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Division of Cardiac Surgery, Department of Surgery, Li Ka Shing Knowledge Institute of St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada
The concept of combining a sodium-glucose cotransporter 2 (SGLT2) inhibitor with either a dipeptidyl peptidase-4 (DPP-4) inhibitor or a glucagon-like peptide-1 receptor agonist (GLP-1RA) has received much attention because incretin agents may complement SGLT2 inhibitors by counteracting the SGLT2 inhibitor-associated rise in glucagon and endogenous glucose production and potentially exert an additive or synergistic effect on glucose lowering. In this commentary, we detail the current state of knowledge surrounding the opposing influences of these drug classes on glucagon secretion, clinical data that support the concept of combining agents from these antihyperglycemic groups, and what we see as the fundamental research gaps requiring urgent attention.
Despite a longstanding acknowledgment that diabetes is a multihormonal disease, it is only recently that glucagon and pancreatic alpha cells have returned to the forefront to share centre stage with insulin and beta cells (
). In normoglycemic individuals, juxtaposed pancreatic alpha and beta cells reciprocally regulate insulin and glucagon secretion to ensure physiologic glucose homeostasis. In those with type 2 diabetes, initial insulin resistance leads to hyperinsulinemia, which evolves into impaired glucose tolerance as compensatory insulin secretion decreases over time due to progressive beta-cell loss (
Significant human beta-cell turnover is limited to the first three decades of life as determined by in vivo thymidine analog incorporation and radiocarbon dating.
) alters intra-islet cross-talk which, together with the blunted suppression of postmeal glucagon release, promotes supranormal fasting and postprandial glucagon levels that, in turn, drive endogenous glucose production (
). The result of these functional and regulatory metabolic derangements is chronic hyperglycemia and diabetes. With time, dampened incretin effects, hyperamylinemia, increased central insulin resistance and heightened renal glucose reabsorption further aggravate the hyperglycemia (
The progressive complexity of type 2 diabetes translates into a need to modify and individualize antihyperglycemic regimens routinely in order to improve glycemic control and delay advancement of the disease (
). Most traditional antihyperglycemic agents mediate their effects through changes in beta-cell function and insulin secretion or action, but the incretin agents—which include the DPP-4 inhibitors and GLP-1RAs—and the SGLT2 inhibitors also impact alpha-cell activity and glucagon secretion. Although it has been established that the DPP-4 inhibitors and GLP-1Ras promote insulin secretion by impeding the degradation of endogenous GLP-1 and augmenting the actions of GLP-1, respectively (
), they have also been shown to indirectly decrease glucagon secretion from pancreatic alpha cells by 9% to 24% and to reduce endogenous glucose production by 20% (
Mechanisms of glucose lowering of dipeptidyl peptidase-4 inhibitor sitagliptin when used alone or with metformin in type 2 diabetes: A double-tracer study.
). However, with chronic exposure, the GLP-1RAs exenatide and liraglutide may have different effects on postprandial glucagon, an area requiring further investigation (
). SGLT2 inhibitors achieve their antihyperglycemic goals by reducing the renal threshold of glucose reabsorption in the proximal renal tubule and promoting glycosuria (
). Recent evidence suggests that the SGLT2 inhibitors dapagliflozin and empagliflozin also trigger a paradoxical 7.5% to 24% increase in postmeal glucagon levels and an associated 8.8% to 20.8% rise in endogenous glucose production, potentially blunting the overall glycemic efficacy of these agents (
). Figure 1 summarizes the effects of incretin agents and SGLT2 inhibitors on glucagon secretion and hepatic glucose production.
Figure 1Incretin agents and SGLT2 inhibitors have contrasting effects on glucagon secretion and hepatic glucose production. Incretin agents, via a GLP-1 effect, are generally associated with a suppression of glucagon production and, in turn, hepatic glucose production. SGLT2 inhibitors act directly on pancreatic alpha cells to promote glucagon secretion and subsequent hepatic gluconeogenesis.
Until recently, the mechanism of the glucagon rise following treatment with an SGLT2 inhibitor remained an unexplained phenomenon. The latest discovery of SLC5A2 (the mRNA that encodes SGLT2) and SGLT2 in human alpha cells (but not beta cells) (
) fundamentally offers, at least in part, an explanation. The parallel findings that hepatocyte nuclear factor 4alpha (HNF4ɑ), otherwise known as the maturity onset diabetes of the young (MODY1) gene, mRNA colocalizes with SLC5A2 in alpha cells and that HNF4ɑ regulates SLC5A2 expression are equally exciting, given the lower SLC5A2 and HNF4ɑ expression but higher levels of the glucagon protein coding gene GCG in pancreatic islets in individuals with type 2 diabetes (
). Preclinical studies revealing enhanced glucagon secretion in SLC5A2-silenced human islets and in euglycemic ex vivo, in vivo and in vitro models in response to the SGLT2 inhibitor dapagliflozin (
) further support the existence of an alpha cell glucose uptake system via SGLT2 that is independent of the well-entrenched glucose transporter 1 (GLUT1) network (
Differences in glucose transporter gene expression between rat pancreatic alpha- and beta-cells are correlated to differences in glucose transport but not in glucose utilization.
). Glucose metabolism within the alpha cell is catalyzed by glucokinase (GK). Until recently, glucose transporter 1 (GLUT1) was thought to be solely responsible for the entry of glucose into pancreatic alpha cells. Recent findings, however, suggest that the SGLT2 transporter, which is believed to be regulated locally by hepatocyte nuclear factor 4alpha (HNF4ɑ), may assist in pancreatic glucose influx. Accordingly, the rise in circulating glucagon may be attributed, in part, to the reduced glucose transport into alpha cells brought about by SGLT2 inhibitors.
Clinical studies have assessed the effects of adding an SGLT2 inhibitor to a DPP-4 inhibitor in the absence or presence of metformin therapy and have demonstrated improved glucose control (as measured by A1C levels, fasting plasma glucose levels and postprandial glucose changes) and significant weight loss (
Dapagliflozin is effective as add-on therapy to sitagliptin with or without metformin: A 24-week, multicenter, randomized, double-blind, placebo-controlled study.
). Rosenstock et al conducted a 3-way study in which metformin-treated participants were randomized to dapagliflozin, saxagliptin or saxagliptin+dapagliflozin (
Dual add-on therapy in type 2 diabetes poorly controlled with metformin monotherapy: A randomized double-blind trial of saxagliptin plus dapagliflozin addition versus single addition of saxagliptin or dapagliflozin to metformin.
). The addition of saxagliptin and dapagliflozin to metformin resulted in significantly greater A1C level reduction from baseline (−1.47%) than saxagliptin (−0.88%) or dapagliflozin (−1.2%) added to metformin. While dual add-on therapy was associated with efficacious glucose lowering, the results were subadditive (0.61% less A1C lowering) compared to combining the effects of each single add-on therapy. The concept of subadditivity with simultaneous combination therapy relates to the fact that the efficacy of individual therapies is dependent on baseline A1C levels, resulting in lower efficacy with the second add-on agent, which act on patients with a lower effective baseline A1C compared to the second agent's being added alone (
Apparent subadditivity of the efficacy of initial combination treatments for type 2 diabetes is largely explained by the impact of baseline HbA1c on efficacy.
). In a separate report, a significant rise in plasma glucagon was observed in the metformin + dapagliflozin group (10.5%), with no significant change in the metformin + dapagliflozin + saxagliptin (−1.4%) study arm, suggesting that saxagliptin may have effectively combatted the rise in glucagon evoked by dapagliflozin (
Postprandial dynamics of plasma glucose, insulin, and glucagon in patients with type 2 diabetes treated with saxagliptin plus dapagliflozin add-on to metformin therapy.
). However, endogenous glucose production (EGP) was not measured, so it is uncertain whether the blunting of the glucagon rise induced by SGLT2 inhibitor therapy also prevented the concurrent rise in EGP. Two other groups evaluated the combination of empagliflozin and linagliptin in drug-naive or metformin-treated patients and found favourable changes in A1C levels and weight at the end of the observation window (
). Glucagon levels and EGP were not reported in these studies. Collectively, the SGLT2 inhibitor/DPP-4 inhibitor combination therapy studies confirm the viability of combining these 2 classes of antihyperglycemic agents to help manage glucose levels in patients with type 2 diabetes. Although the subadditivity of this combination on A1C efficacy maybe attributed completely to the impact of baseline A1C levels (
Apparent subadditivity of the efficacy of initial combination treatments for type 2 diabetes is largely explained by the impact of baseline HbA1c on efficacy.
), other contributors may include an inability of DPP-4 inhibitors to counterbalance the EGP stimulated by SGLT2 inhibitors or perhaps (in)direct reprogramming of alpha, beta and delta cells into an alternative lineage (
). There are few clinical data concerning GLP-1RA plus SGLT2 inhibitor combination therapy. In a study of 95 patients enrolled in a canagliflozin cardiovascular outcome study, the addition of canagliflozin 100 mg and 300 mg to background GLP-1RA, with or without other agents, was associated with statistically significant reductions in A1C levels of 1.00% and 1.06%, respectively, and weight loss of 2.5% to 3.2% (
Dapagliflozin is effective as add-on therapy to sitagliptin with or without metformin: A 24-week, multicenter, randomized, double-blind, placebo-controlled study.
Dual add-on therapy in type 2 diabetes poorly controlled with metformin monotherapy: A randomized double-blind trial of saxagliptin plus dapagliflozin addition versus single addition of saxagliptin or dapagliflozin to metformin.
), many knowledge gaps remain. While incretin agents may prevent the glucagon rise associated with SGLT2 inhibition, the effects on A1C levels are subadditive, and it remains unknown how incretin-SGLT2 inhibitor combinations influence endogenous glucose production, typically increased with SGLT2 inhibitor therapy but reduced with incretin agents. An ongoing study of the impact of liraglutide plus canagliflozin on hepatic glucose production and glucagon should help to clarify this issue (
Effect of combined incretin-based therapy plus canagliflozin on glycemic control and the compensatory rise in hepatic glucose production in type 2 diabetic patients.
). It remains possible that there is a yet unidentified neural or hormonal feedback loop between the kidney and the liver, independent of glucagon, that propels hepatic glucose production while on SGLT2 inhibitor therapy. The possibility of an increase in renal gluconeogenesis with SGLT2 inhibitor therapy that continues despite adding an incretin agent also needs to be explored in future studies. As incretin agent plus SGLT2 inhibitor therapy becomes more commonplace, it is important to understand the long-term impact on glucagon and endogenous glucose production and the durability of this combination. For now, incretin and SGLT2 inhibitor combinations can be used for improving glycemic control with weight loss and rare hypoglycemia. Only further research will help to explain the clinical relevance of the yin and yang of glucagon with incretin agents and SGLT2 inhibitors.
Author Disclosures
RMG reports research support from Abbott, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Medtronic, Merck, Novartis, Novo Nordisk, Roche, Sanofi and Takeda; served on advisory panels for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Janssen, Merck, Novo Nordisk, Roche, Sanofi and Takeda; speaker bureaus for Abbott, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck, Novo Nordisk, Sanofi, and Servier; consultant for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Janssen, Novo Nordisk, and Takeda; SV reports research support from Abbott; served on advisory panels for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen and Merck; speaker bureaus for Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck and Janssen; BAP has received speaker honoraria from Janssen, Medtronic and Lilly; research support from Novo Nordisk, Boehringer-Ingelheim and Medtronic, and has served as an advisor to Neurometrix and Boehringer Ingelheim; JDG has served on advisory panels for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk and Sanofi; speaker bureaus for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck, Novo Nordisk and Sanofi. BZ reports research support from AstraZeneca, Boehringer Ingelheim, Novo Nordisk, has served on advisory panels and received honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk and Sanofi.
Author Contributions
All authors actively discussed the content of the manuscript. RMG drafted the manuscript; RMG, SV, BAP, JDG and BZ critically revised the manuscript.
Acknowledgements
The authors acknowledge the writing support provided by Hwee Teoh, PhD. Support for the generation of this document was provided through unrestricted grants from AstraZeneca (Canada), Boehringer Ingelheim (Canada) and Merck (Canada). The opinions expressed herein are those of the authors and do not necessarily reflect the views of the sponsors. The sponsors were not involved in the preparation, review or approval of the manuscript or in the decision to submit the manuscript for publication or the target journal.
References
Lund A.
Bagger J.I.
Christensen M.
et al.
Glucagon and type 2 diabetes: The return of the alpha cell.
Significant human beta-cell turnover is limited to the first three decades of life as determined by in vivo thymidine analog incorporation and radiocarbon dating.
Mechanisms of glucose lowering of dipeptidyl peptidase-4 inhibitor sitagliptin when used alone or with metformin in type 2 diabetes: A double-tracer study.
Differences in glucose transporter gene expression between rat pancreatic alpha- and beta-cells are correlated to differences in glucose transport but not in glucose utilization.
Dapagliflozin is effective as add-on therapy to sitagliptin with or without metformin: A 24-week, multicenter, randomized, double-blind, placebo-controlled study.
Dual add-on therapy in type 2 diabetes poorly controlled with metformin monotherapy: A randomized double-blind trial of saxagliptin plus dapagliflozin addition versus single addition of saxagliptin or dapagliflozin to metformin.
Apparent subadditivity of the efficacy of initial combination treatments for type 2 diabetes is largely explained by the impact of baseline HbA1c on efficacy.
Postprandial dynamics of plasma glucose, insulin, and glucagon in patients with type 2 diabetes treated with saxagliptin plus dapagliflozin add-on to metformin therapy.
Effect of combined incretin-based therapy plus canagliflozin on glycemic control and the compensatory rise in hepatic glucose production in type 2 diabetic patients.
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