What are the implications of discontinuing Lantus (insulin glargine) and initiating Jardiance (empagliflozin) in a patient with a history of recurrent hypoglycemia who is also taking Ozempic (semaglutide) and Humalog 75-25 (insulin lispro protamine/insulin lispro)?

Discontinuing Lantus and Starting Jardiance in a Patient with Recurrent Hypoglycemia

You should not have discontinued Lantus (basal insulin) in this patient with recurrent hypoglycemia who is also taking Ozempic and Humalog 75-25; instead, you should have discontinued or reduced the Humalog 75-25 first, as this mixed insulin formulation contains both rapid-acting and intermediate-acting components that significantly increase hypoglycemia risk, particularly in patients already on GLP-1 therapy. 1

Critical Assessment of Your Medication Change

Why Discontinuing Lantus Was Problematic

• Lantus (insulin glargine) provides stable basal insulin coverage with no peak action time and is specifically designed to reduce hypoglycemia risk compared to intermediate-acting insulins 1
• Patients with type 1 diabetes or significant insulin deficiency require basal insulin to prevent diabetic ketoacidosis and maintain stable glucose levels between meals 1
• Removing basal insulin entirely creates dangerous glucose instability, particularly overnight and between short-acting insulin doses 1

The Real Culprit: Humalog 75-25

• Humalog 75-25 is a premixed insulin containing 75% insulin lispro protamine (intermediate-acting) and 25% insulin lispro (rapid-acting), and premixed insulins are NOT recommended due to their inflexible dosing and increased hypoglycemia risk 1
• The intermediate-acting component (75% of the formulation) peaks many hours after administration, unrelated to mealtimes, causing hypoglycemia if eating is delayed or physical activity increases 1
• When combined with Ozempic (which delays gastric emptying and reduces appetite), the risk of hypoglycemia from Humalog 75-25 is substantially amplified 1

Jardiance: Wrong Solution for Hypoglycemia

Limited Glycemic Efficacy in This Context

• Jardiance (empagliflozin) has only moderate glucose-lowering action, reducing HbA1c by approximately 0.5% compared to placebo, and this effect is even smaller in patients with renal impairment 2, 3
• SGLT2 inhibitors like Jardiance progressively lose glucose-lowering efficacy as eGFR declines below 45 mL/min/1.73 m², with substantially reduced effects when eGFR falls below 30 mL/min/1.73 m² 4
• Jardiance does NOT replace the physiologic need for basal insulin in patients requiring multiple daily insulin injections 1, 5

Dangerous Combination with Insulin

• The FDA label explicitly warns that the risk of hypoglycemia increases when Jardiance is used in combination with insulin, and a lower insulin dose may be required 5
• Jardiance causes intravascular volume contraction and can precipitate acute kidney injury, particularly in patients on multiple medications including insulin 5
• In patients with insulin deficiency (suggested by need for both basal and bolus insulin), Jardiance increases the risk of euglycemic diabetic ketoacidosis, which can occur even with blood glucose levels below 250 mg/dL 5, 6

What You Should Have Done Instead

Step 1: Identify the Hypoglycemia Source

• Assess hypoglycemia patterns: timing relative to meals, overnight episodes, and relationship to Humalog 75-25 dosing 1
• The intermediate-acting component of Humalog 75-25 (75% of the dose) is the most likely culprit, as it peaks 6-8 hours after administration regardless of food intake 1
• Ozempic reduces the need for mealtime insulin by slowing gastric emptying and reducing appetite, making the fixed-ratio Humalog 75-25 inappropriate 7

Step 2: Discontinue or Reduce Humalog 75-25 First

• Premixed insulins like Humalog 75-25 should be discontinued in patients experiencing recurrent hypoglycemia, especially when already on GLP-1 therapy 1, 7
• If bolus insulin is still needed, switch to rapid-acting insulin only (regular insulin lispro) given with meals, allowing flexible dosing based on actual carbohydrate intake 1
• The dose of rapid-acting insulin should be reduced by 30-50% when used with Ozempic due to the GLP-1's glucose-lowering effects 7

Step 3: Maintain Lantus for Basal Coverage

• Continue Lantus at a potentially reduced dose (typically 16-24 units daily) to maintain stable basal insulin levels 1
• Lantus should be dosed once daily, preferably at bedtime, and adjusted based on fasting glucose readings 1
• Monitor for hypoglycemia at the threshold of 70 mg/dL (3.9 mmol/L), which requires immediate treatment with fast-acting carbohydrates 1

Step 4: Optimize Ozempic

• Continue Ozempic as it provides cardiovascular benefits and reduces the need for insulin without causing hypoglycemia when used alone 7, 4
• Ozempic's glucose-lowering effect is insulin-independent and complements basal insulin therapy 4

Immediate Actions Required Now

Assess for Diabetic Ketoacidosis Risk

• Without basal insulin, patients with significant insulin deficiency are at risk for diabetic ketoacidosis, even with normal or near-normal glucose levels (euglycemic DKA) 5, 6
• Check for symptoms: nausea, vomiting, abdominal pain, generalized malaise, shortness of breath, and signs of dehydration 5
• If ketoacidosis is suspected, discontinue Jardiance immediately, check serum ketones and blood gas, and reinitiate insulin therapy promptly 5

Reinitiate Basal Insulin

• Restart Lantus immediately at a reduced dose (50-75% of previous dose) to prevent hyperglycemia and ketoacidosis 1
• Monitor blood glucose closely (4-6 times daily) for the first week after restarting Lantus 1

Address the Humalog 75-25

• Discontinue Humalog 75-25 entirely and replace with rapid-acting insulin lispro (without the protamine component) given only with meals 1
• Start with 50% of the previous rapid-acting component dose (25% of the total Humalog 75-25 dose) and adjust based on postprandial glucose readings 7

Jardiance Decision

• If the patient has established cardiovascular disease or heart failure, Jardiance may be continued for its cardioprotective benefits, but NOT as a replacement for insulin 1, 4, 3
• If Jardiance was started solely for glucose lowering in a patient requiring insulin, it should be discontinued as it provides minimal benefit and increases risks 5, 2
• Monitor for volume depletion, hypotension, and acute kidney injury, particularly in the first few weeks of Jardiance use 5

Common Pitfalls and How to Avoid Them

Pitfall 1: Assuming SGLT2 Inhibitors Replace Insulin

• SGLT2 inhibitors work through an insulin-independent mechanism and cannot replace the physiologic need for basal insulin in patients with significant insulin deficiency 4, 8
• The cardiovascular and renal benefits of SGLT2 inhibitors are out of proportion to their glucose-lowering effects and do not substitute for adequate insulin therapy 1, 4

Pitfall 2: Not Recognizing Premixed Insulin as High-Risk

• Premixed insulins like Humalog 75-25 have inflexible dosing that does not adapt to variable meal timing, carbohydrate intake, or physical activity 1
• The disadvantages of intermediate-acting insulin (which comprises 75% of Humalog 75-25) outweigh any advantages of tight glucose control 1

Pitfall 3: Discontinuing Multiple Medications Simultaneously

• Stopping Lantus while continuing Humalog 75-25 creates a dangerous situation where the patient has excessive bolus/intermediate insulin without adequate basal coverage 1
• This approach makes it impossible to determine which medication was causing hypoglycemia and increases the risk of both hypoglycemia and hyperglycemia 7, 9

Pitfall 4: Ignoring Euglycemic DKA Risk

• SGLT2 inhibitors can cause diabetic ketoacidosis even with blood glucose levels less than 250 mg/dL, particularly in patients with insulin deficiency, acute illness, or reduced caloric intake 5, 6
• Before initiating Jardiance, factors predisposing to ketoacidosis must be considered, including pancreatic insulin deficiency, caloric restriction, and alcohol use 5

Monitoring Plan Going Forward

Immediate (First Week)

• Check blood glucose 4-6 times daily: fasting, before each meal, 2 hours after meals, and at bedtime 1
• Monitor for symptoms of hyperglycemia (increased thirst, frequent urination, fatigue) and ketoacidosis (nausea, vomiting, abdominal pain, shortness of breath) 5, 6
• Assess for volume depletion and hypotension if Jardiance is continued 5

Short-term (First Month)

• Adjust Lantus dose based on fasting glucose readings, targeting 80-130 mg/dL (4.4-7.2 mmol/L) 1
• Adjust rapid-acting insulin doses based on postprandial glucose readings and carbohydrate intake 1
• Check renal function (eGFR and creatinine) within 2-4 weeks if Jardiance is continued 5

Long-term (3-6 Months)

• Reassess HbA1c after 3 months to evaluate overall glycemic control 1
• Screen for impaired hypoglycemia awareness using validated questionnaires (Clark or Gold scores) at least yearly 1
• Continue monitoring for genital mycotic infections and urinary tract infections if Jardiance is continued 5, 8