Use of SGLT-2 Inhibitors in Patients With Chronic Kidney Disease

Introduction:

Chronic kidney disease (CKD) is a long-term condition characterized by the gradual loss of kidney function over time. The kidneys are vital organs that filter waste and excess fluid from the blood and remove them from the body through urine. In CKD, the kidneys become damaged and are unable to perform their normal functions effectively, leading to waste and fluid buildup in the body.

CKD can be caused by a variety of factors, including high blood pressure, diabetes, infections, and autoimmune diseases. It often develops slowly over time and may not exhibit any symptoms in the early stages. However, patients may experience symptoms such as fatigue, nausea, swelling in the legs and ankles, and difficulty concentrating, as the condition progresses.

What Are SGLT-2 Inhibitors?

SGLT-2 inhibitors are a class of medications mainly used to treat type 2 diabetes. They work by blocking a protein called sodium-glucose cotransporter-2 (SGLT-2) in the kidneys, which is responsible for reabsorbing glucose from the urine back into the bloodstream. By blocking SGLT-2, these medications prevent the kidneys from reabsorbing glucose, increasing glucose excretion in the urine and lowering blood glucose levels.

SGLT-2 inhibitors are often used in combination with other diabetes medications, such as Metformin or Insulin, to help control blood glucose levels. They are usually taken orally once a day and are available in various brand names, such as Canagliflozin, Dapagliflozin, Empagliflozin, and Ertugliflozin.

What Are the Indications of SGLT-2 Inhibitors?

The indications of SGLT-2 inhibitors include:

• Type 2 Diabetes: SGLT-2 inhibitors are FDA (Food and Drug Administration)-approved to treat type 2 diabetes, either as a monotherapy or in combination with other antidiabetic medications. They work by blocking the reabsorption of glucose in the kidneys, lowering blood glucose levels.

• Cardiovascular Disease: Some SGLT-2 inhibitors have been shown to have cardiovascular benefits, such as reducing the risk of heart attack, stroke, and cardiovascular death. These medications may be indicated in patients with type 2 diabetes who have a high risk of cardiovascular disease.

• Chronic Kidney Disease: SGLT-2 inhibitors have also shown potential benefits in patients with chronic kidney disease (CKD). They can help slow CKD progression by reducing intraglomerular pressure and decreasing the workload on the kidneys.

• Obesity: SGLT-2 inhibitors can also lead to weight loss, making them a potential treatment option for patients with obesity or overweight.

• Hypertension: SGLT-2 inhibitors have been shown to lower blood pressure, which may be beneficial in patients with hypertension (high blood pressure).

• Non-alcoholic Fatty Liver Disease (NAFLD): Some studies have suggested that SGLT-2 inhibitors may be helpful in the treatment of NAFLD, a condition in which fat accumulates in the liver.

What Is the Role of SGLT-2 Inhibitors in Chronic Kidney Disease?

SGLT-2 inhibitors work by blocking a protein called sodium-glucose cotransporter-2 (SGLT-2) in the kidneys. This protein is responsible for reabsorbing glucose back into the bloodstream from the urine. By blocking SGLT-2, these medications prevent the kidneys from reabsorbing glucose, increasing glucose excretion in the urine and lowering blood glucose levels.

One of the key benefits of SGLT-2 inhibitors in patients with CKD is their ability to reduce intraglomerular pressure, which can help to protect the kidneys from damage. By blocking glucose reabsorption in the kidneys, SGLT-2 inhibitors reduce the amount of glucose that enters the renal tubules, which decreases the workload on the kidneys. This can slow the progression of CKD and reduce the risk of kidney failure and other complications.

In addition to their glucose-lowering effects, SGLT-2 inhibitors have been shown to have other beneficial effects in patients with CKD. They can reduce blood pressure, which is a common complication of CKD. They have also been shown to improve lipid profiles, which may help reduce cardiovascular disease risk in patients with CKD.

However, there are some concerns about the use of SGLT-2 inhibitors in patients with CKD. One of the main concerns is the risk of dehydration and hypotension, particularly in patients with more advanced CKD. This risk can be mitigated by carefully monitoring fluid and electrolyte balance and blood pressure in patients taking SGLT-2 inhibitors. Another concern is the potential for acute kidney injury (AKI), which has been reported in some patients taking SGLT-2 inhibitors. However, this risk appears to be relatively low and can be minimized by avoiding the use of SGLT-2 inhibitors in patients with severe renal impairment or those at high risk for AKI.

What Are the Findings of Clinical Studies Using SGLT-2 Inhibitors in Patients With Chronic Kidney Disease?

• Treatment with Empagliflozin reduces the worsening of kidney disease or cardiovascular (CV) death by 28 percent compared to placebo, and the benefit was consistent in patients with or without CVD.

• The use of Empagliflozin reduced the need for hospitalization due to any cause by 14 % compared to the placebo group, and this benefit was consistent in patients with or without CVD. Notably, the chronic kidney disease patient population had a high hospitalization rate.

• The trial's primary outcome was dominated by a reduction in kidney disease progression with Empagliflozin, while a low event rate was observed for CV outcomes. Therefore, the reduction in CV outcomes with empagliflozin was non-significant.

• Meta-analysis results showed that the use of empagliflozin resulted in a 14 percent reduction in CV death in patients with or without diabetes. However, the confidence interval was wide in chronic kidney disease trials without diabetes, indicating the need for more data due to the low number of CV death events in this patient population.

• Empagliflozin use also led to a 23 percent reduction in the combined endpoint of CV death or hospitalization for heart failure (HF) in patients with or without diabetes, resulting in an overall reduction of 23 percent. However, the chronic kidney disease trials in patients without diabetes had a wide confidence interval due to the low number of CV death and HF hospitalization events in this population.

What Are the Side Effects of SGLT-2 Inhibitors?

• SGLT-2 inhibitors can increase the risk of genital and urinary tract infections, particularly in women. Symptoms may include pain or burning during urination, frequent urination, and genital itching or discharge.

• SGLT-2 inhibitors can increase urine output, which can lead to dehydration, particularly in older adults or people with kidney problems. Symptoms may include dry mouth, increased thirst, and dark urine.

• SGLT-2 inhibitors can lower blood glucose levels, which can lead to hypoglycemia (low blood sugar). This risk is higher in people taking insulin or other antidiabetic medications.

• Rarely, SGLT-2 inhibitors can cause a serious condition called ketoacidosis, which occurs when the body produces high levels of ketones (acids) in the blood. Symptoms may include nausea, vomiting, abdominal pain, confusion, and fruity-smelling breath.

• There is some evidence that SGLT-2 inhibitors may increase the risk of bone fractures, particularly in women.

• Although rare, SGLT-2 inhibitors have been associated with cases of acute kidney injury, particularly in people with preexisting kidney problems.

• Some studies have suggested that SGLT-2 inhibitors may increase levels of LDL (low-density lipoprotein) cholesterol in some people.

Conclusion:

Clinicians should perform various assessments before initiating SGLT2 inhibitor therapy in patients. These include monitoring hydration status, evaluating bone density, reviewing the patient’s cardiac history, and assessing hepatic and renal function. Certain patient populations may have restrictions on prescribing SGLT2 inhibitors. For optimal benefits and risk management, healthcare providers should take into account the patient's medical conditions and consistently monitor blood glucose levels, renal function, and fluid balance during follow-up appointments.