Treatment of DKD is intended to slow and hopefully stop the progression of the disease, and treatment of DKD includes glycemic control, blood pressure control, and nutritional modifications. Regarding the prevention of DKD, exercise, lipid control, weight loss, and smoking cessation can help prevent diabetic complications, but the “. . . only proven primary prevention interventions for CKD are blood glucose and blood pressure control” (ElSayed et al., 2023a).
The pharmacological treatment of DKD for glycemic control is discussed in the next section.
- Glycemic control: Intensive glucose control and attaining near-normoglycemia has been shown to delay the onset and progression of albuminuria and decrease eGFR (Agrawal et al., 2018; ElSayed et al., 2023a). For patients who have DM, the recommended A1C level is < 7% (ElSayed et al., 2023c). However, CKD changes the benefits and risks of intensive glucose control, increasing the risk of adverse effects. It can take at least two years in T1DM patients and > ten years in T2DM patients to see the renal benefits of intensive glucose control (ElSayed et al., 2023a). Given those factors, an A1C of < 8% may be appropriate for a diabetic patient with CKD (ElSayed et al., 2023a; ElSayed et al., 2023c).
- Blood pressure control: The American Diabetes Association Professional Practice Committee recommends optimizing blood pressure control and minimizing blood pressure variability to reduce the risk of CKD and/or slow its progression (ElSayed et al., 2023a). Antihypertensives have been shown to reduce the risk of albuminuria. In patients with an eGFR <60 mL/min/1.73 m2 and a urinary albumin/creatinine ratio ≥300, antihypertensive therapy can reduce the risk of the progression of CKD to ESRD. (ElSayed et al., 2023a). The target blood pressure level for diabetic patients is < 130/80 mm; a lower level can be considered if the patient has CKD (ElSayed et al., 2023a).
- Nutrition: Patients with DKD who are not dialysis-dependent should restrict their protein intake to approximately 0.8 grams/kg/day (ElSayed et al., 2023a). Compared to higher amounts, a protein intake of 0.8 g/kg/day has been associated with a slower decline in eGFR. A protein intake >20% of the daily caloric intake has been associated with increased albuminuria and an increased rate of decline of kidney function (ElSayed et al., 2023a; Yue et al., 2020). A low-protein diet is considered protective/therapeutic by reducing glomerular hyperfiltration, one of the pathophysiologic mechanisms that cause glomerular injury (Schrauben et al., 2022). Restricting dietary sodium to < 2300 mg/day can help control hypertension. For patients with DKD and a low eGFR, renal excretion of sodium can be impaired, so a sodium-restricted diet may be advisable (ElSayed et al., 2023a). A sodium-restricted diet may also decrease albuminuria (Schrauben et al., 2022).
Two classes of antidiabetic medications are used for glycemic control and have been shown to decrease the progression of CKD (ElSayed et al., 2023b). Sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1-RAs) lower blood glucose, slow CKD progression, and prevent cardiovascular complications caused by DM and CKD.
- SGLT2 inhibitors: SGLT2 is a protein that increases glucose reabsorption from the renal tubules, and SGLT2 accounts for approximately 90% of reabsorbed glucose (Katzung et al., 2021). The SGLT2 inhibitors, canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin, increase the urinary excretion of glucose and lower plasma glucose (Katzung et al., 2021). These drugs are labeled for treating T2DM, and canagliflozin and dapagliflozin are labeled for treating CKD to reduce the risk of sustained decrease in eGFR and ESRD. The SGLT2 inhibitors have been shown to slow the progression of CKD, reduce the risk of kidney failure, and they can provide significant cardiovascular benefits in patients who have T2DM (ElSayed et al., 2023a; ElSayed et al., 2023b; Limonte et al., 2022; Navaneethan et al., 2023).
- GLP-1-RAs: These are analogs of the incretin hormone glucagon-like-peptide-1 (GLP-1). GLP-1 decreases blood glucose by decreasing glucagon secretion and increasing insulin secretion (Powers & D’ Alessio, 2017). The GLP-1-RAs, dulaglutide, exenatide, liraglutide, lixisenatide, and semaglutide, are injectable antidiabetics with a labeled use for treating T2DM. The 2022 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend GLP-1-RAs as a second-line treatment for glucose control in patients who have T2DM and CKD (Navaneethan et al., 2023). The GLP-1-RAs reduce the risk of cardiovascular complications in this patient population (ElSayed et al., 2023c; Limonte et al., 2022; Tong & Adler, 2022), and there is good, albeit inconclusive, evidence that the GLP-1-RAs can slow the progression of DKD (ElSayed et al., 2023a; Navaneethan et al., 2023; Tong & Adler, 2022).
Angiotensin-converting-enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are the first-line treatment for diabetic patients who have hypertension, an eGFR <60 mL/min/1.73 m2, and a urinary albumin/creatinine ratio ≥300 mg/g (ElSayed et al., 2023a). The ACEs and the ARBs can prevent the progression of CKD, and they seem equally effective at doing so (ElSayed et al., 2023d). The American Diabetes Association Standard of Care recommends that in nonpregnant patients with diabetes and hypertension, either an ACE inhibitor or an ARB is recommended for those with modestly elevated urinary albumin-to-creatinine ratio (30–299 mg/g creatinine) and is strongly recommended for those with urinary albumin-to-creatinine ratio ≥ 300 mg/g creatinine and/or an eGFR <60 mL/min/1.73 m2” (ElSayed et al., 2023a).
Metformin is the first-line drug for patients who have T2DM. Metformin is mostly excreted (90%) in the urine, and decreased renal function decreases renal clearance of the drug and increases peak and systemic exposure to metformin. In addition, renal impairment increases the risk of developing lactic acidosis, a potentially deadly adverse effect of metformin (Bosse, 2019). Metformin can be safely used for diabetic patients with DKD (Boddepalli et al., 2022; ElSayed et al., 2023a), but to avoid putting patients at risk, these recommendations below must be followed (Boddepalli et al., 2022; ElSayed et al., 2023a).
- Metformin is contraindicated if the patient’s eGFR is <30 mL/min/1.73 m2.
- The eGFR should be monitored during treatment with metformin. The eGFR, not serum creatinine, should guide treatment with metformin.
- If the patient’s eGFR becomes <45 mL/min/1.73 m2, clinicians should consider the benefits and risks of continuing the use of metformin.
- Treatment with metformin should not be initiated if a patient’s eGFR is <45 mL/min/1.73 m2.
- If a patient’s eGFR is 30 to 60 mL/min/1.73 m2, the use of metformin should be temporarily stopped before or at the time of the use of iodinated contrast dye.