From International Circulation

Strategies of strict blood pressure management and drastic cholesterol reduction have been shown to significantly reduce the risk of atherosclerotic cardiovascular disease (ASCVD) in both diabetic and non-diabetic patients. However, although a large number of basic studies have shown that the disorder of glucose metabolism has extensive and far-reaching adverse effects on blood vessels, heart, brain and kidney, the effect of hypoglycemic treatment on significantly reducing the risk of ASCVD in diabetic patients has not been proven until the results of the EMPA-REG OUTCOMES study [1] and CANVAS study [2] are revealed. The sodium-glucose cotransporter 2 (SGLT-2) inhibitors Engliazine and cagliazine reduced MACE events (death from cardiovascular events, non-fatal myocardial infarction, non-fatal cerebral infarction) and hospitalisations for heart failure in patients with diabetes with cardiovascular disease or high cardiovascular risk. This means that clinical hypoglycemic treatment strategy has entered a new era of cardiovascular protection.

1. Pathophysiology and SGLT-2 inhibitors of SGLT-2

Glucose is the main source of energy for human cells to maintain normal metabolism, but the phospholipid bilayer structure of cell membrane is not permeable to glucose molecules. Glucose can only pass through the cell membrane with the assistance of glucose cotransporters. SGLT is one of the most important ways to transport glucose into cells through the transmembrane Na+ gradient of cell membrane to provide metabolic substrate for the energy generation of intracellular mitochondria.

There are 6 subtypes of SGLT, of which SGLT-1 and SGLT-2 are encoded by the SLC5A family genes. Almost all SGLT-2 was expressed in the proximal convoluted tubule S1 segment of renal tubules. Under normal physiological conditions, about 180 g of glucose per day is filtered through the glomerulus and fully reabsorbed by SGLT-2 and SGLT-1. SGLT-2 is responsible for 90% of the glucose reabsorption and SGLT-1 is responsible for the remaining 10%. When human plasma glucose concentration exceeds 200-250 mg/dl, SGLT-2 reaches saturation threshold and produces glycosuria. Increased expression of SGLT-2 in proximal convoluted tubules in patients with diabetes significantly increases the saturation threshold and leads to increased glucose reabsorption, thus maintaining high plasma glucose levels. By selectively inhibiting the transport function of SGLT-2, SGLT-2 inhibitors significantly reduce the threshold of SGLT-2, inhibit glucose reabsorption, and increase the excretion of glucose out of the body with urine, thus achieving the therapeutic effect of significantly reducing blood glucose levels.

Currently, there are four SGLT-2 inhibitors: empagliflozin, dapagliflozin, canagliflozin and ertugliflozin approved for the marketing of diabetes mellitus as a hypoglycemic treatment. The four SGLT-2 inhibitors showed different degrees of selective inhibition of SGLT-2, with high selectivity being Engliazine, Dagliazine and ertugliflozin, and moderate selectivity being Cagliazine. The four SGLT-2 inhibitors had similar pharmacokinetic characteristics, and were administered orally once a day with a half-life of more than 10 h.

2. Traditional hypoglycemic drugs cannot meet the needs of reducing the risk of ASCVD

Diabetes is one of the most important risk factors for atherosclerosis and cardiovascular disease. Epidemiological studies have shown that more than 75% of people with diabetes die from cardiovascular disease, and the risk of myocardial infarction is four times higher in people with diabetes than in people without diabetes. Therefore, for decades, clinicians and scientists have been searching for drugs and treatment strategies that can safely reduce blood sugar levels while greatly improving cardiovascular outcomes in patients with diabetes.

Since insulin has been successfully extracted and purified and widely used in clinical hypoglycemic treatment, the acute and severe condition that endangers life and health caused by severe hyperglycemia has been significantly controlled. Subsequently, oral hypoglycemic drugs such as biguanides and sulfonylureas have been introduced successively, making the blood glucose management of clinical diabetes increasingly accessible and convenient. Combined hypoglycemic drug therapy makes it possible to strictly manage blood glucose levels. However, intensive hypoglycemic therapy did not significantly reduce the risk of cardiovascular disease in diabetic patients.

Metformin plays a hypoglycemic role by reducing liver sugar production, reducing intestinal glucose absorption, increasing peripheral tissue sugar uptake and utilization, and improving insulin sensitivity. The UKPDS study showed that metformin can reduce the risk of cardiovascular events in long-term hypoglycemic treatment compared with sulfonylureas.

However, several studies have suggested that insulin, thiazolidinediones, sulfonylureas, and α-glycosidase inhibitors, while effective in lowering blood glucose, do not significantly improve cardiovascular outcomes in patients with diabetes. Insulin increases the risk of fluid retention and worsens existing heart failure; Thiazolidinedione and sulfonylureas have been identified in multiple randomized controlled studies to increase the risk of heart failure. Therefore, traditional hypoglycemic drugs should be used cautiously and prohibited in patients with diabetes and cardiovascular diseases, especially in patients with cardiac insufficiency.

3. SGLT-2 inhibitors in the treatment of diabetes: a new model of heart, brain and kidney protection

SGLT-2 inhibitors reduce blood sugar levels by increasing the excretion of glucose from the urine. Several studies have shown that SGLT-2 inhibitors, alone or in combination with other hypoglycemic drugs, can further reduce the level of HBA1c by 0.5% to 1.5%. At the same time, SGLT-2 inhibitors significantly increased urinary sodium excretion, reduced water and sodium retention in the body, and lowered blood pressure by 3 to 4 mm Hg. Basic pharmacological studies suggest that SGLT-2 inhibitors can improve cardiovascular outcomes through the following molecular mechanisms: increasing cell utilization of ketone bodies and β-aminobutyric acid, improving myocardial energy supply at mitochondrial level; Change Na+/H+ transport, reduce the concentration of Na+/H+ in cardiomyocytes, increase the uptake of mitochondrial Ca2+, improve cardiac function; Cardiac preload was reduced by reducing interstitial moisture rather than by changing plasma volume. Inhibition of myocardial fibrosis progression; Changes in renal tubule feedback can reduce glomerular filtration pressure and protect the kidney, and feedback can protect the heart [3,4].

A randomized controlled study of 1SGLT-2 inhibitors

The EMPA-REG OUTCOMES study [1] enrolled 7020 patients with type 2 diabetes mellitus with cardiovascular disease who were randomly assigned to placebo, englezin 10 mg or englezin 25 mg orally once a day. The main endpoint events were MACE and hospitalization for unstable angina.

During a mean follow-up period of 3.1 years, SGLT-2 inhibitors reduced HBA1c by 0.54% to 0.6% at the end of 12 weeks and by 0.24% to 0.36% at the end of follow-up compared with placebo, with no statistically significant difference between the 10 mg and 25 mg treatment groups. However, MACE events were reduced by 14% (95%CI: 0.74~0.99, P=0.04). Cardiovascular deaths were reduced by 38% (95%CI: 0.49-0.77, P<0.001), all-cause deaths by 32% (95%CI: 0.57-0.82, P<0.001), and hospitalizations for heart failure by 35% (95%CI: 0.5-0.85, P=0.002). Kaplan-Meier curve suggested that the cardiovascular protective effect of the treatment group was observed from the first few months of the follow-up period and continued during the follow-up period. Among them, what is most noteworthy is the effect of engliazine on reducing hospitalization for heart failure. In the Engliazine treatment group, first-time hospitalization for heart failure and hospitalization for recurrent heart failure were significantly reduced. Therefore, engliazine treatment can significantly prevent and delay the occurrence of heart failure and prolong the life span of patients with diabetes mellitus complicated with cardiovascular disease.

CANVAS study [2] also draws similar conclusions to EMPA-REG. The CANVAS program integrated two sister studies, CANVAS (4330 cases) and CanVAS-R (5812 cases), and included a total of 10,142 participants with type 2 diabetes mellitus with definite cardiovascular disease (>30 years old) or more than 2 cardiovascular risk factors (>50 years old) and a disease course of more than 10 years. Randomized to Cagliazine 300 mg group, cagliazine 150 mg group, placebo group (CANVAS), or cagliazine 100 mg group and supplemented to 300 mg at week 13, placebo group (Canvas-R) to observe cardiac and renal end events, mean follow-up 188.2 weeks. The primary endpoint of the CANVAS program was MACE events, and the secondary endpoint was all-cause death, cardiovascular death, and changes in the progression of proteinuria (a 30% reduction in proteinuria from baseline; Proteinuria evolved into microalbuminuria or macroalbuminuria; Microalbuminuria evolved into macroalbuminuria).

Compared with placebo, the Caglizin group had a 14% decrease in MACE events (95%CI: 0.75 to 0.95, non-inferiority test P<0.001, efficacy test P=0.02) and a 33% decrease in hospitalizations for heart failure (95%CI: 0.52 to 0.87). Cardiovascular deaths decreased by 13% (95%CI: 0.72-1.06), and all-cause deaths also decreased (-13%, 95%CI: 0.74-1.01). In renal protection, Caglizin significantly reduced proteinuria progression by 27% (95%CI: 0.67-0.79) compared with placebo group. In addition, there was a 40% decrease in renal composite endpoints including renal replacement therapy and renal death estimated by eGFR (95%CI: 0.47 to 0.77).

Post-hoc analysis of EMPA-REG and CANVAS for cardiovascular death events and heart failure hospitalization events showed little difference in the statistical conclusions between the two groups. Among diabetic patients with no previous history of heart failure, Engliazine treatment reduced hospitalization events of heart failure by 37% compared with placebo group, showing a statistically significant difference. The Cagliazine group had a 13% reduction. For patients with a preexisting heart failure basis, Engliazine treatment resulted in a 28% reduction in heart failure hospitalizations compared with placebo. Cagliazine treatment reduced hospitalization for heart failure by 39%, showing a statistically significant difference.

The CREDENCE study [5] followed up 4401 diabetic patients with nephropathy, randomized into the 100 mg caglizin group or placebo group, with a follow-up period of 5.5 years. The primary endpoint events were ESKD, increased creatinine doubling, and cardiac and renal death. At the end of follow-up, this RCT study found a 20% reduction in primary endpoint events in the treatment group, confirming that cagliazine has a significant cardiorenal protective effect in diabetic patients with nephropathy.

Real world studies of 2SGLT-2 inhibitors

In addition to RCT, more scholars began to pay attention to data from the real world to make a more comprehensive evaluation of the objective world. RCT study design is the gold standard for testing treatment. It avoids bias and confounding factors of the treatment itself and thus accurately evaluates the effect of the drug on disease status and outcome in a given population. RCTs may overestimate the efficacy and safety of patients with complex conditions and inadequate adherence to treatment in real clinical practice. Therefore, complete data from large real-world cohorts, based on good design and statistical processing, can provide more reliable data for a comprehensive and complete examination of the true efficacy and safety of drug interventions. Published CVD-REAL, CVD-REAL Nordic, OBSERVE 4D studies have used excellent database resources to balance the baseline data of the two groups with propensity scores to avoid the influence of confounding factors on the conclusions of regression analysis. Their conclusions are worth paying attention to.

The CVD-REAL study completed by Kosiborod et al. [6] collected clinical data from the United States, Norway, Sweden, Denmark, Germany and the United Kingdom through medical history data and national registry database to observe whether the initial use of SGLT-2 inhibitors was more effective than the initial use of other hypoglycemic drugs in reducing heart failure hospitalization events and all-cause deaths. After propensity score matching, a total of 309 056 patients were enrolled in the cohort analysis in a 1:1 ratio, with Cagliere net accounting for 53%, dagliere net accounting for 42%, and Engliere net accounting for 5%. The incidence of total heart failure hospitalization events was 0.51/100 person-year, and the incidence of total death events was 0.87/100 person-year. Compared with other hypoglycemic agents, SGLT-2 inhibitors reduced hospitalization for heart failure by 39% (95%CI: 0.51 to 0.73; P<0.001), all-cause deaths were 49% lower (95%CI: 0.41-0.57; P<0.001), the incidence of heart failure or death was reduced by 46% (95%CI: 0.48-0.60; P<0.001), there was no significant difference among countries.

CVD-REAL Nordic studies [7] included patient data from Denmark, Sweden and Norway through prescription drug registration system, cause of death registration system and national patient registration system. After baseline data matching, the SGLT-2 inhibitor group (22 830 cases) and the other hypoglycemic drug treatment group (68 490 cases) were included in the statistical analysis, with a follow-up of 0.9 years, of which 94% were dagliazine, 5% were engliazine, and 1% were cagliazine. Compared with other hypoglycemic medications, SGLT-2 inhibitors reduced cardiovascular death events by 47% (95%CI: 0.40-0.71, P<0.0001) and major cardiovascular events by 32% (95%CI: 0.69~0.87, P<0.0001), reduced hospitalization for heart failure by 30% (95%CI: 0.61-0.81, P<0.0001), showing statistical differences. There was no significant difference between the two groups in non-fatal cerebral infarction and non-fatal myocardial infarction.

OBSERVE 4D study [8] observed and compared the effects of Calaglizin with other SGLT-2 inhibitors or other hypoglycemic drugs on hospitalizations for heart failure and lower limb amputations using four US databases. During the follow-up period, 142 800 patients received cagliazin, 110 897 patients received other SGLT-2 inhibitors, and 460 885 patients received other types of hypoglycemic drugs. Excluding the lost follow-up population analysis, Cagliazine significantly reduced hospitalization for heart failure by 61% (95%CI: 0.26-0.60) compared with other types of hypoglycemic drugs. Similar to other -SGLT-2 inhibitors. Compared with other hypoglycemic drugs, Caglizin did not show statistically significant difference in lower limb amputation.

Safety evaluation of four SGLT-2 inhibitors

In the CANMAS study, however, there was an increase in lower limb amputation in the Cagliezin group compared to the control group (HR=1.97, 95%CI: 1.41-2.75). However, in the OBSERVE 4D real world study, no significant increase in the risk of amputation was observed after treatment with Cagliazine compared with other types of hypoglycemic drugs. In addition, no such adverse effect was found in EMPA-REG. Currently, the risk of amputation and fracture with SGLT-2 inhibitors is subject to further investigation.