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Evidence-Based Diabetes Management June 2019

2019 ADA Coverage: Renal Outcomes

Mary Caffrey
Coverage of DECLARE, CARMELINA, and other studies that highlight the connection between diabetes and renal outcomes
  1. American Heart Association. Cardiovascular disease and diabetes. AHA website. cardiovascular-disease--diabetes. Updated August 30, 2015. Accessed June 16, 2019. 
  2. National Kidney Foundation. Diabetes—a major risk factor for kidney disease. NKD website. Updated 2015. Accessed June 16, 2019. 
  3. Peter Rossing, MD, DMSc, receives the American Diabetes Association’s 2019 Edwin Bierman Award [press release]. Arlington, VA: American Diabetes Association; May 30, 2019. newsroom/press-releases/2019/2019-edwin-bierman-award.html. Accessed June 16, 2019. 
  4. Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events (DECLARE-TIMI58). NCT01730534. Updated October 2, 2018. Accessed June 16, 2019. 
  5. Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy. ct2/show/NCT02065791. Updated April 10, 2019. Accessed June 16, 2019. 
  6. American Diabetes Association issues critical updates to the 2019 Standards of Medical Care in Diabetes [press release]. Arlington, VA: American Diabetes Association; March 27, 2019. Accessed June 16, 2019 
  7. American Diabetes Association issues critical updates to the 2019 Standards of Medical Care in Diabetes [press release]. Arlington, VA: American Diabetes Association; June 3, 2019. press-releases/2019/updates-standards-medical-care-diabetes.html. Accessed June 16, 2019. 
  8. Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease (FIDELIO-DKD). NCT02540993. Updated June 12, 2019. Accessed June 16, 2019. 
  9. Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and the Clinical Diagnosis of Diabetic Kidney Disease (FIGARO-DKD). Updated May 20, 2019. Accessed June 16, 2019. 
  10. Avdin O, Nieuwdorp M, Gerdes V. The gut microbiome as a target for the treatment of type 2 diabetes. Curr Diab Rep. 2018;18(8):55. doi: 10.1007/ s11892-018-1020-6. 
  11. Pradhan AD, Paynter NP, Everett BM, et al. Rationale and design of the pemafibrate to reduce cardiovascular outcomes by reducing triglycerides in patients with diabetes (PROMINENT) study. Am J Heart. 2018;206:80-93. doi: 10.1016/j.ahj.2018.09.011. 
  12. American Diabetes Association. Standards of medical care in diabetes—2009. 2009;32(suppl 1):S13-S61. doi: 10.2337/dc09-S013. 
  13. Tuttle KR, Brosius FC, Adler SG, et al. JAK1/JAK2 inhibition by baricitinib in diabetic kidney disease: results from a phase 2 randomized controlled clinical trial. Nephrol Dial Transplant. 2018;33(11):1950-1959. doi: 10.1093/ndt/gfx377. 
  14. Aday AW, RIdker PM. Anti-inflammatory therapy in clinical care: the CANTOS trial and beyond. Front Cardiovasc Med. 2018;5:62. doi: 10.3389/ fcvm.2018.00062. 
  15. Everett BM, Donath MY, Pradhan AD, et al. Anti-inflammatory therapy with canakinumab for the prevention and management of diabetes. J Am Coll Cardiol. 2018;71(21):2392-2401. doi: 10.1016/j.jacc.2018.03.002. 

CARMELINA Results in Linagliptin Show Neutral Renal Outcomes in Elderly Patients

A symposium on renal outcomes in type 2 diabetes (T2D) therapies held June 11, 2019, at the 79th Scientific Sessions of the American Diabetes Association (ADA) featured results from CARMELINA,1 a study that evaluated the effect of linagliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, on cardiovascular and kidney safety. During a press briefing ahead of the program, investigators emphasized that patients with T2D and kidney disease have received less attention in trials of DPP-4 inhibitors. 

Results showed, compared with placebo, there was no significant difference in the 3-part major adverse cardiovascular events (MACE) and neutral findings for renal outcomes in elderly patients. 

Before results for CARMELINA were presented, Boehringer Ingelheim and Eli Lilly, which market linagliptin as Tradjenta, announced results for CAROLINA,2 which compared linagliptin with glimepiride, a second-generation sulfonylurea. Officials touted CAROLINA as “the only active comparator outcome trial” for a DPP-4 inhibitor, with the results showing that linagliptin was not inferior to glimepiride in the first occurrence of 3-part MACE and similar in a secondary end point of 3-part MACE plus hospitalization for unstable angina. 

More patients taking linagliptin achieved a second composite outcome of reaching a glycated hemoglobin level of 7% without a rescue medication, moderate or severe hypoglycemia, or 2% weight gain. 

When asked during a press briefing where DPP-4 inhibitors generally and linagliptin specifically fit in among T2D therapies, investigator Julio Rosenstock, MD, director of the Dallas Diabetes Research Center, said the results from CARMELINA show that linagliptin is safe to use for older patients who need help with glycemic control. “We can state with a great deal of confidence that using a DPP-4, including linagliptin, is safe from a cardiovascular point of view and safe if they have kidney disease—and safe in older people,” he said. “That’s my take-home message.” 

  1. Petrovic V, Rosenstock J. CREDENCE and CARMELINA—results from two major clinical trials in kidney and cardiovascular disease in diabetes. Presented at: 79th Scientific Sessions of the American Diabetes Association; June 7-11, 2019; San Francisco, CA. 
  2. Detailed findings from CAROLINA outcome trial support long-term cardiovascular safety profile of Tradjenta [press release]. Ridgefield, CT, and Indianapolis, IN: Boehringer Ingelheim and Eli Lilly and Company; June 10, 2019. Accessed July 11, 2019. 

DECLARE Shows Dapagliflozin Prevented Renal Decline in T2D, Even for Those With Good Kidney Health

Data from the DECLARE-TIMI 58 study, the cardiovascular outcomes trial (CVOT) for dapagliflozin (Farxiga), reveal that the type 2 diabetes (T2D) drug significantly reduced the risk of renal decline, kidney failure, and renal death, according to results presented June 9, 2019.

Findings, reported at the 79th Scientific Sessions of the American Diabetes Association (ADA), held in San Francisco, California, and published simultaneously in Lancet Diabetes & Endocrinology show that treatment with the sodium glucose cotransporter 2 (SGLT2) inhibitor made a difference even for those in good renal health when the study began. The study authors noted this point, because a dedicated renal outcomes trial for dapagliflozin is forthcoming.

“The effect of SGLT2 inhibitors on nephropathy is being examined in dedicated studies of renal outcomes, both in patients with and without type 2 diabetes,” wrote the study authors, led by Ofri Mosenzon, MD, of Hadassah Hebrew University Hospital in Jerusalem. “However, these trials focus on populations with nephropathy at baseline, and therefore should be considered as complementary to our findings.”1

The need for better solutions to prevent renal decline in diabetes—and the apparent ability of SGLT2 inhibitors to offer options—were a major focus of the Scientific Sessions. Diabetes, cardiovascular disease, and chronic kidney disease (CKD) often occur together, and having 1 condition increases the risk of developing the others, along with other comorbidities; for this reason, CKD is often called a “disease multiplier.”3 Those with CKD are at least 6 times more likely to develop end-stage renal disease (ESRD), one of the most debilitating conditions for patients and one of the costliest for the health system.4  

The cost of dialysis per patient is estimated at $89,000 per year; patients who reach this point automatically qualify for Medicare. Estimates show that 750,000 people in the United States have ESRD, and this number has been projected to increase due to the rising rate of obesity.

Like other CVOTs, DECLARE was required to demonstrate safety under a 2008 FDA guidance. Investigators expanded the trial to include hospitalization for heart failure as a second primary end point, after the 2015 EMPA-REG OUTCOME trial unexpectedly showed that the SGLT2 inhibitor empagliflozin reduced cardiovascular death by 38% and hospitalization for heart failure by 35%.

Thus, DECLARE is the only trial for an SGLT2 inhibitor to report reduced hospitalization for heart failure and cardiovascular death as a primary end point.7 ​​​​​​​

DECLARE investigators previously presented findings at the American Heart Association meeting in November 20187 and the American College of Cardiology (ACC) Scientific Session in March, focusing on the drug’s ability to prevent complications from heart failure.

Taken together, the results hold much promise, according to Kiersten Combs, vice president for US cardiovascular and metabolic disease for AstraZeneca, the maker of dapagliflozin. “We’re almost at a turning point here in treating the diabetic patient and their comorbidities or complications,” Combs said in an interview with The American Journal of Managed Care® (AJMC®). 

In the past, the conversation with health systems has been about how well a T2D therapy controlled blood glucose levels, but the growing body of evidence for cardiorenal results generates a broader conversation, said Naeem Khan MD, vice president of medical for US Cardiovascular and Metabolic Diseases at AstraZeneca, in the interview with AJMC®. “Now the evidence has brought us to a point where we say [that] diabetes is a risk factor that affects other vital organs, and the organs are the heart and the kidney,” Khan said. 

The DECLARE data had already produced a primary end point showing that dapagliflozin reduced hospitalization for heart failure and cardiovascular death, Khan said, and now the data show benefits for the renal system. Given the grim trajectory for patients with diabetes who develop cardiovascular disease and CKD, the results “change the whole paradigm,” he said. 

“What you’re seeing, which is so exciting, with the SGLT2 class—and with Farxiga specifically, with DECLARE—is this body of evidence around how treating beyond the A1C [glycated hemoglobin] improves these patients’ quality of life and slows not only the diabetes [but also] the disease that the diabetes can exacerbate,” Combs said. 

These latest results are from a prespecified exploratory analysis of renal-only outcomes, examining results from 17,160 patients with T2D and mostly preserved renal function, regardless of underlying atherosclerotic cardiovascular disease. Follow-up was 4.2 years.

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