Dapagliflozin and Lipoprotein Metabolism in Type 2 Diabetes: Preserving LDL Catabolism and Normalizing VLDL Processing

Highlight

• Dapagliflozin treatment does not reduce LDL-ApoB100 catabolism in patients with type 2 diabetes.
• A shift from direct to indirect catabolism of VLDL1 and VLDL2 ApoB100-containing lipoproteins resembles more physiological lipid metabolism.
• The changes in lipoprotein kinetics might partially explain the atherosclerosis risk reduction observed with SGLT2 inhibitors.
• Dapagliflozin improves glycemic control and reduces body weight without adversely affecting plasma LDL or triglyceride levels.

Study Background

Type 2 diabetes mellitus (T2DM) is a major global health concern characterized by hyperglycemia and often accompanied by atherogenic dyslipidemia, including elevated triglycerides, low high-density lipoprotein cholesterol (HDL-C), and qualitative LDL particle changes. These lipid abnormalities contribute significantly to the accelerated atherosclerosis and cardiovascular disease risk associated with T2DM.

Recently, sodium-glucose cotransporter 2 (SGLT2) inhibitors such as dapagliflozin have emerged as important antidiabetic agents that improve glycemic control and reduce cardiovascular events and mortality beyond glucose lowering. Despite their proven cardiovascular benefits, the mechanisms by which SGLT2 inhibitors reduce atherosclerosis remain incompletely understood, particularly regarding their effects on lipid metabolism.

Previous animal studies suggested that SGLT2 inhibitors might downregulate hepatic LDL receptors, potentially impairing LDL clearance and increasing atherogenic risk. However, the direct impact of these drugs on lipoprotein metabolism, especially the kinetics of ApoB100-containing lipoproteins (which include low density lipoprotein [LDL], very low density lipoprotein 1 and 2 [VLDL1/VLDL2], and intermediate-density lipoprotein [IDL]) has not been comprehensively studied in humans.

Understanding such effects is crucial because lipoprotein catabolism dynamics influence circulating lipid levels and atherosclerotic plaque development. This study aimed to assess how dapagliflozin influences the metabolism of ApoB100-containing lipoproteins in individuals with type 2 diabetes using a robust kinetic study design.

Study Design

This was a randomized, parallel-group, double-blind, placebo-controlled in vivo kinetic study conducted in 24 individuals with type 2 diabetes. Participants were randomized to receive either dapagliflozin (10 mg/day) or placebo for 6 months.

Lipoprotein metabolism was examined using stable isotope kinetic techniques: tri-deuterated ([2H3]) L-leucine was employed to label ApoB100 proteins, enabling measurement of fractional catabolic rates, production rates, and pool sizes of LDL, VLDL1, and VLDL2 particles. These kinetic parameters provide insight into the metabolic pathways and clearance efficiency of atherogenic lipoproteins.

Primary endpoints included changes in LDL-ApoB100 fractional catabolism, production rate, and pool size post-treatment. Secondary endpoints evaluated VLDL1 and VLDL2 ApoB100 fractional catabolic pathways, particularly distinguishing direct catabolism versus indirect conversion through lipoprotein remodeling.

Clinical parameters such as body weight, HbA1c, plasma triglycerides, LDL-cholesterol, and ApoB100 concentrations were also measured to establish correlations with lipoprotein kinetics.

Key Findings

Twenty-four participants completed the study: 17 received dapagliflozin and 7 placebo. Dapagliflozin significantly reduced body weight (p<0.001) and HbA1c (p=0.001) relative to placebo, confirming its expected metabolic benefits.

Importantly, plasma triglyceride, LDL-cholesterol, and total ApoB100 concentrations did not undergo significant changes after dapagliflozin treatment compared to placebo, suggesting stable steady-state lipoprotein levels.

Regarding LDL metabolism, dapagliflozin did not affect the fractional catabolism of LDL-ApoB100 (0.88 ± 0.37 vs 0.79 ± 0.31 pool/day, p=0.16), nor were there significant variations in LDL-ApoB100 pool size or production rate. This finding addresses concerns from animal studies about potential LDL receptor downregulation by SGLT2 inhibitors, reassuring that LDL catabolism is preserved in humans.

The most notable metabolic effect was observed in VLDL kinetics. Dapagliflozin caused a significant reduction in the direct catabolism of VLDL1-ApoB100 (0.33 ± 0.65 vs 2.37 ± 2.31 pool/day, p=0.001). Conversely, indirect catabolism of VLDL1-ApoB100—via conversion to VLDL2 and IDL—and subsequent indirect catabolism of VLDL2-ApoB100 towards IDL were significantly increased (p=0.001 and p=0.049, respectively). This shift is consistent with a more physiologic lipoprotein remodeling pattern typically disrupted in type 2 diabetes, wherein direct hepatic clearance of triglyceride-rich VLDL1 is reduced in favor of stepwise lipolytic processing.

No significant adverse events or side effects were reported, underscoring the safety of dapagliflozin in this cohort.

Expert Commentary

This well-designed, randomized kinetic study provides compelling evidence that dapagliflozin spares LDL catabolism in type 2 diabetes, disproving prior concerns derived from animal models. Maintaining efficient LDL receptor-mediated clearance is crucial in limiting circulating LDL and related cardiovascular risk.

Moreover, dapagliflozin’s induction of a metabolic shift from direct hepatic catabolism of VLDL1 to an indirect pathway through VLDL2 and IDL may restore the physiological cascade of lipoprotein remodeling. This pathway is generally impaired in diabetic dyslipidemia, contributing to atherogenic lipid profiles. By correcting this abnormality, dapagliflozin could counteract the proatherogenic lipid environment beyond glycemic control.

Mechanistically, the findings align with known dapagliflozin effects on weight reduction and insulin sensitivity, which collectively improve lipid metabolism at multiple levels. The robustness of stable isotope kinetic methodology adds rigor to the interpretations, allowing precise dissection of ApoB100 metabolic fluxes.

Study limitations include modest sample size and relatively short duration. Larger studies and exploration in diverse populations would enhance generalizability. Additionally, the effects on other lipid classes such as HDL metabolism warrant further research.

Conclusion

In summary, dapagliflozin treatment in individuals with type 2 diabetes does not impair LDL catabolism and favorably remodels VLDL1 and VLDL2 ApoB100 catabolic pathways towards physiological patterns. These alterations, combined with improved glycemic control and weight loss, likely contribute to the cardiovascular benefits documented with SGLT2 inhibitors.

The study highlights the importance of evaluating lipid kinetics for novel antidiabetic treatments and supports dapagliflozin as a metabolically beneficial agent in managing diabetic dyslipidemia and reducing atherosclerosis risk.

Funding and Trial Registration

This study was funded by AstraZeneca, the French National Research Agency (ANR) under the “Investissements d’Avenir” program, University of Burgundy-Franche-Comté, National Institute of Health and Medical Research (Inserm), Region Burgundy – Franche Comté, and the European Regional Development Fund (FEDER).

Trial registration number: ClinicalTrials.gov NCT03269058.

References

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2. Zelniker TA, Braunwald E. Cardiac and renal effects of sodium-glucose co-transporter 2 inhibitors in diabetes: JACC State-of-the-Art Review. J Am Coll Cardiol. 2018;72(15):1845-1855.

3. Taskinen MR, Boren J. Emerging evidence that SGLT2 inhibitors suppress atherosclerosis in type 2 diabetes: The evolving role of lipid metabolism. Diabetologia. 2020;63(2):265-275.