The Medical Letter on Drugs and Therapeutics
Invokamet and Xigduo XR - Two New Combinations for Type 2 Diabetes
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 Select a term to see related articles  canagliflozin   canagliflozin/metformin   dapagliflozin   dapagliflozin/metformin   Farxiga   Invokamet   Invokana   Metformin   type 2 diabetes   Xigduo 

The FDA has approved fixed-dose combinations of metformin with either canagliflozin (Invokamet) or dapagliflozin (Xigduo XR) for treatment of patients with type 2 diabetes not adequately controlled with any one of these drugs, or in those already being treated with both metformin and either canagliflozin or dapagliflozin.

MECHANISMS OF ACTION — Metformin decreases hepatic glucose production and, to a lesser extent, increases peripheral glucose uptake. Canagliflozin and dapagliflozin inhibit SGLT2 (sodium-glucose cotransporter 2); they decrease renal glucose reabsorption, thereby increasing urinary glucose excretion.

STANDARD TREATMENT — Metformin is generally the preferred first-line treatment for type 2 diabetes, but most patients eventually require multi-drug therapy, which may include insulin, to achieve glycemic control. There is no consensus agreement on which drug should be added to metformin, which is already available in fixed-dose combinations with many other antihyperglycemic drugs.1

CLINICAL STUDIES — No new clinical trials were required for approval of the combination products, but both have been shown to be bioequivalent to the individual tablets of metformin and either canagliflozin or dapagliflozin taken together. In randomized, double-blind trials with the individual drugs in patients who had not achieved glycemic goals with metformin alone, addition of either canagliflozin or dapagliflozin lowered A1C by 0.4-0.9%. Direct comparisons are lacking, but A1C reductions with either canagliflozin or dapagliflozin appear to be similar. Both canagliflozin and dapagliflozin reduce body weight by 2-3 kg and lower systolic blood pressure by 3-5 mm Hg.2,3

ADVERSE EFFECTS — Metformin commonly causes gastrointestinal adverse effects (metallic taste, nausea, diarrhea, abdominal pain), which can be minimized by starting with a low dose, titrating slowly, dividing doses, and taking the drug with food. Lactic acidosis is a rare, but potentially fatal, complication that can occur with accumulation of metformin. Decreases in vitamin B12 serum concentrations have occurred in patients taking metformin long-term and have rarely been associated with anemia.

Canagliflozin and dapagliflozin can cause genital mycotic infections and urinary tract infections in both men and women. Both drugs have a diuretic effect, which can lead to dehydration, hypovolemia, and hypotension, particularly in elderly patients with renal dysfunction and in those taking loop diuretics. Increased serum creatinine levels, decreased estimated glomerular filtration rate (eGFR), hyperkalemia, hypermagnesemia, hyperphosphatemia, and increased LDL-cholesterol can occur. An increased incidence of fracture has been reported with both drugs; the risk may be greater in patients with renal impairment.

In clinical trials, patients treated with dapagliflozin had a higher incidence of bladder cancer (10/6045; 0.17%) than those taking placebo (1/3512; 0.03%). When patients treated for less than one year before diagnosis were excluded, there were 4 cases of bladder cancer with dapagliflozin and none with placebo. Canagliflozin has not been associated with an increase in the incidence of bladder cancer.

View our detailed online table: SGLT-2 Inhibitors

CONCLUSION — The fixed-dose combinations of metformin and canagliflozin (Invokamet) and metformin plus dapagliflozin (Xigduo XR) should be more convenient than taking the drugs separately. Neither canagliflozin nor dapagliflozin offers any advantage in glycemic efficacy over other second-line drugs for type 2 diabetes, but both cause weight loss rather than weight gain and do not cause hypoglycemia.

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