ENDO Online 2020: The Endocrine Society's Virtual Meeting:

Treating Diabetic Nephropathy: Which Way Forward in Patient Care?

with Matthew R. Weir, MD, and George Bakris, MD

Diabetic kidney disease affects about 25% of all individuals with diabetes.1 At the 17th World Congress on Diabetes Insulin Resistance and Cardiovascular Disease, Matthew R. Weir, MD, professor and director of the division of nephrology at the University of Maryland School of Medicine in Baltimore provided an overview of the pros and cons of the traitional and newer treatments available to manage these patients.2

New drugs lessen kidney disease affecting one-quarter of patients with type 2 diabetes. Combination therapies should be considered in patients with type 2 diabetes in order to improve cardiovascular and renal disease outcomes. Photo: peterschreiber.media @ iStock.

Avoiding Nephropathy in Patients with Type 2 Diabetes

Dr. Weir began with a reminder that traditional treatment strategies are chosen to reduce progression of kidney disease, specifically aimed at blood pressure control, renin-angiotensin-aldosterone system (RAAS) blockade and serum glucose control, by targeting renal pathophysiology including glomerular capillary hypertension and inflammation.2

Based on current American Diabetes Association guidelines,3 optimal treatment considerations should include:

  • Treating to blood pressure below 130/80 mmHg
  • RAAS inhibition
  • Tight glycemic control  
  • Anti-platelet therapy
  • Full dose statin
  • Limiting dietary sodium and dietary protein to 0.8 g/kg body weight (for anyone not on dialysis)
  • Monitoring of eGFR and urinary albumin (every 5 years for T1D and annually for T2D)

Confounding the usual clinical observations, however, are added concerns that patients with diabetes may develop renal insufficiency without albuminuria. Also, some patients with diabetes and low eGFR do not always have diabetic nephropathy. Lastly, patients with diabetes and microalbuminuria are susceptible to a decline in eGFR at a rate similar to those with macroalbuminuria,2 Dr. Weir said.

Albuminuria, a marker of renal damage, is associate with increased cardiovascular disease (CVD) morbidity and mortality. Dr. Weir cited data from the United Kingdom Prospective Diabetes Study (UKPDS), where the annual transition rates differed among people with diabetes.4

  • From diagnosis of diabetes to onset of microalbuminuria, the rate of occurrence was 2% per year
  • From microalbuminuria to macroalbuminuria, the conversion rate was 2.8% annually
  • From macroalbuminuria to elevated plasma creatinine (> 175 µmol/L) or renal replacement therapy at 2.3% per year

For perspective, a decade after CDK diagnosis, the prevalence of microalbuminuria in this patient population had advanced to 24.9%; macroalbuminuria was essentially double (5.3%); and elevated plasma creatinine or RRT was 0.8%, with an annual death rate in these patients of 19.2% (95% CI, 14.0 to 24.4%).4

Effective Utilization of Traditional Therapies in DKD

Blood pressure lowering. "Any approach that helps lower blood pressure is going to help protect kidney function," Dr. Weir said. "As such, managing blood pressure remains a significant initial and ongoing consideration."

However, no randomized clinical trials (RCT) have examined different blood pressure goals and clinical renal outcomes, he said. Nor have there been RCTs looking at the impact of reducing proteinuria independent of blood pressure, and renal disease progression.2 However, there are secondary analyses from a variety of trials in people with type 2 diabetes and CKD to inform patient management.

Glycemic goals. Citing implications reported based on the combined data from ACCORD, ADVANCE and VADT for microvascular risk,5 Dr. Weir indicated that lowering hemoglobin A1c (to 7% or less) assures a reduction in both microvascular and neuropathic complications in individual with type 2 diabetes. And, when feasible, lower goals may be suggested for those with a shorter duration (recent onset) of diabetes, long life expectancy, and no significant symptoms of cardiovascular disease (CVD).2

Lipid goal. Aggressive LDL-C lowering in diabetes pays off.

Intensive Traditional Risk Modification. Newer evidence suggests that intensive treatment to modify traditional risks does pay off in better survival, Dr. Weir said, with earlier research lending support to tighter glucose regulation, and the use of RAAS blockers, aspirin and lipid-lowering agents to reduce the risk of nonfatal CVD events among those with type 2 diabetes and microalbuminuria.2

That is until this approach was refuted by results reported by Gaede et al whose team randomized 160 patients with type 2 diabetes and persistent microalbuminuria to intensive or conventional therapy. Over a 13.3-year follow-up, 20 patients died in the intensive therapy group and 40 deceased in the conventional group.5

CarioRenal Benefits of Newer Therapeutics 

Among the newer medications with demonstrated benefit in reducing progression of diabetic kidney disease in patients with type 2 diabetes, are:

  • C-C motif chemokine receptor-2 (CCR2) inhibition (ie, CCX 140-B)
  • Endothelin receptor antagonist (eg, atresentan)
  • Pentoxifylline
  • JAK2 inhibitor (baricitinib)
  • Glucagon-like peptide 1 receptor agonists (GLP-1RAs)
  • Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) 
  • Finerenone,

Among the many factors to consider when contemplating use of these newer therapies, besides safety and efficacy, to be considered, Dr. Weir told EndocrineWeb:

  • Is the medication complementary with RAAS blockers?
  • Would you see the effect if systolic blood pressure was at 110 mm Hg, 130mmHg?
  • Does the effect persist after drug cessation?
  • Is albuminuria an adequate surrogate measure, or is an observable stabilization of eGFR needed?
  • Are these therapies incremental to intensive traditional modification of risk factors?

Weighing CVD Outcomes in Kidney Preservation

Dr. Weir reviewed numerous study results but of most relevance to diabetic kidney disease management:

  • The CREDENCE trial was designed to provide definitive evidence about the effects of canagliflozin (Invokana) on kidney and cardiovascular outcomes in patients with type 2 diabetes and established kidney disease, when compared with placebo plus standard of care.6

    In the primary composite cardiorenal outcomes, canagliflozin demonstrated a significant 30% relative risk reduction in end-stage renal disease, doubling of serum creatinine, death from kidney causes or CVD events. As might be expected, those with worse baseline renal function did better.6
  • Additional trials are ongoing to affirm renal protective benefits of newer therapeutics in patients with CKD with or without type 2 diabetes: The DAPA-CKD trial will randomize patients to dapagliflozin (Farxiga) or placebo, and EMPA-KIDNEY in which patients will be assigned to empagliflozin (Jardiance) or placebo.7,8 Completion dates are November 2020 and June 2022, respectively.

What is not yet clear, Dr. Weir said, is whether the newer studies will alter the standard of care for CVD and CKD in patients with diabetes. Thus, what is still needed, he said, is a comprehensive evaluation of the benefit:risk ratio for both traditional and newer therapies.

Even with these newer, promising therapies, Dr. Weir said, intensification of traditional treatment goals remains a mainstay of diabetes management to prevent and reduce comorbid complications such as CVD and DKD.   

Newer Drugs Offer Wise Choice for At-Risk Diabetics

With the knowledge gleaned from cardiovascular outcome trials in diabetes and focused studies on nephropathy progression, ''it is clear we have slowed nephropathy progression from 10 ml/min/year decline now down to 1.8-2 ml/min/yr. This is with combinations of glycemic control, lipid control and blood pressure control using a variety of agents. said George Bakris, MD, professor of medicine and director of the Ameircan Heart Association Comprehensive Hypertension Center at The University of Chicago Medicine in Illinois, who commented on this presentation topic for EndocrineWeb. "However, we still have a ways to go since normal decline is 0.8 ml/min/year." 

Dr. Bakris participated in designing the CREDENCE Trial and observed that the participants who had maximal glycemic, blood pressure, and lipid management did even better than in clinical practice. He speculated that inflammation is implicated in the onset and progression of nephropathy, and ''the evidence for inflammation is overwhelming such that the SGLT2i agents definitely reduce it significantly."

Thus, for patients with type 2 diabetes whose status suggests the need for cardiorenal protection, adding an SGLT2i to their current treatment plan is well worth considering. But we should not be satisfied where we are, as there is most certainly room to lessen progression of cardiovascular disese outcomes and avoid renal failure.

Dr. Weir is a scientific advisor to Jansen, Astra, BI, MSD, Akebia, Relypsa, Boston Scientific, Lexicon, Bayer, Vifor and CareDX. Dr. Bakris is principal investigator of the Fidelio study (Bayer), on the steering committee for the CREDENCE study (Janssen) and consults for Novo Nordisk.

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