Cardiovascular Risk Management in T2D with established ASCVD: Current Evidence for Dapagliflozin and Sitagliptin-Dr Piyas Gargari

Type 2 diabetes (T2D) frequently presents with cardiovascular complications already established, with cardiovascular diseases (CVD) accounting for 40–80% of deaths in patients with T2D. Once atherosclerotic cardiovascular disease (ASCVD) is diagnosed in T2D, glucose-lowering alone remains necessary but insufficient. HbA1c remains central for assessment of glycemic control, whereas cardiovascular risk is determined by established ASCVD, heart failure, chronic kidney disease, blood pressure, lipid parameters and other parameters. Therapeutic decisions should therefore incorporate parameters beyond only glycemic control [1,2,3] We review the potential role and scope of Dapagliflozin and Sitagliptin in this setting.

Dapagliflozin & Sitagliptin: Orbit of Action in the Context of ASCVD in T2D

Dapagliflozin's Pleiotropic Effects in the Heart: In experimental and imaging studies involving T2D and established ASCVD scenario, dapagliflozin suggest reduction of epicardial adipose tissue and local pro-inflammatory cytokine release, restoration of nitric oxide bioavailability in coronary endothelial cells, and attenuation of oxidative stress. In DECLARE-TIMI 58, dapagliflozin reduced cardiovascular death or hospitalization for heart failure by 17% (HR 0.83; 95% CI 0.73–0.95) in this population, and in DAPA-MI,

Improved cardiometabolic recovery assessed by a hierarchical win-ratio endpoint (win ratio 1.34; 95% CI 1.20–1.50).[4]

Sitagliptin's Anti-inflammatory and Vasculo-protective Effects: In T2D with ASCVD setting, experimental evidence shows sitagliptin suppresses mononuclear cell expression of TLR-2, TLR-4, NF-κB, and downstream IL-6, TNF-α, and C-reactive protein. It improves endothelial function via AMPK/SIRT1/Nrf2 activation and reduces platelet-activating factor acetyl hydrolase activity, attenuating ox-LDL-C formation and thrombotic burden in chronic atherosclerosis. [5]

Dapagliflozin and Sitagliptin: T2D with ASCVD Evidence

The combination of dapagliflozin and sitagliptin in T2D-ASCVD rests on three pillars of evidence: post-myocardial infarction remodeling with dapagliflozin, slowing progression of carotid intima-medial thickness with sitagliptin, and complementary gluco-metabolic and hemodynamic control with both agents.

Dapagliflozin After Myocardial Infarction: In the DAPA-MI trial of 4,017 patients with acute MI and impaired left ventricular function but without prior diabetes, dapagliflozin 10 mg improved cardiometabolic outcomes versus placebo (win ratio 1.34; 95% CI 1.20–1.50). In the subgroup with LVEF <50%, NYHA Class II–IV symptoms improved from 33.9% to 29.6% (HR 0.83; 95% CI 0.73–0.95), and severe NYHA III–IV symptoms fell from 7.2% to 4.3% (HR 0.58; 95% CI 0.42–0.79). New-onset T2DM was reduced from 4.2% to 2.0% (HR 0.46; 95% CI 0.30–0.72), and body weight decreased by 1.65 kg versus placebo. [6]

Sitagliptin and Atherosclerotic Plaque Regression in T2D: In the SPIKE randomized trial, 282 insulin-treated patients with T2DM received either sitagliptin (n=142) or conventional therapy (n=140, using drugs other than DPP-4i) for 104 weeks. Mean carotid intima-media thickness was 0.84 mm at baseline and 0.81 mm at 104 weeks with sitagliptin, versus 0.84 mm at baseline and 0.86 mm with conventional therapy (between-group p=0.008). Left maximum IMT was 1.10 mm at baseline and 1.04 mm with sitagliptin, versus 1.10 mm at baseline and 1.13 mm with conventional therapy (p=0.033). Sitagliptin treatment and higher baseline IMT were independent predictors of plaque regression. [7]

Cardiovascular Safety with Sitagliptin: In TECOS trial, Sitagliptin demonstrated cardiovascular safety with no increase in major adverse cardiovascular events or hospitalization for heart failure compared with placebo, supporting it’s use as a cardiovascular- neutral glucose-lowering agents in patients with established ASCVD. [8]

Dapagliflozin Sitagliptin FDC- Cardio-gluco-metabolic Benefits in Indian T2D with CAD: A retrospective observational study evaluated the dapagliflozin–sitagliptin fixed-dose combination in 328 Indian patients with T2DM, of whom 90 had established coronary artery disease. Overall, HbA1c was 8.36% at baseline and 7.31% (−1.05%) after 12 weeks, fasting plasma glucose fell from 165.5 to 123.8 mg/dL (−41.7 mg/dL), and postprandial glucose from 242.2 to 170.2 mg/dL (−72.0 mg/dL). Systolic blood pressure decreased from 147.0 to 132.4 mmHg (−14.6 mmHg), LDL-C from 121.4 to 103.2 mg/dL (−18.2 mg/dL), and weight from 74.9 to 72.8 kg (−2.1 kg). In the CAD subgroup, HbA1c reduced from 8.36% to 7.34% (−1.02%), FPG from 165.5 to 111.0 mg/dL (−54.5 mg/dL), and PPBG from 242.2 to 153.5 mg/dL (−88.7 mg/dL), demonstrating that the Dapagliflozin Sitagliptin FDC delivers gluco-metabolic and hemodynamic benefits specifically in patients with established ASCVD. [9]

Dapagliflozin Sitagliptin FDC: Smart Clinical Application Considerations

The clinical consideration of Dapagliflozin and Sitagliptin FDC and the potential clinical benefits of each of these agents have been tabulated below:

Figure: Dapagliflozin & Sitagliptin in T2D with ASCVD

Key takeaways

✔ In T2D with ASCVD, glucose-lowering remains necessary, but not sufficient, and cardiometabolic protection through pleiotropic mechanisms becomes important to improve clinical outcomes.

✔ Dapagliflozin reduces epicardial adipose tissue, restores nitric oxide bioavailability, and attenuates oxidative stress, while sitagliptin suppresses TLR-2, TLR-4, NF-κB, and downstream IL-6, TNF-α, and CRP, improving endothelial function and attenuating vascular inflammation in chronic atherosclerosis associated with T2D.

✔ Dapagliflozin sitagliptin combination offers complementary cardiometabolic benefits, extending beyond HbA1c reduction, integrating plaque stabilisation, anti-inflammatory effects, weight and BP reduction, and improved functional recovery, thereby supporting a CV-first therapeutic approach in T2D patients with ASCVD.

Abbreviations: T2D, type 2 diabetes; CVD, cardiovascular disease; ASCVD, atherosclerotic cardiovascular disease; HbA1c, glycated haemoglobin; MACE, major adverse cardiovascular events; HR, hazard ratio; CI, confidence interval; MI, myocardial infarction; TLR-2, toll-like receptor 2; TLR-4, toll-like receptor 4; NF-κB, nuclear factor kappa B; IL-6, interleukin-6; TNF-α, tumour necrosis factor-alpha; CRP, C-reactive protein; AMPK, AMP-activated protein kinase; SIRT1, sirtuin 1; Nrf2, nuclear factor erythroid 2-related factor 2; PAF-AH, platelet-activating factor acetylhydrolase; ox-LDL, oxidised low-density lipoprotein; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; T2DM, type 2 diabetes mellitus; IMT, intima-media thickness; FDC, fixed-dose combination; CAD, coronary artery disease; FPG, fasting plasma glucose; PPBG, postprandial blood glucose; LDL-C, low-density lipoprotein cholesterol; BP, blood pressure; LV, left ventricular; HF, heart failure; CV, cardiovascular.