What is the best treatment option for a 56-year-old male construction worker with uncontrolled type 2 diabetes, chronic kidney disease (CKD) stage IV, and impaired renal function (eGFR 29 mL/min), who has not been seen by a medical provider in over 5 years and has no prior medical records?

Treatment Approach for Uncontrolled Type 2 Diabetes with CKD Stage IV

You should initiate insulin glargine as planned and avoid SGLT2 inhibitors at this eGFR level, but you must also strongly consider adding a GLP-1 receptor agonist (such as dulaglutide, liraglutide, or semaglutide) to provide superior cardiovascular and renal protection beyond glycemic control alone. 1, 2

Why SGLT2 Inhibitors Are Not Appropriate at eGFR 29 mL/min

Pharmacodynamic Limitations

• SGLT2 inhibitors work by blocking glucose reabsorption in the proximal tubule of the kidney, but their glucose-lowering efficacy is substantially reduced when eGFR falls below 30 mL/min/1.73 m² because there is insufficient glomerular filtration to deliver glucose to the tubule for blockade. 1
• While SGLT2 inhibitors provide cardiovascular and kidney protection independent of glucose lowering, current FDA labeling and guidelines do not recommend initiating these agents when eGFR is below specific thresholds. 1

Specific Drug Restrictions at eGFR 29 mL/min

• Canagliflozin: Initiation is not recommended at eGFR <30 mL/min/1.73 m²; may continue 100 mg daily if already established and tolerated for kidney/CV benefit until dialysis. 1
• Dapagliflozin: Initiation is not recommended at eGFR <25 mL/min/1.73 m²; technically could be initiated at eGFR 29, but this patient is borderline and declining function makes this impractical. 1
• Empagliflozin: Use is not recommended when eGFR <45 mL/min/1.73 m² per FDA labeling. 1
• The consensus is that SGLT2 inhibitors should be initiated when eGFR ≥20 mL/min/1.73 m² for proven kidney and cardiovascular benefits, but at eGFR 29 with acute presentation and no baseline data, initiation carries uncertainty about trajectory. 1, 2

Safety Considerations for SGLT2 Inhibitors

• Hypovolemia risk increases with SGLT2 inhibitors due to osmotic diuresis, which is particularly concerning in a construction worker with high fluid losses and a patient presenting with possible volume depletion (BUN 44, Cr 2.8). 1
• Euglycemic diabetic ketoacidosis can occur with SGLT2 inhibitors, especially in patients requiring insulin therapy—this patient will be started on insulin glargine, placing him at particular risk. 1
• Genital mycotic infections occur in approximately 6% of patients on SGLT2 inhibitors (vs. 1% on placebo), with higher risk in women but still relevant for counseling. 1

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Insulin Glargine Pharmacokinetics: Patient-Friendly Explanation

Absorption

• "After you inject insulin glargine under your skin, it forms tiny deposits that slowly release insulin into your bloodstream over 24 hours, providing steady background insulin coverage without peaks." 3
• The subcutaneous injection creates a depot with gradual, consistent absorption that mimics the body's natural basal insulin secretion. 3

Distribution

• "Once absorbed, insulin glargine travels through your bloodstream to reach cells throughout your body, where it helps glucose enter cells for energy." 3
• Insulin glargine has similar distribution characteristics to endogenous insulin, binding to insulin receptors on target tissues. 3

Metabolism

• "Your body breaks down insulin glargine primarily in your liver and kidneys into smaller inactive pieces that are then eliminated." 3
• Insulin undergoes proteolytic degradation, with the liver being the primary site of metabolism. 3

Excretion

• "The breakdown products are removed from your body through your kidneys in urine, but because your kidney function is reduced (eGFR 29), insulin stays in your system longer than normal, which means you may need lower doses than typical to avoid low blood sugar." 3
• In patients with CKD stage 4-5, insulin clearance is reduced by approximately 25% or more, necessitating dose reductions of 25% or more when eGFR <45 mL/min/1.73 m². 4, 5

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Critical Safety Considerations for This Patient

Hypoglycemia Risk Management

• Start insulin glargine conservatively with careful titration—the risk of hypoglycemia increases substantially in CKD stage 4 due to decreased renal gluconeogenesis and reduced insulin clearance. 1, 4
• Monitor fasting blood glucose closely and adjust doses slowly; this patient's baseline glucose of 326 mg/dL will require gradual reduction to avoid precipitous drops. 3
• Educate the patient on hypoglycemia symptoms (shakiness, sweating, confusion, rapid heartbeat) and ensure he carries fast-acting glucose at all times, especially critical for a construction worker at risk for falls and injury. 1

Hypokalemia Correction

• This patient has significant hypokalemia (K 2.9 mEq/L) that must be corrected before or concurrent with insulin initiation, as insulin drives potassium intracellularly and can precipitate dangerous cardiac arrhythmias. 3
• The irregular heart rate noted on exam (HR 76, irregular) may be related to hypokalemia and requires immediate attention. 3

Volume Status Assessment

• The patient's BUN:Cr ratio of 15.7 (44:2.8) suggests possible prerenal component; assess for volume depletion given his construction work in potentially hot environments and polyuria from uncontrolled diabetes. 6
• Ensure adequate hydration before considering any future SGLT2 inhibitor therapy if kidney function stabilizes or improves. 1

Metformin Contraindication

• Metformin is absolutely contraindicated at eGFR 29 mL/min/1.73 m² due to increased risk of lactic acidosis from impaired renal excretion and accumulation. 1, 6
• The FDA label specifies that metformin should not be initiated when eGFR <45 mL/min/1.73 m² and must be discontinued when eGFR <30 mL/min/1.73 m². 6

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Optimal Treatment Strategy Beyond Insulin Alone

Add GLP-1 Receptor Agonist for Comprehensive Protection

• GLP-1 receptor agonists (dulaglutide, liraglutide, or semaglutide) maintain glucose-lowering efficacy at eGFR <30 mL/min/1.73 m² and provide proven cardiovascular and renal benefits that insulin alone cannot offer. 1, 2, 4
• These agents require no dose adjustment in renal impairment (except exenatide, which should be avoided), making them ideal for this patient. 1
• GLP-1 RAs reduce albuminuria, slow eGFR decline, and lower cardiovascular events—critical for this patient with 2+ proteinuria and likely diabetic nephropathy. 2, 7

Specific GLP-1 RA Recommendations

• Dulaglutide, liraglutide, or semaglutide are preferred over exenatide in severe CKD; start with the lowest dose and titrate based on tolerability. 4
• When combining GLP-1 RA with insulin, reduce the insulin dose by approximately 20% at initiation to prevent hypoglycemia, then titrate both agents based on glucose monitoring. 8
• Educate the patient to report severe abdominal pain immediately, as pancreatitis risk exists (though rare), and monitor for gastrointestinal side effects (nausea, vomiting) that typically improve over 4-8 weeks. 8

Why GLP-1 RAs Are Superior to Insulin Monotherapy

• GLP-1 RAs promote weight loss (average 6-13 kg), whereas insulin typically causes weight gain—this patient has BMI 32.2 kg/m² and would benefit from weight reduction. 8
• Hypoglycemia risk is minimal with GLP-1 RAs when used without insulin or sulfonylureas, providing safer glycemic control. 8
• Cardiovascular mortality reduction has been demonstrated with liraglutide and semaglutide in patients with established cardiovascular disease or high risk. 2

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Additional Management Priorities

Investigate Cause of CKD Stage IV

• This patient has no known medical history but presents with eGFR 29, significant proteinuria (2+), and uncontrolled diabetes—diabetic nephropathy is likely, but acute kidney injury superimposed on chronic disease must be excluded. 1
• Repeat metabolic panel in 1-2 weeks after correcting hyperglycemia and ensuring adequate hydration to determine if kidney function improves or stabilizes. 6
• Consider renal ultrasound to assess kidney size and rule out obstruction, and check urine albumin-to-creatinine ratio for quantification of proteinuria. 1

Initiate Renoprotective Therapy

• Start an ACE inhibitor or ARB if blood pressure remains elevated on repeat measurement (current BP 100/60 may reflect volume depletion), as RAS blockade slows CKD progression in diabetic nephropathy. 2, 4
• Target blood pressure <130/80 mmHg in patients with diabetes and CKD with albuminuria. 1

Monitor for Progression and Complications

• Recheck eGFR, electrolytes, and HbA1c in 3 months; increase monitoring frequency to every 3-6 months given eGFR <60 mL/min/1.73 m². 1, 6
• Screen for anemia, secondary hyperparathyroidism, and metabolic bone disease, which are common in CKD stage 4. 4
• Refer to nephrology for co-management given advanced CKD and need for preparation for potential renal replacement therapy if function continues to decline. 1

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Common Pitfalls to Avoid

• Do not delay insulin initiation due to fear of hypoglycemia—this patient has severe hyperglycemia (glucose 326, HbA1c 9.5%) that requires immediate treatment, but start conservatively and titrate slowly. 1, 3
• Do not assume SGLT2 inhibitors are completely contraindicated at eGFR 29—while initiation is not recommended per most guidelines, if kidney function stabilizes or improves slightly, dapagliflozin could be considered at eGFR ≥25 for cardiorenal protection. 1, 2
• Do not use sulfonylureas in this patient—they carry high hypoglycemia risk in advanced CKD due to accumulation of active metabolites, and glipizide would be the only acceptable option if absolutely necessary. 1, 4, 5
• Do not forget to correct hypokalemia before aggressive insulin therapy—failure to do so can precipitate life-threatening arrhythmias. 3
• Do not overlook the need for diabetes education—this patient has been without medical care for 5 years and requires comprehensive teaching on glucose monitoring, hypoglycemia recognition, medication administration, and lifestyle modifications. 1