As might be expected, the efficacy of the SGLT2 inhibitors is reduced in chronic kidney disease. Canagliflozin and empagliflozin are contraindicated in patients with estimated GFR less than 45 mL/min per 1.73 m2. Dapagliflozin is not recommended for use in patients with estimated GFR less than 60 mL/min per 1.73 m2. The main adverse effects are increased incidence of genital infections and urinary tract infections affecting about 8–9% of patients. The osmotic diuresis can also cause intravascular volume contraction and hypotension. Canagliflozin and empagliflozin caused a modest increase in LDL cholesterol levels (4–8%). In clinical trials patients taking dapagliflozin had higher rates of breast cancer (nine cases versus none in comparator arms) and bladder cancer (nine cases versus one in placebo arm). These cancer rates exceeded the expected rates in an age-matched reference diabetes population. Canagliflozin has been reported to cause a decrease in bone mineral density at the lumbar spine and the hip. In a pooled analysis of 8 clinical trial (mean duration 68 weeks), an increase in fractures by about 30% was observed in patients on canagliflozin. It is likely that the effect on the bones is a class effect and not restricted to canagliflozin. A modest increase in upper limb fractures was observed with canagliflozin therapy. It is not known if this is due to an effect on bone strength or related to falls due to hypotension. Interim analysis of the Canagliflozin Cardiovascular Assessment Study clinical trial reported an approximately doubled risk of leg and foot amputations in the trial group assigned to Canagliflozin; in 2017 the FDA issued a drug safety communication regarding the association. Cases of diabetic ketoacidosis have been reported with off-label use of SGLT2 inhibitors in patients with type 1 diabetes. Type 1 patients are taught to give less insulin if their glucose levels are not elevated. Because type 1 patients on an SGLT2 inhibitor may have normal glucose levels, they may either withhold or reduce their insulin doses to such a degree as to induce ketoacidosis. Therefore, SGLT2 inhibitors should not be used in patients with type 1 diabetes and in those patients labelled as having type 2 diabetes but who are very insulin deficient and prone to ketosis.
Pramlintide is an islet amyloid polypeptide (IAPP, amylin) analog. IAPP is a 37-amino-acid peptide present in insulin secretory granules and secreted with insulin. It has approximately 46% homology with the calcitonin gene-related peptide (CGRP; see Chapter 17) and physiologically acts as a negative feedback on insulin secretion. At pharmacologic doses, IAPP reduces glucagon secretion, slows gastric emptying by a vagally mediated mechanism, and centrally decreases appetite. Pramlintide is an IAPP analog with substitutions of proline at positions 25, 28, and 29. These modifications make pramlintide soluble, non-selfaggregating, and suitable for pharmacologic use. Pramlintide is approved for use in insulin-treated type 1 and type 2 patients who are unable to achieve their target postprandial blood glucose levels. It is rapidly absorbed after subcutaneous administration; levels peak within 20 minutes, and the duration of action is not more than 150 minutes. It is metabolized and excreted by the kidney, but even at low creatinine clearance there is no significant change in bioavailability. It has not been evaluated in dialysis patients.