Outcomes Trials Set Stage for Future of Diabetes Management in Patients With Renal Disease

The evidence for optimal management of diabetes continues to evolve at a feverish pace. Since the FDA introduced its guidance on evaluating the cardiovascular risk of new diabetes drugs in 2008, investigators have made significant progress in amassing evidence that therapeutic agents reduce the risk of major clinical end points.¹ These clinical advances are best represented by data from pivotal trials demonstrating a reduction in major adverse cardiovascular events (MACE) associated with both the sodium glucose cotransporter type 2 (SGLT2) inhibitors and the glucagon-like peptide-1 (GLP-1) receptor agonists in particular. The dipeptidyl peptidase 4 (DPP-4) inhibitors have not been shown in major investigations to increase cardiovascular risk. Large, prospective, cardiovascular outcomes studies have demonstrated the efficacy of various agents from the SGLT2 inhibitor and GLP-1RA classes in reducing MACE, including EMPA-REG OUTCOME (empagliflozin),² CANVAS (canagliflozin),³ LEADER (liraglutide),⁴ and SUSTAIN 6 (semaglutide).⁵ In fact, the American Diabetes Association (ADA)'s Standards of Medical Care in Diabetes—2019 has incorporated the evidence from these studies to guide clinicians on which therapies may be optimal in patients with established atherosclerotic cardiovascular disease or other comorbidities, such as chronic kidney disease (CKD).⁶

Numerous opportunities remain to advance the science regarding optimization of diabetes treatment in reducing the risk of microvascular and macrovascular manifestations of diabetes. Further, investigators have presented several studies at the ADA's 79th Scientific Sessions, June 7-11, 2019, in San Francisco, California (see SP233-SP236). Some of the Scientific Sessions presentations demonstrating results from these anticipated outcomes studies are highlighted below.

Investigators have conducted a number of trials to evaluate the effects of the SGLT2 inhibitors in slowing the progression of CKD as well as the progression of kidney

disease as a secondary outcome. In a post hoc analysis of the EMPA-REG OUTCOME trial, renal outcomes associated with empagliflozin—including incident or worsening nephropathy or progression to macroalbuminuria, doubling of serum creatinine, initiation of renal replacement therapy, and death from renal disease—were evaluated.⁷ A total of 7020 patients received at least 1 dose of study medication, with the following outcomes:

• Incident or worsening nephropathy occurred in 525 of the 4124 patients (12.7%) receiving empagliflozin and in 388 of 2061 patients (18.8%) receiving placebo (hazard ratio [HR] for empagliflozin, 0.61; 95% CI, 0.53-0.70; P <.001).

• Progression to macroalbuminuria occurred in 459 of 4091 patients (11.2%) receiving empagliflozin compared with 330 of 2033 (16.2%) in the placebo group,

representing a 38% reduction in risk of progression of kidney disease (HR for empagliflozin, 0.62; 95% CI, 0.54-0.72; P <.001).

• A doubling of serum creatinine occurred in 70 of the 4645 patients (1.5%) receiving empagliflozin compared with 60 of 2323 (2.6%) in the placebo group, representing

a relative risk reduction of 44% (HR for empagliflozin, 0.56; 95% CI, 0.39-0.79; P <.001).

Furthermore, the EMPA-REG OUTCOME analysis demonstrated additional reductions in the need for renal replacement therapy initiation (13 of 4687 patients [0.3%] receiving empagliflozin vs 14 of 2333 [0.6%] receiving placebo; relative risk reduction, 55%), though renal disease led to more deaths in the empagliflozin arm (3 in the empagliflozin group [0.1%] vs none in the placebo group, [0.0%]).⁷ Results of this analysis have suggested beneficial renal outcomes attributed to treatment with empagliflozin, independent of cardiovascular risk reduction.

Investigators have also evaluated renal outcomes associated with dapagliflozin therapy in a post hoc pooled analysis of 2 phase 3 clinical trials in patients with type 2 diabetes and uncontrolled hypertension.⁸ The analysis included data from 356 patients (dapagliflozin, n = 167; placebo, n = 189) with microalbuminuria or macroalbuminuria at baseline. Patients randomized to receive dapagliflozin experienced a greater reduction in albuminuria at 12 weeks, based on urine albumin/creatinine ratio, compared with those receiving placebo (absolute difference, —33.2%; 95% CI, –45.4 to –18.2). Investigators also observed a decrease in estimated glomerular filtration rate (eGFR) in patients receiving dapagliflozin (–2.80 mL/min/1.73 m2 at 12-week follow-up; 95% CI, –5.43 to –0.16), which was reversed after stopping therapy.⁸

Whether the reduction in renal outcomes is a class-wide effect remains unknown, so the presentation of key findings and data analysis from the CREDENCE trial were a highlight of the 79th Scientific Sessions. This is the first randomized, prospective, double-blind, placebo-controlled, multicenter, parallel-group trial specifically powered to evaluate the effects of canagliflozin on major renal outcomes. Its primary end point is time to first occurrence of any event in the primary composite end point (end-stage kidney disease, doubling of serum creatinine, renal or cardiovascular death) in patients with diabetes, CKD (defined as an eGFR of 30 to less than 90

mL/min/1.73 m2), and macroalbuminuria, who are receiving a maximally tolerated angiotensin-converting enzyme inhibitor or angiotensin receptor blocker.⁹ The recent publication of the CREDENCE findings has shed light on these potential benefits and, importantly, helped to show that these benefits may represent a class-wide effect. Notably, the CREDENCE trial was concluded after an interim analysis, as its prespecified efficacy objectives had been met. Patients treated with canagliflozin

had an average event reduction of 30% for the composite primary end point, and from a safety perspective, CREDENCE did not identify a higher risk of fractures or amputation in the canagliflozin group. The risk of diabetic ketoacidosis was significantly higher in patients treated with canagliflozin compared with placebo (2.2 vs 0.2 events per 1000 patientyears, respectively), though this is not a surprising finding for an SGLT2 inhibitor.¹⁰

Investigators also presented the results from the CARMELINA trial, published earlier this year, at the 79th Scientific Sessions. The major study evaluated the effect of linagliptin compared with placebo on the composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke in patients with elevated baseline cardiovascular and renal risk. Background standard-of-care diabetes management was offered to the 6979 patients in both treatment arms (linagliptin, n = 3494; placebo, n = 3485), though the use of DPP-4 inhibitors, SGLT2 inhibitors, and GLP-1 receptor agonists was disallowed via predefined exclusion criteria. For the 3-point MACE primary outcome, linagliptin (12.4%) was shown to be noninferior to placebo (12.1%) groups (HR, 1.02; 95% CI, 0.89-1.17; P <.001 for noninferiority). Subsequent testing for superiority for this primary outcome was not statistically significant (P = 0.74). Similarly, the secondary composite outcome of time to first occurrence of end-stage renal disease, death due to renal failure, or sustained decrease in eGFR by 40% from baseline was not statistically different between the linagliptin (9.4%) and placebo (8.8%) groups (HR, 1.04; 95% CI, 0.89-1.22; P = 0.62).11 Although some exploratory outcomes of CARMELINA showed promise (eg, reduction in albuminuria progression) in the linagliptin arm, the overall results are not likely practice changing to the same degree as the cardiovascular and renal outcomes trials conducted with other pharmacotherapy options in other antidiabetic drug classes.

Beyond these trials, several additional study announcements included the role of vitamin D in diabetes prevention, the role of lifestyle intervention in preventing diabetes, the possible use of SGLT2 inhibitors in managing type 1 diabetes, and the efficacy and safety of an oral semaglutide formulation. Further, additional safety data are necessary to inform and elucidate risks associated with both drug classes (euglycemic diabetic ketoacidosis and amputation risk with SGLT2 inhibitor use and cancer risks associated with GLP-1 receptor agonists and DPP-4 inhibitors) and provide clarification on risk factors associated with these specific adverse events. In the meantime, the growing body of outcomes data related to cardiovascular and, now, renal outcomes has begun to shed some light on the potential role of multiple

pharmacotherapy options in the individualized management of diabetic patients. Author Information

Joseph Cruz, PharmD, BCPS, a graduate of the Ernest Mario School of Pharmacy (EMSOP) at Rutgers University, completed an American Society of Health-System Pharmacists—accredited PGY-1 pharmacy residency and a PGY-2 drug information specialty residency at Robert Wood Johnson University Hospital.

Mary Barna Bridgeman, PharmD, BCPS, BCGP, is a graduate of EMSOP. She completed a phar macy residency at Robert Wood Johnson University Hospital and is a clinical professor in the Department of Pharmacy Practice and Administration at Rutgers University. She maintains volunteer faculty appointments in the Department of Medicine, Rutgers—Robert Wood Johnson Medical School, and in the Physician Assistant Program, Rutgers School of Health Professions, in addition to her practice site in internal medicine at Robert Wood Johnson University Hospital.References

1. Guidance for industry: diabetes mellitus — evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. FDA website. www.fda.gov/downloads/Drugs/Guidances/ucm071627.pdf. Published December 2008. Accessed March 26, 2019.

2. Zinman B, Wanner C, Lachin JM, et al; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128. doi: 10.1056/NEJMoa1504720.

3. Neal B, Perkovic V, Maheffey KW, et al; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-657. doi: 10.1056/NEJMoa1611925.

4. Marso SP, Daniels GH, Brown-Frandsen K, et al; LEADER Steering Committee, LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311-322. doi: 10.1056/NEJMoa1603827.

5. Marso SP, Bain SC, Consoli A, et al; SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834-1844. doi: 10.1056/NEJMoa1607141.

6. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes—2019. Diabetes Care. 2019;42(suppl 1):S90-S102. doi: 10.2337/dc19-S009.

7. Wanner C, Inzucchi SE, Lachin JM, et al; EMPA-REG OUTCOME Investigators. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375(4):323-334. doi: 10.1056/NEJMoa1515920.

8. Heerspink HJ, Johnsson E, Gaulse-Nilsson I, Cain VA, Sjöström CD. Dapagliflozin reduces albuminuria in patients with diabetes and hypertension receiving renin-angiotensin blockers. Diabetes Obes Metab. 2016;18(6):590-597. doi: 10.1111/dom.12654.

9. Jardine MJ, Mahaffey KW, Neal B, et al; CREDENCE study investigators. The canagliflozin and renal endpoints in diabetes with established nephropathy clinical evaluation (CREDENCE) study rationale, design, and baseline characteristics. Am J Nephrol. 2017;46(6):462-472. doi: 10.1159/000484633.

10. Perkovic V, Jardine MJ, Neal B, et al; CREDENCE Trial Investigators. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy [published online April 14, 2019]. N Engl J Med. doi: 10.1056/ NEJMoa1811744.

11. Rosenstock J, Perkovic V, Johansen OE, et al; CARMELINA Investigators. Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the CARMELINA randomized clinical trial. JAMA. 2019;321(1):69-79. doi: 10.1001/jama.2018.18269.

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