Dulaglutide in Type 2 Diabetes: Do GLP-1 agonists delay progression of diabetic nephropathy?

Hemodialysis bloodline tubes in dialysis machine

By Connor Emdin
June 27, 2018

Forty percent of patients with type 2 diabetes go on to develop chronic kidney disease (CKD).1 These patients are at markedly elevated risk of death from cardiovascular disease.2 They also suffer from reduced quality of life, particularly when CKD progresses to end-stage renal disease and dialysis.3 Despite the substantial morbidity and mortality associated with diabetic kidney disease, therapies are limited. In the National Kidney Foundation Clinical Practice Guidelines for Diabetes and CKD from 2012, only angiotensin converting-enzyme-inhibitors (ACE-inhibitors) and angiotensin-receptor blockers were recommended for protection of renal function in patients with CKD and diabetes with albuminuria.4

Glucagon-like peptide-1 (GLP1) agonists have been shown to be effective at reducing hyperglycemia and preventing cardiovascular events in type 2 diabetes.5 Basic science studies indicate that GLP-1 agonists may decrease inflammation and protect against endothelial dysfunction. In trials designed to test the cardiovascular efficacy of GLP1 agonists, these drugs were also observed to decrease the development of albuminuria.6,7 These findings suggest that GLP1 agonists may have protective effects against diabetic kidney disease.

The Study

This hypothesis was tested in the AWARD-7 trial, recently published in The Lancet Diabetes and Endocrinology.8 This study was designed to assess the noninferiority of dulaglutide compared to insulin glargine by examining HbA1c at 26 and 52 weeks. Secondary end points included changes in eGFR and urine albumin/creatinine ratio (ACR). Enrolled patients had HbA1c between 7.5 and 10.5% and CKD Stage 3-4, with eGFR between 15 and 60mls/min/1.73m2. i

Five hundred and seventy-seven individuals were enrolled into three study arms,  dulaglutide 1.5 mg once weekly (n=192), dulaglutide 0.75 mg once weekly (n=190), or insulin glargine (n=194). At baseline, patients were well matched across groups with mean eGFR ~35mls/min/1.73m2 and mean urine ACR 200-220mg/g at enrollment. However, more than 40% had overt diabetic nephropathy with macroalbuminuria and greater than 300mg albumin excretion per day.

The Results

At both 26 weeks and at 52 weeks, mean HbA1c fell in the three study arms with no difference between the two dulaglutide-dosing regimens versus insulin glargine treatment (Table 1; p < 0.0001 for noninferiority). However, dulaglutide showed some positive effects on renal function as compared with insulin glargine. For individuals on dulaglutide, eGFR did not significantly decline from baseline to 1-year follow up (-0.7 ml/min for both 1.5 mg and 0.75 mg). In contrast, those treated with insulin experienced a decline in eGFR of ~3.3 ml/min over the year (p<0.05 for superiority of dulaglutide over insulin glargine).

Table 1. Primary and secondary outcomes of the AWARD-7 trial.

Outcome Dulaglutide 1.5 mg once weekly (n=192) Dulaglutide 0.75 mg once weekly (n=190) Insulin Glargine (n=194)
HbA1c Change from Baseline at 26 Weeks, % -1.2 (0.1) -1.1 (0.1) -1.1 (0.1)
Change in eGFR from Baseline to 52 Weeks (ml/min) -0.7 (0.9)# -0.7 (0.9)# -3.3 (0.9)
UrineACR Change from Baseline at 52 Weeks mg/g (%) -23 (7.0)# -20 (7.3) -13 (7.9)

(Values reported as mean change (standard error). #p<0.05 vs. insulin , ##p<0.0001 vs. insulin)

This effect was largely driven by a reduction in GFR loss among those with macroalbuminuria (-0.5mls/min in dulaglutide versus -5.5mls/min in insulin treated at 52 weeks). Much smaller differences were observed in rates of GFR decline among those without macroalbuminuria. For the overall group, numerically greater reductions in albuminuria were observed with dulaglutide, although these differences did not reach statistical significance (Table 1). However, when broken down by level of baseline albuminuria, a significantly greater benefit was seen in those with macroalbuminuria at enrollment who were then treated with dulaglutide (-29.0 mg/g vs 0.1mg/g, p <0.01).

In addition, dulaglutide led to fewer adverse events. Rates of hypoglycemia were lower with dulaglutide, seen in only 2-5% versus 8% of insulin glargine-treated patients. Dulaglutide also led to weight loss by 52 weeks (-2.7 kg change for 1.5 mg dose and -1.7 kg change for 0.75 mg dose, p<0.0001 relative to baseline), while insulin glargine caused weight gain (1.1 kg change from baseline, p<0.0001).

Indications

These findings indicate that dulaglutide is noninferior for management of type 2 DM in patients with CKD stage 3 and 4, and appears to be better tolerated than insulin, with several additional favorable effects. Enrolled patients with macroalbuminuria experienced a significant improvement in urinary protein excretion after treatment with dulaglutide. Furthermore, the reduction in GFR decline observed with dulaglutide treatment is encouraging; diabetic nephropathy progresses over many years and even a small change in trajectory of GFR decline can translate into years of dialysis-free survival. Larger studies and long-term follow-up will be needed to confirm these effects.

However, based in this study and prior data, it appears that dulaglutide is a safe and effective option for patients with type 2 DM in CKD stage 3 to 4, and may have additional renal benefits when used in combination with standard ACEi/ARB therapy.

References:

  1. KDOQI. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease. Am J Kidney Dis. 2007;49(2 Suppl 2):S12-S154. doi:10.1053/j.ajkd.2006.12.005.
  2. Pálsson R, Patel UD. Cardiovascular complications of diabetic kidney disease. Adv Chronic Kidney Dis. 2014;21(3):273-280. doi:10.1053/j.ackd.2014.03.003.
  3. Merkus MP, Jager KJ, Dekker FW, De Haan RJ, Boeschoten EW, Krediet RT. Quality of life over time in dialysis: the Netherlands Cooperative Study on the Adequacy of Dialysis. NECOSAD Study Group. Kidney Int. 1999;56(2):720-728. doi:10.1046/j.1523-1755.1999.00563.x.
  4. National Kidney Foundation. KDOQI Clinical Practice Guideline for Diabetes and CKD: 2012 Update. Am J Kidney Dis. 2012;60(5):850-886. doi:10.1053/j.ajkd.2012.07.005.
  5. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22):2117-2128. doi:10.1056/NEJMoa1504720.
  6. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016;375(4):311-322. doi:10.1056/NEJMoa1603827.
  7. Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016;375(19):1834-1844. doi:10.1056/NEJMoa1607141.
  8. Tuttle KR, Lakshmanan MC, Rayner B, et al. Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial. Lancet Diabetes Endocrinol. June 2018. doi:10.1016/S2213-8587(18)30104-9.

Connor Emdin_headshot_150x127Connor Emdin is a post-doctoral research fellow in Sek Kathiresan’s lab at the Broad, specializing in the genetics of cardiovascular disease. He completed his doctorate in cardiovascular epidemiology at the University of Oxford from 2009-2013.

Follow Connor on Twitter: @connoremdin

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