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

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.