Summary:
In individuals with type 2 diabetes (T2D), combined treatment with Empagliflozin and Linagliptin significantly improved glycemic control and restored a healthy urinary microbiota compared to Empagliflozin alone or healthy controls, though it was associated with fewer incidences of urinary dysbiosis and potential infection-related side effects.
| PICO | Description |
|---|---|
| Population | Adults with type 2 diabetes (T2D); 30 participants recruited for a 12-week open-label randomized study. Fifteen additional healthy individuals served as baseline controls. |
| Intervention | Combined therapy of Empagliflozin and Linagliptin administered over a 12-week period with evaluation of clinical markers and urinary microbiota via RT-qPCR and 16S rRNA sequencing. |
| Comparison | Empagliflozin alone in T2D subjects and healthy controls not receiving any treatment. |
| Outcome | The combination therapy led to significant improvements in fasting glucose and HbA1c levels, reduced BMI, and restored urinary microbiota composition similar to healthy controls. In contrast, Empagliflozin alone increased total bacterial load and specific pathogens (e.g., Bacillota, Aerococcus), suggesting a possible risk for urinary infections. Combination therapy reduced the prevalence of potential uropathogens and may improve long-term treatment compliance. |
Clinical Context
Type 2 diabetes management increasingly involves combination therapy with SGLT2 inhibitors and DPP-4 inhibitors to achieve glycemic targets. However, SGLT2 inhibitors’ mechanism of increasing urinary glucose excretion raises concerns about urinary tract infections. The urinary microbiota, an emerging area of research, may mediate this infection risk. While SGLT2 inhibitors alone can disrupt urinary bacterial balance by creating a glucose-rich environment favorable to pathogen growth, the addition of DPP-4 inhibitors might modify this effect through immunomodulatory properties and metabolic improvements. This 12-week randomized study investigated whether combining empagliflozin with linagliptin could restore healthy urinary microbiota composition while maintaining glycemic benefits. Understanding these microbiome effects has implications for patient selection, monitoring strategies, and potentially explaining variable UTI rates seen in clinical practice with SGLT2 inhibitor use.
Clinical Pearls
- Microbiota Restoration: Dual therapy with SGLT2i plus DPP-4i restored urinary microbiota composition to patterns similar to healthy controls, potentially reducing UTI risk that concerns some clinicians.
- Pathogen Reduction: While empagliflozin alone increased uropathogens like Bacillota and Aerococcus, adding linagliptin reduced these potential infection-causing bacteria.
- Metabolic Benefits: The combination improved HbA1c, fasting glucose, and BMI more effectively than SGLT2i monotherapy, supporting guideline recommendations for dual therapy.
- Treatment Adherence: Reduced UTI concerns with combination therapy may improve long-term medication adherence in patients worried about genitourinary infections.
Practical Application
Clinicians prescribing empagliflozin for diabetes management should strongly consider adding a DPP-4 inhibitor like linagliptin, particularly in patients concerned about UTI risk or those with a history of recurrent urinary infections. This combination not only enhances glycemic control but may protect against urinary dysbiosis. For patients on SGLT2 inhibitor monotherapy experiencing recurrent UTIs, adding a DPP-4 inhibitor represents a rational strategy based on this microbiome data. Patient education should emphasize that while SGLT2 inhibitors alone may increase bacterial load, combination therapy mitigates this concern. Monitor for UTI symptoms during the first 12 weeks, though combination therapy appears protective. The metabolic and microbiome benefits support combination therapy as a preferred strategy over SGLT2i monotherapy in appropriate candidates without contraindications to DPP-4 inhibitors.
Broader Evidence Context
This study adds novel microbiome data to the extensive literature on SGLT2i/DPP-4i combination therapy. Previous cardiovascular and renal outcome trials have established benefits of SGLT2 inhibitors, while concerns about UTI risk have tempered enthusiasm in some patients and providers. DPP-4 inhibitors have demonstrated immune-modulating effects beyond glucose lowering, which may explain the microbiome normalization seen here. This research suggests UTI risk with SGLT2 inhibitors may be mechanistically linked to urinary dysbiosis rather than glucose alone. Other studies have shown variable UTI rates with different SGLT2 inhibitors, potentially explainable by concurrent medication use. The microbiome approach represents a novel biomarker for monitoring diabetes medication effects and personalizing therapy.
Study Limitations
- Small sample size (n=30 T2D participants) limits statistical power and generalizability of microbiome findings.
- Open-label design without placebo control introduces potential bias in subjective assessments and adherence.
- Twelve-week duration may be insufficient to assess long-term microbiome stability and clinical UTI rates.
- Study doesn’t report actual UTI incidence rates, only microbiome composition changes as a surrogate marker.
- Limited to empagliflozin and linagliptin; other SGLT2i/DPP-4i combinations may show different microbiome effects.
- Microbiome analysis methods (RT-qPCR and 16S rRNA sequencing) provide compositional but not functional data.
Bottom Line
For patients with type 2 diabetes, combining empagliflozin with linagliptin not only improves glycemic control and BMI but also restores healthy urinary microbiota composition, potentially reducing infection risk compared to SGLT2 inhibitor monotherapy. This dual therapy strategy addresses both metabolic goals and urinary microbiome health, supporting combination use especially in patients concerned about UTI complications.
Source: Marco Calvigioni, et al. “Effect of SGLT2 Inhibitors + DPP-4 Inhibitors on Urine Microbiota in Type 2 Diabetes.” Read article here.
