What is Dapagliflozin Propanediol?
How Does Dapagliflozin Propanediol Work?
Medical Uses and Approved Indications
Potential Benefits and Risks
How Dapagliflozin Propanediol Compares to Other SGLT2 Inhibitors
Dapagliflozin propanediol is a sodium-glucose co-transporter-2 (SGLT2) inhibitor used to treat type 2 diabetes, heart failure, and chronic kidney disease. By reducing glucose reabsorption in the kidney, it improves glycemic control. It also provides cardiovascular and renal protection, making it a valuable therapy in both diabetic and non-diabetic patients.
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What is Dapagliflozin Propanediol?
Dapagliflozin Propanediol primarily functions by inhibiting the SGLT2 protein, which is located in the proximal tubule of the nephron in the kidneys. SGLT2 is responsible for reabsorbing approximately 90% of the glucose filtered by the kidneys under normal physiological conditions.1
By inhibiting this transporter, dapagliflozin reduces the reabsorption of glucose, leading to increased glucose excretion in the urine, which is particularly beneficial for patients with type 2 diabetes.1
Dapagliflozin's inhibition of SGLT2 disrupts this process, leading to decreased renal threshold for glucose, causing glucose to appear in the urine at lower plasma glucose concentrations than normal, increased glucosuria or glucose excretion, and reduced blood glucose levels.1
Beyond its primary action on glucose reabsorption, dapagliflozin exhibits several additional metabolic effects, such as blood pressure reduction.2 Dapagliflozin exerts protective effects on kidney function by reducing hyperfiltration and intraglomerular pressure, which are key contributors to kidney damage in both diabetic and non-diabetic CKD.3
Dapagliflozin has also been associated with reduced inflammatory markers, which are beneficial for cardiovascular health.2,4
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How Does Dapagliflozin Propanediol Work?
By blocking SGLT2 in the proximal tubule of the kidneys, it reduces glucose reabsorption, promoting the elimination of glucose through urine.1 This mechanism improves glycemic control and may also aid in weight loss.
Under normal circumstances, the kidneys filter about 180 grams of glucose daily, which is almost entirely reabsorbed back into the bloodstream via SGLT2 in the proximal convoluted tubules.1
On average, dapagliflozin doses of 5 or 10 mg daily can lead to the excretion of approximately 70 grams of glucose per day after 12 weeks of treatment, with near-maximum glucose excretion observed at a 20 mg dose.5
In addition to its glycemic effects, dapagliflozin has a consistent, although modest, blood pressure-lowering effect. Increased urinary glucose excretion leads to increased water excretion, resulting in a slight decrease in plasma volume. In addition, there is a slight increase in sodium excretion, which may contribute to blood pressure reduction. However, the exact mechanism of blood pressure regulation requires further investigation.3
Long-term studies have shown that dapagliflozin slows the progression of kidney disease, not only in individuals with type 2 diabetes but even in those without diabetes.3
The exact mechanisms underlying this renoprotection are still under investigation but likely involve a combination of factors, including reduction of glomerular hyperfiltration, decreased albuminuria, mitigation of inflammation, and reduced renal fibrosis.3
Medical Uses and Approved Indications
Different clinical trials have demonstrated significant cardiovascular and renal benefits of dapagliflozin.3,6
It is now approved to reduce the risk of cardiovascular death and hospitalization for heart failure in adults with reduced ejection fraction (HFrEF); a left ventricle malfunction and also to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in adults with this condition.3
Dapagliflozin has also been approved to slow the progression of chronic kidney disease (CKD).3,6 In the DAPA-CKD trial, dapagliflozin significantly delayed kidney failure, all-cause mortality, kidney function decline, and heart failure hospitalization.3,6
It slowed CKD progression, extending the time to kidney failure by 6.6 years in the DAPA-CKD population.6
Another clinical trial, the DECLARE-TIMI trial, also revealed that dapagliflozin significantly reduced the risk of a renal composite outcome, including a sustained decrease in eGFR by ≥40%. Specifically, this decline was 46% less with dapagliflozin.3
It has been shown that the administration of this inhibitor affects HbA1c levels. After treatment, HbA1c decreased by 0.8% in the dapagliflozin group compared to 0.2% in the placebo group.1
Additionally, dapagliflozin patients have experienced glycosuria (52-85g/day), reduced fasting blood glucose, and weight loss, highlighting its modulating role in type 2 diabetes patients.1
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Potential Benefits and Risks
The benefits of Dapagliflozin are accompanied by potential risks that need careful patient selection and ongoing monitoring.7 The most common adverse effects are related to the drug's mechanism of action.7
Increased glucose levels in the urine create a favorable environment for microbial growth, elevating the risk of genitourinary infections, including urinary tract infections and genital mycotic infections.7
The osmotic diuresis induced by dapagliflozin can also lead to dehydration, particularly in vulnerable populations like older adults, individuals taking diuretics, or those with pre-existing renal impairment.7
A less common but more serious risk is diabetic ketoacidosis (DKA).7 While typically associated with type 1 diabetes, dapagliflozin can increase the risk of DKA even in patients with type 2 diabetes, particularly during acute illness, periods of reduced insulin secretion, or with significant carbohydrate restriction.7
Prescribing this drug requires a thoughtful approach and a thorough assessment of the patient's volume status prior to initiating therapy, taking into account factors like age, concomitant diuretic use, and baseline renal function.7
Patients must receive comprehensive education about the increased risk of genitourinary infections and the importance of maintaining good hygiene.7 They also need to be educated about the signs and symptoms of DKA, emphasizing that it can occur even with near-normal blood glucose levels.7
How Dapagliflozin Propanediol Compares to Other SGLT2 Inhibitors
While all SGLT2 inhibitors share the same fundamental mechanism of action, subtle differences exist between individual agents like dapagliflozin, empagliflozin, canagliflozin, and ertugliflozin.3,8
All SGLT2 inhibitors offer similar benefits in terms of glycemic control, cardiovascular events, and kidney disease risk reduction.3,8
However, there are differences when looking at the specific outcomes of each trial. For example, while both dapagliflozin (in the DECLARE-TIMI 58 trial) and empagliflozin (in the EMPA-REG OUTCOME trial) showed cardiovascular benefits, empagliflozin showed a more pronounced reduction in cardiovascular death. In contrast, dapagliflozin showed a significant reduction in hospitalization for heart failure.9
Data about canagliflozin suggested a potential increased risk of lower limb amputation, primarily in patients with established peripheral vascular disease. However, this has not been consistently observed with other SGLT2 inhibitors to the same extent.10
The choice between dapagliflozin and other SGLT2 inhibitors often depends on individual patient factors, including their specific cardiovascular and renal risk profile, co-existing conditions, and tolerability to previous medications.7
References
- Perez Lopez, G., Gonzalez Albarran, O. & Cano Megias, M. [Sodium-glucose cotransporter type 2 inhibitors (SGLT2): from familial renal glucosuria to the treatment of type 2 diabetes mellitus]. Nefrologia 30, 618-625 (2010). https://doi.org/10.3265/Nefrologia.pre2010.Sep.10494
- Hao, Z. et al. Effects and Mechanisms of Dapagliflozin Treatment on Ambulatory Blood Pressure in Diabetic Patients with Hypertension. Med Sci Monit 26, e925987 (2020). https://doi.org/10.12659/MSM.925987
- Bailey, C. J., Day, C. & Bellary, S. Renal Protection with SGLT2 Inhibitors: Effects in Acute and Chronic Kidney Disease. Curr Diab Rep 22, 39-52 (2022). https://doi.org/10.1007/s11892-021-01442-z
- Wang, D. D. et al. Dapagliflozin reduces systemic inflammation in patients with type 2 diabetes without known heart failure. Cardiovasc Diabetol 23, 197 (2024). https://doi.org/10.1186/s12933-024-02294-z
- Drugbank. Dapagliflozin, <https://go.drugbank.com/drugs/DB06292> (n.d.).
- McEwan, P. et al. The long-term effects of dapagliflozin in chronic kidney disease: a time-to-event analysis. Nephrol Dial Transplant 39, 2040-2047 (2024). https://doi.org/10.1093/ndt/gfae106
- Zala, A., Maple-Brown, L. J., Shaw, J. E. & Hare, M. J. Current evidence and practical guidance for the use of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes. Aust J Gen Pract 50, 225-230 (2021). https://doi.org/10.31128/AJGP-05-20-5432
- Hsia, D. S., Grove, O. & Cefalu, W. T. An update on sodium-glucose co-transporter-2 inhibitors for the treatment of diabetes mellitus. Curr Opin Endocrinol Diabetes Obes 24, 73-79 (2017). https://doi.org/10.1097/MED.0000000000000311
- Kluger, A. Y. et al. Cardiorenal Outcomes in the CANVAS, DECLARE-TIMI 58, and EMPA-REG OUTCOME Trials: A Systematic Review. Rev Cardiovasc Med 19, 41-49 (2018). https://doi.org/10.31083/j.rcm.2018.02.907
- Lin, C. et al. SGLT2 inhibitors and lower limb complications: an updated meta-analysis. Cardiovasc Diabetol 20, 91 (2021). https://doi.org/10.1186/s12933-021-01276-9
Further Reading