Where Does Combination Therapy With an SGLT2 Inhibitor Plus a DPP-4 Inhibitor Fit in the Management of Type 2 Diabetes?

Hyperglycemia is the critical risk factor for diabetic microvascular complications. Several landmark studies, e.g., UK Prospective Diabetes Study (UKPDS) and Diabetes Control and Complications Trial (DCCT), have demonstrated that lowering the HbA_1c by 1% decreases microvascular complications by approximately 35% (1,2). Despite the unequivocal evidence for the importance of achieving good glycemic control in patients with type 2 diabetes mellitus (T2DM), approximately half of individuals with T2DM fail to achieve the American Diabetes Association (ADA) goal of glycemic control (HbA_1c <7.0%) (3). Thus, novel therapeutic agents and strategies are required to improve glycemic control in T2DM patients.

Two novel classes of antihyperglycemic drugs have been developed during the last decade for the treatment of T2DM: dipeptidyl peptidase-4 inhibitors (DPP-4i) (4) and sodium–glucose cotransporter 2 (SGLT2) inhibitors (SGLT2i) (5).

DPP-4i have been in clinical use for the treatment of T2DM for more than a decade. DPP-4i inhibit the enzyme that degrades the incretin hormones, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), and result in elevated plasma GLP-1 and GIP concentrations. The increase in plasma GLP-1 and GIP concentrations stimulates insulin secretion from the β-cell and inhibits glucagon secretion from the α-cell, leading to inhibition of endogenous glucose production (EGP) and reduction in plasma glucose concentration (6).

SGLT2i are a novel class of antidiabetes drugs that recently have been approved for the treatment of T2DM. Members of this class reduce the plasma glucose concentration by inhibiting renal glucose reabsorption and producing glucosuria. Urinary glucose loss results in negative energy balance and because SGLT2i also block sodium absorption in the proximal tubule, they cause weight loss (∼2–3 kg) and decrease in blood pressure (4–6/1–2 mmHg systolic/diastolic) (5).

Because the pathogenesis of T2DM is complex and involves multiple metabolic defects (7), the use of combination therapy with antidiabetes drugs with different mechanisms of action has the advantage of preventing compensatory mechanisms and has the potential of producing an additive reduction in HbA_1c.

Thus, the combination of SGLT2i plus DPP-4i has the potential to produce a robust reduction in HbA_1c. This combination is particularly appealing in light of recent findings that glucosuria produced by SGLT2i is associated with an increase in the rate of EGP (8,9), which offsets the glucose-lowering effect by approximately 50% (8). As DPP-4i inhibit glucagon secretion and reduce EGP, one can speculate that the combination of DPP-4i plus SGLT2i would prevent the increase in EGP following SGLT2 inhibition and produce an additive, even synergistic, effect to reduce HbA_1c.

In this issue of Diabetes Care, Rosenstock et al. (10) examine this hypothesis. They randomized 534 poorly controlled, metformin-treated T2DM patients to receive dapagliflozin (10 mg) alone, saxagliptin (5 mg) alone, or a combination of saxagliptin plus dapagliflozin for 24 weeks. While saxagliptin alone lowered the HbA_1c by 0.88% and dapagliflozin alone lowered the HbA_1c by 1.2%, the combination of dapagliflozin plus saxagliptin lowered the HbA_1c by only 1.47%, which is significantly lower than expected from this combination. Similarly, the effect of saxagliptin plus dapagliflozin on both the fasting and postprandial plasma glucose concentrations was far less than additive. As expected, dapagliflozin alone or in combination with saxagliptin caused a modest weight loss (2–3 kg) and a small decrease in systolic blood pressure (2–4 mmHg), while saxagliptin alone had no effect on blood pressure or body weight.

This well-designed double-blind randomized clinical trial provides a definitive answer to the question of the efficacy of combination therapy with SGLT2i plus DPP-4i in poorly controlled T2DM patients. The only limitation of the study is lack of placebo group. In light of the 2015 position statement of the ADA and European Association for the Study of Diabetes (11) about the management of hyperglycemia in T2DM that recommends the SGLT2i as one of the treatment options in metformin-failing T2DM patients, this study is likely to provide important information that will aid clinicians making therapeutic decisions in metformin-failing patients.

The results of this study are strikingly similar to those recently reported by DeFronzo et al. (12), who examined the effect of combined therapy with empagliflozin plus linagliptin versus each agent alone on glycemic control in poorly controlled T2DM patients treated with metformin. Taken at face value, collectively these results demonstrate that combined SGLT2i/DPP-4i therapy not only does not produce a synergistic reduction in HbA_1c but also produces an effect on HbA_1c that is much smaller than the additive effect of each agent alone. In fact, if one compares the reduction in HbA_1c produced by the combination of dapagliflozin plus saxagliptin with that produced by dapagliflozin alone, the overall additional benefit from the addition of saxagliptin to dapagliflozin is very small (0.28%) and of questionable cost-effectiveness.

Why did DPP-4i fail to produce an additive or synergistic effect to lower the plasma glucose concentration or HbA_1c when combined with the SGLT2i? Inhibition of SGLT2 has been shown to stimulate EGP and the magnitude of increase in EGP strongly correlates with the amount of glucose excreted in the urine (8), suggesting a close relationship between the amount of glucosuria and the increase in EGP. Although the signal responsible for mediating the increase in glucosuria and the increase in EGP remains to be determined, the increase in EGP was accompanied with a small decrease in plasma insulin concentration and a large increase in plasma glucagon concentration (8,9). Although the effects of dapagliflozin and saxagliptin on EGP and plasma glucagon and insulin concentrations were not reported in the study by Rosenstock et al. (10), it is well documented that the primary mechanism by which DPP-4i lower the plasma glucose is by suppressing glucagon secretion and inhibiting EGP (6). Thus, one can speculate that the inhibitory effect of the DPP-4i on EGP is not sufficiently strong to overcome the stimulatory effect of the SGLT2i and, as a result, the majority of the glucose-lowering effect of the DPP-4i is lost. Further studies are required to test this hypothesis.

Another interesting observation in the study by Rosenstock et al. (10) is that when subjects were stratified based on the baseline HbA_1c, the higher the baseline HbA_1c, the greater the decrease in HbA_1c is with each monotherapy. This is entirely as expected. However, as previously predicted (13), the impact of the increase in baseline HbA_1c on the clinical efficacy of dapagliflozin is much greater than that of saxagliptin. The decrease in HbA_1c (−0.45%) produced by dapagliflozin in subjects with an HbA_1c <8.0% was lower than that observed with saxagliptin (−0.69%). However in subjects with an HbA_1c >9.0% (mean HbA_1c = 10.0%), dapagliflozin produced a −1.87% decrease in HbA_1c compared with −1.32% produced by saxagliptin. Stated otherwise, a 2.5% increase in baseline HbA_1c (from 7.5 to 10%) caused a more than fourfold increase in the efficacy of SGLT2i, while a similar difference in baseline HbA_1c caused a less than twofold increase in the reduction in HbA_1c produced by DPP-4i. The greater impact of the elevated baseline HbA_1c on SGLT2i efficacy can be explained by the greater amount of glucose removed from the body by SGLT2i at the higher plasma glucose concentration. This observation has important clinical relevance because it demonstrates that SGLT2i will have a greater advantage in lowering HbA_1c over other antidiabetes therapies in subjects with a high initial HbA_1c (e.g., HbA_1c >9.0%). Importantly, the additive effect of HbA_1c reduction produced by the addition of DPP-4i to SGLT2i would be expected to be markedly decreased with increasing baseline HbA_1c. While the combination of saxagliptin plus dapagliflozin resulted in additional 0.35% decrease in HbA_1c compared with dapagliflozin alone in subjects with HbA_1c <8.0%, it decreased the HbA_1c by only 0.16% in subjects with HbA_1c >9.0%. As the amount of glucosuria produced by the SGLT2i is expected to increase with the increase in baseline HbA_1c and the increase in EGP strongly correlates with the amount of glucosuria, one can speculate that with increasing baseline HbA_1c the stimulation of EGP by glucosuria is so powerful that it overcomes the ability of the DPP-4i to inhibit EGP and results in a clinically small benefit (−0.16%) in subjects with high baseline HbA_1c (>9.0%). This emphasizes the importance of the concept that not one therapy fits every T2DM patient and underscores the need of individualizing the antidiabetes therapy based on the individual conditions of the patient, as suggested by the recent ADA guidelines (11) for the management of T2DM patients.

• © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.