Updates in the Treatment of Diabetic Kidney Disease - A Focus on Incretin Mimetics and Sodium Glucose Co- Transporter 2 Inhibitors

Review Article

J Endocr Disord. 2020; 6(1): 1033.

# Updates in the Treatment of Diabetic Kidney Disease - A Focus on Incretin Mimetics and Sodium Glucose Co- Transporter 2 Inhibitors

Irons BI1*, Minze MG1, Chastain LM1 and McMurry ME2

¹Department of Pharmacy Practice, Texas Tech University Health Sciences Center, USA

²Department of Internal Medicine-Nephrology Division, Texas Tech University Heath Sciences, USA

*Corresponding author: Irons BI, Department of Pharmacy Practice, Texas Tech University Health Sciences Center, USA

Received: March 14, 2020; Accepted: March 31, 2020; Published: April 07, 2020

## Abstract

The prevalence of Diabetic Kidney Disease (DKD) continues to rise and implications on morbidity, mortality and expenditures in health care resources. Glucagon-Like Peptide 1 (GLP1) agonists, Sodium Glucose Co-Transporter 2 (SGLT2) inhibitors and Dipeptidyl peptidase 4 (DPP4) inhibitors have been evaluated to assess renal outcomes though show widely variable differences in outcomes. DPP4 inhibitors and GLP1 agonists improvements in albuminuria but have not shown to impact renal outcomes such as doubling of serum creatinine or progression in renal insufficiency. Better data exist on the benefits of SGLT2 inhibitors in improving DKD outcomes. Safety studies involving SGLT2 inhibitors have shown reductions in albuminuria, but compared to the other two class of agents have also shown reductions in progression of renal insufficiency and reductions in the development of end-stage renal disease. Canagliflozin in a trial designed to evaluate the agents use in patients with DKD, showed significant less risk in doubling of serum creatinine, progression to end-stage renal disease compared to placebo. The agent also demonstrated a reduction in cardiovascular morbidity. It can be considered the first therapeutic agent in nearly twenty years to provide substantial improvement in outcomes in the treatment of DKD.

Keywords: Diabetes; Kidney disease; Renal disease

## Abbreviations

CKD: Chronic Kidney Disease; US: United States; DKD: Diabetic Kidney Disease; ESRD: End Stage Renal Disease; RAS: Renin- Angiotensin System; DPP4: Dipeptidyl Peptidase 4; CI: Confidence Interval; GLP: Glucagon-Like Peptide; SGLT2: Sodium Glucose Co-Transporter 2; FDA: Food and Drug Administration; CVOT: Cardiovascular Outcome Trial; UACR: Urine Albumin: Creatinine Ration; eGFR: Estimated Glomerular Filtration Rate; CREDENCE: Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation, MI: Myocardial Infarction; SBP: Systolic Blood Pressure; CVD: Cardiovascular Disease; CrCl: Creatinine Clearance; HR: Hazard Ratio; Subcut: Subcutaneous

## Introduction

The association between diabetes and Chronic Kidney Disease (CKD) has progressed into a complex multifactorial public health problem that continues to grow in spite of past advances in therapeutics and medications. CKD and subsequent development of End-Stage Renal Disease (ESRD) is associated with an increased risk of cardiovascular morbidity as well as mortality [1,2]. The increasing and often under recognized incidence of CKD corresponds to the dramatic rise in diabetes. Diabetes remains the leading cause of CKD, referred to as Diabetic Kidney Disease (DKD) and subsequently increases the risk for ESRD. With current therapeutic options the disease is often slowed but rarely completely stopped. Approximately 20-40% of patients with diabetes will progress to the development of DKD though the severity varies from increased albuminuria to significant declines in renal function and ESRD [3,4]. Early detection and appropriate management of diabetes and associated cardiovascular risk factors are essential to the reduction in DKD related morbidity, mortality and health care expenditures. Medicare expenditures for CKD patients in 2017 reached $72 billion, accounting for 25% of the total spending for all fee for service Medicare beneficiaries aged 65 and older [5]. Care of beneficiaries with CKD and concurrent diabetes mellitus required$39 billion in 2017. Leading recommendations to combat the consequences of DKD have for decades promoted the importance of glycemic and blood pressure control, the latter with the use of agents that block the Renin-Angiotensin System (RAS) [6]. The use of angiotensin converting enzyme inhibitors and angiotensin receptor blockers has improved over the last two decades but use in patients with CKD remains suboptimal [7]. Intensive glucose control decreases the risk of microalbuminuria and microalbuminuria, but the evidence is lacking as to whether intensive glycemic control reduces the risk of significant renal outcomes such as ESRD or death from renal disease. The effects of routine blood pressure lowering and intensive glucose control are independent of one another and when combined they produce additional reduction in clinically relevant outcomes [8].

Newer treatment options in the management of type 2 diabetes have been developed that offer effective improvements in glycemic control and in some cases may improve cardiovascular morbidity or mortality based on Food and Drug Administration-required safety studies. These include Dipeptidyl Peptidase-4 (DPP-4) inhibitors, Glucagon-Like Peptide (GLP) 1 agonists, and Sodium Glucose Co- Transporter 2 (SGLT2) inhibitors. This review assesses each class as to potential renal benefits evaluating clinical trials in patients with type 2 diabetes with or without DKD, large scale Cardiovascular Outcome Trials (CVOT) that also evaluated renal outcomes, and one large landmark study specifically designed to assess a SGLT2 inhibitor effects on renal outcomes in patients with DKD.

## Dipeptidyl peptidase 4 inhibitors

Renal outcomes from diabetes studies: potential renal benefits of DPP4 inhibitors have been studied in a handful of trials involving patients with diabetes with or without existing CKD. The studies are mixed in patient population evaluated, length of study and specific renal outcomes explored. Sitagliptin in conjunction with a sulfonylurea was shown to reduce Urine Albumin-To-Creatinine Ratio (UACR) by 43 mg/g in 82 Japanese patients as a secondary outcome of an efficacy and safety study assessing the combination of agents for one year [9]. Alogliptin was also shown to reduced UACR mildly (5 mg/g) at 12 weeks compared to placebo in 61 Japanese patients with type 2 diabetes [10]. UACR with the use of linagliptin in combination with a RAS inhibitor was assessed in a pooled retrospective analysis of four phase III clinical trials in patients with type 2 diabetes [11]. Linagliptin showed a greater reduction in adjusted geometric mean UACR (28%) compared to placebo. In another linagliptin study the agent, when added to a RAS inhibitor in 360 patients with type 2 diabetes and residual albuminuria did not significantly reduce UACR or improve estimated glomerular filtration rate (eGFR) compared to placebo over 24 weeks [12]. In a pooled analysis of the use of saxagliptin either as monotherapy or in combination with other agents involving 20 controlled studies and including over 9000 patients found no effect, positive or negative, on renal function [13].

Renal outcomes from cardiovascular safety studies: Sitagliptin’s effect on change in eGFR was analyzed as a secondary outcome in its CVOT. Sitagliptin had a very small, but statistically significant, change in eGFR from baseline compared to placebo with an estimated difference of -1.34 mL/min/1.73m2 (95% CI, -1.76 to -0.91;p<0.001) between groups and no significant changes in eGFR were noted in patients with chronic kidney disease at baseline over the 3 year study [14,15]. Additionally in the analysis for safety in patients with CKD with an eGFR < 60 mL/min/1.73m2 was compared to those without CKD (eGFR > 60 mL/min/1.73m2), serious adverse events were higher in those with poorer baseline renal function but the study found no significant difference in the development of microalbuminuria or renal failure in patients receiving sitagliptin compared to placebo. An exploratory analysis of saxagliptin’s renal safety and efficacy compared to placebo over 2.1 years the saxagliptin CVOT did not show a difference in the prespecified composite outcome (doubling of serum creatinine, initiation of chronic dialysis, renal transplant, or serum creatinine >6.0 mg/dL), and change in eGFR was similar between groups over the time frame analysed [16]. With regards to alogliptin, no difference in a change in eGFR or initiation of dialysis was seen in patients with type 2 diabetes in the agent’s CVOT [17]. The linagliptin CVOT showed the agent did not significantly alter the composite renal outcome (sustained end-stage renal disease, renal failure death, or sustained decrease of >40% in eGFR from baseline) but did show a favorable 14% relative reduction in progression of albuminuria [18]. Thus DPP-4 inhibitors show positive to neutral effect in reducing UACR but fail to show any profound evidence that the class reduces the risk for inhibiting significant decline in renal function or attenuating the risk for the development of CKD.

## Glucagon-like Peptide 1 Receptor Agonists

Renal outcomes from diabetes studies: There are a handful of studies that directly assess the use of GLP-1 agonists on renal outcomes. The outcomes assessed in these studies, the populations evaluated, and duration of study vary significantly. In a twelve-week study of 55 overweight patients with type 2 diabetes with no history of chronic kidney disease, neither liraglutide or sitagliptin showed an effect on eGFR or UACR [19]. In a study involving 31 subjects with type 2 diabetes and baseline microalbuminuria, exenatide twice daily by subcutaneous administration showed a reduction in 24-hour urinary albumin compared to subjects taking glimepiride after 16 weeks of treatment [20]. After 12 months of therapy with liraglutide in 84 patients with Type 2 diabetes another study found an improvement in eGFR in subjects with a baseline eGFR < 90 ml/min/1.73 m2 (absolute change 5-6 ml/min) but no change in those with a baseline eGFR > 90 ml/min/1.73 m2 [21]. Urine albumin excretion in twenty-four hours improved mildly in both groups. No changes compared to placebo in eGFR or UACR were noted in 277 subjects with type 2 diabetes and moderate renal impairment (30-59 ml/min/1.73 m2) in a 26-week trial designed to assess efficacy and safety of liraglutide in this population [22]. Oral semaglutide has also been evaluated for safety and efficacy in 324 patients with type 2 diabetes and moderate renal impairment (30-59 ml/min/1.73 m2) [23]. After 26 weeks of treatment, the study found no difference between semaglutide or placebo in changes in eGFR or urine albumin:creatinine ratio. Once-weekly dulaglutide was compared to insulin glargine for efficacy and safety in 577 patients with type 2 diabetes and moderate-to-severe chronic kidney disease (baseline eGFR at randomization 38 ml/min/1.73 m2) [24]. While the primary outcome of this study was the evaluation of changes in A1c, prespecified secondary outcomes included changes in eGFR and UACR. After one year of treatment, eGFR in subjects receiving dulaglutide was 2.7 ml/min/1.73 m2 higher than in subjects receiving insulin therapy despite similar reductions in A1c. Changes in UACR were not statistically different between the two groups however dulaglutide did reduce the ratio more than insulin treated subjects in those with macroalbuminuria (>300 mg/g) at baseline. The latter three studies discussed were not designed to assess renal benefit but rather to assess A1c reduction in subjects with renal insufficiency. Together, the above studies provide some insight into improvements in urinary albumin excretion within this class of agent and variable, limited improvement in eGFR. As in the case of DPP4 inhibitors, the studies do not provide sufficient insight into reducing more robust renal outcomes such as decreasing the likelihood of significant renal insufficiency or progression to end stage renal disease.

Renal outcomes from cardiovascular safety studies: Some of the GLP1 agonist CVOT studies performed pre-specified secondary outcome or post-hoc exploratory assessment of renal outcomes in patients with or at high risk for cardiovascular disease. Table 1 describes some of these differences in these studies. The trials differ in many ways including baseline cardiorenal risk, duration of study and hence drug exposure time, duration of diabetes, and type of renal outcomes assessed. Some studies included a specific composite renal outcome while others made no general renal outcome assessment. However, these trials are significantly larger in scope and length than the trials described above. Baseline subject renal insufficiency is mild in each of the studies. UACR are inconsistently reported among the studies but doesn’t appear a significant issue in the subjects in these trials. The use of RAS inhibitors was high (80+%) and consistent between studies that reported the use of these agents.