Efficacy and safety evaluation of SGLT2i on blood pressure control in patients with type 2 diabetes and hypertension: a new meta-analysis

Hypertension and diabetes mellitus are independent risk factors for cardiovascular disease [1]. The risk of cardiovascular disease in type 2 diabetes is three times that of non-diabetic patients. In China, the prevalence of hypertension is nearly 90% among the elderly aged ≥ 80 years old, which is the primary risk factor for stroke, myocardial infarction, and even cardiovascular death. Patients with type 2 diabetes often have hypertension, and the incidence of hypertension in patients with diabetes is twice that in patients without diabetes [2]. Although diabetes mellitus and hypertension are increasing yearly, the two diseases’ awareness, treatment, and control rates are still low in different countries. Blood glucose and blood pressure levels are continuously, independently, and positively related to cardiovascular risk [3]. The risk of cardiovascular complications in patients with type 2 diabetes and hypertension is 2 to 4 times higher than in patients with common diabetes mellitus or hypertension, and the risk of all-cause mortality and cardiovascular events is 1.7 times and 1.5 times higher, respectively, than in patients with normal blood pressure [4]. Therefore, strict control of blood sugar and blood pressure can effectively reduce cardiovascular and cerebrovascular complications.

According to the latest China guidelines, the blood pressure reduction target for patients with type 2 diabetes mellitus and hypertension is < 130/80 mmHg [5]. This requires a combination of antidiabetic and antihypertensive drugs to minimize the risk of later cardiovascular disease and avoid the increased morbidity and mortality associated with drug abuse. Traditional antihypertensive drugs are not effective in blood glucose management. The high incidence of hypertension and cardiovascular risk in type 2 diabetes mellitus urges us to find a safe and effective antihypertensive drug. As a new antidiabetic drug, the antihypertensive effect of sodium-glucose co-transporter 2 (SGLT2i) inhibitors has been confirmed [6, 7]. Meta-analyses have shown that SGLT2i significantly reduces systolic and diastolic blood pressure in patients with diabetes, with renal and cardiovascular protection [8]. However, there is still a lack of big data to support how to guide the use of such drugs in patients with type 2 diabetes mellitus and hypertension, as well as the discussion on the safety and effectiveness of SGLT2i as an add-on to first-line antihypertensive drugs in patients with diabetes mellitus and hypertension.

In summary, finding the ideal drug to achieve both blood pressure and glycemic goals, avoid the side effects of multiple drugs, and achieve optimal efficacy is daunting. The use of SGLT2i could be beneficial to achieve this goal, and this study was conducted with this aim in mind.

The global prevalence of diabetes has risen sharply. According to statistics, in the past 40 years, 34.2 million people in the United States have diabetes, 95% of whom are type 2 diabetes. The risk of cardiovascular disease in adults with diabetes accounts for 10–12% of all vascular deaths compared with adults without diabetes [18]. Hypertension is a common disease coexisting with diabetes mellitus and a definite risk factor for Atherosclerotic cardiovascular disease (ASCVD). Two-thirds of patients with diabetes have hypertension, and the risk of cardiovascular disease in patients with diabetes with hypertension is four times higher than that in normotensive patients with diabetes [19]. Patients with type 2 diabetes mellitus and hypertension have a significantly higher risk of complications such as myocardial infarction, stroke, and chronic renal failure (CKD) [20]. A substantial benefit is seen when multiple cardiovascular risk factors are resolved simultaneously. Therefore, active control of blood pressure is essential for people with type 2 diabetes.

WHO recommends that antihypertensive drugs be started when systolic blood pressure is 130–139 mmHg in patients diagnosed with hypertension, concomitant cardiovascular disease, or high cardiovascular risk (such as diabetes mellitus or chronic kidney disease).In the initial treatment, any two of angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin-receptor blockers (ARBs), diuretics (thiazide or thiazide-like) and long-acting dihydropyridine calcium channel blockers (CCBs) can be selected for combination therapy. Compared with CCBs and β-blockers, ACEIs/ARBs can better reduce the risks of MACE, heart failure, cardiovascular death, and all-cause death and are the first drugs of choice for treating hypertension in patients with diabetes mellitus and coronary artery disease [21]. For patients with diabetes and hypertension, blood pressure targets should be individualized through a shared decision-making process that addresses cardiovascular risk, potential adverse effects of antihypertensive medications, and patient preferences [21]. Maintaining blood pressure and blood glucose at an ideal level is complicated, and multi-drug combination therapy is required. Therefore, excessive treatment should be avoided when formulating a treatment regimen to reduce the occurrence of adverse drug events [22]. Currently, the choice of therapeutic drugs for patients with type 2 diabetes mellitus complicated with hypertension still lacks extensive data support at home and abroad.

As a new oral antidiabetic drug, SGLT2i reduces renal reabsorption of glucose and sodium by inhibiting sodium-glucose co-transporter 2, thus exerting hypoglycemic and antihypertensive effects [23, 24]. Recently, Sha Chen proposed that myocardial cells will start intracellular plasmalemma sodium loaders when stimulated by hypoxia, oxidative stress, validation, acidosis, etc. The protective effect of SGLT2i on the heart and kidney benefits from their inhibition of sodium loaders in the plasma membrane (NHE-1, Nav1.5, SGLT) affecting intracellular sodium-homeostasis (the sodium-interactome), thus reducing corresponding damage [25]. Compared with previous antidiabetic drugs, such as sulfonylureas (sulfonylureas), biguanides, and thiazolidinediones (TZDs), SGLT2i can reduce the occurrence of adverse drug events such as cardiovascular, liver function and renal function injury [26, 27]. The CCS/CHFS heart failure guidelines recommend SGLT2i for preventing or treating heart failure in patients with or without type 2 diabetes [28]. Clinical trials have demonstrated that SGLT2i drugs such as empagliflozin, canagliflozin, and GLP-1 receptor agonists reduce the risk of cardiovascular adverse events, and Dapagliflozin reduces the risk of cardiovascular death or hospitalization for heart failure [5, 29]. Dapagliflozin effectively reduces albuminuria after renin-angiotensin system blockade therapy in patients with T2DM and hypertension, improves glycemic control, reduces systolic blood pressure, and promotes uric acid excretion, thus reducing renal and cardiovascular risks [15]. Empagliflozin reduced major cardiovascular deaths regardless of treatment-resistant hypertension status. Arterial stiffness is an established risk factor for cardiovascular events and mortality. The underlying mechanism of blood pressure reduction by SGLT2i may be related to the improvements in endothelial function and arterial stiffness associated with empagliflozin [2]. SGLT2i induced clinically relevant reductions in systolic blood pressure and HbA1c, a dual effect that should be considered in patients with hypertension and T2D, as demonstrated in this study.

Systolic blood pressure is more clinically significant than diastolic blood pressure in patients with hypertension. The former is a more robust indicator of the risk of cardiovascular disease, which has led to an increasing emphasis on systolic blood pressure control in recent guidelines. This study preliminarily confirmed that SGLT2i can reduce 24-h systolic blood pressure and office systolic blood pressure in patients with type 2 diabetes and hypertension. SGLT2 reduced 24H systolic blood pressure by 5.06 mmHg and office systolic blood pressure by 4.53 mmHg, on average, compared with the equivalent dose of placebo. For 24H and mean office diastolic blood pressure, SGLT2i also showed a certain antihypertensive effect. The antihypertensive efficacy of SGLT2i is partly influenced by choice of first-line antihypertensive agents. Because SGLT2i lowers blood pressure by increasing urine volume, Dapagliflozin’s blood pressure lowering properties are especially beneficial in patients who are already taking beta-blockers or calcium channel blockers, and the addition of Dapagliflozin may result in slightly more tremendous blood pressure lowering than in patients who are already taking thiazide diuretics [12]. The analysis found that this literature [2] was the primary source of heterogeneity. The intervention in this study was 25 mg empagliflozin with a treatment course of 12 weeks. Compared with other studies, there was no significant difference in the screening criteria of subjects and baseline data of population blood pressure in this literature. At the same time, the dose of SGLT2i was more prominent, and the treatment course was more protracted. Therefore, considering the combined effect of SGLT2i dose and course is the reason for the considerable heterogeneity, suggesting that the antihypertensive effect of the same type of SGLT2i may increase with the prolongation of the course. Keith [16, 30] leads to a similar conclusion: the effect of empagliflozin on blood pressure increased from 12 to 24 weeks, suggesting that at least 6 months of treatment is required for the full antihypertensive effect. In patients with type 2 diabetes combined with hypertension, aggressive medication to lower blood pressure is effective in reducing the incidence of stroke, heart failure and microangiopathy. The 2022 American Diabetes Association Standards of Medical Therapy for Diabetes recommend that patients with diabetes combined with hypertension who are at high cardiovascular risk may have their blood pressure reduced to < 130/80 mmHg as long as the target can be safely met. In these patients, symptomatic hypoglycaemic and antihypertensive therapy is the mainstay, with ACEI/ARB drugs recommended for blood pressure control. For those who need to combine multiple drugs to lower blood pressure, SGLT2i can be considered as the preferred option to reduce cardiac and renal damage while exerting the dual effect of lowering glucose and blood pressure and avoiding drug over-treatment.

Our study confirmed that SGLT2i could effectively reduce HbA1c in patients with type 2 diabetes mellitus and hypertension. Sensitivity analysis showed that this literature [17] was highly sensitive and was the primary source of heterogeneity. By analyzing the experimental design scheme of this literature, the dose of antihypertensive and antidiabetic drugs was not maintained at the pretreatment dose but changed at the investigator’s discretion, which impacted the final HbA1c and blood glucose level. In addition, the sample size of this study was small, the basic hypoglycemic regimen of patients was unknown, and the proportion of patients using DPP-4 inhibitor showed severe inclination (n > 50%). Therefore, the bias caused by the sample size and experimental protocol of the original hypoglycemic drug could not be excluded.

Controversial risk of serious adverse events (SAEs) such as genital infections, urinary tract infections (UTIs), and hypotension associated with SGLT2i has limited its clinical use. Younes [31] found a significantly higher risk of genital infections, urinary tract infections, and hypotension with SGLT2i compared to a placebo. This study preliminary confirmed that SGLT2i was well tolerated and did not increase the risk of hypoglycemia. Although the incidence of hypoglycemia was slightly higher in the dapagliflozin and placebo groups than in the placebo group, the difference was not statistically significant [12]. This study confirmed that SGLT2i does not increase the risk of urinary tract infection, the included literature is not heterogeneous, and the conclusion is reliable. Women are the main subjects of urinary tract infections, and there is no apparent relationship with whether they take empagliflozin [2]. A higher percentage of empagliflozin patients experienced genital infections, hypoglycemia events, and comparable rates of urinary tract infections compared with placebo [2]. There are consistent reports that SGL2i increases the risk of genital infection. Compared with metformin, SGLT2i has a similar glucose-lowering effect and additional cardiovascular protection but an increased potential risk of genital infections. Patients treated with Dapagliflozin had slight increases in volume depletion, urinary tract or genital infections, and renal impairment compared with placebo [15]. Michael [14] compared the incidence of adverse events between the dapagliflozin group and the placebo group and concluded that there was no statistical difference in the incidence of genital and urinary tract infections between the two groups. Our study concluded that SGLT2i had a 2.32-fold increased risk of genital infections compared with placebo, I² = 16.9, RR = 2.32, 95% CI [1.57, 3.42], z = 4.23, p = 0.00, and the conclusion has a certain reference value and needs to be further confirmed by expanding the research sample. Sensitivity analysis suggested that this literature [9] was the primary source of heterogeneity. The risk of genital infection was significantly higher in an empagliflozin group than in a placebo group in two subgroups (refractory and non-refractory hypertension) in the literature (6.6% > 1.5%; 5.7% > 2.9%), but the document did not describe the baseline data of genital infection in different treatment groups in subgroups, so the possibility of uneven distribution of genital infection population at the time of grouping cannot be excluded. Compared with other literature, the sample size of subjects in this literature is more significant, which also causes heterogeneity to some extent. In subsequent studies, more multi-center clinical studies with rigorous designs and moderate sample sizes should be included for conclusion verification.

Although some studies have reported a higher frequency of serum creatinine increase or glomerular filtration rate (eGFR) decrease in the dapagliflozin group [15]. However, our study concluded that SGLT2i does not cause renal injury, which is consistent with the previously reported renal protective effect of SGLT2i [32]. SGLT2i also provided renoprotection by lowering intraglomerular hypertension by modulating the pre- and post-glomerular vascular tone. A meta-analysis confirmed that SGLT2i reduced the risk of progression of renal disease, and the magnitude of the benefit was positively correlated with baseline renal function, with more severe renal disease and weaker inhibition of the risk of disease progression.

Limitations of this study: (1) the included studies were few, and it was not possible to study the effect of SGLT2i on blood pressure control based on baseline blood pressure and the impact of cardiovascular risk factors. (2) The number of studies included was minimal, and the screening criteria for the literature were too wide, failing to analyze subgroups by geography, disease duration, gender, age, concomitant underlying condition, ethnicity, blood pressure, and underlying antihypertensive drug status. (3) The results of this study are somewhat biased due to the tiny study base, diverse location, ethnicity, and sample size. (4) The majority of research times ranged from 4 to 12 weeks, and SGLT2i’s long-term antihypertensive effectiveness is uncertain. (5) To further address these issues, additional clinical studies with sizable sample sizes, multicenter, prolonged study periods, and thorough study methods must be added.

There is a considerable risk of cardiovascular events in patients with type 2 diabetes mellitus and hypertension, and antihypertensive management strategies for this high-risk population are particularly important. In our study, the efficacy and safety of SGLT2i in patients with type 2 diabetes mellitus and hypertension were verified. SGLT2i has dual efficacy in lowering blood pressure and blood glucose and has a protective effect on cardiovascular, cerebrovascular, renal, and other composite outcomes and mortality. We can try to employ SGLT2i as an adjuvant medication in the first-line antihypertensive regimen for patients with type 2 diabetes and hypertension because this conclusion has some therapeutic work-guiding significance.