Farxiga Month-by-Month: What Really Happens in the First 3 Months

What the drug does in the first days

Farxiga blocks SGLT2 in the kidney, the transporter that reclaims filtered glucose, and glucose that is not reclaimed leaves in the urine [1]. The label describes the result as an osmotic diuresis that may reduce intravascular volume [1]. Blood levels peak within about 2 hours of a dose, the half-life is about 12.9 hours, and glucose excretion continues for roughly 3 days after the last tablet [1]. A high-fat meal can lower the peak concentration by up to 50% without changing total exposure, and the tablet can be taken with or without food [1].

The label calls for kidney function and volume status to be assessed before the first dose, with volume depletion corrected first [1]. An eGFR below 60, older age, and loop diuretic use are listed as factors that raise the risk of volume depletion or hypotension [1].

Side effects reported across 12 to 24 weeks

The most reliable early figures are the label's adverse reaction rates. Across 12 pooled placebo-controlled glycemic trials lasting 12 to 24 weeks (placebo 1,393 people; 5 mg 1,145; 10 mg 1,193), the rates for placebo, 5 mg and 10 mg were:

• Female genital yeast infection: 1.5%, 8.4%, 6.9% [1]
• Male genital yeast infection: 0.3%, 2.8%, 2.7% [1]
• Urinary tract infection: 3.7%, 5.7%, 4.3% [1]
• Increased urination: 1.7%, 2.9%, 3.8% [1]
• Nasopharyngitis: 6.2%, 6.6%, 6.3% [1]
• Volume depletion events: 0.4%, 0.6%, 0.8% [1]

Those percentages span whole trials, with a mean exposure of 21 weeks, so they are not first-month rates [1]. The label lists the reactions occurring in 5% or more of patients as female genital mycotic infections, nasopharyngitis and urinary tract infections [1]. Volume depletion was uncommon in the short trials, and in DECLARE-TIMI 58, which followed people for a median of 4.2 years, it was reported in 2.4% of the placebo group and 2.5% of the 10 mg group [1].

The label notes that people with a history of genitourinary infections are more likely to develop them while taking Farxiga, and it lists Fournier's gangrene (necrotizing fasciitis of the perineum) among the serious genitourinary infections, with serious outcomes including multiple surgeries and death [1]. For pain or tenderness, erythema, or swelling in the genital or perineal area along with fever or malaise, the label says to evaluate immediately for necrotizing fasciitis and, if it is suspected, to discontinue Farxiga and start medical or surgical treatment promptly [1].

A1C and weight: what was measured, and when

At 24 weeks in the monotherapy trial, A1C fell 0.9 points with 10 mg and 0.8 points with 5 mg versus 0.2 points with placebo (treatment differences of 0.7 and 0.5 points), and A1C came in under 7% for 50.8% of people on 10 mg and 44.2% on 5 mg versus 31.6% on placebo [1]. In the initial-combination study with metformin XR, A1C fell 2.0 points versus 1.5 with dapagliflozin alone and 1.4 with metformin XR alone, starting from a baseline near 9.0% [1].

Farxiga has no weight-management indication [1]. The weight numbers available come from a 52-week trial against glipizide in 814 people whose metformin alone was not controlling their diabetes: weight fell 3.2 kg on dapagliflozin and rose 1.2 kg on glipizide, while A1C fell the same 0.52 points in both groups [5].

Glucose lowering also depends on kidney function. The label does not recommend Farxiga for glycemic control at an eGFR below 45 mL/min/1.73 m2, where it is likely to be ineffective, while the 10 mg dose used for heart failure and chronic kidney disease can be started at an eGFR of 25 or higher [1].

Heart and kidney outcomes run on a different clock

The benefit figures most often quoted for Farxiga come from trials far longer than 90 days.

• DAPA-HF: 4,744 adults with heart failure and ejection fraction of 40% or less, median 18.2 months. Worsening heart failure or cardiovascular death 16.3% vs 21.2% (HR 0.74); cardiovascular death 9.6% vs 11.5% (HR 0.82) [3].
• DAPA-CKD: 4,304 adults with chronic kidney disease, eGFR 25 to 75 and urine albumin-to-creatinine ratio 200 to 5,000, median 2.4 years and stopped early for efficacy. The composite of sustained eGFR decline of 50% or more, end-stage kidney disease, or kidney or cardiovascular death occurred in 9.2% vs 14.5% (HR 0.61; number needed to treat 19); death from any cause 4.7% vs 6.8% (HR 0.69) [4].
• DELIVER: 6,263 adults with heart failure and ejection fraction above 40%, median 2.3 years. Worsening heart failure or cardiovascular death 16.4% vs 19.5% (HR 0.82); cardiovascular death alone 7.4% vs 8.3%, not significant [6].
• DECLARE-TIMI 58: 17,160 adults with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease, median 4.2 years. Major adverse cardiovascular events 8.8% vs 9.4% (HR 0.93, not significant); cardiovascular death or heart failure hospitalization 4.9% vs 5.8% (HR 0.83), driven by heart failure hospitalization (HR 0.73); ketoacidosis 0.3% vs 0.1% [2].

What the label says to watch for

• Ketoacidosis. The label warns that ketoacidosis, including fatal cases in type 2 diabetes, can present with blood glucose below 250 mg/dL, and that risk factors include type 1 diabetes, acute febrile illness, reduced caloric intake, a ketogenic diet, surgery, volume depletion, alcohol abuse and missed or reduced insulin doses [1]. Its listed signs are nausea, vomiting, abdominal pain, generalized malaise and shortness of breath [1]. It says to assess for ketoacidosis regardless of glucose level and to discontinue Farxiga if it is suspected [1]. Farxiga is not recommended for glycemic control in type 1 diabetes [1].
• Volume depletion and kidney injury. The label warns of symptomatic hypotension, acute transient creatinine changes and postmarketing acute kidney injury, some requiring hospitalization and dialysis, in people with type 2 diabetes [1].
• Hypoglycemia. Risk rises when Farxiga is combined with insulin or an insulin secretagogue such as a sulfonylurea, and the label says a lower dose of the insulin or secretagogue may be required [1].
• Tests. Urine glucose tests will be positive and 1,5-anhydroglucitol measurements are unreliable on Farxiga, so the label directs monitoring with other methods; serum lithium concentrations may fall and the label says to monitor them more often at initiation and with dose changes [1].
• Surgery and fasting. The label says to withhold Farxiga for at least 3 days, if possible, before surgery or procedures involving prolonged fasting [1].
• Pregnancy and breastfeeding. Farxiga is not recommended in the second and third trimesters, based on animal kidney findings, or while breastfeeding [1].

The current Farxiga label carries no boxed warning and no amputation or bladder cancer warning; its warnings are ketoacidosis, volume depletion, genitourinary infections and hypoglycemia with insulin or secretagogues [1].

Dosing questions that come up in the first 90 days

For glycemic control the starting dose is 5 mg once daily, which can be raised to 10 mg once daily for more effect [1]. For chronic kidney disease, heart failure, and reducing heart failure hospitalization risk in type 2 diabetes with cardiovascular disease or risk factors, the dose is 10 mg once daily [1]. The tablet is taken with or without food, and the label says a missed dose should be taken as soon as possible without doubling the next one [1].