Safety and efficacy of dapagliflozin versus empagliflozin as add-on therapy in type 2 diabetes mellitus management

INTRODUCTION

Type 2 diabetes mellitus (T2DM), the highly prevalent form of diabetes, makes up more than 90% of all cases. Its defining traits include insulin resistance in tissues, inadequate compensatory insulin release and insufficient synthesis of insulin by pancreatic islet β-cells.^[1] The increasing rates of obesity, sedentary lifestyles, high-calorie diets and ageing populations are contributing to the global increase in the incidence of T2DM. This has led to a four-fold increase in T2DM incidence and prevalence, posing a significant public health concern.^[2]

Injectable therapy such as insulin, oral antidiabetic drugs, lifestyle modifications and more recent pharmacological medicines are all part of the multimodal approach that is the current standard of care for T2DM. By increasing insulin sensitivity and glycaemic control, lifestyle adjustments, including controlling weight, getting regular exercise and eating differently, are essential for the management of type 2 diabetes.^[3]

Various oral antidiabetic drugs, such as metformin, sulfonylureas, sodium-glucose cotransporter 2 (SGLT-2) inhibitors and dipeptidyl peptidase 4 (DPP-4) inhibitors, among others, are frequently recommended to maintain blood sugar within target ranges.

SGLT-2 inhibitors, including dapagliflozin and empagliflozin, were approved by the Food and Drug Administration (FDA) in 2014 to help improve glycaemic control in adults with T2DM when used alongside diet and exercise. These medications can be used alone or with other antidiabetic drugs. Dapagliflozin and empagliflozin increase the urine excretion of glucose through SGLT-2 inhibition in the kidneys, thereby decreasing blood glucose levels. These medications provide additional treatment options for individuals with T2DM.^[4,5] These medications work by preventing glucose reabsorption in the kidney’s proximal renal tubule epithelial cells, which lowers blood glucose and glycated haemoglobin levels. Research has demonstrated that dapagliflozin lowers the chance of a lupus flare in randomised controlled trials.^[6] In T2DM patients, dapagliflozin and empagliflozin have both shown a considerable decrease in cardiovascular events. SGLT-2 inhibitors have been shown to be nephroprotective in non-diabetic chronic kidney disease. This makes them appealing candidates for treating patients with systemic lupus erythematosus, particularly those with lupus nephritis.^[6]

SGLT-2 inhibitors have been demonstrated to have direct and indirect physiological mechanisms that support their nephroprotective and cardiovascular protective effects in addition to their glucose-lowering actions. These include lowering lipotoxicity, raising insulin sensitivity, enhancing lipid metabolism, lowering intraglomerular pressure and lowering kidney hypoxia. Moreover, mild osmotic diuretic effects have been connected to SGLT-2 inhibitors, which may help lower blood pressure. Since this impact is distinct from insulin, it can be administered to people with different levels of insulin resistance or β-cell activity. As a result, SGLT-2 inhibitors become a highly flexible therapeutic option that can be used to treat comorbidities like hypertension in addition to controlling hyperglycaemia. This allows patients with T2DM and its associated cardiovascular risk factors to receive comprehensive care.^[7] This study aimed to assess the efficacy and the safety of drugs SGLT-2 inhibitors (dapagliflozin and empagliflozin) when combined with existing treatments such as DPP-4 inhibitors, biguanides and sulfonylureas in T2DM patients.

MATERIALS AND METHODS

Our prospective observational study was conducted at PSG Hospital in Coimbatore, spanning 9 months from July 2021 to March 2022. The research focused on patients with T2DM who were prescribed dapagliflozin and empagliflozin in addition to other classes of anti-diabetic medications to manage their condition. The study received approval from the Institutional Human Ethics Committee (IHEC, PSG IMSR) under proposal number PSG/IHEC/2021/Appr/Exp/159, dated 2 July 2021, and adhered strictly to the principles outlined in the Declaration of Helsinki.

RESULTS

The study’s initial recruitment of 109 participants was determined by the inclusion and exclusion criteria. Of these, nine patients were excluded due to incomplete follow-up data, leaving 100 patients included in the study. The demographic breakdown included 56 males and 44 females, with an average age of study participants found to be 54 years. The age group of 51–60 years was the most prevalent among the patients, representing a significant portion of the study population. Of these, 73% of the participants were elderly. Out of 50 patients, 25 males and 25 females made up Group A and 31 men and 19 women made up Group B. In both groups, the patient’s age category 51–60 is more predominant than other age groups. In Group A, 78% of patients have hypertension, while in Group B is 60%. The number of patients taking other anti-diabetic medications is shown in Table 1.

After 6 months, the effectiveness of treatments in Group A and Group B was evaluated. Both groups showed notable decreases in body weight, with mean reductions of 3.14 kg in Group A and 2.29 kg in Group B compared to baseline. However, the difference was not statistically significant (P = 0.385). Similarly, reductions in BMI were observed in both groups, with mean differences of 0.65 kg/m² in Group A and 0.84 kg/m² in Group B. When comparing body weight and BMI levels between the two groups, the differences were not significant. Both drugs were equally effective in reducing body weight as well as BMI.

After 6 months of treatment, both Group A and Group B experienced significant reductions in HbA1c, FBS and PPBS levels. In Group A, the mean reductions in HbA1c were 0.36%, whereas in Group B, they were 0.55%. Empagliflozin demonstrated a more pronounced decrease in HbA1c compared to dapagliflozin. For FBS, the reductions were 19.6 mg/dL in Group A and 17.4 mg/dL in Group B, and for PPBS, the reductions were 10.93 mg/dL in Group A and 21.9 mg/dL in Group B. However, the difference in FBS and PPBS was not statistically significant between the groups, indicating both medications were equally effective in lowering these parameters.

Furthermore, significant reductions in SBP were seen in hypertensive patients in both groups from the beginning to the end of the 6-month period. Dapagliflozin showed a greater reduction in SBP of 10.26 mmHg compared to 4.2 mmHg with empagliflozin. In addition, dapagliflozin increases DBP by 2.25 mmHg, while empagliflozin reduces DBP by 3.61 mmHg. While both groups experienced reductions in SBP, only the group using empagliflozin showed a significant reduction in DBP. In non-hypertensive, we observe that SBP shows reduction in both groups. Dapagliflozin showed a greater reduction in SBP of 3.22 mmHg compared to 1.47 mmHg with empagliflozin. In addition, dapagliflozin increases DBP by 5.83 mmHg, while empagliflozin reduces DBP by 4.63 mmHg, empagliflozin showed a significant reduction in DBP as illustrated in Table 2. In addition, large sample sizes need to be proven for the non-hypertensive patients.

Over the 6-month study duration, cardiovascular risk assessment was done using the Framingham risk score, revealing notable decreases in mean differences in both Group A (1.08%) and Group B (2.17%). However, the difference was not statistically significant (P = 0.225), indicating that dapagliflozin and empagliflozin had similar effects in preventing cardiovascular diseases, as depicted in Table 3.

After 6 months of treatment, differences in the occurrence of adverse events between Group A and Group B were not significant. Both medications demonstrated similar safety profiles, with only mild-to-moderate adverse events and no severe adverse were reported during the study. The most observed adverse events were urinary tract infections (UTIs) and hypoglycaemia. In Group A, UTIs were observed in 18% of patients, compared to 12% in Group B. Hypoglycaemia occurred in 24% of Group A participants and 20% in Group B participants, as indicated in Table 4.

DISCUSSION

We found that treatment with dapagliflozin and empagliflozin led to significant reductions in body weight and BMI in patients diagnosed with T2DM. This outcome is similar to the findings of a study conducted on the Italian population by Mirabelli et al.,^[8] which investigated the long-term effectiveness and safety of SGLT-2 inhibitors. This suggests that treatment with SGLT-2 inhibitors directly induces weight loss by excreting glucose (or) calories through the kidneys.

Regarding glycaemic control, significant reductions were noted in HbA1c, FBS and PPBS levels in both groups. Empagliflozin led to a more significant reduction in HbA1c compared to dapagliflozin. When comparing FBS and PPBS levels between the two groups, the differences were not significant. These findings align with a study conducted in China by Lee et al.^[9]

In addition to decreasing blood sugar, these drugs also function as osmotic diuretics, which help people with type 2 diabetes decrease their blood pressure. Our findings also align with previously reported meta-analysis by Li et al.^[10] which assessed both short-term and long-term effectiveness of SGLT-2 inhibitors, whether used alone or in combination with other therapies. Both patients with hypertension and those without hypertension experienced a decrease in SBP when treated with dapagliflozin, while DBP increased in both groups. These findings are consistent with a study conducted by Sjöström et al.,^[11] which reported significant reductions in both SBP and DBP among patients treated with dapagliflozin, irrespective of hypertension status.

We noted decreases in SBP, DBP and cardiovascular risk among T2DM patients treated with empagliflozin and dapagliflozin. These results align with a meta-analysis study. Treatment with empagliflozin led to decreases in SBP, DBP and cardiovascular risk, consistent with findings from the EMPA-REG trials and the DECLARE-TIM 58) trial conducted by Imprialos et al.^[12] Their study showed that SGLT-2 inhibitors improved cardiovascular morbidity and mortality and decreased risk of cardiovascular death and hospitalisation.

Both empagliflozin and dapagliflozin were well tolerated in terms of adverse effects, with mild cases of hypoglycaemia and UTIs observed regardless of the treatment group. Other similar adverse events were noted in both groups, including nausea reported by some patients. These findings are consistent with those of a study conducted by Ku et al.^[13]

CONCLUSION

SGLT-2 inhibitors dapagliflozin and empagliflozin have favourable efficacy and safety in management of T2DM. Both drugs show equal effects in reducing HbA1c level when added to oral antihyperglycemic agents. Empagliflozin has the upper hand in reducing HbA1c level when compared to dapagliflozin. Furthermore, both dapagliflozin and empagliflozin resulted in significant reductions in the FBS and PPBS levels and decreased the body weight and BMI. In both hypertensive and non-hypertensive patients, dapagliflozin exhibited greater systolic blood pressure reduction compared to empagliflozin, whereas empagliflozin exhibited greater reduction in diastolic blood pressure compared to dapagliflozin. In contrast, dapagliflozin has shown to increase DBP. Further, investigation is required to explore the blood pressure effects of SGLT-2 inhibitors in a large population.

Both medications exhibited favourable safety profiles, with fewer instances of hypoglycaemic episodes and UTIs. In addition, in patients with T2DM, using the Framingham risk score, these drugs show decreases in cardiovascular risk. The safety and efficacy profile of dapagliflozin and empagliflozin establish them a suitable add-on therapy with conventional oral hypoglycaemic agents for T2DM patients.