By Natalie Pirkola, Pharm.D., M.B.A., BCACP, BCGP, BC-ADM, CDE, pharmacist, Oakland Southfield Physicians, Southfield
Sodium-glucose Co-transport Type-2 Inhibitors (SGLT2)
SGLT-2 inhibitors decrease reabsorption of filtered glucose in the kidney, thereby increasing urinary excretion of glucose. These oral agents lower both fasting and post prandial glucose levels, but the greatest interest has been generated due to the ability to lower blood pressure, as well as induce modest weight loss. Empagliflozin (Jardiance) is emerging as a preferred agent due to the EMPA-REG OUTCOME trial which showed improvements in cardiovascular mortality. Secondary analysis from this trial is generating further interest in potential renoprotective effects which merits further study. In contrast, canagliflozin (Invokana) studies have generated concerns about increased risk for amputations, acute kidney injury and bone fractures. Dose-dependent increases atypical fractures which seems a possible class effect. Concerns across the class include genital mycotic infections, urinary tract infections (including cases of urosepsis and pyelonephritis), ketoacidosis and hyperkalemia. Renal adjustment is required across the class and all should be taken before the first meal of the day.
Incretin Therapies - Dipeptidyl Deptidase-4 (DPP4) Inhibitors
DPP4-inhibitors reduce the breakdown of endogenous glucagon-like peptide-1 GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). Early interest was generated as this class is weight neutral, available orally and may have a beta-cell sparing effect. Concerns have emerged due to serious hypersensitivity reactions, including skin and airways reactions. A1c reduction is small and the patient expense is still relatively high. Linagliptin (Tradjenta) is the lone agent that does not require renal dose adjustment. As post marketing use increased, concerns emerged regarding safety of these agents in patients with cardiovascular disease, particularly heart failure. Concerns continue regarding possible increased risk of heart failure hospitalization for saxagliptin (Onglyza); however, trials such as SAVOR-TIMI, EXAMINE and TECOS are demonstrating no increased risk for other agents in the class. Risk of pancreatitis seems small, however, but continues to remain a concern.
Incretin Therapies - Glucagon-Like Peptide-1 (GLP-1) Agonists
Glucagon-Like Peptide-1 (GLP-1) agonists are synthetic analogs of human GLP-1, which result in supra-endogenous levels. Weight loss, particularly with longer acting therapies, is a stand out feature of these medications. Injectable formulation, reconstitution for longer acting therapies and cost are still potential barriers for patients. Labelling concerns remain regarding medullary thyroid carcinoma. Risk of pancreatitis remains a concern; however, debate exists whether this is due to drug or underlying diabetes. Liraglutide (Victoza) stands out with evidence for macrovascular beneficial outcomes in very high-risk patients (LEADER).
Studies have examined combining SGLT2 inhibitors with DPP4 inhibitors or GLP-1 agonists. Greater reductions in A1c, weight and blood pressure have been seen with SGLT2 in combination with GLP-1, than either agent alone. Similarly, overlapping risks regarding with renal impairment, worsening chronic renal failure, are also increased. Combination use is growing, therefore, pharmacists should support monitoring for reduced renal function, particularly in elderly patients and/or those with nausea, vomiting, diarrhea, or other risk factors for dehydration.
Taking it Further
Mora PF, Johnson EL. Cardiovascular Outcome Trials of the Incretin-Based Therapies. Endocr Pract.
Pratley RE, Cersosimo E. Use of Canagliflozin in Combination With and Compared to Incretin-Based Therapies in Type 2 Diabetes. Clin Diabetes
Heerspink HJ, Perkins BA, et al. Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Cardiovascular and Kidney Effects, Potential Mechanisms, and Clinical Applications. Circulation