Clinical effect of combined treatment of sodium–glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1Ra) have attracted attention. They have cardiorenal benefits for decreased major adverse cardiovascular events (MACE). Compared with only GLP-1Ra, combined SGLT2i /GLP-1Ra showed lower risk of MACE (HR 0.70) and severe renal events (HR 0.43). It was examined whether renal outcome may be different when SGLT2i or GLP1Ra was provided first or second. Consequently, the addition of SGLT2i to baseline GLP1Ra may contribute rather favorable renal outcomes. As annual eGFR decline (pre /post), cases for SGLT2i first followed by GLP1Ra showed -3.5/-0.4 mL/min/1.73m2/year

In recent years, adequate treatment for type 2 diabetes (T2D) has been in discussion across the world. Several types of oral hypoglycemic agents (OHAs) have been introduced to medical practice, including sodium–glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1Ra). Each OHA has showed the reduced risk of cardio-renal outcomes and also related death in T2D patients [1]. Clinical effect of combined these agents, however, has not been clarified widely for cardio-renal outcomes. Various cardio-renal problems in T2D have been analyzed and future perspectives would be expected for the comparison with single and combination of SGLT2i and GLP1Ra.

For the purpose of the novel study, the combination treatment of GLP1Ra and SGLT2i may contribute the decreased risk of major adverse cardiovascular events (MACE) and some crucial renal events, when compared with either agent for T2D patients [2]. Another purpose includes the assessment of clinical efficacy of combined treatment in the light of each factor of MACE, all-cause mortality and heart failure. The design of the study was applied as population-based cohort investigation.

By effective United Kingdom database, the researchers have applied about 6700 cases with long diabetes history [3]. The applicants were started GLP1Ra and provided SGLT2i in simultaneous or subsequent manners for lasting 8 years. These cases were matched for similar cases who were given 6700 cases that began GLP1Ra without SGLT2i. Furthermore, about 8900 cases that started SGLT2i associated with GLP1Ra were also matched with 8900 cases that began SGLT2i without GLP1Ra. For these protocols, the follow-up period for both compared study was about 9 months in median.

As main outcome measure, cox proportional hazard models were applied for evaluation of Hazard ratios (HR) and 95% confidence intervals of MACE and severe renal events. They are compared with combined two agents and background agent. For secondary outcomes, individual factors of heart failure, all-cause mortality and MACE. In this study, impressive results were shown [3]. Compared with only GLP1Ra, combined SGLT2i and GLP1Ra showed 30% lower risk of MACE (HR 0.70, 95%, 0.44-0.99, 7.0 vs 10.3 events per 1000 person-years), and 57% lower risk of renal evens (HR 0.43, 0.23-0.80, 2.0 vs 4.6), respectively. Compared with only SGLT2i, combined agents showed 29% lower risk of MACE, and serious renal events showed wider confidence interval (HR 0.67, 0.32-1.41). Secondary outcomes revealed similar results, associated with wider confidence intervals. In conclusion, this cohort study showed combined agents showed lower risk of MACE and renal evens in comparison with either agent alone.

Among three OHAs of SGLT2i, GLP1Ra, and DPP4i, comparative efficacy was evaluated for preventing hyperkalemia in T2D patients [4]. Population-based cohort study was conducted for 9 years. The participants included 1:1 propensity score (PS)-matched T2D adults who started SGLT2i vs DPP4i (n=778 thousand), GLP1Ra vs DPP4i (n=729 thousand), and SGLT2i vs GLP1Ra (n=873 thousand). Main outcome was evaluated as hyperkalemia diagnosis. Secondary outcomes included definition of hyperkalemia as K (potassium) ?5.5 mmol/L for various situations. SGLT2i treatment showed lower hyperkalemia incidence than DPP4i as HR 0.75, and slight decrease than GLP1Ra (HR 0.92). GLP1Ra showed lower hyperkalemia than DPP4i (HR 0.79). Three-year risk showed 2.4% lower in SGLT2i than DPP4i, 1.8% lower for GLP1Ra than DPP4i. These findings showed similarity for secondary outcomes. In comparison with DPP4i, lower incidence of hyperkalemia was observed for individual agents in SGLT2i and GLP1Ra.

From the standard guideline of the International Diabetes Practice Guidelines for CKD, Kidney Disease Improving Global Outcomes (KDIGO) 2022, SGLT2i and metformin have been listed as the first-line drug therapies for diabetes-associated CKD, and GLP1Ra has been preferred as the second-line drug therapy [5]. Despite of reno-protective efficacy of both SGLT2i and GLP1Ra, actual effect of combined treatment has not been fully studied. In order to clarify this, a research group was established which name is RECAP study. It stands for the renoprotective effects of combination treatment with SGLT2i and GLP1Ra in patients with T2D according to their preceding medication in Japan. For the recent result concerning the combined therapy, the preceding agent did not influence renal composite outcome [6]. Then, further study of RECAP has been conducted.

Among T2D patients, approximately 40% cases develop CKD, and 15.3% of T2D cases show decreased renal function (eGFR <60 mL/min/1.73m²) [7]. From RECAP data, it was examined whether renal outcome may be different when SGLT2i or GLP1RA was provided first or second. For protocol, the PS-matched model was analyzed for 132 paired cases [8]. As a result, the incidence of renal composite outcomes was not different between the two groups. However, the win ratio of GLP1RA vs SGLT2i was significant. Consequently, these results suggest the addition of SGLT2i to baseline GLP1RA may contribute rather favorable renal outcomes.

The significance of the report can be summarized into three points. They are i) it is the first report in real-world data for the comparison of SGLT2i and GLP1RA whether differences in the preceding agent may be present for renal prognosis of CKD cases, ii) when related background factors were matched by PS matching, analysis method showed that GLP1RA-first group may have more effective protection on renal function than SGLT2i-first group, and iii) GLP1Ra-first group may show higher efficacy in inhibiting the progression of albuminuria [8].

As to albuminuria, meta-analysis was performed for 34412 cases in 17 studies [9]. The combined therapy with SGLT2i and MRA showed lower albuminuria compared with treatment of MRA, SGLT2i, or placebo alone as -32.3%, -32.4%, and -65.2% respectively. Therapy of MRA or SGLT2i alone showed significant decrease in UACR compared with placebo as -32.9%, -31.0%, respectively. Thus, combined treatment of MRA and SGLT2-i contributed lower albuminuria in T2D patients than monotherapy.

The combination of SGLT2i and GLP1Ra contribute cardio-renal protection for T2D patients. As research protocol, 643 T2D cases included 331 cases for GLP1Ra given first, and 312 SGLT2i given first [10]. As annual eGFR decline (pre /post), cases for SGLT2i first followed by GLP1Ra showed -3.5/-0.4 mL/min/1.73m²/year (p<0.001), and cases for GLP1Ra followed by SGLT2i showed -2.0/-1.8 mL/min/1.73m²/year (p=0.83). These data suggested that eGFR decline may be affected by the preceding agent.

In summary, the latest perspectives concerning cardio-renal effect for SGLT2i and GLP1Ra were described in this article. It will hopefully become useful reference for diabetic research and practice.

Conflict of Interest

The authors declare no conflict of interest.

Funding

There was no funding received for this paper.

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