Effects on Metabolic Parameters of Addition of SGLT‐2 Inhibitors on Patients with Type2 Diabetes Inadequately Controlled with DPP‐IV Inhibitors and Metformin

Introduction

It has been seen that modest and sustained weight loss improves glycaemic control and reduces the need for glucose-lowering medications in overweight and obese patients with T2DM [1, 2, 3]. Because the pathogenesis of T2DM is complex and involves multiple metabolic defects, the use of combination therapy with antidiabetic drugs with different mechanisms of action has the advantage of combining complementary mechanisms and has the potential of producing an additive reduction in HbA1c [4].

DPP-4 inhibitors and SGLT-2 inhibitors exert their glucose-lowering effects via different and complementary mechanisms. DPP-4 inhibitors prevent the enzymatic degradation of endogenous incretin hormones (active glucagon-like peptide [GLP]-1 and glucose-dependent insulinotropic polypeptide [GIP]) [5, 6]. Increased plasma concentrations of GLP-1 and GIP stimulate insulin secretion from pancreatic β-cells and inhibit glucagon secretion from pancreatic α-cells, which causes inhibition of endogenous glucose production and a reduction in plasma glucose concentration [7]. SGLT-2 inhibitors reduce the plasma glucose concentration by inhibiting renal glucose reabsorption and producing glucosuria [8]. Metformin and SGLT2 inhibitors are agents associated with weight loss whereas DPP4 inhibitors appear to be weight neutral. When one single pharmacological class does not reach HbA1c target as monotherapy or even when added to metformin, a combination of a DPP-4 inhibitors and a SGLT-2 inhibitors could be helpful with a low risk of adverse events, such as hypoglycaemia or weight gain and the potential advantage of cardiovascular protection [9, 10, 11].

However Indian data regarding combination therapy with metformin withDPP‐4 inhibitors plus SGLT‐2 inhibitors are scanty. In this study we present data Chatterjee S, et al. Effects on Metabolic Parameters of Addition of SGLT‐2 Inhibitors on Patients with Type2 Diabetes Inadequately Controlled with DPP‐IV Inhibitors and Metformin. Diabetes Obes Int J 2019, 4(2): 000201.

regarding the glycaemic and other metabolic parameters after treatment with SGLT‐2 inhibitors-canagliflozin or dapagliflozin or empagliflozin in type 2 DM patient inadequately controlled (HbA1c >7.5%) with DPP‐4 inhibitors plus metformin.

Results

Table 1 shows the baseline characteristics of the study subjects (n=101). The mean age of the patient was 47.76 years, mean height 162 meters, mean weight and body mass index (BMI) 81.48 kgs and 30.72kg/m2 respectively. The mean systolic and diastolic blood pressures (SBP and DBP) were 131.21 and 79.5 mm of mercury. Mean FBG and PPBG level were 155.55 and 220.33 mg/dl respectively and HbA1c was maintained at 8.17. Obesity was the commonest comorbidity (72.27%) among the study group followed by dyslipidaemia (70.29%), hypertension (63.36%), micro-albuminuria (22.77%), hypothyroidism (20.79%), coronary heart disease (12.87%), fatty liver (11.88%), nephropathy (1.98%).

Chatterjee S, et al. Effects on Metabolic Parameters of Addition of SGLT‐2 Inhibitors on Patients with Type2 Diabetes Inadequately Controlled with DPP‐IV Inhibitors and Metformin. Diabetes Obes Int J 2019, 4(2): 000201.

Copyright© Chatterjee S, et al.

P<0.05 considered as statistically significant, p computed by paired t-test.

P<0.05 considered as statistically significant, p computed by Signed rank test. Table 2: Change in Parameters in the Study Subjects after treatment with DPP-IV Inhibitors+ SGLT-2 Inhibitors + Metformin, N=101.

Chatterjee S, et al. Effects on Metabolic Parameters of Addition of SGLT‐2 Inhibitors on Patients with Type2 Diabetes Inadequately Controlled with DPP‐IV Inhibitors and Metformin. Diabetes Obes Int J 2019, 4(2): 000201.

Copyright© Chatterjee S, et al.

(p=0.0024) but no such changes were noted in PPBG values.

significant reduction in HbA1c values (p=0. 008 and p=0.0005 respectively) but empagliflozin failed to show statistically significant changes (p=0.65).

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Chatterjee S, et al. Effects on Metabolic Parameters of Addition of SGLT‐2 Inhibitors on Patients with Type2 Diabetes Inadequately Controlled with DPP‐IV Inhibitors and Metformin. Diabetes Obes Int J 2019, 4(2): 000201.

Copyright© Chatterjee S, et al.

Figure 2 shows the changes in weight in the study group after treatment with SGLT-2inhibitors.When the baseline mean body weights were compared to the mean body weight at follow up all the three SGLT-2 inhibitors showed significant reduction in body weight-canagliflozin (p=0.007), dapagliflozin (p=0.002) and empagliflozin (p<0. 0001).

Click to enlarge

There are many choices for therapy in patients with T2DM requiring treatment intensification. The rationale, mechanism, and clinical data on combination therapy with DPP-4 inhibitors and SGLT-2 inhibitors have been Chatterjee S, et al. Effects on Metabolic Parameters of Addition of SGLT‐2 Inhibitors on Patients with Type2 Diabetes Inadequately Controlled with DPP‐IV Inhibitors and Metformin. Diabetes Obes Int J 2019, 4(2): 000201.

A meta-analysis has evaluated the efficacy and safety of a combination therapy comprising a SGLT-2 inhibitor and DPP-4 inhibitor in type 2 diabetes [18]. Eight randomised controlled trials (RCT) comparing SGLT-2 inhibitor/DPP-4 inhibitor and DPP-4 inhibitor, and five RCTs comparing SGLT-2 inhibitor/DPP-4inhibitor and SGLT-2 inhibitor, with three RCTs involving both comparisons, were included in the review. SGLT-2 inhibitor/DPP-4 inhibitor resulted in a greater mean HbA1c reduction [weighted mean difference (WMD]): - 0.62%]), than did DPP-4inhibitor alone, which was a much less marked reduction (WMD: -0.35%) than with SGLT-2 inhibitor alone. Interestingly, the authors thereafter suggest that additional glucose control is significant when SGLT-2inhibitors are combined with or added to DPP-4 inhibitors but not vice versa, as was also suggested previously [19].

Copyright© Chatterjee S, et al.

Body weight changes little when a DPP-4 inhibitor is added to a metformin/SGLT-2 inhibitor combination but, in patients with baseline BMI 30-32kg/m2, adding the SGLT-2 inhibitor to a metformin/DPP-4 inhibitor combination is associated with weight loss of approximately 1.5-3.0kg compared with 0.3-0.4kg among placebo recipients [21, 23]. In this study there was 2.67 kg weight loss when SGLT-2 inhibitor was added to metformin/DPP-4 inhibitor combinations in the study group with mean BMI of 30.85kg/m2 and mean body weight of 81.55 kgs at baseline .This was statistically significant (p<0. 0001).

Chatterjee S, et al. Effects on Metabolic Parameters of Addition of SGLT‐2 Inhibitors on Patients with Type2 Diabetes Inadequately Controlled with DPP‐IV Inhibitors and Metformin. Diabetes Obes Int J 2019, 4(2): 000201.

Adding an SGLT-2 inhibitor to metformin/DPP-4 inhibitor is also associated with a small reduction in blood pressure of about 1.0–2.5mmHg above the effect of placebo for systolic and diastolic pressures but there is little impact when a DPP-4 inhibitor is the third drug added [21, 22, 23, 24]. In the present study in the empagliflozin treated group there was 8.17mmHgreduction of SBP (p=0.0002) and 3.03 mmHg reduction in DBP (p= 0.049).

Finally, the limitations of this study must be considered. First, this is a real world study (RWS). Randomisation and placebo controlling were not done. Secondly, due to small number of cases dose related subgroup analysis of the three SGLT-2 inhibitors couldn’t be done. Thirdly, the DPP-4 inhibitors were not individually analysed. These issues might have implication in the result and outcome of the study.

Conclusion

The present study showed addition of SGLT2 inhibitors as an add-on to DPP-4 inhibitors and metformin in inadequately controlled T2DM produce favourable effects on metabolic parameters with the advantage of weight loss. This only Indian real world study is thus consistent with RCTs and real world studies of western world.

Conflict of Interest

The authors have no multiplicity of interest to disclose.