Combination use with insulin cause fluid retention and should be considered with caution because of the increased risk of serious heart failure. Increased risk of bone fractures (particularly in elderly women)- avoid in persons with pre-existing osteoporosis Increased risk of bladder cancer Consider the balance of benefits and risks carefully both before and during treatment due to age-related risks Risk of macular edema May reduce the risk of dementia [197]. This evidence concerns the gene INS and urinary bladder cancer.