Combination therapy with SGLT-2 inhibitors and GLP-1 receptor agonists as complementary agents that address multi-organ defects in type 2 diabetes

ABSTRACT

Type 2 diabetes (T2D) has a complex pathophysiology composed of multiple underlying defects that lead to impaired glucose homeostasis and the development of macrovascular and microvascular complications. Of the currently available glucose-lowering therapies, sodium–glucose cotransporter-2 inhibitors (SGLT-2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) both provide effective glycemic control and have been shown to reduce cardiovascular (CV) events in patients with T2D and a high CV risk or established CV disease. Because these agents have complementary mechanisms of action, they are able to act on multiple defects of T2D when used in combination. This review discusses the rationale for and potential benefits of SGLT-2i plus GLP-1RA combination therapy in patients with T2D. A search of the PubMed database was conducted for studies and reviews describing the combined use of SGLT-2is and GLP-1RAs, with a specific focus on identifying clinical studies of combination therapy in patients with T2D. In clinical studies, glycated hemoglobin (A1c) was significantly reduced over 28–52 weeks with SGLT-2i plus GLP-1RA therapy versus the individual agents or baseline. Several CV risk factors, including body weight, blood pressure, and lipid parameters, were also improved. SGLT-2i plus GLP-1RA therapy was generally well tolerated, with a low risk of hypoglycemia and no unexpected findings. Taken together with results from large CV outcomes trials of SGLT-2is and GLP-1RAs, combination therapy with these agents potentially provides effective durable glycemic control and CV benefits due to their complementary actions on the defects of T2D.

KEYWORDS:

• Cardiovascular risk
• combination therapy
• glucagon-like peptide-1 receptor agonists
• sodium–glucose cotransporter-2 inhibitors
• type 2 diabetes

1. Introduction

The pathophysiology of type 2 diabetes (T2D) is complex, with multiple underlying defects that each play a role in the impairment of glucose metabolism [1,2]. These pathophysiologic defects include decreased insulin secretion and decreased incretin effect and glucose uptake in addition to increased glucagon secretion, increased renal glucose reabsorption, and increased hepatic glucose production and lipolysis; and neurotransmitter dysfunction (Figure 1). Different types of glucose-lowering therapies, including biguanides (metformin), sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 inhibitors (DPP-4is), insulin, and newer agents, such as glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT-2is), vary in their mechanisms of action and how they target these defects [1,2].

Figure 1. The multiple defects in type 2 diabetes and the classes of drugs that affect each defect. Reprinted by permission from Macmillan Publishers Limited, Nat Rev Dis Primers, DeFronzo RA, Ferrannini E, Groop L, Henry RR, et al, Type 2 diabetes mellitus, 15,019, Copyright (2015) [22].

AMPK: AMP-activated protein kinase; DPP-4: dipeptidyl peptidase-4; GLP1-RA: glucagon-like peptide 1 receptor agonists; IκB: inhibitor of NF-κB; MAPK: mitogen-activated protein kinase; NF-κB: nuclear factor-κB; RA: receptor agonist; ROS: reactive oxygen species; SGLT-2: sodium–glucose cotransporter-2; TLR4: Toll-like receptor 4; TNF: tumor necrosis factor; TZDs: thiazolidinediones.

The American Diabetes Association (ADA) 2019 Standards of Care and the ADA and European Association for the Study of Diabetes (EASD) 2018 consensus report recommend starting treatment with lifestyle management and first-line metformin monotherapy in patients with T2D, checking glycemic targets regularly every 3 months, and adding new treatments as needed at each assessment if glycemic targets are not met (Figure 2) [3,4]. In contrast to earlier recommendations, the ADA 2019 Standards of Care and the ADA and EASD 2018 consensus report recognize the importance of considering the presence of cardiovascular (CV) disease (CVD), heart failure (HF), and chronic kidney disease (CKD) when selecting the appropriate glucose-lowering therapy after metformin, with the use of SGLT-2is or GLP-1RAs with proven CV benefit being recommended as part of glycemic management in patients with established CVD [3,4]. The American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) 2019 consensus report recommends that consideration should be given to GLP-1RAs or SGLT-2is as first-line therapy in patients with T2D and atherosclerotic CVD and/or CKD [5]. Based on these recommendations, most patients with T2D may require more aggressive therapy early in the course of treatment [3–5].

Figure 2. Summary of guideline recommendations (ADA, AACE/ACE, ADA/EASD) for add-on glucose-lowering therapy in patients with type 2 diabetes [3–5].

A1c: glycated hemoglobin; AACE: American Association of Clinical Endocrinologists; ACE: American College of Endocrinology; ADA, American Diabetes Association; CVD: cardiovascular disease; CKD: chronic kidney disease; DPP-4i: dipeptidyl peptidase-4 inhibitor; EASD: European Association for the Study of Diabetes; GLP-1RA: glucagon-like peptide-1 receptor agonist; HF: heart failure; INS: insulin; MET: metformin; SGLT-2i: sodium–glucose cotransporter-2 inhibitor; SU: sulfonylurea; TZD: thiazolidinedione.

Early and more aggressive treatment approaches for T2D in patients with a low risk of hypoglycemia may improve patients’ chances of achieving and maintaining glycemic targets (Figure 3) [6,7]. The choice of add-on glucose-lowering therapy should be tailored to the patient’s individual preferences and needs, taking into account the presence of CVD or CKD and how treatment may affect CV outcomes, risk factors, body weight, and renal function, in addition to achieving glycemic control [3–5]. Therefore, when choosing add-on or combination therapy, candidate therapies with complementary mechanisms of action should be considered in order to target multiple T2D defects [8].

Figure 3. Effect of stepwise treatment approach compared with early and aggressive treatment of type 2 diabetes on A1c target attainment. Reprinted from Mayo Clin Proc, Vol. 85(12 Suppl), Schwartz SS, Kohl BA, Glycemic control and weight reduction without causing hypoglycemia: the case for continued safe aggressive care of patients with type 2 diabetes mellitus and avoidance of therapeutic inertia, S15-S26, Copyright (2010) with permission from Mayo Foundation for Medical Education and Research [6].

A1c: glycated hemoglobin; OAD: oral antidiabetes drug.

Given the high level of therapeutic inertia in the management of T2D, most studies report that fewer than 50% of patients receive treatment intensification even when they are not at glycated hemoglobin (A1c) goal [9–11]. Therefore, many patients spend an unnecessarily long period of time with inadequate glycemic control. An integrated United States (US) health system study of patients with T2D showed that only 50% of patients with a A1c of >8.0% on metformin monotherapy for 6 months or more had received a second add-on therapy, and only 32% of those with an A1c of >7.0% were prescribed an additional treatment [12]. Other data on prescribing patterns in patients with newly diagnosed T2D indicate that the time from initiating metformin to a change in treatment regimen is as long as 3 years [13].

Among the currently available glucose-lowering therapies, SGLT-2is and GLP-1RAs have been shown to provide effective glycemic control, as well as reductions in CV events, in patients with T2D and established CVD or multiple CVD risk factors [14–21]. These agents target different aspects of the defects in T2D (Figure 1), and, therefore, can provide complementary effects on several of the underlying pathophysiologic components of T2D [22], particularly when added on to other therapies such as metformin, which may also reduce CV risk according to a 10-year follow-up of the UK Prospective Diabetes Study (UKPDS) [3,23]. In contrast, other glucose-lowering therapies, including older agents in the sulfonylurea class (which may increase the risk of CV events and mortality) [24] and certain DPP-4is and insulin (which may increase the risk of HF) [25] have demonstrated limited or neutral effects on metabolic and CV outcomes [3,5].

This review describes the rationale for using SGLT-2is and GLP-1RAs in combination in patients with T2D based on their effects on the pathophysiologic defects in T2D and discusses the potential benefits of this combination therapy in patients with T2D.

2. Search strategy

A search of the PubMed database was conducted on 4 September 2018, using the following search terms and limited to English-language articles: (sodium-glucose cotransporter 2 inhibitors OR SGLT2 inhibitors OR SGLT-2 inhibitors OR SGLT2i) AND (glucagon-like peptide-1 receptor agonists OR GLP-1RAs OR GLP1RAs). Articles describing the combined use of SGLT-2is and GLP-2RAs were selected, with a specific focus on identifying clinical studies assessing combination therapy with these agents in patients with T2D. This search was supplemented by a search for relevant articles on a topic-by-topic basis to describe these agents’ mechanisms of action.

3. The physiological defects in T2D

The primary defects of T2D that contribute to abnormalities in glucose homeostasis are insulin resistance (in muscle, liver, and fat), pancreatic β-cell dysfunction leading to reduced insulin secretion, and increased glucagon secretion from the pancreatic α cells [22]. As β-cell function progressively fails, these cells become resistant to the incretin hormones GLP-1 and gastric inhibitory polypeptide, while the α cells increase glucagon secretion [22]. In response to increased glucagon levels and enhanced hepatic sensitivity to glucagon, the liver ramps up glucose production [22]. Adipocytes also develop insulin resistance, which results in enhanced lipolysis and the release of higher levels of free fatty acids into the plasma, which in turn aggravates hepatic and muscular insulin resistance and exacerbates β-cell dysfunction [22]. As expression of SGLT-2 transporters in the proximal tubule is increased, the kidneys reabsorb more glucose, which increases the threshold for urinary glucose excretion [22].

Insulin resistance also affects the brain, particularly the appetite regulation centers in the hypothalamus, with patients increasing their food intake and gaining weight as they become more resistant to the appetite-suppressant effects of insulin, leptin, GLP-1, amylin, and peptide YY [8,22,26]. In the peripheral vasculature, blood vessels develop insulin resistance, impairing endothelium-dependent vasodilation, and consequently affecting the delivery of insulin and glucose to peripheral tissues [22]. In addition, inflammation in the liver and adipose tissue releases pro-inflammatory cytokines that contribute to insulin resistance and lipolysis; the increase in free fatty acid levels associated with T2D pathophysiology also stimulates inflammation through the activation of Toll-like receptors [22]. The complex interactions between the multi-organ defects in T2D highlight the need for a multifaceted approach to treatment that not only normalizes blood glucose levels, but also favorably affects the risk factors for macrovascular and microvascular complications in patients with T2D.

4. SGLT-2is

The primary site of action for SGLT-2is is the renal proximal tubule, where they promote glucose excretion into the urine by decreasing reabsorption of glucose, as well as increasing sodium excretion (natriuresis) [27,28]. The increase in urinary glucose excretion reduces plasma glucose levels, while the natriuretic effect reduces blood pressure (BP) [27]. SGLT-2is also have a favorable effect on body weight and fat mass because of an increase in lipolysis and a shift in substrate utilization from carbohydrates to fats [27]. Because the pharmacodynamic effects of SGLT-2is are independent of insulin, SGLT-2is are associated with a low risk of hypoglycemia [28], and their actions are not affected by deterioration in β-cell function [27]. However, their efficacy on glycemic parameters decreases as renal function declines.

SGLT-2is’ effects on a number of CV risk factors include significant reductions in BP, body weight, and waist circumference [29], and increases in low-density lipoprotein cholesterol and high-density lipoprotein cholesterol [14–16]. In large-scale randomized CV outcomes trials (CVOTs), the SGLT-2is empagliflozin (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients [EMPA-REG OUTCOME] study) and canagliflozin (Canagliflozin Cardiovascular Assessment Study) [CANVAS]) both significantly reduced the risk of three-point major adverse CV events (MACE; composite of CV death, nonfatal myocardial infarction, or nonfatal stroke) by 14% compared with placebo in patients with T2D and established CVD (EMPA-REG OUTCOME) or established CVD and high CV risk (CANVAS) [14,15]. These studies also showed a reduction in the risk of hospitalization for HF with SGLT-2is versus placebo [14,15]. In the Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 (DECLARE–TIMI 58) study, dapagliflozin showed noninferiority to placebo with regard to three-point MACE and significantly reduced the risk of the primary composite end point of CV death or hospitalization for HF by 17% versus placebo in patients with T2D and established CVD or multiple CVD risk factors [16]. Of note, as the proportion of patients with established CVD varied among the 3 CVOTs: EMPA-REG OUTCOME (>99%) [14]; CANVAS (65.5%) [15]; and DECLARE–TIMI 58 (40.6%) [16], it is difficult to make comparisons of the outcomes across the trials. However, in a meta-analysis of EMPA-REG OUTCOME, CANVAS, and DECLARE–TIMI 58, SGLT-2is were associated with significant reductions in the risk of CV death or hospitalization for HF (by 23%) and the risk of hospitalization for HF (by 31%) across patients with or without established CVD, while a modest reduction in MACE (by 11%) was only observed in patients with established CVD [30]. A large-scale study is currently investigating the CV safety and efficacy of ertugliflozin (Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial [VERTIS-CV], NCT01986881]) in patients with established CVD [31], with results expected in 2019.

SGLT-2is also have shown improvements in renal outcomes in CVOTs [15,16,32]. Compared with placebo, canagliflozin was associated with a significant reduction in the risk of new-onset albuminuria and the composite renal end point (40% decrease in estimated glomerular filtration rate [eGFR], renal replacement therapy, or death from renal causes) in CANVAS [15,33]. The risk of incident or worsening nephropathy was significantly reduced with empagliflozin in a secondary analysis of EMPA-REG OUTCOME [32]. Dapagliflozin was associated with a 47% reduction in the risk of the composite renal end point (≥40% reduction in eGFR to <60 mL/min/1.73 m², end-stage renal disease, or death from renal causes) in DECLARE–TIMI 58, however, this renal outcome was considered hypothesis-generating [16]. The Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation (CREDENCE) study was recently stopped early due to achievement of its prespecified efficacy outcomes, which indicates that SGLT-2is have an important role in reducing CKD progression in patients with T2D [34]. Two ongoing randomized studies are currently examining the effects of dapagliflozin (A Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With Chronic Kidney Disease [DAPA-CKD], NCT03036150) or empagliflozin (The Study of Heart and Kidney Protection With Empagliflozin [EMPA-KIDNEY], NCT03594110) on renal outcomes and CV mortality in patients with CKD (with or without T2D), with estimated completion dates of 2020 and 2022, respectively.

The findings of these randomized CVOTs are complemented by data from observational studies. In the Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium Glucose Cotransporter-2 Inhibitors (CVD-REAL) study, which investigated CV outcomes in patients with T2D in real-world clinical practice, patients who had initiated therapy with SGLT-2is (n = 166,033) were compared with those who received another form of glucose-lowering therapy (n = 226,221) [35]. In this largely low-risk population (only 13% of patients had established CVD and <3% had CKD), the risks of hospitalization for HF, all-cause mortality, and the composite endpoint of hospitalization for HF or all-cause mortality were significantly lower in patients receiving SGLT-2is than in those receiving other glucose-lowering therapy [35].

As the CV benefits of SGLT-2is in CVOTs were observed after only 2.4–4.2 years of treatment [14–16], it is thought that these effects cannot be explained by an improvement in glycemic control and a reduction in body weight. One hypothesis to explain this relatively rapid effect is that the SGLT-2i effect on ventricular-loading is mediated by natriuresis and osmotic diuresis, resulting in a reduction of plasma volume and a lowering of cardiac preload and afterload [36]. Additionally, SGLT-2i–associated hemodynamic effects are also attributed to alternations in circulating levels of RAAS mediators, such as angiotensin and aldosterone [37]. Other potential mechanisms for the CV benefits of SGLT-2is include improved endothelial function and reductions in glomerular hyperfiltration [36]. The exact mechanisms underlying the beneficial effects of SGLT-2is are yet to be fully understood.

The Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure (DAPA-HF) trial has investigated the effect of dapagliflozin, added to standard of care in patients with chronic HF with reduced ejection fraction (both with and without T2D) on CV death and worsening HF [38,39]. Dapagliflozin significantly reduced the relative risk for the primary outcome (composite of worsening HF or CV death) by 26% versus standard of care alone (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.65–0.85; p= 0.00001) [38,39]. Significant reductions in the relative risk of the components of the primary outcome were also observed (risk of worsening HF event [30%; p = 0.00003] and risk of CV death [18%; p = 0.029]) [38,39]. Additional ongoing studies are investigating the effects of dapagliflozin and empagliflozin in patients having HF with preserved ejection fraction or HF with reduced ejection fraction (Supplemental Table). These studies may provide further confirmatory data about the benefits of SGLT-2is on clinical outcomes in patients with HF, regardless of whether or not they have T2D.

SGLT-2is are also associated with improvements in markers indicative of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, including visceral fat, hepatic fat index, and alanine aminotransferase [40–43].

5. GLP-1RAs

GLP-1RAs mimic the endogenous GLP-1 hormone by activating GLP-1 receptors [44], which are present in many tissues throughout the body, including the gastrointestinal tract, heart, lung, kidney, pancreas, and brain [45]. GLP-1RAs stimulate insulin secretion through activation of GLP-1 receptors on the surface of pancreatic β cells [44] and reduce glucagon secretion from pancreatic α cells, either through direct action on GLP-1 receptors or indirectly by β-cell secretion of insulin, γ-aminobutyric acid, or zinc [46].

GLP-1RAs are associated with decreases in body weight, reductions in food intake being mediated by a direct anorexigenic effect of central GLP-1 receptor agonism, and regulation of the food reward pathways in the brain [45]. Along with slowed gastric emptying during GLP-1RA therapy, these central effects mediate feelings of satiety [47]. In this respect, GLP-1RAs differ from DPP-4is, which increase circulating GLP-1 levels without affecting satiety or gastric emptying and, therefore, do not markedly affect body weight [47]. GLP-1RAs may also affect body weight by increasing thermogenesis within brown adipose tissue, a downstream effect of central GLP-1 receptor agonism [45]. GLP-1RAs have a glucose-dependent mechanism of action and thus have a low risk of hypoglycemia.

The effects of GLP-1RAs on CV events have been evaluated in CVOTs of patients with T2D and established CVD and/or multiple CVD risk factors [17–21,48,49]. In the CVOTs for liraglutide (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results [LEADER] study), semaglutide (Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes [SUSTAIN-6] study), albiglutide (Albiglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Cardiovascular Disease [Harmony Outcomes] study), and dulaglutide (Researching Cardiovascular Events with a Weekly Incretin in Diabetes [REWIND] study) in patients with T2D and a high CV risk or established CVD, significant reductions in the risk of three-point MACE were reported for liraglutide, semaglutide, albiglutide, and dulaglutide compared with placebo [17–19,48,49]. The EXenatide Study of Cardiovascular Event Lowering (EXSCEL) study, which evaluated exenatide once weekly (QW) in patients with T2D and a wide range of CV risk using a pragmatic design, found that there were fewer CV events with exenatide QW versus placebo; however, the difference in MACE did not reach statistical significance [20]. A subgroup analysis of EXSCEL outcomes in patients with T2D and established CVD at baseline showed a 10% reduction in the risk of MACE with exenatide QW versus placebo (p = 0.047) [50]. Additionally, a post hoc analysis of EXSCEL showed that patients in the exenatide QW group treated with SGLT-2i during study followup had a numerical reduction in the risk of MACE (adjusted HR 0.85 [0.48–1.49] and 0.68 [0.39–1.17], respectively) and a significant reduction in all-cause mortality (adjusted HR 0.41 [0.17–0.95] and 0.38 [0.16–0.90], respectively) as compared with exenatide alone and placebo [51]. In the CVOT for lixisenatide (Evaluation of Lixisenatide in Acute Coronary Syndrome [ELIXA] study) in patients with T2D and recent acute coronary syndrome, the risk of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina was not significantly different between the lixisenatide and placebo groups [21].

The observed differences in the results from CVOTs of the different GLP-1RAs may be explained by variations in the short-acting compared to long-acting nature of the formulations, different study designs, and different patient populations [52]. Lixisenatide is a short-acting exenatide-based formulation that has a half-life of ~3 hours and the characteristics of the patient population of the ELIXA trial were very different from that of other CVOTs. Furthermore, exenatide QW is a long-acting formulation like albiglutide, dulaglutide, liraglutide, and semaglutide; however, the pragmatic study design of the EXSCEL trial was fundamentally different from the other CVOT designs and may have impacted the trial results [52]. However, a meta-analysis that included data from the LEADER, SUSTAIN-6, EXSCEL, ELIXA, HARMONY, REWIND, and PIONEER 6 studies indicated that GLP-1RAs as a class reduce the risk of three-point MACE, CV mortality, and all-cause mortality compared with placebo [53]. These findings suggest that GLP-1RAs reduce the risk of CV events over time through antiatherogenic mechanisms, including decreased BP and effects on cardiac output, anti-inflammatory pathways, endothelial function, and ischemic conditioning [53,54].

In addition, the metabolic alterations associated with GLP-1RA therapy may enhance glucose utilization by cardiac myocytes, which when combined with the BP-lowering effects may potentially improve ventricular function [55], although improvements in left ventricular ejection fraction with GLP-1RAs in clinical studies have been inconsistent [56]. GLP-1RA therapy is associated with visceral fat reductions, as well as decreases in hepatic fat, in patients with T2D and nonalcoholic steatohepatitis [57]. GLP-1RAs may also have anti-inflammatory effects, which contribute to cardioprotection [55] and have been shown to reduce levels of C-reactive protein, a marker of systemic inflammation [58].

GLP-1RAs have also shown potentially renoprotective effects in some CVOTs [17,18,48,59]. Both liraglutide, semaglutide, and dulaglutide were associated with significant reductions in nephropathy (defined as new-onset macroalbuminuria or doubling of serum creatinine plus an eGFR of ≤45 mL/min/1.73 m², the need for renal replacement therapy, or renal death) compared with placebo in the LEADER [17], SUSTAIN-6 [18], and REWIND [48,59] studies, respectively.

6. The rationale for combining SGLT-2is and GLP-1RAs

6.1 Glycemic effects

A fundamental goal of T2D management is effective glycemic control based on individualized A1c targets [60]. According to 2019 ADA Standards of Care, a target A1c of <7% is appropriate for many patients, but more stringent targets may be considered for patients who can realistically achieve these, and less stringent targets may be set for those with long-standing T2D or who are at high risk of hypoglycemia [60]. As described earlier, a small proportion of patients with T2D reach or maintain their A1c goal on metformin monotherapy, while most will require combination therapy to achieve glycemic control.

In randomized and nonrandomized clinical studies investigating the combination of an SGLT-2i and a GLP-1RA, significant reductions in A1c at 52 weeks were observed compared with monotherapy with either an SGLT-2i or GLP-1RA (Table 1) [61–64]. In the Exenatide Once Weekly Plus Dapagliflozin Once Daily Versus Exenatide or Dapagliflozin Alone in Patients With Type 2 Diabetes Inadequately Controlled With Metformin Monotherapy (DURATION-8) study – the largest and longest clinical trial of SGLT-2i and GLP-1RA combination therapy to date – patients with T2D on metformin monotherapy were randomized to 52 weeks of double-blind treatment with exenatide QW plus dapagliflozin (n = 228), exenatide QW plus placebo (n = 227), or dapagliflozin plus placebo (n = 230) [61]. At 52 weeks, A1c had decreased by – 1.75% in the group receiving exenatide QW plus dapagliflozin compared with – 1.38% in the group receiving exenatide QW plus placebo (p = 0.006) and – 1.23% in the those receiving dapagliflozin plus placebo (p < 0.001) [61]. In the Assessment of Weekly Administration of LY2189265 (dulaglutide) in Diabetes-10 (AWARD-10) study, addition of the GLP-1RA dulaglutide to stable SGLT-2i therapy was associated with significantly greater reductions in A1c from baseline to 24 weeks (–1.21% and – 1.34% for the 0.75-mg and 1.5-mg doses, respectively) compared with placebo (–0.54%; p < 0.0001 for both doses) [64]. In real-world observational studies, in which an SGLT-2i was added to GLP-1RA background therapy (with or without other glucose-lowering therapies), the mean incremental change in A1c with the combination ranged from – 0.39% to −1.5% [62,63,65–67].

Table 1. Summary of clinical studies of combination therapy with a SGLT-2i and a GLP-1RA in patients with type 2 diabetes.

Study (duration)	Design	No. of pts	Background therapy	Add-on therapy	Clinical outcomes^a
DURATION-8 (52 weeks) [61]	R, DB	695	MET	ExQW + DAPA	↓ A1c, FPG, BW, and SBP
				ExQW + PBO	No major hypoglycemia reported
				DAPA + PBO
AWARD-10 (24 weeks) [64]	R, DB	424	SGLT-2i ± MET	DULA 0.75 mg	↓ A1c (both DULA doses)
				DULA 1.5 mg	↓ FPG, BW, and SBP (DULA 1.5 mg)
				PBO	1 episode of severe hypoglycemia
Curtis et al. (48 weeks) [65]	Ret, Obs	14	GLP-1RA ± MET ± SU	SGLT-2i	↓ A1c and BW
					Most common AEs were UTI and polydipsia
Deol et al. (3–6 months) [67]	Ret, Obs	79	GLP-1RA ± MET ± INS	SGLT-2i	↓ A1c, BW, BMI, and INS dose
Harashima et al. (52 weeks) [63]	Non-R, PMS	71	LIRA	CANA	↓ A1c, FPG, BW, and SBP; ↑ HDL-C
					Mild hypoglycemia only
Saroka et al. (mean 10.7 months) [66]	Obs	75	GLP-1RA ± other GLTs	CANA	↓ A1c, BW, SBP, and DBP; ↑ HDL-C
					Drug-related AEs were yeast infections, UTI, dry mouth, diarrhea, and hypotension
Seino et al. (52 weeks) [62]	Non-R	76	LIRA	LUSEO	↓ A1c, FPG, BW, fat mass, and waist circumference
					Mild hypoglycemia only
					Most common AE was nasopharyngitis

^aWith combination therapy versus comparator (in randomized studies) or baseline (in non-randomized or observational studies); downward arrow indicates significant reduction; upward arrow indicates significant increase.

A1c: glycated hemoglobin; AE: adverse event; BMI: body mass index; BW: body weight; CANA: canagliflozin; DAPA: dapagliflozin; DB: double blind; DBP: diastolic blood pressure; DULA: dulaglutide; ExQW: exenatide once weekly; FPG: fasting plasma glucose; GLP-1RA: glucagon-like peptide-1 receptor agonist; GLT: glucose-lowering therapy; HDL-C: high-density lipoprotein cholesterol; INS: insulin; LIRA; liraglutide; LUSEO: luseogliflozin; MET: metformin; Non-R: non-randomized; Obs: observational; PBO: placebo; PMS: postmarketing study; R: randomized; Ret: retrospective; SBP: systolic blood pressure; SGLT-2i: sodium–glucose cotransporter-2 inhibitor; SU: sulfonylurea; UTI: urinary tract infection.

6.2 Non-glycemic effects

A multifaceted approach to the management of T2D is important not only to achieve glycemic control by targeting multiple pathophysiologic mechanisms but also to address the risk burden associated with this disease. Most patients with T2D already have CV risk factors before they are even diagnosed. A National Health and Nutrition Examination Survey analysis of the prevalence of risk factors in patients with undiagnosed T2D found that 61.9% of patients had hypertension, 82.6% had hypercholesterolemia, 56.8% were obese, and an additional 29.5% were overweight [68].

According to the 2019 ADA Standards of Care and the 2019 AACE/ACE consensus report, T2D treatment should take a patient-centric approach based on individual patient preferences and needs, including the effects of treatment on CV outcomes, risk factors, body weight, and renal function [3,5]. Furthermore, the ADA Standards of Care and the ADA/EASD and AACE/ACE consensus reports recommend consideration of the patient’s history of CVD when selecting glucose-lowering therapy [3–5]. They recommend SGLT-2is and GLP-1RAs with proven CV benefit for patients with established atherosclerotic CVD, as well as those with HF or CKD.

SGLT-2is and GLP-1RAs have favorable effects on CV risk factors when used alone, but these effects are often augmented when these glucose-lowering therapies are used in combination (Table 2) [43,57]. In the DURATION-8 study, in patients receiving exenatide QW plus dapagliflozin versus those receiving exenatide QW plus placebo or dapagliflozin plus placebo, there were significantly greater reductions in systolic BP (–4.3 vs – 1.2 and – 1.8 mm Hg, respectively; p ≤ 0.022) and body weight (–3.6 vs – 1.6 and – 2.2 kg, respectively; p < 0.001) [69]. There were also greater reductions in triglyceride levels with exenatide QW plus dapagliflozin (–0.31 mmol/L), which reached statistical significance when compared with dapagliflozin plus placebo (–0.11 mmol/L; p = 0.036), but not with exenatide QW plus placebo (–0.18 mmol/L; p = 0.181) [69]. In the AWARD-10 study, addition of dulaglutide 1.5 mg to SGLT-2i therapy was associated with significant reductions compared with placebo in body weight (–3.1 vs – 2.1 kg; p = 0.028) and systolic BP (–4.5 vs – 1.4 mm Hg; p = 0.021) [64]. Other studies in which SGLT-2i therapy was added to GLP-1RA treatment showed similar results, with significant improvements in BP and body weight (Table 1) [62,63,67].

Table 2. Effect of SGLT-2is, GLP-1RAs, and their combination on cardiovascular risk factors or pathophysiologic mechanisms [43,57].^a

	SGLT2is	GLP-1RAs	SGLT-2is + GLP-1RAs
Glycemia (A1c)	↓↓	↓↓	↓↓↓
Insulin sensitivity	↑	↑	↑↑
β-cell function	↑↑	↑↑↑	↑↑↑
Hemodynamics	↑↑	↑	↑↑
Blood pressure	↓	↓	↓↓
Lipid profile	–	↑	↑
Body weight	↓	↓↓	↓↓↓
Visceral fat	↓	↓	↓↓
Endothelial function	–	↑	↑
Natriuresis	↑↑	↑	↑↓
Inflammation	–	↓	↓

Adapted from DeFronzo RA. Combination therapy with GLP-1 receptor agonist and SGLT2 inhibitor. Diabetes Obes Metab. 2017;19(10):1353–1362, Copyright 2017, with permission from John Wiley & Sons Ltd [57].

^aUpward arrows indicate improvement or increase; downward arrows indicate reduction; dashes indicate neutral effect. The number of arrows represent the relative potency of the effect where ↓ = moderate, ↓↓ = strong, and ↓↓↓ = very strong.

A1c: glycated hemoglobin; GLP-1RA: glucagon-like peptide-1 receptor agonist; SGLT-2i: sodium–glucose cotransporter-2 inhibitor.

In addition to their impact on CV risk, SGLT-2is and GLP-1RAs are both potentially beneficial among patients with T2D and nonalcoholic fatty liver disease [40–42,57,70]. As discussed above, both classes of glucose-lowering therapies are associated with improved glycemic control, as well as reductions in body weight and fat tissue, inflammatory markers, lipogenesis, and oxidative stress, and increases in free fatty acid oxidation [70]. Studies have also demonstrated that the reductions in body weight achieved with SGLT-2is and GLP-1RAs can lead to significant improvements in the symptoms of obstructive sleep apnea [71,72]. These data suggest that the combination of an SGLT-2i with a GLP-1RA may be beneficial to patients with T2D and nonalcoholic fatty liver disease or obstructive sleep apnea, although further studies are needed to confirm this hypothesis.

6.3 Safety considerations

Both SGLT-2is and GLP-1RAs are generally well tolerated, with well-known safety profiles [73]. Individually, agents from either class are associated with a low risk of hypoglycemia, which is due to GLP-1RAs’ glucose-dependent mechanism of action and SGLT-2is’ insulin-independent mechanism of action [73]. Although in DURATION-8, the incidence of hypoglycemia was low with no major events observed; minor and other hypoglycemic events were more frequent with the combination of exenatide QW plus dapagliflozin (1.7% and 6.9%, respectively) compared with exenatide QW plus placebo (0% and 3.5%) or dapagliflozin plus placebo (0.4% and 3.4%) [74].

The most common adverse events (AEs) with SGLT-2is as a class are genital mycotic infections in female and male patients [75], while nausea and vomiting are common with GLP-1RAs, reflecting their mechanisms of action (genitourinary system for SGLT-2is and gastrointestinal tract for GLP-1RAs) [73]. Therefore, the combination of an SGLT-2i and a GLP-1RA was not associated with an increased risk of any AE, serious AEs, or specific AEs compared with the individual use of these agents in the DURATION-8 study [61].

The US prescribing information for canagliflozin carries a boxed warning regarding the risk of lower limb amputation in patients with established CVD or high CVD risk and risk factors for amputation (diabetic foot ulcers, history of prior amputation, neuropathy, or peripheral vascular disease) [76]. This warning was based on an increased risk of lower limb amputation versus placebo seen in the CANVAS study (6.3 vs 3.4 events per 1000 patient-years; HR, 1.97; 95% CI, 1.41–2.75; p < 0.001), which was highest in patients who had a history of amputation or peripheral vascular disease [15]. However, in the CREDENCE trial, treatment with canagliflozin was not associated with an increased risk of lower limb amputation [77]. Similarly, an increased risk of fracture was observed in the canagliflozin arm versus the placebo arm of the CANVAS study (15.4 vs 11.9 fractures per 1000 patient-years; HR, 1.26; 95% CI, 1.04–1.52; p = 0.02) [15]. Ertugliflozin US prescribing information also has warnings and precautions about the increased risk of lower limb amputation based on observations in ertugliflozin clinical studies. Nontraumatic lower limb amputations were reported in 11 ertugliflozin-treated patients (3 [0.2%] with ertugliflozin 5 mg and 8 [0.5%] with ertugliflozin 15 mg) across seven ertugliflozin phase 3 clinical trials [78]. Although a number of analyses have been undertaken to examine the relationship between SGLT-2is and lower limb amputation or fracture, additional studies may be required as the data are inconsistent and there is no conclusive answer as to whether these agents increase the risk of these events, outside of the safety signal identified in the CANVAS study [73,79–81].

Cases of euglycemic ketoacidosis during SGLT-2i therapy have been reported in patients with T2D and type 1 diabetes (off-label use) [82,83], most of which were associated with precipitating factors, such as infection, dose reduction or discontinuation of exogenous insulin therapy, alcohol use, and food restriction [83]. Therefore, the US Food and Drug Administration recommends discontinuation of SGLT-2i therapy in patients who develop symptoms of ketoacidosis, including nausea, vomiting, abdominal pain, fatigue, and dyspnea [83].

Long-acting GLP-1RAs carry a boxed warning about the potential for thyroid C-cell tumors, which is based on animal data. While it is not known if these agents cause thyroid tumors in humans, they are contraindicated in patients with a personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [84–87].

7. Clinical considerations and conclusions

In most patients with T2D, an effective treatment strategy includes a combination therapy regimen that targets more than one of the underlying pathophysiologic defects [22]. However, more than half of patients do not achieve their A1c goal when treated with an add-on therapy to metformin [88]. The majority of patients with T2D will require more comprehensive management of disease-related risk factors, since most patients present with at least one CV risk factor before being diagnosed with T2D, such as overweight/obesity, hypertension, or dyslipidemia [68].

Although treatment guidelines do not advocate one specific add-on therapy over another, the AACE/ACE consensus report suggests a hierarchy of recommended usage for add-on glucose-lowering therapy drug classes [5], and all guidelines provide recommendations based on the presence or absence of CVD or CKD (Figure 2) [3–5]. The guidelines recommend agents with proven effectiveness on CV outcomes for patients with established CVD, such as SGLT-2is and GLP-1RAs [3–5]. For patients with and without CVD, the recommendations also highlight the importance of choosing a therapy designed to address the patient’s risk profile (eg, hypoglycemia or body weight gain), AEs, cost, and patient preferences [3–5]. Therefore, guideline-compliant treatment choices for most patients would include agents that have favorable effects on CV risk factors, such as body weight, BP, and lipid parameters, as well as renal function.

Despite these recommendat ions, US physicians tend to prescribe older agents such as sulfonylureas and DPP-4is when choosing add-on therapy to metformin [89]. In fact, a study of second-line therapy for T2D in the United States showed that 42% of prescriptions for second-line therapy were sulfonylureas [89], despite the known effects of these agents on weight gain and hypoglycemia [22], and the US prescribing information for sulfonylureas carrying a special warning of the increased risk of CV mortality [90–92].

As described in this review, the combination of an SGLT-2i and a GLP-1RA has an additive or nearly additive effect on A1c, BP, body weight, and potentially lipids, compared with either of these agents alone [69]. Therefore, the use of SGLT-2i plus GLP-1RA combination therapy may lead to some patients requiring less-intensive BP therapy to meet therapeutic targets, thereby limiting the number and/or dose of other medications that are needed.

Use of subcutaneous GLP-1RAs may lead to poor treatment adherence, as some patients may be resistant to the use of an injected therapy [93]. However, GLP-1RA injectable therapy is probably less burdensome for patients than injection of insulin because many GLP-1RAs (exenatide QW [approved in 2012] and exenatide QW in an autoinjector [2018], dulaglutide [2014], and semaglutide [2017]) require only once-weekly dosing and have improved injection devices [85–87,94]. In addition, SGLT-2is and GLP-1RAs are associated with weight loss and a low incidence of hypoglycemia [73,95], both of which may be more acceptable to patients than insulin. Data from the United Kingdom indicate that a combination of an SGLT-2i and a GLP-1RA may delay the introduction of insulin by 5–6 years [96]. However, the potential risk of hypoglycemia, although low but more frequent with exenatide QW plus dapagliflozin therapy in DURATION-8 [61], will need to be considered in relation to other agents such as sulfonylurea and insulin when contemplating therapy with this option.

In summary, the complementary effects of SGLT-2is and GLP-1RAs on the defects associated with T2D make the combination an effective option for achieving durable glycemic control along with reducing CV risk. Additional long-term clinical studies may provide further insights into the durability of glycemic control and CV risk mitigation with combination therapy in patients with T2D.

Declaration of interest

R Lajara has received consulting fees from and participated on speakers bureaus for AstraZeneca, Boehringer Ingelheim–Lilly, Novo Nordisk, Sanofi, and Valeritas.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Acknowledgments

Catherine Rees and Sarah Greig, PhD, of inScience Communications, Springer Healthcare (Auckland, New Zealand), provided medical writing support funded by AstraZeneca.

Supplementary Materials

The supplementary data for this article can be accessed here.

Additional information

Funding

The development of this manuscript was supported by AstraZeneca. A reviewer on this manuscript has disclosed that they are a regional, speaker for canagliflozin under sponsorship, by Janssen Pharmaceuticals. The other peer reviewers on the manuscript have no other relevant financial relationships or otherwise to disclose.