Brief Review of Newer Antiglycemic Agents as Options in the Treatment of Diabetic Kidney Disease

CKD: Chronic Kidney Disease; T2DM: Type 2 Diabetes Mellitus; US: United States; DKD: Diabetic Kidney Disease; DPP4: Dipeptidyl Peptidase 4 inhibitors, glucagon-like peptide 1 agonists; FDA: Food and Drug Administration; CVOT: Cardiovascular Outcome Trial; UACR: Urine Albumin Creatinine Ration; eGFR: estimated Glomerular Filtration Rate; CREDENCE: Canaglifl ozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation

ever-increasing prevalence of diabetes, the incidence of CKD continues to rise as well. In older patients in particular, CKD rates increase with advanced age and in the United States (US) Medicare population, this increase resulted in an estimated $39 billion in health care expenditures in 2017 for patients with CKD and concurrent diabetes [4]. For the past two decades, leading US guidelines in the treatment of diabetes have stressed the need for improved glycemic and hypertension control as a means to limit the onset of diabetic kidney disease (DKD) or to reduce its progressive nature [5]. Despite these recommendations there remains a signifi cant residual risk for the onset or progression of DKD. Efforts have been called for to improve overall health outcomes for patients with DKD and for the development of new therapeutic entities that can stem this tide. [1,6]. This review assesses the renal benefi ts of three classes of antidiabetic agents. This includes agents that affect the incretin system, i.e. Dipeptidyl Peptidase 4 inhibitors (DPP4i) and Glucagon-Like Peptide (GLP)-1 agonists, or affect kidney glucosuria i.e. Sodium Glucose co-Transporter 2 inhibitors (SGLT2). These three classes are highlighted due to the fact there is renal data, positive or neutral, with each agent from glycemic effi cacy studies, in patients with or without existing DKD, and each agent within these classes has undergone a Food and Drug Administration (FDA)-mandated Cardiovascular Outcome Trial (CVOT). These CVOT studies are typically much larger and most included a prespecifi ed evaluation of a composite renal outcome or post-hoc analysis of such. Lastly, one landmark study specifi cally designed to evaluate an agent in patients with DKD showing robust benefi t in this patient population will be discussed. It is the intent of this brief review to provide the reader with synopses of each class and if or where the agents may play a role in treating DKD.

DPP4 inhibitors
In studies designed to assess glycemic effi cacy in patients with or without existing DKD, the DPP4i data has shown this class of agents likely has a positive effect on reducing albuminuria via changes in Urine Albumin-to-Creatinine Ratio (UACR). These trials differ in duration of therapy, extent of baseline DKD, and how changes in DKD were reported. The changes in UACR vary from baseline by 5-43 mg/g depending on study and agent evaluated [7][8][9]. The studies to date, however, have not shown a signifi cant reduction in progression of more robust renal outcomes such as doubling of serum creatinine, progression to end-stage renal disease, or renal death. The CVOT studies involving the DPP4is each included a composite renal outcome. It should be noted the CVOT studies mandated by the FDA are to demonstrate cardiovascular safety compared to placebo and are not specifi cally designed to evaluate renal outcomes. Subjects evaluated in these studies tended to be older with established cardiovascular disease or at high risk for such and baseline renal function and degree of albuminuria varied between study. None of the studies showed a statistically signifi cant or clinically relevant reduction in progression of renal insuffi ciency, need for dialysis, or renal death [10][11][12][13].
Currently, none of the agents within this class are approved for use in DKD and based on the limited data described above should not be used off-label for such.

GLP1 agonists
The data for GLP1 agonists in studies evaluating glycemic benefi t in patients with T2DM with or without existing DKD show mixed results in UACR improvements or changes in renal function. Three agents within this class, liraglutide, dulaglutide, and oral semaglutide have each assessed renal outcomes in patients with T2DM and moderate renal impairment (baseline estimated glomerular fi ltration rate (eGFR) between 30 and 59 ml/min/1.73m 2 ). In a six-month study of over 300 patients no changes in UACR or improvement in eGFR were found in those receiving oral semaglutide compared to placebo [14]. A twelvemonth study comparing dulaglutide to insulin glargine in over 570 patients showed a modest improvement in eGFR with dulaglutide (<3 ml/min/1.73m 2 ) compared to those receiving insulin therapy but failed to show a difference in UACR between the two groups [15]. Liraglutide failed to show a change in either albuminuria or change in eGFR compared to placebo in a six-month study in over 270 patients [16]. Renal outcomes in the much larger CVOT studies were evaluated for many of the agents within this class including lixisenatide, liraglutide and once-weekly formulations of semaglutide, dulaglutide, and exenatide (Table 1). Each study varied in baseline cardiovascular risk and duration of study. The average baseline renal function was greater than 70 ml/min/1.73m 2 and how baseline UACR was expressed varied widely between study but most patients had normal albuminuria. Lixisenatide and oral semaglutide did not have a prespecifi ed composite renal outcome embedded in their respective CVOT studies. However, lixisenatide showed a smaller percent change in UACR over the two-year study compared to placebo but did not show an improvement in the development of persistent macroalbuminuria (>300 mg/g), change in eGFR, or in doubling of serum creatinine [17]. In contrast to the CVOT studies with DPP4is, the studies with the GLP1 agonists that included a composite renal outcome each showed a signifi cant 15-36% relative reduction though the composite outcome differed between studies (Table 1). [18][19][20][21] However, upon closer evaluation, it appears that the driving force behind the reduction in the composite outcome was change in albuminuria and no study showed an ability to slow the progression of eGFR decline or need for renal replacement therapy. Currently, none of the agents within this class are approved for use in DKD and based on the limited data described above should not be used off-label for such.

SGLT2 Inhibitors
Studies evaluating glycemic effi cacy in patients with and without baseline DKD show that the SGLT2 inhibitors also improve albuminuria. Empaglifl ozin in patients with microalbuminuria (UACR 30-300 mg/g) has demonstrated a 32% reduction in UACR and a 41% reduction in those with baseline macroalbuminuria (>300 mg/d) [22]. Ertuglifl ozin has also shown a 29-33% reduction in UACR in a 24-month study compared to subjects receiving placebo or glimepiride [23]. Canaglifl ozin in greater than 260 patients with stage 3  CKD demonstrated a 21-30% reduction in UACR compared to placebo in a six-month study [24]. Lastly, dapaglifl ozin in 166 patients with diabetes, DKD, and baseline microalbuminuria showed a 44-57% reduction in UACR compared to placebo [25].
The argument for use of this class of agent to stem progression of DKD gets more compelling upon assessment of composite renal outcomes from the three published CVOT studies involving empaglifl ozin, canaglifl ozin, and dapaglifl ozin [26][27][28][29]. (Table 1) As in the CVOT studies involving GLP1 agonists, in the SGLT2 inhibitor CVOT studies the majority of patients had normal baseline albuminuria and renal function and the studies varied in duration, size, and baseline cardiovascular risk. A 24%-40% relative reduction in the composite renal outcomes were found in these three studies and in the case of both canaglifl ozin and dapaglifl ozin the composite outcome did not include changes in UACR suggesting albuminuria is not the driving force in these outcomes [26][27][28][29]. Each study when looking at changes in renal function showed a signifi cant reduction in slowing decline in eGFR and in the case of both empaglifl ozin and dapaglifl ozin these two studies found a signifi cant, albeit small, reduction in those requiring renal replacement therapy or progressing to end-stage renal disease.
Despite the CVOT studies not being specifi cally designed to show renal benefi t, each showed more robust renal outcomes than the other two classes discussed above.  will also hold true for the other agents in this class remains to be determined but both dapaglifl ozin and empaglifl ozin have ongoing studies evaluating this concept. New research opportunities exist to assess if SGLT2 inhibitors have a positive effect on treating patients with Type 1 diabetes and DKD or in patients with CKD not due to diabetes. Clinicians should stay abreast of any new published studies in DKD with any of these class of agents.