IJCDS Journal

Introduction

Cardiometabolic Syndrome (CMS) is a collection of various metabolic abnormalities that are substantial risk factors for Cardiovascular Disease (CVD) [1]. CMS has now emerged as a complex clinical syndrome involving factors like insulin resistance, obesity, dyslipidemia, and increased Blood Pressure (BP) [1,2]. It is also known as insulin resistance syndrome since it is hypothesized that insulin resistance is the primary mechanism responsible for the metabolic abnormalities of the syndrome[1]. It is essential to accurately diagnose CMS considering its increasing incidence to ensure that patients at risk receive the proper screening and care. Several guidelines have defined CMS, which are summarized in Table 1 [3].

Table 1: Definition of CMS in various guidelines.

AHA, American Heart Association; CMS, cardiometabolic syndrome; BMI, body mass index; BP, blood pressure; FPG, fasting plasma glucose; HDL-C, high-density lipoprotein cholesterol; IDF, International Diabetes Federation, NIH, National Institutes of Health, NHLBI, National Heart, Lung, and Blood Institute; TG, triglycerides; WC, water column; WHO, World Health Organization.

Insulin resistance and CMS are widespread conditions in India [4-13]. CMS was found in around 42.7% of patients with Type 2 Diabetes Mellitus (T2DM) [14]. A study by Bhalwar et al. estimated that approximately 13–15% of India’s adult population have CMS, with females being more affected (approximately 18– 19% among adult females and 8%–9% among adult males) [4]. Genetic predisposition, sedentary lifestyle, environmental factors, and diet might be responsible for establishing the syndrome [15]. The pathophysiology of CMS includes a) alterations in fatty acid metabolism, b) excess visceral fat, c) ectopic accumulation of fat in the liver and muscles, d) inflammatory cytokines produced by the adipose tissue, e) increased blood pressure due to insulin resistance and f) increased renal sodium reabsorption due to hyperinsulinemia [1].

Cardiometabolic Disease (CMD) includes CMS in addition to dyslipidemia, obesity, diabetes, prediabetes, obesity, NonAlcoholic Fatty Liver Disease (NAFLD), and chronic Kidney Disease (CKD) [16]. Sodium-Glucose Cotransporter-2 Inhibitors (SGLT2is) have been shown to enhance Cardiovascular (CV) and renal outcomes in patients with CMD. The clinical benefits of SGLT2is have been confirmed in patients with and without T2DM. As a result, SGLT2is play an increasingly important role in managing Heart Failure (HF) and CKD, extending beyond T2DM treatment. They have diuretic and natriuretic effects, which lead to decreased preload, Left Ventricular (LV) filling pressure, and improvements in other surrogates of afterload. They also decrease sympathetic tone and uric acid levels, increase hemoglobin levels, and are believed to have anti-inflammatory properties [17].

Need for expert opinion

SGLT2is, like dapagliflozin, have been shown to target various conditions of CMD. The availability of emerging evidence for the beneficial effects of dapagliflozin across the spectrum of CMD is likely to affect the trend in the usage of dapagliflozin in such patients. Considering the evolving landscape of management and the promising role of dapagliflozin, expert opinion is essential to inform clinical practice and advance our understanding of the therapeutic options available for this challenging condition. This review outlines the authors’ perspective on dapagliflozin’s position across the CMD spectrum.

Methodology

A panel of 550 expert diabetologists and endocrinologists from India convened digitally for 55 advisory board meetings to discuss the role of dapagliflozin in CMD. The discussions spanned several categories, including T2DM, prediabetes, obesity, hypertension, NAFLD, CVD, HF, and CKD. The collected evidence on these specific topics was presented during the meetings, followed by discussions highlighting dapagliflozin’s role and positioning across CMD. The writing committee prepared the manuscript, which all expert panel members reviewed to ensure a comprehensive and well-structured document. The recommendations in this article are based on the evidence presented and the discussions summarized from the minutes of the meetings.

Literature Review and Expert Opinion Type 2 Diabetes Mellitus

Current Evidence: SGLT2is reduce the HbA1c by 0.5-1%, favoring body weight and BP [18]. The results of a subgroup analysis performed in a meta-analysis by Xu et al. based on a combination of hypoglycemic agents concluded that dapagliflozin is more effective as add-on therapy with insulin, metformin, or exenatide, among other hypoglycaemic agents in reducing HbA1c levels (P<0.00001 for all) [19].

Pan, et al. conducted a meta-analysis of 18 studies on the effects of SGLT2is in T2DM patients. Results showed significant reductions in body weight, waist circumference, Body Mass Index (BMI), skeletal muscle mass, body fat percentage, subcutaneous fat, fat mass, lean mass, and visceral fat compared to control drugs (sulfonylureas, insulin, metformin, thiazolidinediones, DPP-4i, and GLP-1 Receptor Agonists [GLP-1RA]) [20]. Dapagliflozin has been categorized as an antidiabetic drug associated with moderate weight reduction (between 3.2% and 5%) [21].

A systematic review and meta-analysis of Cardiovascular Outcome Trials (CVOT) by Zelniker et al. showed that both SGLT2is and GLP-1RA have robustly reduced the risk of atherosclerotic Major Adverse Cardiovascular Event (MACE), while only SGLT2is have a profound beneficial effect for reducing the risk of HF and progression of CKD [22]. A network meta-analysis of 13 Randomized Controlled Trials (RCTs) by Ghosal et al. showed that SGLT2is reduced CV death risk in patients with T2DM by 12% (Relative Risk [RR]: 0.88, 95% confidence interval [CI]

0.80–0.96) in comparison with standard treatment. Among all SGLT2is, dapagliflozin brought the highest benefit in the T2DM with HF patient group (11% RR reduction), while empagliflozin has shown a more significant decrease in CV death in patients of Atherosclerotic Cardiovascular Disease (ASCVD) and multiple CV risk factors [23]. Meta-analysis of 23 CVOTs has shown significantly reduced risk (CV) death (RR: 0.88), overall death (RR: 0.87), and MACE with SGLT2is compared to DPP-4is. SGLT2is scored over GLP-1RAs for reducing the risk of HF and renal outcome by 24% and 22%, respectively, while both the classes of drugs were comparable for MACE, CV, and total death. In a systematic review and meta-analysis by Yamada T et al., SGLT2is reduced the risk of renal events by 21% compared to GLP-1RAs in patients with T2DM and CKD[24]. A meta-analysis of 25 RCTs by Chen et al. revealed an increased risk of genital infection (GI), urinary tract infection (UTI), and nasopharyngitis compared to other treatments or placebo [25]. Increased risk of GI and UTI was found in female patients, those with BMI ≥ 30 kg/m² and receiving SGLT2is treatment for ≥ 6 months [26].  

A network meta-analysis of 13 RCTs by Ghosal et al. found that SGLT2is reduced CV death risk by 12% (RR: 0.88, 95% CI: 0.80–0.96) in T2DM patients compared to standard treatment. Dapagliflozin showed the most significant benefit in T2DM with HF (11% RR reduction), while empagliflozin significantly reduced CV death in patients with ASCVD and multiple CV risk factors.

Position: Guideline recommendation for SGLT2is in T2DM

American Diabetes Association (ADA) 2024 guidelines recommend SGLT2is as a preferred choice of therapy in T2DM patients with HF  (with either reduced or preserved Ejection Fraction (EF)), CKD (with confirmed eGFR of 20–60 mL/min per 1.73 m² and/or albuminuria), ASCVD, indicators of high CV risk (including obesity, hypertension, dyslipidemia or albuminuria) and high BMI [27].

Expert Opinion

Pharmacotherapy for hyperglycemia in T2DM should be individualized based on comorbidities, hypoglycemia risk, glycemic goals, and medication availability. While metformin remains the standard first-line treatment, SGLT2is can be used as initial therapy (with or without metformin) in T2DM patients with HF, CKD, CVD, or high BMI. SGLT2is show comparable glycemic efficacy and safety. Empagliflozin may be preferred for T2DM with ASCVD and dapagliflozin for T2DM with HF. Counseling on SGLT2i side effects is advised before initiation. Combining SGLT2is and GLP-1RAs may offer additional cardiovascular benefits, with sequential combination therapy as an option.

Role of SGTL2i in Prediabetes Current Evidence

Prediabetes is defined as an intermediate state of hyperglycemia with glucose levels above the normal state but below the diagnostic levels of diabetes [28]. According to the Indian Council of Medical Research (ICMR)–India DIABetes study, 5.8-14.7% of the population in rural and 7.2-16.2% in urban India have prediabetes. The prevalence of prediabetes exceeds that of diabetes in most Indian states, indicating a large population that may soon develop T2DM. Conversion rate to diabetes is 58.9% among Indians with prediabetes [29].

Intensive lifestyle intervention and antidiabetic drugs such as metformin, thiazolidinediones, and α-Glucosidase Inhibitors (AGI) have shown significant reduction in the incidence of diabetes [30,31]. Recent 2024 ADA guidelines recommend intensive lifestyle modification such as moderate-intensity physical activity for ≥ 150 minutes/week to achieve a weight loss of 7% and metformin in the age group of 25-59 years and BMI of ≥ 35 kg/m². Additionally, Research Society for Study of Diabetes in India (RSSDI) guideline recommends AGI such as acarbose or voglibose in case of non-tolerance to metformin [32,33]. Several emerging data show the benefits of antidiabetic drugs such as GLP-1RA and SGLT2is in preventing T2DM.

Insulin-resistant conditions such as HF and CKD are linked to a high prevalence of diabetes [34]. A systematic review and metaanalysis conducted by Singh et al. included 5 RCTs to assess the effect of SGLT2is on New-Onset Diabetes (NOD) in adult patients with prediabetes having CKD and HF. The results showed that SGLT2is could significantly reduce the occurrence of NOD in these patients (HR 0.81, P=0.005). However, there was no effect of SGLT2is on HbA1c, indicating that the decrease in the occurrence of NOD observed is unrelated to these drugs’ blood glucose masking effect [35]. A pooled analysis of two phase 3 trials, DAPA-CKD and DAPA-HF demonstrated a reduction in the incidence of NOD in patients with T2DM and CKD with dapagliflozin treatment (Hazard Ratio [HR] 0.67 [95% CI 0.51– 0.88]). Subgroup analysis also showed no difference in the effect of dapagliflozin in the subgroups of age, sex, BMI, glycemic status, baseline CV medication use, SBP, and glomerular filtration rate [34]. A randomized, double-blind crossover trial by Veelen et al. showed that two weeks of dapagliflozin treatment in prediabetic patients lowered 24-hour glucose levels and improved 24-hour and nocturnal fat oxidation, as well as ex vivo mitochondrial oxidative capacity without significant changes in hepatic glycogen stores [36]. The PRE-D trial found a greater reduction in glycemic variability measured by Mean Amplitude Of Glycemic Variability (MAGE) by 17% with dapagliflozin compared to metformin in overweight or obese individuals with prediabetes [37].

Possible mechanisms for a beneficial effect of dapagliflozin in prediabetes include protecting pancreatic beta-cells from glucotoxicity, weight loss, and improvement in hepatic insulin sensitivity. Improving CKD and HF may have contributed to insulin sensitivity [34].

Expert Opinion

Prediabetes is an independent risk factor for CVD, and given its high prevalence in India, clinic-based screening of high-risk individuals (overweight, hypertension, sedentary) is crucial for early detection. Management should be individualized, starting with lifestyle changes, followed by metformin for those with high BMI or poor lifestyle compliance. Other classes of drugs, such as AGIs, may be considered for patients intolerant to metformin. While SGLT2is reduce T2DM incidence in HF and CKD, their long-term benefit in individuals without these conditions needs to be confirmed from clinical trials.

Obesity Current Evidence

Obesity is the primary risk factor for the onset of diabetes. Obesity and diabetes rates have been rising simultaneously, posing a threat to patient mortality and driving up community healthcare costs. A 5% weight loss or more of total body weight improves quality of life, lowers the requirement for diabetes medication, and improves glycemic control. Treatment of diabetes and obesity necessitates a multimodal medical strategy that includes medication, potentially surgical management, and intense lifestyle modification [38].

A meta-analysis by Lazzaroni, et al. has categorized the antidiabetic drugs into the following three groups based on their efficacy for weight loss:

1. Mild efficacy for weight loss (less than 3.2% of initial weight): metformin, acarbose, empagliflozin, and exenatide.
2. Moderate efficacy for weight loss (between 3.2% and 5%): canagliflozin, ertugliflozin, dapagliflozin, dulaglutide.
3. Strong efficacy for weight loss (greater than 5%): liraglutide, semaglutide, tirzepatide.

ADA 2024 guideline recommends high weight loss efficacy antidiabetic drugs such as GLP-1RAs, dual GIP and GLP-1RA, and SGLT2is in patients of T2DM associated with obesity or high BMI [39].

Role of SGLT2is in weight reduction

SGLT2is promote weight loss through several mechanisms. They induce weight loss by excreting glucose via the kidneys and shift energy metabolism toward fat and glucose utilization, increasing oxygen consumption and carbon dioxide exhalation. Additionally, SGLT2is regulate adiponectin and leptin in white adipose tissue, boost fatty acid oxidation, and promote lipolysis, leading to more significant energy expenditure and weight reduction (Figure 1).

Figure 1: Effect of SGLT2is in reduction of weight.

Several studies have confirmed the effect of SGLT2is in reducing body fat (Table 2).

Table 2: Clinical studies for weight reduction associated with SGLT2is.

Expert Opinion

Weight management is crucial alongside glycemic control in T2DM patients with overweight or obesity. Aiming for at least 5% weight loss is recommended. Lifestyle modification remains vital, and antidiabetic drugs with weight-lowering effects, such as SGLT2is and GLP-1RAs, should be preferred. While GLP-1RAs offer greater weight loss, SGLT2is are favored in practice due to lower cost and oral administration. Drug choice depends on desired weight loss, patient preferences, and conditions like HF/CKD (favoring SGLT2is) or ASCVD (favoring GLP-1RAs). Dapagliflozin typically reduces weight by 3-5 kg, with greater loss in higher baseline BMI, peaking within 4-6 weeks.

Hypertension

SGLT2is effectively reduces BP by the mechanisms mentioned in Figure 2.

Figure 2: Role of SGLT2is in the reduction of hypertension

Current Evidence

The coexistence of T2DM and hypertension is common. T2DM increases the sodium-glucose transporters’ activity, leading to volume load due to sodium retention. Therefore, controlling BP is crucial to prevent CVD in patients with T2DM[47]. Among antidiabetic drugs, GLP-1RA (semaglutide, liraglutide, exenatide) and SGLT2is (dapagliflozin, empagliflozin, canagliflozin, and ertugliflozin) have shown BP lowering effect over 1 year of treatment in the meta-analysis by Tsapas  A, et al. [48].

A summary of clinical studies assessing the antihypertensive effect of dapagliflozin has been enlisted in the table 3.

Abbreviations: ACEi: angiotensin-converting enzyme inhibitors; ARB: angiotensin receptor blockers; CrCl, Creatinine clearance;  DBP, diastolic blood pressure; EF, Ejection fraction; HF, Heart Failure; HFmrEF, Heart Failure with mildly reduced ejection fraction; HFpEF,  Heart Failure with preserved ejection fraction; HFrEF, Heart failure with reduced ejection fraction; HbA1c, haemoglobin A1C; SBP: systolic blood pressure; T2DM, type 2 diabetes mellitus.

Table 3: Clinical studies evaluating the effect of SGLT2is on blood pressure

Non-alcoholic fatty liver disease (NAFLD)/, Non-alcoholic steatohepatitis (NASH) Effect of antidiabetic drugs on NAFLD has been summarized in table 4.

Table 4: Effects of antidiabetic agents on NAFLD [60,61].

Studies show that SGLT2is Lower Aspartate Aminotransferase (ALT), Gamma-Glutamyl Transferase (GGT), and Liver Fat Content (LFC) in overweight or obese NAFLD patients. SGLT2is also reduce body weight in patients with or without T2DM, lower plasma triglycerides, and raise HDL, which helps improve dyslipidemia and alleviate hepatic steatosis in NAFLD [62].

Table 5: Summary of clinical evidence of SGLT2is in NAFLD/NASH.

Expert Opinion

NAFLD is associated with nearly half of the patients with T2DM. Screening of high-risk populations should be performed for early diagnosis of NAFLD. Lifestyle modification, which promotes weight loss, is the mainstay of therapy for NAFLD. The weight loss and improvement in insulin resistance associated with SGLT2is may be useful to improve the outcome of NAFLD. SGLT2is are a promising therapy for T2DM patients unsuitable for pioglitazone (a commonly used antidiabetic drug for NAFLD associated with T2DM), such as those overweight/obese, HF/at risk of HF.

Cardiovascular disease and Heart Failure

Various mechanisms of SGLT2is are thought to be involved in HF (Figure 3).   

Figure 3: Mechanism of SGLT2is in heart failure.

BP, blood pressure; RBC: Red blood cells.

Current Evidence

Several studies have investigated the effect of SGLT2is on HF and CV outcomes, which are listed below:

Table 6: Clinical evidence for SGLT2is on HF and CV outcomes.

In the 2023 update of the European Society of Cardiology (ESC) guidelines for HF, the recommendation for SGLT2is has been updated to class IA from class IIa (2021, ESC guideline for HF). Thus, SGLT2is have class IA recommendation across the spectrum of EF in HF [77].

Expert Opinion

Rapid initiation of four Guidelines-Directed Medical Therapy (GDMT) classes for HF within 4 weeks enhances outcomes, with maximum GDMT benefits seen within 30 days. SGLT2is should be initiated once patients are stable, before discharge, without needing dose titration. Dapagliflozin and empagliflozin are suitable for HF patients across the EF spectrum, regardless of diabetes status. Volume status and renal function should be evaluated before starting SGLT2is, which are not recommended if eGFR is <25 ml/min/m².

Renoprotective benefits of SGLT2i in CKD

Current Evidence

Several hypotheses have been proposed to explain the nephroprotective effects of SGLT2is, including reduced renal hyperfiltration via tubuloglomerular feedback, decreased proximal tubule sodium reabsorption, and decreased energy consumption by proximal tubular cells. Additionally, SGLT2is have been shown to protect proximal tubular cells from glucotoxicity, enhance erythropoiesis, improve mitochondrial function, reduce oxidative stress, and decrease autophagy, podocyte injury, and renal inflammation (Figure 4) [78].

Figure 4: Renoprotective mechanisms of SGLT2is.

The clinical studies evaluating the effects of SGLT2is in CKD are summarised in the table below:

Table 7: Summary of clinical evidence of SGLT2is in CKD.

Although ACEis and ARBs are the foundational therapy for CKD, they are underused due to adverse effects like hyperkalemia, hospitalization, or Acute Kidney Injury (AKI). Fletcher, et al. assessed the impact of SGLT2is on the discontinuation of these drugs by conducting a joint analysis of CREDENCE and DAPA-CKD trials. Results showed that only 8.7% of patients discontinued ACEi/ARB use. It can be concluded that SGLT2is facilitates the use of ACEis/ARB in patients with albuminuric CKD with and without T2DM [84].

A cost analysis study was conducted by McEwan, et al. to assess the potential medical care cost offsets associated with reduced rates of cardio-renal outcomes. Patients treated with dapagliflozin and standard therapy experienced fewer incidents of End-Stage Kidney Disease (ESKD), and reductions in clinical events were associated with a 33% reduction in total costs [85].

The KDIGO 2024 guideline suggests initiating an SGLT2is as first-line drug therapy for patients with  CKD who have an eGFR ≥ 20 ml/min per 1.73 m² or UACR ≥ 200 mg/g or HF irrespective of the level of albuminuria (1A) [86].

Expert Opinion

Dapagliflozin and other SGLT2is represent the most impactful first-line therapy for individuals with CKD, irrespective of diabetes status. SGLT2is should be initiated as early as possible regardless of dose of Renin-Angiotensin System (RAS) blockers in patients with CKD. They can be continued till the advanced stage of CKD, even in patients on dialysis. The initial drop in eGFR with SGLT2is initiation necessitates monitoring for renal function. Careful monitoring for renal function and adverse effects of SGLT2is should be done with more frequent assessment in patients with advanced CKD.

Positioning of dapagliflozin across CMD

Based on the available clinical evidence and experts’ opinions, we propose the following positioning of dapagliflozin across the spectrum of CMD.

Table 8: Positioning of dapagliflozin across cardiometabolic disease.