Scoping Review

The databases and resource searches yielded 1753 records. After duplicates were removed, 860 were screened, and 54 were selected on the basis of title and abstract evaluation. Four studies were excluded following the full-text article assessment. Finally, 50 studies were included in the final report [12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61]. See Fig. 1 for the PRISMA flow diagram for selecting studies and the reasons for excluding full-text articles. The main characteristics of the studies included are summarized in Supplementary Table 2.

Fig. 1

PRISMA flow diagram. GLP-1Ras Glucagon-like peptide-1 receptor agonists. SGLT2is Sodium-glucose cotransporter-2 inhibitors. DPP4is Dipeptidyl Peptidase IV inhibitors

The combined use of these medications was first reported in 2014 [61], and the number of studies has grown exponentially since then. Observational studies, clinical trials, and post hoc analyses were the most common types of designs used. Figure 2 shows the distribution of the years of publication of the 50 studies in this review.

Fig. 2

Temporal distribution of studies included in this review

The number of patients included in the studies ranges from 1 (case report) to 440.089, with a median of 355 (IQR 1295) subjects. This reveals great variability in sample size derived from various methodological designs. Figure 3 shows the distribution of the total number of subjects in the studies included in this review.

Fig. 3

Distribution of sample sizes in the included studies

Studies reporting metabolic outcomes were the most common, followed by renal and cardiovascular outcomes. The follow-up time ranges from 1.5 to 60 months. Most studies reported the use of several SGLT2is and GLP1-RAs simultaneously. However, in the studies that reported the use of a specific medication, the most frequently used SGLT2i was dapagliflozin (10/54), followed by empagliflozin (5/54) and canagliflozin (5/54) and the most frequently used GLP1-RA was exenatide (10/54) followed by semaglutide (6/54) and liraglutide (5/54). Additionally, 21 studies reported the use of combination therapy as an add-on prescription.

Metabolic Outcomes

Thirty-five of the studies reported changes in HbA1c or body weight. A critical aspect of glycemic control studies is the number of years since the population’s DM diagnosis, and most studies have reported this characteristic, which ranges from around 5 to 16 years.

Studies Without a Comparison Group

Table 1 provides a summary of studies that did not include a comparison group. Six of these studies reported the combination therapy as an add-on treatment. All studies documented reductions in HbA1c, ranging from 0.2% to 0.92%, as well as reductions in body weight, ranging from 1.3 to 1.5 kg.

Table 1 Metabolic outcome studies without comparison groupStudies with a Comparison Group and GLP1-RAs and SGLT2is Used Simultaneously

Table 2 presents the studies that examined the simultaneous use of combined therapy. Eleven out of 15 studies reported changes in HbA1c, with the most significant reductions observed when compared to placebo. Studies comparing the combined therapy to individual medications found greater reductions against SGLT2is than GLP1-RAs. Nine studies reported changes in body weight, with the most substantial reductions observed in comparisons against placebo.

Table 2 Metabolic outcome studies with the combination used simultaneously, glycemic outcome

Only one study compared GLP1-RAs [51]. Combination therapy with liraglutide yielded greater HbA1c and weight reductions compared to dulaglutide.

Studies with Comparison Group and GLP1-RAs or SGLT2is Used As Add-on Therapy

Six studies reported metabolic outcomes with an add-on treatment modality. The results are summarized in Table 3. There is no difference in glucose reduction compared to the add-on of GLP1-RAs first or the SGLT2is first. However, weight reduction appears to be more substantial when the GLP1-RA is added first.

Table 3 Metabolic outcome studies with the combination used as add-on therapy: glycemic outcome and weight outcomeSystematic Reviews and Meta-analyses

Four meta-analyses analyzed the metabolic outcomes of the combined therapy. The results from these studies are presented in Table 4. Two meta-analyses evaluated the add-on modality of treatment. In all the studies, the combined therapy was superior to other diabetes treatment options or each medication separately in reducing HbA1c and weight. The effect is more significant when compared to SGLT2is.

Table 4 Metabolic outcome from meta-analysisCardiovascular Outcomes

Cardiovascular outcomes were assessed in 14 studies; one was a meta-analysis, and all had a comparison group. Most of the studies evaluated the cardiovascular outcomes using a composite outcome of major adverse cardiac events (MACE) or one of its components, cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Table 5 summarizes the results from cardiovascular studies. In most studies, the combination therapy was related to a significant reduction of the risk of MACE, heart failure, or death from any cause. Only two studies evaluated the add-on therapy [31, 39] with similar results to the simultaneous use.

Table 5 Cardiovascular outcomes studiesSystematic Reviews and Meta-analyses

One collaborative meta-analysis that synthesized the cardiovascular outcomes reported the results from four studies and 45,568 patients on the add-on therapy modalities [20]. SGLT2is reduced the risk of major adverse cardiovascular events (MACE) in participants both receiving and not receiving GLP1-RAs, HR 0.81 (95% CI 0.63–1.03) vs HR 0.90 (95% CI 0.86–0.94; p heterogeneity = 0.31).

Renal Outcomes

Sixteen studies, including one meta-analysis, reported at least one renal outcome. Six studies used a composite outcome, and the component outcomes differed. Table 6 summarizes the studies with renal outcomes.

Table 6 Renal outcome studies reporting a composite outcomeStudies Using a Composite Outcome

Most composite outcomes included changes in the estimated glomerular filtration rate (eGFR) or urine albumin-to-creatinine ratio (ACR). Half of them included end-stage renal disease, and two included death either by kidney disease or cardiovascular causes. Half of the studies reported a reduction in the risk of the composite outcome, similar to the add-on therapy or simultaneous use of the medications.

Studies Using a Simple Outcome

Most studies assessed changes in the eGFR or ACR. When compared to monotherapy, the majority reported nonsignificant changes. However, compared to standard treatment or other forms of treatment, the combination was associated with significant reductions in these outcomes.

Adverse Effects

Adverse effects were primarily reported descriptively. Twenty-seven studies reported adverse effects, which are summarized in Supplementary Table 3. Gastrointestinal adverse effects were more commonly reported in the GLP-1 receptor agonist groups, while genital mycotic infections and volume depletion-related adverse effects were more frequently observed in the SGLT2 inhibitor groups. No increase in the risk of amputations or ketoacidosis was reported.

Nominal Group TechniqueBenefits of Combining SGLT2 Inhibitors with GLP-1 Receptor Agonists on Metabolic Outcomes

The experts agreed that both medications operate through distinct mechanisms, resulting in a complementary pharmacodynamic effect related to insulin resistance, hemodynamic factors, and inflammatory pathways.

The data analysis from the scoping review indicates that the impact of combined use on glucose control is more pronounced than the effect on weight reduction. Additionally, sequential use of the medications, starting with GLP-1 receptor agonists, appears to lead to more significant weight loss.

Finally, summarizing the data on metabolic outcomes is challenging because of significant variability in effects. Nonetheless, the net effect from the meta-analysis supports the combined therapy, although it exhibits considerable heterogeneity and includes very few studies.

Benefits of Combining SGLT2 Inhibitors with GLP-1 Receptor Agonists on Cardiovascular Outcomes

The summarized information indicates that the evidence from primary prevention studies is less robust than that derived from secondary prevention studies. Additionally, the effects of combined therapy appear to differ between major cardiovascular events and heart failure-related outcomes.

The experts concurred that the differences in the action mechanisms may partially explain these results and could also help mitigate the undesirable cardiovascular physiological effects such as the increase of heart rate.

Finally, a discussion emerged regarding a specific population that may significantly benefit from combined therapy: individuals with obesity and T2D and high or very high cardiovascular risk or obesity.

Benefits of Combining SGLT2 Inhibitors with GLP-1 Receptor Agonists on Renal Outcomes

Experts believe that one of the main challenges surrounding kidney outcomes is the lack of consensus on the definition of composite outcomes used in different studies. Several competing risks may hinder the identification of positive results in kidney trials, particularly cardiovascular outcomes. Furthermore, the benefits observed in surrogate outcomes may stem from changes in glucose control, weight reduction, or alterations in blood pressure, complicating results analyses.

Despite the contradictory data regarding kidney outcomes, two surrogate outcomes benefit the most from combined therapy: the decline in eGFR slope and the reduction in urinary albumin-to-creatinine ratio.

How Quickly Should Treatment Be Initiated in First-Line Combination Therapy or Sequential Therapy, and Does This Depend on Any Specific Circumstances?

The experts agreed that the choice between sequential and combined therapy largely depends on patient factors such as cardiovascular risk, stages of chronic kidney disease, comorbidities, body weight, and HbA1c levels. Therapeutic goals and patient tolerance should guide decisions, which may also be influenced by the circumstances of the healthcare system and reimbursement policies. Sequential therapy is more common in clinical practice, and decisions should be made promptly within 3–6 months and based on clinical or biochemical established goals.

When the moderator asked the experts to describe an ideal patient for combined therapy, each group of specialists reached a different conclusion. These are summarized in Fig. 4.

Cardiologists recommended combined therapy for patients with established cardiovascular disease or high cardiovascular risk who were already on treatment with one of the two drugs and had an HbA1c above target. On the other hand, patients with heart failure irrespective of LVEF were advised to receive SGLT2is, and those with atherosclerotic cardiovascular disease were advised to receive GLP1-RAs irrespective of their HbA1c levels.

Nephrologists defined their ideal patient as someone with diabetic kidney disease exhibiting persistently elevated urinary albumin-to-creatinine ratio (ACR) or decline in eGFR with proper renin–angiotensin–aldosterone system (RAAS) blockade, starting with SGLT2is first and subsequently adding GLP1-RAs.

Endocrinologists viewed their ideal patient as an individual with established cardiovascular disease or high cardiovascular risk, including those with diabetic kidney disease, who are already being treated with more than one oral medication (including either SGLT2is or GLP1-RAs) and an HbA1c level exceeding the established target.

Fig. 4

Patient phenotypes and recommended treatments according to metabolic, cardiovascular, or renal risk. A1c Glycosylated hemoglobin; ASCVD Atherosclerotic cardiovascular disease; CV Cardiovascular; eGFR Estimated glomerular filtration rate; UACR Urine albumin-creatinine ratio; CKD Chronic kidney disease; T2D Type 2 diabetes; HF Heart failure; LVEF Left ventricular ejection fraction; SGLT2 inh Sodium-glucose co-transporter type 2 inhibitors; GLP-1Ra Glucagon-like peptide receptor antagonists. ASCVD includes coronary disease, stroke, and peripheral arterial disease

What Could Be the Main Challenges Associated with the Combination of SGLT2is and GLP1-RAs in Daily Clinical Practice?

During the item generation and discussion and clarification phases, the experts identified 14 distinct challenges: costs, supply challenges, lack of evidence, polypharmacy, barriers to prescription, lack of knowledge, adherence concerns, aversion to injection therapy, clinical inertia, titration needs, perceived health state, fear of adverse effects, lack of clinical guideline recommendations, and lack of measurable outcomes to guide therapy. Each expert independently ranked these challenges. One panel member, an endocrinologist, was absent from this discussion. Figure 5 displays individual rater scores and the combined score for each challenge. The experts perceived costs, barriers to prescription, and adherence concerns as the primary challenges.

Fig. 5

Challenges associated with the combination of SGLT2is and GLP-1Ras in daily clinical practice. a Heat map of the individual scores from each panelist. b Radar chart showing the total score for each challenge (a higher number indicates greater importance)

Does the Medication of Each Group Make a Difference or Is There a Class Effect?

The evidence suggests that specific GLP1-RAs have differing effects, primarily on weight reduction and glucose-lowering. There appear to be no significant differences for other outcomes and for different SGLTis. For that reason, at the time of prescription, the decision of an specific GLP1-RA should be made on the basis of its differential effect on HbA1c and weight.

Do the Benefits Outweigh the Risks of Combined Therapy?

The experts believe that the complementary rather than synergistic mechanisms of action make it unlikely that the well-known class effects of GLP1-RAs and SGLT2is will differ in combination. The evidence suggests a low frequency of serious adverse effects, and these do not impact the effectiveness of the combination.

One of the expert panel’s main concerns is identifying which medication is responsible for an unusual adverse effect when both are initiated simultaneously. However, this is less of an issue for well-known class-specific adverse effects. Evidence from combination studies reinforces findings from studies on individual medications, indicating that most adverse effects are transient and frequent ones are easily managed.

Expert Insights

Most people with T2D will eventually need combined therapy, and the GLP1-RAs/SGLT2is combination may prove more effective in some groups of patients.

Combining GLP1-RAs/SGLT2is for glucose control could be more effective than other antidiabetic combinations. This is probably due to the effectiveness of GLP1-RAs in reducing glucose. However, evidence suggests that the combination’s effect is not additive.

Sound mechanistic evidence supports the need for further research on the GLP1-RAs/SGLT2is combination’s ability to modify specific risk outcomes, such as cardiovascular risk and the progression of diabetic kidney disease.

Combined sequential therapy has become more common in real-world medical practice. Experts believe that this approach is more suitable for most situations. Clear clinical or biochemical goals should guide the decision regarding the order and timing for combined therapy, but the decision needs to be made promptly.

Experts believe that for heart failure and diabetic kidney disease, SGLT2is should come first.

For patients with diabetic kidney disease, the glucose-lowering effect of SGLT2is may be impaired. Poor glycemic control, persistent albuminuria, and continuous decline in eGFR should lead to the addition of a GLP1-RAs with proven renal benefit.

Although most studies included several medications, current guidelines recommend selecting GLP1-RAs and SGLT2is on the basis of their clinically proven benefits rather than class alone. These benefits include cardiovascular risk reduction, heart failure hospitalization rate reduction, kidney disease progression risk reduction, and weight loss. Experts believe that this approach should also guide the selection of medications combined therapy.

Experts agree that nonmedical conditions such as availability, reimbursement policies, and costs may limit GLP1-RAs/SGLT2is combined therapy.