SGLT1/SGLT2/DPP4 Inhibitor(Tonghua Dongbao Pharmaceutical Co., Ltd.)

Some sodium-glucose co-transporter-2 (SGLT2) inhibitors showed benefits on heart failure (HF), but different SGLT2/SGLT1 selectivity might influence the treatment effect. This study aimed to meta-analyze the treatment effects of SGLT2 inhibitors and the diversity of receptor selectivity for patients with and without HF.

Randomized controlled trials were searched in PubMed, Embase, Cochrane databases and ClinicalTrials.gov registry from inception to October 2020. The interest outcomes were analyzed with random-effects models and presented with a risk ratio (RR) and 95% confidence interval (CI). Subgroup analyses examined the treatment effects among SGLT2 inhibitors with different SGLT2/SGLT1 selectivity.

The final analyses included 10 trials and 52,607 patients. The RR of total cardiovascular (CV) death or hospitalization for HF (HHF) between SGLT2 inhibitors and placebo was 0.79 (95% CI 0.74–0.84, I2 = 31%). With SGLT2 inhibitors, HF patients had reduced mortality risks (RR 0.89, 95% CI 0.80–0.99, I2 = 0), and non-HF patients had lower risks of major adverse CV events (RR 0.92, 95% CI 0.85–0.99, I2 = 0). The risk reduction of HHF was consistent in groups of HF (RR 0.72, 95% CI 0.64–0.80, I2 = 8%) and non-HF (RR 0.74, 95% CI 0.61–0.89, I2 = 0), but the effect of the low SGLT2/SGLT1 selectivity inhibitor was insignificant in non-HF patients.

The efficacy of SGLT2 inhibitors on risk reduction of total CV death or HHF is consistent with the previous studies. The regimen is beneficial for reducing mortality in patients with HF and major adverse CV events in those without HF. Different SGLT2/SGLT1 selectivity may differ in the treatment effects in patients with and without HF.

The Role of Combined SGLT1/SGLT2 Inhibition in Reducing the Incidence of Stroke and Myocardial Infarction in Patients with Type 2 Diabetes Mellitus (T2DM) we disagree with few of the statements, and we have some diferent opinions for the arguments in this paper.First of all, the statements we disagree with are as follows: InSCORED, the authors pointed that "the relative increase in SGLT1 vs SGLT2 inhibition with sotaglifozin resulting in a greater reduction in MI and stroke" and "sotaglifozin reduced total fatal and nonfatal MI by 32, total fatal and nonfatal stroke by 34, and HHF and urgent visits for HF by 33," but the authors misquoted SOLOIST instead of SCORED in the reference On the contrary, the relative risk of MI and stroke was not reduced in patients with diabetes and recent worsening heart failure (WHF) from the SOLOIST trial .Therefore, we believe that "the patients with diabetes and chronic kidney disease (CKD)" should be added as a restriction. As shown in Table 1, the P values of MI and stroke in the SOLOIST trial were 0.451 and 0.377, resp., which were not statistically signifcant.They were statistically signifcant in the SCORED trial. However, if we combine the two studies, 68 patients (1.2) on sotaglifozin had MI vs. 94 patients (1.6) on placebo, which showed that the diference was statistically signifcant (P value=0.04), whereas even if these two studies were combined, the diference in stroke was still not statistically signifcant, so we do not have current support for sotaglifozin in reducing MI or stroke in patients with T2DM and heart failure.Secondly, we have some ideas to explain the discrepancy in the rate of MI and stroke between patients with diabetes and CKD and patients with diabetes and WHF.SGLT1 was highly expressed in normal human cardiomyocytes. Glucose reabsorption can be maintained 40-50after using SGLT2 inhibitors, which was due to the compensatory increase in the reabsorption of glucose by SGLT1.SGLT1 could mediate the response to insulin and leptin to increase cardiac glucose uptake.In the stage of ischemiareperfusion injury, cardiac SGLT1 played an active role by compensatory increasing the absorption of glucose and providing energy for the heart.Furthermore, the SGLT1 knockout mice developed a glucose-galactose malabsorption syndrome.This shows that the presence of SGLT1 is necessary for heart function. In patients with diabetes and WHF, the use of sotaglifozin may inhibit the compensatory increase of SGLT1, which may lead to the reduction or even loss of the beneft of failing heart (compared to the use of SGLT2 inhibitors alone).However, in patients with diabetes and CKD, the absolute fltered glucose content decreased due to impaired renal function, and inhibition of SGLT1 would help alleviate the harm caused by excessive glucose retention in the body due to impaired renal function.However, most of these data come from animal models, and data from clin. trials hierarchically are more important than data from animal studies. Therefore, further clin. trials need to be carried out to answer existing questions. On the other hand, the SOLOIST was a relatively small study that ended early because of a loss of funding. The median followup was only 9 mo (vs. 16 mo in the SCORED trial).This could be an explanation for the less of efects on MI and stroke in SOLOIST.In a nutshell overall, although the lack of SGLT1 was harmful to heart function, the overexpression of SGLT1 could lead to severe pathol. changes, even leading to cardiac hypertrophy and heart failure.In addition, sotaglifozin had a more increased risk of diabetic ketoacidosis when combined with insulin treatment.Therefore, we put forward the hypothesis that maintaining SGLT1 in an appropriate range is necessary for normal heart function.We believe that the statement regarding the use of SGLT1/ SGLT2 inhibitors to reduce MI and stroke risk remains to be discussed.According to the manuscript that the authors mainly relied on, currently, the conclusion could only be cautiously drawn in patients with diabetes and CKD.Furthermore, the use of SGLT1/SGLT2 inhibitors should exclude a deleterious effect on the heart.