. Check hematocrit before initiating SGLT2 inhibitors and periodically thereafter. Baseline erythrocytosis is identifiable with a simple CBC. For men with elevated hematocrit (particularly >50%), the risk-benefit of SGLT2 inhibitors should be carefully considered. Monitoring hematocrit during treatment allows detection of concerning increases.
Practical Application
Screen for erythrocytosis before starting SGLT2 inhibitors in men: Check a CBC before initiating canagliflozin (or other SGLT2 inhibitors) in male patients. If hematocrit is elevated (>50% or institution-specific upper limit), investigate the cause (OSA, COPD, testosterone therapy, polycythemia vera) and consider whether the benefit-risk of SGLT2 inhibitors favors use.
Be especially cautious in men on testosterone therapy: Testosterone replacement commonly causes erythrocytosis, and men on TRT who also have diabetes are at particular risk. Coordinate with the prescribing provider to monitor hematocrit and consider dose reduction or alternative diabetes medications if erythrocytosis is significant.
Consider alternative agents for diabetics with significant erythrocytosis: GLP-1 receptor agonists provide similar cardiovascular and metabolic benefits to SGLT2 inhibitors without hemoconcentrating effects. For male patients with erythrocytosis where diabetes medication choice is being made, GLP-1 agonists may be preferable. If SGLT2 inhibitors are used, closer monitoring is warranted.
Educate patients about hydration: For men with borderline erythrocytosis who are started on SGLT2 inhibitors, counsel about adequate hydration to mitigate volume contraction. While this won’t eliminate the risk, severe dehydration compounds hemoconcentration and should be avoided.
How This Study Fits Into the Broader Evidence
SGLT2 inhibitor cardiovascular outcome trials (CANVAS, EMPA-REG, DECLARE-TIMI 58) consistently showed overall cardiovascular benefit. However, subgroup analyses have identified specific risks: amputation signal with canagliflozin (possibly related to volume depletion and peripheral perfusion), Fournier’s gangrene, and diabetic ketoacidosis. This erythrocytosis-thrombosis signal adds to the safety profile understanding.
The hematocrit-raising effect of SGLT2 inhibitors has been documented in clinical trials and is considered mechanism-based (volume contraction concentrates red cells). Whether this contributes to benefit (some have speculated hemoconcentration improves tissue oxygenation) or harm (increased viscosity and thrombosis) may depend on baseline hematocrit.
Erythrocytosis from testosterone therapy is increasingly recognized, with guidelines recommending hematocrit monitoring during testosterone replacement. This study adds SGLT2 inhibitor use to the list of considerations for men with testosterone-induced or other causes of erythrocytosis.
Limitations to Consider
This is a post-hoc subgroup analysis, not a prespecified endpoint. Subgroups with erythrocytosis were likely small, limiting statistical power and increasing risk of chance findings. Definition of “erythrocytosis” (specific hematocrit cutoffs) affects which patients are captured. The mechanism is presumed but not proven. Whether findings apply to other SGLT2 inhibitors (empagliflozin, dapagliflozin) is unknown—though the mechanism would be shared.
Bottom Line
In this post-hoc analysis of the CANVAS program, canagliflozin significantly increased thromboembolic events in males with erythrocytosis compared to placebo, while no increased risk was observed in females. The mechanism likely involves SGLT2 inhibitor-induced hemoconcentration exacerbating pre-existing high blood viscosity. For male diabetic patients with elevated hematocrit—particularly those on testosterone therapy or with secondary erythrocytosis—exercise caution with SGLT2 inhibitors, consider alternative agents like GLP-1 agonists, and monitor hematocrit if these drugs are used. This doesn’t change the favorable benefit-risk profile for most diabetic patients, but identifies a subgroup requiring individualized assessment.
Source: Yohei Doi, et al. “Canagliflozin may increase thromboembolic events in males with erythrocytosis but not in females.” Read article here.