Type 2 diabetes and chronic kidney disease (CKD) are strongly interconnected, forming a dangerous duo in which each condition increases the risk and severity of the other. In fact, diabetes is the leading cause of kidney disease. Approximately 1 in 3 adults with diabetes has CKD, and diabetes accounts for around 40-50% of new cases of end-stage kidney disease (ESKD), the most severe form of CKD in which dialysis or a kidney transplant is needed.
Sustained high blood sugar (hyperglycemia) in type 2 diabetes damages the small blood vessels throughout the body, including the tiny, delicate blood vessels (glomeruli) within the kidneys. These glomeruli are crucial for filtering waste products from the blood. This damage is called diabetic nephropathy.
Diabetes often co-exists with high blood pressure (hypertension), and both conditions exacerbate each other. High blood pressure puts extra strain on the already damaged blood vessels in the kidneys, accelerating the progression of CKD. Damaged kidneys themselves also contribute to high blood pressure through the renin-angiotensin-aldosterone system that becomes overactive, creating a vicious cycle.
In the other direction, CKD can worsen insulin resistance, making it harder for the body's cells to use glucose effectively. This can lead to further increases in blood sugar levels. The severity of insulin resistance generally correlates with the stage of CKD, with more advanced CKD associated with more severe insulin resistance. Although the mechanism is not clear, inflammatory molecules like C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) are elevated in CKD, and this systemic inflammation can exacerbate insulin resistance.
In summary, type 2 diabetes and chronic kidney disease are closely linked, with each condition significantly impacting the other. This interconnected relationship helps to explain in part the action of a new treatment for CKD, the drug Farxiga, which was original developed as a medication for type 2 diabetes.
Farxiga (dapagliflozin) is a prescription medication primarily used to manage type 2 diabetes (T2D) by improving glycemic control. It belongs to a class of drugs called SGLT2 inhibitors, which work by preventing the kidneys from reabsorbing glucose, allowing excess glucose to be excreted through urine. Additionally, Farxiga has demonstrated benefits in reducing the risk of hospitalization for heart failure and slowing the progression of chronic kidney disease (CKD). Approved by the FDA in 2014, Farxiga is generally well-tolerated, though common side effects include urinary tract infections and dehydration. Notably, the glucose-lowering effect of Farxiga does not rely on insulin secretion or sensitivity, making it effective even in insulin-resistant conditions or advanced stages of diabetes.
Sodium-Glucose Cotransporter-2 (SGLT2) is a protein located in the proximal tubule of the nephron (basic functional unit of kidney). SGLT2 cotransports sodium and glucose from the tubular filtrate (urine precursor) back into the bloodstream. Farxiga blocks SGLT2, reducing glucose and sodium reabsorption from the tubular filtrate into the blood. This results in higher sodium and glucose levels in the remaining filtrate, which are excreted in the urine.
Farxiga has been more recently approved as a medication to treat CKD. Lowering blood glucose directly helps T2D. Lower blood sodium reduces blood volume (via osmosis) and hence blood pressure. High blood pressure is one of the most important risk factors for CKD. In addition, Farxiga can act through a second mechanism to ameliorate CKD. With SGLT2 inhibition, more sodium reaches the kidney distal tubule, leading to enhanced signaling through the tubuloglomerular feedback mechanism. This response results in afferent arteriole constriction (curtailing blood flow into kidneys), reducing glomerular hyperfiltration and protecting kidney function. Finally, as mentioned above, type 2 diabetes adversely affects the kidneys, and so reducing T2D risk can benefit CKD.
A clinical trial published in The New England Journal of Medicine in 2020 demonstrated the statistically significant efficacy of Farxiga on CKD. As a reminder, kidney function is assessed via estimated glomerular filtration rate (eGFR), which is calculated from a blood test that measures the level of creatinine, and by the amount of albumin (a protein) relative to creatinine that is excreted in the urine. The trial included 4,304 patients aged 18–75 with CKD (eGFR 25–75 mL/min/1.73m²) and albuminuria (urinary albumin-to-creatinine ratio 200–5,000 mg/g), which represent a moderate stage of the disease. Patients with and without type 2 diabetes were enrolled, and they were randomized to receive either dapagliflozin (10 mg daily) or a placebo, in addition to standard care. The median follow-up time was 2.4 years.
The primary outcome was the composite risk of sustained eGFR decline, end-stage kidney disease, or death from cardiovascular/renal causes. Farxiga (dapagliflozin) reduced this risk 39% compared to placebo (hazard ratio, HR = 0.61). Interestingly, the salutory effect was observed in both those with (HR = 0.64) and without (HR = 0.50) T2D. In the treatment group, the primary outcome incidence rate at 32 months was approximately 12% (Figure 1).
The authors concluded:
"Among patients with chronic kidney disease, regardless of the presence or absence of diabetes, the risk of a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes was significantly lower with dapagliflozin than with placebo."
Shortly thereafter, Farxiga was approved by the FDA for the treatment of chronic kidney disease (CKD) in adults on April 30, 2021.
Figure 1. Kaplan-Meier curve of those treated with dapagliflozin (Farxiga) or placebo. The primary outcome was the composite risk of sustained eGFR decline, end-stage kidney disease, or death from cardiovascular/renal causes. A significant benefit was observed in the drug treatment group (Heerspink et al. NEJM, 2024).
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