From the Guidelines
Yes, SGLT2 inhibitors can be given with metformin and gliptins (DPP-4 inhibitors) for type 2 diabetes management, particularly for patients with chronic kidney disease (CKD) and eGFR ≥30 ml/min per 1.73 m2, as recommended by the KDIGO 2022 clinical practice guideline 1.
Key Considerations
- The combination of SGLT2 inhibitors, metformin, and gliptins works through complementary mechanisms to provide additive glucose-lowering effects without significantly increasing hypoglycemia risk.
- SGLT2 inhibitors promote urinary glucose excretion independent of insulin, while metformin reduces hepatic glucose production and improves insulin sensitivity, and gliptins increase insulin secretion and decrease glucagon by prolonging the action of incretin hormones.
- Common SGLT2 inhibitors include empagliflozin, dapagliflozin, and canagliflozin, which are usually started at their lowest dose and can be titrated based on response.
- Patients should be monitored for potential side effects including urinary tract infections, genital mycotic infections, and volume depletion from SGLT2 inhibitors.
Benefits and Harms
- The combination may also offer cardiovascular and renal benefits beyond glycemic control, particularly in high-risk patients, as suggested by the KDIGO 2022 guideline 1.
- However, the benefits and harms of additional pharmacologic treatment beyond the initial add-on treatment are unknown, and clinical evidence on patient mortality, morbidity, and hospitalizations and economic evidence are lacking for use of SGLT-2 inhibitors and GLP-1 agonists as initial treatment for patients with type 2 diabetes, as noted in the Annals of Internal Medicine study 1.
Clinical Decision-Making
- The decision to use SGLT2 inhibitors with metformin and gliptins should be based on individual patient needs and characteristics, including the presence of CKD and eGFR level, as well as the potential benefits and harms of the combination.
- Clinicians should carefully monitor patients for potential side effects and adjust the treatment regimen as needed to optimize glycemic control and minimize adverse effects.
From the FDA Drug Label
Add-on Combination Therapy with Metformin HCl plus an SGLT2 Inhibitor A total of 315 patients with type 2 diabetes mellitus participated in this 24-week randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of saxagliptin added to dapagliflozin (an SGLT2 inhibitor) and metformin HCl in patients with a baseline of HbA1c ≥7% to ≤10. 5%. The group treated with add-on saxagliptin had statistically significant greater reductions in HbA1c from baseline versus the group treated with placebo
- Key Points:
- Saxagliptin can be given with metformin and an SGLT2 inhibitor.
- The combination of saxagliptin, metformin, and an SGLT2 inhibitor provided significant improvements in HbA1c.
- Clinical Decision: It is possible to give SGLT2 with metformin and gliptin, as evidenced by the trial with saxagliptin, metformin, and dapagliflozin 2.
From the Research
Combination Therapy with SGLT2 Inhibitors and Metformin
- The combination of SGLT2 inhibitors and metformin has been shown to be effective in improving glycemic control with a low risk of hypoglycemia 3, 4.
- Studies have demonstrated that this dual therapy is more effective in reducing HbA1c and body weight compared to metformin monotherapy 4.
- The FDA has approved fixed-dose combination tablets with SGLT2 inhibitors (canagliflozin, dapagliflozin, and empagliflozin) and metformin 3.
Addition of Gliptin to Combination Therapy
- There is limited direct evidence on the use of SGLT2 inhibitors with metformin and gliptin.
- However, SGLT2 inhibitors have been shown to be effective in combination with other glucose-lowering agents, including dipeptidyl peptidase 4 (DPP-4) inhibitors, which are similar to gliptin 5.
- The use of SGLT2 inhibitors in combination with other agents, including gliptin, requires careful consideration of the potential risks and benefits, including the risk of metabolic acidosis and other adverse effects 3, 5.
Efficacy and Safety of SGLT2 Inhibitors
- SGLT2 inhibitors have been shown to be effective in reducing glycated hemoglobin, with a minimal risk of hypoglycemia 6.
- They also have additional benefits, including significant reductions in body weight and blood pressure 6.
- However, caution is recommended in fragile elderly patients and patients with chronic kidney disease, and there is an increased risk of genital mycotic infections and euglycemic ketoacidosis 6, 7.