New agents, novel targets show promise for diabetic kidney disease

Photo by Jean Lachat for University of Chicago Medicine printed with permission.

Diabetic kidney disease is one of the most frequent complications in both type 1 and type 2 diabetes and the most common cause of chronic kidney disease in the United States. The condition, also the leading cause of end-stage renal disease in the United States, has been termed a “disease multiplier,” according to the National Institute of Diabetes and Digestive and Kidney Diseases; nearly half of individuals with chronic kidney disease also have diabetes or self-reported cardiovascular disease, bringing added risks with those complications.

“Over half of my clinic is people with diabetic kidney disease (DKD), and they are harder to manage,” Ian H. de Boer, MD, MS, a nephrologist and associate professor of medicine at the University of Washington in Seattle, told Endocrine Today. “They frequently have comorbidities. ... In both type 1 and type 2 diabetes, they often have little residual beta-cell function, so their glycemic management can be difficult.”

Patients with DKD are at elevated risk for vascular disease, infection, impaired physical function, frailty and cognitive dysfunction, de Boer said, further complicating clinical management. In addition, CV mortality remains a competing outcome to the development of ESRD in patients with DKD. According to data from the Global Kidney Health Atlas, published in the April issue of The Lancet, patients with CKD are up to 20 times more likely to die of other causes — largely CVDs, such as myocardial infarction or stroke — before they ever reach the point of dialysis or transplant care.

“Diabetes, we know, has a very high CV event rate, higher than people without diabetes,” George Bakris, MD, professor of medicine and director of the ASH Comprehensive Hypertension Center at University of Chicago Medicine, told Endocrine Today. “You add kidney disease to it ... that adds a whole other layer of complexity and further increases CV risk, independent of diabetes. One of the highest, if not the highest CV risk patient, is the one with DKD.”

A growing problem

The number of patients with DKD is unclear; markers such as estimated glomerular filtration rate and albuminuria can be imprecise, and patients labeled with DKD may have another diagnosis. But numbers suggest a growing problem reaching a critical point. According to 2016 data from the United States Renal Data System (USRDS), the overall prevalence of CKD in the general population was 14.8% between 2011 and 2014; approximately 40% of adults with CKD also have diabetes.

The numbers are also reflected in the cost. According to the USRDS, Medicare spending for beneficiaries aged 65 years and older who have CKD exceeded $50 billion in 2014, representing 20% of all spending in that age group, whereas spending for beneficiaries with CKD who were younger than 65 years exceeded $8 billion in 2014, representing 44% of spending for that age group.

A more accurate reflection of the impact of DKD can be observed in ESRD data. In a 2014 analysis, Robert C. Stanton, MD, chief of the kidney and hypertension section at Joslin Diabetes Center and associate professor of medicine at Harvard Medical School, noted that the number of new ESRD cases reported each year has been steady since 2002, but the prevalence of patients with ESRD continues to increase at a rapid rate, with diabetes the principal cause. As of December 2014, the unadjusted prevalence (crude proportion) of ESRD cases was 2,067 per million in the U.S. population, according to USRDS. Although the number of ESRD incident cases plateaued in 2010, the number of ESRD prevalent cases continues to rise by about 21,000 cases per year.

“Considering that there is greater likelihood of death than progressing to end-stage kidney disease and that mortality rates on dialysis therapy are 15% to 20% per year, there must be a very large CKD population, even if the exact number is not well defined,” Stanton wrote.

As DKD continues to grow as a worldwide public health issue, so does the need for effective treatments that can either slow or prevent disease progression. Although disease management has improved in recent years, challenges and controversies remain, according to experts.

“Although there have been significant improvements in management, the increasing numbers of patients with DKD illustrate that current management is not wholly adequate,” Stanton wrote. “The reasons for suboptimal management include the lack of early diagnosis, lack of aggressive interventions, and lack of understanding about which interventions are most successful.”

‘A multi-pronged approach’

The severity of kidney disease, manifest not just by a reduced GFR, but by an increase in proteinuria, further exacerbates CV risk, making for an ever higher-risk patient in the setting of DKD, Bakris said. Experts continue to debate ideal treatment targets in this population.

“It’s very difficult because there is no single attack line that will reduce all the risk substantially,” Bakris said. “It’s a multi-pronged approach.”

Multifactorial, targeted treatment offers the best line of defense in slowing the progression of DKD, according to Bakris, who cited three main goals. Optimal glycemic control, he said, is often not appreciated as a mitigating factor in DKD; it will lead to slower declines in kidney function, although it can take 6 to 8 years before there is any observable effect. Blood pressure control, often managed with renin-angiotensin- aldosterone system (RAAS) inhibitors in DKD, is “critical,” Bakris said, leading to slower declines in 3 to 4 years, whereas lipid control can specifically reduce CV risk in DKD.

Data from the STENO diabetes group have shown that intensive control of all three targets increases both life span and years free from CVD, in addition to fewer renal disease events. In a recent study, Peter Gaede, MD, DMSc, of the department of cardiology and endocrinology at Slagelse Hospital, Denmark, and colleagues analyzed long-term data from 160 patients with type 2 diabetes and microalbuminuria randomly assigned to either conventional therapy or intensive treatment, which included behavioral and pharmacologic approaches targeting blood glucose, lipids and BP for a mean of 21 years, beginning in 1993. Primary endpoint was difference in median survival time between treatment groups with and without CVD at 21.2 years after the intervention.

Researchers found that intensive treatment was associated with a mean 7.9-year longer median life span during follow-up, matched by the years gained free from incident CVD and CV mortality.

But comorbidities typically complicate the management of DKD on several levels, according to Daniel S. Donovan Jr., MD, MS, CDE, professor of diabetes, endocrinology and bone disease at the Icahn School of Medicine at Mount Sinai. Many patients with diabetes and kidney disease also have hypertension and dyslipidemia, among other conditions, and many agents used to treat them may need a dose adjustment, he said.

“Certain drugs, like metformin, may need a dose modification or discontinuation if the GFR is low,” Donovan told Endocrine Today. “Secretagogues and insulin can cause hypoglycemia, and sulfonylureas may have active metabolites that aren’t cleared well. Certainly, thiazolidinediones may be associated with fluid retention and [congestive heart failure] in patients who already have a problem with volume. Certain GLP-1 receptor agonists have to be stopped for a low GFR, and the newer class of SGLT2 inhibitors has lower efficacy at lower GFRs, and may also interact with diuretics. It’s really a challenge.”

Advanced kidney disease in diabetes also brings increased risks for hypoglycemia, said Katherine R. Tuttle, MD, FASN, FACP, executive director for research at Providence Health Care, Spokane, Washington, and a clinical professor of medicine in the nephrology division at the University of Washington School of Medicine. Both the American Diabetes Association and the National Kidney Foundation recommend a modification of HbA1c goals in these patients.

“Patients with CKD are at markedly increased risk for hypoglycemia related to a number of factors,” Tuttle told Endocrine Today. “Decreased clearance of drugs, oral as well as insulin, that promotes hypoglycemia, but also the kidney, is an abundant source of gluconeogenesis in response to hypoglycemia, and that capacity diminishes with lower kidney function. So, the risks are amplified.”

The ADA, National Kidney Foundation and others recommend an HbA1c goal of at least 7% in patients with advanced DKD, Tuttle said, adding she typically aims for a goal between 7% and 8%.

“Because the mortality is so high in this population, sadly, patients don’t live long enough to really accrue the benefits of tight glycemic control,” Tuttle said. “The risk/benefit ratio has really changed once kidney disease develops.”

In addition, as renal function progressively declines, HbA1c may not be the best indicator of glycemic control because there is a decreased red cell life, Donovan said.

“They’re not living 120 days, and it’s certainly worse on dialysis,” Donovan said, referring to red blood cells. “There may also be anemia, where there is rapid cell turnover. It is a challenge. You may have to find another way, such as glycated albumin, of looking at the average glucose levels and perhaps changing the way you use HbA1c in CKD.”

New tools for treatment

In the past 2 years, large CV outcome trials for antidiabetes agents in two drug classes have yielded interesting data with respect to their secondary renal outcomes. Both SGLT2 inhibitors, such as empagliflozin (Jardiance, Boehringer Ingelheim), and GLP-1 receptor agonists, such as liraglutide (Victoza, Novo Nordisk), have shown promise as therapies that not only improve glycemic control and reduce CV risk in patients with established CVD, but also slow the progression of renal disease.

“The diabetes community had been desperately in need of agents that not only control glucose, but do so in a way that will not be associated with hypoglycemia and will have a tolerability profile that is actually good and, moreover, do something beyond glucose control, ie, affecting other CV risk factors that may or may not be related to glycemic control,” Bakris said. “And, you have that with the SGLT2 inhibitors, but also, to an extent, with the GLP-1 receptor agonists.”

Christoph Wanner, MD, from the department of medicine, division of nephrology at Würzburg University Clinic, Germany, and colleagues analyzed renal data in a subgroup of participants from the EMPA-REG Outcome trial, which assessed CV outcomes in 7,020 patients worldwide with type 2 diabetes and established CVD. Included patients had an eGFR of 30 mL/min/1.73 m2 to 59 mL/min /1.73 m2; 4,124 participants were assigned to empagliflozin and 2,061 to placebo. Renal outcomes included incident or worsening nephropathy (progression to macroalbuminuria, doubling of serum creatinine level, starting renal replacement therapy or death from kidney disease) and incident albuminuria.

The results, showed that, in the overall empagliflozin group compared with the placebo group, incident or worsening nephropathy occurred in 12.7% vs. 18.8%, respectively (HR = 0.61; 95% CI, 0.53-0.7). The composite endpoint of incident or worsening nephropathy or CV death was lower in the empagliflozin group vs. the placebo group (HR = 0.61; 95% CI, 0.55-0.69). Progression to macroalbuminuria occurred in 11.2% vs. 16.2%, respectively (RR reduction = 38%); doubling of serum creatinine level occurred in 1.5% vs. 2.6%, respectively (RR reduction = 44%); and initiation of renal replacement therapy occurred in 0.3% vs. 0.6%, respectively (RR reduction = 55%). Rates of incident albuminuria were similar across groups.

“With EMPA-REG Outcome, if you look at the renal data, it’s interesting,” Bakris said. “If you look at the subgroup with DKD and look at their rate of decline, it was further slowed to 1.8 mL per minute per year. That may not sound like a huge leap, but it’s huge. You’re approaching normality.”

There is no single mechanism behind this benefit, Bakris said; improvement likely comes from a combination of metabolic changes, tubuloglomerular enhancement and a reduction in BP.

“Even though there was not a large number of people who progressed to ESRD, there was also a significant decrease in people going to dialysis and transplantation,” Ralph A. DeFronzo, MD, of the University of Texas Health Science Center in San Antonio, told Endocrine Today. “The decreases were robust — we’re talking 35% to 45% decreases in these individual endpoints. So, I’m impressed with the data.”

Concerns remain, however, regarding the long-term safety and efficacy of SGLT2 inhibitors. Although the data from EMPA-REG Outcome are promising, Stanton said, the “jury is still out” on renal benefits of the drug class, and only dedicated renal outcomes trials will provide a clear answer.

“A lot of my colleagues are very excited about SGLT2 inhibitors,” Stanton told Endocrine Today. “My issue is that these studies [showing renal benefit] are not kidney studies. The FDA is not going to give them an indication as being kidney protective unless the primary outcomes of the study include kidney outcomes. If the SGLT2 inhibitor findings are verified, I think it’s great. It would be exciting to have something new. Most of the drug companies are extremely interested in new targets because nothing has really changed in 30 years, and that’s a long time.”

The LEADER trial, designed to assess the CV safety of liraglutide in more than 9,300 patients with poorly controlled type 2 diabetes and established CVD or chronic renal failure, also yielded surprising CV and renal data. In addition to reducing the risk for CV death, nonfatal MI and stroke vs. those assigned a placebo over a mean of 3.8 years, the risk for kidney disease progression fell by 22% (HR = 0.78; 95% CI, 0.67-0.92). The key renal outcome was a composite endpoint of development of macroalbuminuria, doubling of serum creatinine, ESRD or renal death.

The mechanisms behind any renal benefit with liraglutide remain a subject of debate, Bakris said.

“A lot of nephrologists are skeptical about the LEADER results because they can’t link it to any mechanism,” Bakris said. “It’s not that I don’t believe it, but I would need to see confirmation in another trial.”

DeFronzo, who called the LEADER data “encouraging,” noted that the renal outcome in LEADER was primarily driven by albuminuria, a less firm endpoint than progression to ESRD. However, LEADER revealed a general decrease in all major adverse cardiac event endpoints — an important outcome for patients with DKD.

“I personally like GLP-1 receptor agonists as a first-line therapy [for diabetes], DeFronzo said. “I think they can be used safely in people with advanced renal disease. One could argue that [liraglutide], plus an SGLT2 inhibitor, would be an excellent combination from the renal standpoint, an excellent combination from the CV and weight-loss standpoint, and provides glycemic control. I like that combination and use it a lot.”

Patient education, screening

Kidney disease is often called a “silent killer” with no symptoms, and the disease can go undetected until it is in the advanced stages. A 2014 report from an ADA consensus conference on DKD, published in Diabetes Care, recommends screening for kidney disease once a patient is diagnosed with type 2 diabetes and then annually thereafter; for type 1 diabetes, screenings should begin 5 years after diagnosis. Any screening should assess urine albumin-to-creatinine ratio as well as serum creatinine to estimate GFR.

Patient education regarding DKD, de Boer said, is often a challenge.

“For patients, oftentimes it is difficult for them to understand what is going on with their kidney when all they have are numbers from lab tests and no symptoms to go along with them,” de Boer said. “Patients often have a great fear of kidney failure ... but they don’t understand the process that leads up to it, and they don’t understand how we monitor that process or use that to guide their therapy. So most of what I do in clinic is education.”

De Boer said he often encounters two problems with patients: They are reluctant to add more medications, even if these are demonstrated to be useful, and they can get confused.

“There are medications we use that have treatment interactions, such as diuretics and RAAS inhibitors, the newer glucose-lowering drugs and antihypertensives, and patients can get confused and stop or start medications inappropriately. Clarity and trying to make things simple for patients is important.”

Stanton said it is also important to manage patient expectations.

“I often say, ‘Nobody is thrilled about seeing the kidney doctor,’” Stanton said. “[Patients] all know some terrible story about dialysis. Part of managing DKD depends on where they are. It’s not etched in stone that if you have signs of kidney disease you’re going to progress.”

New targets, novel therapies

Despite optimal blood glucose control, BP control and the use of RAAS inhibitors, DKD continues to progress in many patients, said Elvira O. Gosmanova, MD, FASN, chief of the nephrology section at Samuel S. Stratton VA Medical Center in Albany, New York, and associate professor of medicine at Albany Medical College.

“There’s always a search for novel therapies, and several are being currently investigated in clinical trials for patients with DKD,” Gosmanova told Endocrine Today. “Examples include mineralocorticoid receptor antagonists, such as finerenone, vitamin D receptor activators, endothelin receptor antagonists, and, of course, SGLT2 inhibitors. The limited data suggest that all of these agents can reduce proteinuria in patients with DKD; however, further data are needed to establish efficacy of these therapeutic modalities.”

“Hopefully, in a few years, we will have more specific therapies we can offer our patients,” Gosmanova said.

Three large trials investigating renal outcomes in DKD are currently underway.

The Study of Diabetic Nephropathy with Atrasentan (SONAR), expected to be completed by 2018, is evaluating the effects of the endothelin 1 receptor blocker vs. placebo in a worldwide, randomized, double blind trial. The CREDENCE trial, estimated to be completed by 2020, will assess whether canagliflozin (Invokana, Janssen) has a renal and vascular protective effect in reducing the progression of renal impairment relative to placebo in participants with type 2 diabetes, stage 2 or 3 CKD and macroalbuminuria. The FIDELIO-DKD trial, estimated to be completed in 2019, will evaluate whether oral finerenone, in addition to standard daily therapy, is effective and safe in treating patients with type 2 diabetes and DKD vs. placebo.

“There are also studies going on in phase 2 with very novel mechanisms that show a lot of promise, at least in animal models,” Bakris said. “If we can get them to the bedside, if they show even 70% of the benefit of what is in animal models, that could potentially be really exciting.”

“Sometimes we study these drugs and they don’t get very far,” Donovan said. “But, it’s an interesting time because we do have many more options. ... There is a lot of collaboration between diabetologists and nephrologists in the area.”

The “next great bet,” according to Tuttle, will be on novel, anti-inflammatory strategies that target mechanisms activated in the diabetic kidney that have been shown to promote damage and loss of function.

“One of the things we will need will be better biomarkers, so we can identify people who have that particular mechanism and target the right therapy for the right patient at the right time —really getting to this idea of precision medicine,” Tuttle said. “I think that is coming. The NIDDK is sponsoring a precision medicine initiative. No matter how it turns out, it’s going to be exciting to move to an era where we are identifying specific molecular signatures that help us make a more precise diagnosis, and hone in on individualizing therapy.” – by Regina Schaffer

• References:
• Gaede P, et al. Diabetologia. 2016;doi:10.1007/s00125-016-4065-6.
• Levin A, et al. Lancet. 2017;doi:10.1016/S0140-6736(17)30788-2.
• NIDDK. Kidney Disease Statistics for the United States. Available at: https://www.niddk.nih.gov/health-information/health-statistics/kidney-disease. Accessed April 26, 2017.
• Stanton RC. Am J Kidney Dis. 2014;doi:10.1053/j.ajkd.2013.10.050.
• Tuttle KR, et al. Diabetes Care. 2014;doi:10.2337/dc14-1296.
• Wanner C, et al. N Engl J Med. 2016;doi:10.1056/NEJMoa1515920.

• For more information:
• George L. Bakris, MD, can be reached at University of Chicago Medicine, 5841 S. Maryland Ave., Chicago, IL 60637; email: gbakris@medicine.bsd.uchicago.edu.
• Ian H. de Boer, MD, MS, can be reached at the Division of Nephrology and Kidney Research Institute at the University of Washington, 1959 NE Pacific St., Box 356521, Health Sciences Building, BB-1271, Seattle, WA 98195; email: IDeBoer@Nephrology.washington.edu.
• Ralph A. DeFronzo, MD, can be reached at University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229; email: defronzo@uthscsa.edu.
• Daniel S. Donovan Jr., MD, MS, CDE, can be reached at the Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1055, New York, NY 10029; email: Daniel.donovan1@mssm.edu.
• Elvira O. Gosmanova, MD, FASN, can be reached at Samuel S. Stratton VA Medical Center, 113 Holland Ave., Albany, NY 12208; email: elvira.gosmanova@va.gov.
• Robert C. Stanton, MD, can be reached at the Joslin Diabetes Center, Kidney and Hypertension Section, 1 Joslin Place, Boston, MA 02215; email: Robert.stanton@joslin.harvard.edu.
• Katherine R. Tuttle, MD, FASN, FACP, can be reached at Providence Medical Research Center, Providence Sacred Heart Medical Center, 104 W. Fifth Ave., #350 E, Spokane, WA 99204; email: Katherine.tuttle@providence.org.

Disclosures: Bakris reports consulting for AbbVie, Bayer, Janssen, Merck and Relypsa. De Boer reports receiving research support from Abbott and Medtronic and consulting fees from Ironwood Pharmaceuticals. DeFronzo reports serving on advisory boards for AstraZeneca, Boehringer Ingelheim, Intarcia, Janssen and Novo Nordisk and on the speakers’ bureau for AstraZeneca and Novo Nordisk and receiving support from AstraZeneca, Boehringer Ingelheim, Janssen and Takeda. Stanton reports serving as a consultant to Boehringer Ingelheim. Tuttle reports receiving consulting fees from Boehringer Ingelheim, Eli Lilly and Gilead. Donovan and Gosmanova report no relevant financial disclosures.

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