From the Guidelines
The combination of saxagliptin (DPP-4 inhibitor) and dapagliflozin (SGLT2 inhibitor) with gliclazide (sulfonylurea) requires careful monitoring due to an increased risk of hypoglycemia, as noted in the 2018 consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) 1. When using these medications together, consider reducing the gliclazide dose by 25-50% initially (e.g., from 80mg to 40-60mg daily) and adjust based on blood glucose monitoring.
- Patients should be educated to recognize hypoglycemia symptoms (shakiness, sweating, confusion) and instructed to carry fast-acting carbohydrates.
- The hypoglycemia risk occurs because these medications lower blood glucose through different mechanisms: gliclazide stimulates insulin secretion regardless of glucose levels, while saxagliptin enhances glucose-dependent insulin release and dapagliflozin increases urinary glucose excretion.
- This triple therapy can be effective for patients with inadequately controlled type 2 diabetes, but requires regular monitoring of renal function, as both saxagliptin and dapagliflozin require dose adjustments in kidney impairment, as highlighted in the 2021 synopsis of the 2020 KDIGO clinical practice guideline 1. Additionally, patients should be monitored for other potential side effects including:
- Urinary tract infections
- Genital mycotic infections
- Rare cases of pancreatitis, as reported in the 2019 scientific statement from the American Heart Association and the Heart Failure Society of America 1.
From the FDA Drug Label
7 DRUG INTERACTIONS
Table 4: Clinically Relevant Interactions with DAPAGLIFLOZIN TABLETS Insulin or Insulin Secretagogues Clinical Impact The risk of hypoglycemia may be increased when DAPAGLIFLOZIN TABLETS are used concomitantly with insulin or insulin secretagogues (e.g., sulfonylurea) [see Warnings and Precautions (5. 4)]. Intervention Concomitant use may require lower doses of insulin or the insulin secretagogue to reduce the risk of hypoglycemia.
The potential interactions between saxagliptin (DPP-4 inhibitor) plus dapagliflozin (SGLT2 inhibitor), with gliclazide (sulfonylurea) include an increased risk of hypoglycemia.
- To minimize this risk, a lower dose of gliclazide may be required when used in combination with dapagliflozin.
- Monitor patients for signs and symptoms of hypoglycemia.
- Adjust the dose of gliclazide as needed to reduce the risk of hypoglycemia 2.
From the Research
Potential Interactions between Saxagliptin plus Dapagliflozin and Gliclazide
The potential interactions between saxagliptin (a DPP-4 inhibitor) plus dapagliflozin (an SGLT2 inhibitor) and gliclazide (a sulfonylurea) can be understood by examining the effects of these medications on glucose control and their potential synergies or adverse effects when used together.
- Mechanisms of Action:
- Saxagliptin works by inhibiting the enzyme DPP-4, which is responsible for the inactivation of incretin hormones, thereby increasing the levels of incretin hormones and enhancing the release of insulin when glucose is elevated 3.
- Dapagliflozin inhibits the sodium-glucose cotransporter 2 (SGLT2) in the kidney, reducing glucose reabsorption and increasing glucose excretion in the urine, thus lowering blood glucose levels 3.
- Gliclazide, a sulfonylurea, stimulates insulin release from the pancreatic beta cells, which helps to lower blood glucose levels.
Efficacy and Safety of Combination Therapy
- Efficacy: The combination of saxagliptin and dapagliflozin has been shown to be effective in improving glycemic control in patients with type 2 diabetes. Studies have demonstrated that this combination can lead to significant reductions in HbA1c levels compared to monotherapy with either agent alone 4, 5.
- Safety: The combination of saxagliptin and dapagliflozin is generally well-tolerated, with a low risk of hypoglycemia, which is a significant advantage over sulfonylureas like gliclazide that can cause hypoglycemia due to their mechanism of action 4, 5, 6.
Considerations for Combination with Gliclazide
- Hypoglycemia Risk: When considering the addition of gliclazide to a regimen of saxagliptin plus dapagliflozin, the risk of hypoglycemia may increase due to the insulin-stimulating effect of gliclazide. However, the actual risk may be mitigated by the glucose-dependent nature of saxagliptin's action and the glucose-excreting effect of dapagliflozin.
- Glycemic Control: The combination of saxagliptin, dapagliflozin, and gliclazide could potentially offer enhanced glycemic control due to their complementary mechanisms of action. However, the evidence for this specific combination is limited, and careful monitoring of blood glucose levels and potential side effects is necessary.
Clinical Implications
- The decision to use saxagliptin plus dapagliflozin with gliclazide should be based on individual patient factors, including the degree of glycemic control, risk of hypoglycemia, and potential benefits of improved glycemic control versus the risks of increased hypoglycemia and other side effects 7.
- Continuous glucose monitoring and regular assessment of patient-reported outcomes can provide valuable insights into the effectiveness and tolerability of this combination therapy.
Given the current evidence, there is no direct study on the interaction between saxagliptin plus dapagliflozin and gliclazide. However, understanding the mechanisms of action and the efficacy and safety profiles of these medications can guide clinical decision-making. Further research is needed to fully elucidate the potential benefits and risks of this specific combination therapy 4, 3, 5, 6, 7.