American Diabetes Association 79th Scientific Sessions:

Treatment Guidelines Updated to Reflect Cardiorenal Benefits in Diabetes

with George Bakris, MD, Kenneth W. Mahaffey, MD, Amanda Vest, MBBS, MPH, and Susanne Nicholas, MD, PhD, MPH

In patients with type 2 diabetes at high risk of renal disease, primary results of two major clinical trials offer new guidance in the standard of care for these patients in both timing of intervention and aggressiveness of treatment.

Long anticipated data from the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) and the CArdiovascular and Renal Microvascular outcome study with LINAgliptin in individuals with type 2 diabetes mellitus (CARMELINA) were presented at the American Diabetes Association 79th Scientific Sessions in San Francisco, California, with guideline-changing impact on the future management of these patients.1-4

In effect, patients with established diabetic kidney disease should be treated with both a sodium-glucose cotransporter-2 (SGLT2) inhibitor and a dipeptidyl peptidase 4 (DPP-4) inhibitor, according to the findings from CREDENCE and CARMELINA.1

First Proven Treatment of Type 2 Diabetes with CardioRenal Safety

“For the first time in many years, we have new treatments that we can use to provide both glycemic benefit and improved cardiovascular outcomes in patients with renal disease,”2 said Peter Rossing, MD, DMSc, professor of internal medicine and head of Diabetes Complications Research at the Steno Diabetes Center at the University of Copenhagen, Denmark.

The data from these two large clinical trials were compelling enough to warrant calls for an immediate change in clinical practice. “If you intervene early enough, you can reduce the absolute risk in any given patient by at least 20% against developing not only diabetic kidney disease but also cardiovascular death,” said George Bakris, MD, professor of medicine and director of the American Heart Association Comprehensive Hypertension Center at the University of Chicago, Illinois.

“We have had angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) since the early 2000s,” he told EndocrineWeb. “Since then, however, nothing new until the SGLT inhibitors and glucagon-like peptide 1 (GLP-1) agonists “Validated biomarkers of not only kidney disease progression but also cardiovascular risk point to inflammation as a common factor.”

New Therapeutic Approach for High Risk Diabetes Patients

CREDENCE, a randomized, double-blind clinical outcomes trial specifically designed and powered to assess the progression of kidney disease as well as cardiovascular outcomes, following treatment with the sodium-glucose cotransporter-2 inhibitor (SGLT2i), canagliflozin against a placebo, for major kidney outcomes.1

Canagliflozin lowered the risk of the primary composite outcome (inclusive of end-stage kidney disease, doubling of serum creatinine, or death from renal or cardiovascular diseases) by 30%,according to the investigators.

In fact, the relative risk of the renal-specific composite— end-stage kidney disease, a doubling of the creatinine level, or death from renal causes—was 34% lower in the group receiving canagliflozin.3

Additionally, canagliflozin was found to lower the risk of cardiovascular death, myocardial infarction or stroke, as well as lower risk of hospitalizations for heart failure, and for the composite of cardiovascular death or hospitalization for heart failure.3

In terms of safety, there was no significant increase in the rate of lower-limb amputations, fractures, acute kidney injury, or hyperkalemia reported for canagliflozin relative to placebo. However, there was an increased risk for diabetic ketoacidosis with canagliflozin.

The trial was stopped early as interim data achieved prespecified efficacy criteria. In fact, on June 3, 2019, the American Diabetes Association issued important updates to the 2019 Standards of Care on improving cardiovascular and renal health in patients with type 2 diabetes, taking into account findings from these two major trials—CREDENCE and CANVAS.5,6

 “We now have a single therapy for patients with type 2 diabetes and chronic kidney disease that improves their metabolic profile, reduces kidney failure, and improves cardiovascular outcomes,” Kenneth W. Mahaffey, MD, professor of medicine at the Stanford University Medical Center in Palo Alto, California, told EndocrineWeb,

Positive Effects of DDP-4 in Vulnerable Diabetic Population

The CARMELINA Randomized Clinical Trial evaluated the effects of linagliptin, a dipeptidyl peptidase-4 inhibitor, was designed to assess cardiovascular and kidney outcomes against placebo when added to the standard care in patients with T2D and established cardiovascular and/or kidney complications.1

When evaluated against the spectrum of cardiovascular outcome trials conducted in patients with type 2 diabetes, CARMELINA reflected the highest number of individuals with prevalent kidney disease, including a large proportion of patients with severe kidney impairment and/or elevated albuminuria.

These at-risk individuals were also at very high of cardiovascular disease, so much so that the options for glucose-lowering treatment were limited, as much because they were largely underrepresented in previous cardiovascular outcomes trials of patients with type 2 diabetes.

Initiating the CARMELINA trial provided direct assessment of the inherent effects of linagliptin on cardiovascular and kidney events in a vulnerable population with significantly elevated cardiorenal risk.

The investigators reported no demonstrated increase in the risk of cardiovascular events, heart failure, or kidney dysfunction with linagliptin relative to placebo, confirming the safety of this DPP-4 in a very vulnerable population of patients with both type 2 diabetes and chronic kidney disease.1

In addition, a significant risk reduction in worsening of albuminuria and dramatic improvement in glycemic control were observed in the cohort receiving linagliptin without increasing their risk of hypoglycemia.

“The SGLT2 inhibitor and GLP-1 agonist drug classes, developed to control glucose levels for patients with T2D, have now been shown to reduce the rate of cardiovascular death, with SGLT2 inhibitors additionally preventing hospitalizations for heart failure,” said Amanda Vest, MBBS, MPH, Medical Director of the Cardiac Transplantation Program and Assistant Professor of Medicine at Tufts University School of Medicine in Boston, Massachusetts. 

Need for Better Adoption of Guidelines in Practice 

“In so many patients with diabetes and heart failure,” Dr. Vest said, “there’s also the challenge of chronic kidney disease. With heart failure, in particular, there’s a bidirectional relationship in which diabetes significantly increases the risk of heart failure and heart failure fuels progression of diabetes.”

“The concept of prescribing diabetes medications to help cardiovascular outcomes hasn’t quite permeated the field, yet,” she said. “At Tufts Medical Center, for example, we created a pocket card to guide for our endocrinology, cardiology, and primary care colleagues who see patients with type 2 diabetes and cardiovascular disease or cardiovascular risk factors.”

“There is a lot of enthusiasm in the cardiology field for the SGLT2 inhibitors,” Dr. Vest told EndocrineWeb. “Given the history of worsened heart failure event rates with several usual T2D therapies, including rosiglitazone, saxagliptin, and possibly the sulfonylureas, it is refreshing to now have a medication class that is associated with fewer heart failure hospitalizations.”

“The most anticipated question, though, is whether empagliflozin and dapagliflozin can reduce hospitalizations in patients with a baseline diagnosis of heart failure. The EMPagliflozin outcomE tRial in Patients With chrOnic heaRt failure (EMPEROR)-reduced, -preserved, and DAPA-HF studies are expected to address this added concern in the next few years,” she said.  “These findings will provide clearer insights into the future role of SGLT2 inhibition for patients with established heart failure.” 

Hypoglycemia Remains Signal of Future Cardiovascular Events

Julio Rosenstock, MD, principal Investigator of CARMELINA, who is also director of the Dallas Diabetes Research Center at Medical City, and a clinical professor of medicine at the University of Texas Southwestern Medical Center in Dallas, reported on the interrelationship between hypoglycemia and cardiovascular and mortality outcomes in the trial.

He and colleagues assessed the interrelationship between time to first severe hypoglycemic event (plasma glucose < 54 mg/dL), which occurred in 557 patients taking linagliptin (15.9%) and 572 (16.4%) in placebo cohort, and three-point major adverse cardiovascular event (MACE) or all-cause mortality, using adjusted Cox models.

Hypoglycemia preceded MACE in 146 participants (at a median of 58 days in 74 patients who received linagliptin and 55 days in 72 patients who received placebo), and was associated with a 43% higher risk (hazard ratio 1.43 [95% confidence interval 1.23, 1.66]), when adjusted for region and hypoglycemia.1

Higher adjusted risk of all-cause mortality was also associated with preceding hypoglycemia (hazard ratio 1.31 [95% confidence interval 1.11, 1.53]) in 129 participants who died (at a median of 65 days in 65 patients who received linagliptin and at 49 days in 64 patients who received placebo).

More frequent hypoglycemia was associated with a greater magnitude of incremental risk that attenuated with further adjustment. According to Dr. Rosenstock, preceding hypoglycemia was independently associated with increased risk for MACE and overall mortality.1

Acting to Reduce Cardiorenal Burden in Patients with Type 2 Diabetes

The CARMELINA investigators also analyzed first + recurrent cardiovascular and hospitalization events in this high-risk patient population.1 The goal was to characterize the effects of linagliptin on net cardiovascular disease and hospitalization burden among these hard to treat patients.

Using a negative binomial model, 6,979 participants were enrolled (with a mean age of 66 years), with an estimated glomerular filtration rate (eGFR) of 54.6 mL/min/1.73m2, and median urine albumin-to-creatinine ratio of 162 mg/g.1

A total of 58.5% of these patients had a history of ischemic heart disease, and 26.8% were diagnosed with prior heart failure.  

Linagliptin showed a similar risk of either a first or recurrent cardiovascular or hospitalization events when compared to the placebo group, all of whom were diagnosed with type 2 diabetes as well as cardiorenal disease.1

Dr. Rosenstock concluded that the data supported the overall safety and that of cardiovascular outcomes with linagliptin and, considering the number of recurrent events, he underscored the significant reduction in cardiovascular disease burden experienced by patients with type 2 diabetes and concomitant cardiorenal disease.1

Linagliptin Proves Efficacious, Expanding Treatment Options

Chandrasekar Gopalakrishnan, MD, MPH, a senior research specialist at Brigham and Women’s Hospital in Boston, Massachusetts, and colleagues have been monitoring cardiovascular safety and effectiveness of linagliptin in routine care. In a poster presentation, Dr. Gopalakrishnan reported on final results of his team’s five-year postmarketing monitoring program.4

Dr. Gopalakrishnan explained that real world data on the cardiovascular safety and effectiveness of linagliptin complemented the findings out of the CARMELINA trial.  In the 5-year postmarketing monitoring program from 2011 - 2016, two large insurance claims databases were used to assess the risk of composite cardiovascular outcomes: hospitalization for myocardial infarction, stroke, unstable angina, or coronary revascularization.4

Three 1:1 propensity score - matched cohorts of patients with type 2 diabetes were identified. They initiated linagliptin or a comparator [other DPP-4 inhibitors (n=39,834 pairs), pioglitazone (n=29,646 pairs), or sulfonylureas (n=25,285 pairs).8 Pooled hazard ratios and 95% confidence intervals were estimated, controlling for over 180 baseline characteristics; after propensity score matching, patient characteristics were similar.

Mean follow-up duration was 0.8 years during which linagliptin exhibited a similar risk of the composite cardiovascular outcome as other DPP-4 inhibitors [hazard ratio 0.90 (95% confidence interval 0.80 - 1.02)] and pioglitazone [hazard ratio 0.99 (95% confidence interval 0.86 - 1.13)].4

However, of significance, linagliptin was associated with less risk than sulfonylureas [hazard ratio 0.77 (95% confidence interval 0.66 - 0.90)]. The investigators reports robust results across numerous sensitivity analyses.

Dr. Gopalakrishnan said, “These real world results showed that linagliptin confers reassuring effectiveness and safety on composite cardiovascular outcomes vs other DPP-4 inhibitors and pioglitazone.” Linagliptin was associated with less risk than sulfonylureas. 

Use of Effective Drugs Should be Done in Concert with Guidelines

Regarding both prevention of cardiovascular and renal disease and the slowing disease progression, Dr. Bakris said, “Controlling blood pressure, lipids, and glucose mitigates against high levels of inflammatory biomarkers if you do it early enough to prevent damage.”

“While we acknowledge these new treatments may improve glycemic control and cardiovascular outcomes in patients with kidney disease, we must not neglect the importance of maximizing the use of current guidelines, especially for early screening,” session moderator Susanne Nicholas, MD, PhD, MPH, professor of medicine at the Ronald Reagan Medical Center at the University of California at Los Angeles, told EndocrineWeb.

Without following the guidelines, we still may not be able to take full advantage of these new therapies for all of our patients,” she said.

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