Why do blood sugar levels fluctuate throughout the day in diabetics treated with insulin and oral metformin (Glucophage) + dapagliflozin (Farxiga)?

Blood Sugar Fluctuations in Diabetics on Insulin, Metformin, and Dapagliflozin

Blood sugar fluctuations throughout the day in diabetics treated with insulin, metformin, and dapagliflozin occur due to multiple physiological and pharmacological factors including variable medication absorption rates, insulin sensitivity changes, food intake timing, exercise, stress hormones, and the specific mechanisms of action of each medication.

Physiological Causes of Blood Sugar Fluctuations

• Blood glucose values naturally fluctuate throughout the day even in people without diabetes, but these fluctuations are more pronounced in diabetic patients due to impaired glucose regulation mechanisms 1
• The same euglycemic state can disguise very different counter-regulatory hormonal activities and metabolic states that aren't reflected by actual blood glucose values 1
• Stress hormones (catecholamines, glucagon, glucocorticoids, growth hormone, and thyroid hormone) can mobilize endogenous glucose, counteracting insulin effects and causing blood sugar elevations 1
• Exercise increases blood flow to the skin and can increase insulin absorption rates from injection sites, potentially causing unexpected drops in blood glucose 1

Medication-Specific Factors

Insulin-Related Fluctuations

• Insulin absorption rates vary between injection sites, with the abdomen having the fastest absorption, followed by arms, thighs, and buttocks 1
• Lipohypertrophy (thickened tissue at injection sites) can slow insulin absorption, causing unpredictable glucose responses 1
• Rotating injection sites within one area (e.g., systematically within the abdomen) rather than between different areas can decrease day-to-day variability in absorption 1
• Intramuscular versus subcutaneous injection can significantly alter absorption rates and timing of insulin action 1

Metformin-Related Factors

• Metformin decreases hepatic glucose production, decreases intestinal glucose absorption, and improves insulin sensitivity by increasing peripheral glucose uptake 2
• Metformin's peak plasma levels are reached within 24-48 hours of starting therapy, with steady-state concentrations generally less than 1 μg/mL 2
• Food can decrease the extent and slightly delay the absorption of metformin, as shown by approximately 40% lower peak plasma concentration when taken with food 2
• Metformin is considered a metabolic promoter that can improve cellular metabolism in a blood glucose-independent way 1

Dapagliflozin-Related Factors

• Dapagliflozin works by inhibiting SGLT2 in the kidneys, preventing glucose reabsorption and inducing urinary glucose excretion (glucuresis) 3, 4
• Dapagliflozin reduces both fasting and postprandial glucose levels through its glucuretic mechanism 5
• Studies show dapagliflozin increases the proportion of time spent in target glucose range (70-180 mg/dL) compared to placebo 5
• Dapagliflozin's effect on glucose excretion continues throughout the day but may vary based on filtered glucose load, which depends on blood glucose levels 4, 6

Meal-Related Fluctuations

• Postprandial glucose excursions are common in diabetic patients due to the timing mismatch between carbohydrate absorption and insulin action 1
• Patients using intensive insulin regimens should check glucose levels prior to meals and snacks, at bedtime, occasionally postprandially, and before/after exercise to monitor these fluctuations 1
• The combination of metformin and dapagliflozin provides complementary mechanisms that can help reduce postprandial glucose excursions 7
• Food composition (carbohydrate content, fat, protein) affects the rate of glucose absorption and subsequent blood glucose response 1

Monitoring and Management Strategies

• Self-monitoring of blood glucose (SMBG) is especially important for insulin-treated patients to monitor for and prevent hypoglycemia and hyperglycemia 1
• Most patients using intensive insulin regimens should check glucose 6-10 times daily, including before meals and snacks, at bedtime, before/after exercise, and when hypoglycemia is suspected 1
• Continuous glucose monitoring (CGM) can provide more detailed information about glucose patterns and fluctuations throughout the day 1
• For patients using basal insulin with oral agents like metformin and dapagliflozin, assessing fasting glucose with SMBG to inform dose adjustments helps achieve blood glucose targets 1

Common Pitfalls and Caveats

• Hypoglycemia risk is lower with the combination of dapagliflozin and metformin compared to insulin secretagogues, but still requires monitoring, especially in patients on insulin 4, 7
• Urinary tract infections and genital infections are more common with dapagliflozin than placebo and may affect treatment adherence 3, 4
• Diabetic ketoacidosis, although rare, can occur with SGLT2 inhibitors like dapagliflozin 4
• Metformin should be used cautiously in patients with renal impairment, with dose reduction if eGFR is 45-59 mL/min/1.73m² and discontinuation if eGFR is below 45 mL/min/1.73m² 1

By understanding these various factors affecting blood glucose fluctuations, healthcare providers can better help patients optimize their diabetes management and minimize unwanted glucose excursions throughout the day.