Combination of SGLT2 inhibitors with metformin in terms of mechanism of action

Metformin

Metformin is the first-line drug in T2D therapy due to its proven efficacy, safety, and low cost. It belongs to the biguanides and suppresses glucose production in the liver while improving insulin sensitivity. In monotherapy, it leads to good glycaemic control (HbA_1c reduction of 1.12%), and it also improves endothelial dysfunction and hemostasis, reduces oxidative stress and insulin resistance, improves lipid profile, and redistributes fat. It is associated with minimal risk of hypoglycemia and is suitable for combination therapy.

Some patients may experience gastrointestinal intolerance with metformin, but this can usually be managed through gradual dose titration or the use of extended-release tablets. Metformin is contraindicated in chronic kidney disease patients with estimated glomerular filtration rate (eGFR) < 0.5 ml/s/1.73 m²; in patients with eGFR < 0.75 ml/s/1.73 m², metformin should not be newly initiated, and continuation of treatment should be reconsidered based on the benefit/risk ratio.

Gliflozins (SGLT2 inhibitors)

SGLT2 inhibitors reduce the reabsorption of glucose in the kidneys, thus lowering hyperglycemia. Normally, the kidney reabsorbs all filtered glucose; SGLT2 inhibitors reduce this reabsorption by 30–50%, excreting glucose via urine. A recent meta-analysis of 34 studies showed that SGLT2i therapy leads to an average reduction in HbA_1c by 0.69%, weight loss of 2.1 kg, and a decrease in systolic blood pressure by 3.9 mmHg. A significant finding came from the EMPA-REG OUTCOME study, which showed that empagliflozin significantly lowers CV mortality, overall mortality, and heart failure hospitalizations in T2D patients with CV disease. CV benefits were later found in other SGLT2 inhibitors. Compared to placebo, empagliflozin also reduces the risk of nephropathy progression, macroalbuminuria, doubling of serum creatinine, and the need for renal function replacement.

Due to their mechanism of action, SGLT2 inhibitors can be combined with any other class of antidiabetics or insulin at any disease stage, including patients with long-standing T2D and minimal insulin secretion. Fixed combinations are also available on the market.

SGLT2 inhibitors are well-tolerated and are associated with a low risk of hypoglycemia. Treatment may lead to genital mycotic infection, urinary tract infection, and symptoms of orthostatic hypotension or postural dizziness in susceptible individuals (elderly patients, those with kidney disease, or low blood pressure) due to osmotic diuresis and reduction of intravascular volume. The effect of SGLT2 inhibitors depends on kidney function, and they are not recommended for patients with eGFR < 0.75 ml/s/1.73 m² (empagliflozin, canagliflozin) and < 1 ml/s/1.73 m² (dapagliflozin).

Conclusion

A recently published meta-analysis of randomized controlled trials comparing metformin monotherapy with a combination of metformin and SGLT2 inhibitors showed that combination therapy is more effective in reducing HbA_1c and body weight. Several studies have concluded that SGLT2 inhibitors, due to their innovative mechanism of action, not only benefit glycemic and weight reduction but also provide renoprotection and cardiovascular safety in T2D treatment.

(epa)

Sources:
1. Molugulu N., Yee L. S., Ye Y. T. et al. Systematic review of metformin monotherapy and dual therapy with sodium glucose co-transporter 2 inhibitor (SGLT-2) in treatment of type 2 diabetes mellitus. Diabetes Res Clin Pract 2017 Jul 25, pii: S0168-8227(17)30827-6, doi: 10.1016/j.diabres.2017.07.025 [Epub ahead of print].
2. Thrasher J. Pharmacologic management of type 2 diabetes mellitus: available therapies. Am J Cardiol 2017 Jul 1; 120 (1S): S4−S16, doi: 10.1016/j.amjcard.2017.05.009.