The “Management of Patients with Progressing Diabetic Kidney Disease” session was held at the ASN KidneyWk on Oct 26, 2018.

This topic is relevant to every nephrologist’s practice, and the speakers gave us a nice review of the literature.

Part 1. “Specific Considerations of Blood Pressure Control in Diabetic Kidney Disease” by Dr. George Bakris:

The different medical societies and expert reports have multiple BP goal guidelines, which are overall similar, either recommending a BP of <130/80 or <140/90. The most recent KDIGO/KDOQI guidelines recommend a BP <140/90. This goal is focused on renal protection and not cardiovascular (CV) outcomes, a point that will become important in the rest of the section.

In a recent analysis of the ACCORD trial applying the SPRINT criteria to evaluate whether there is a benefit in CV risk reduction, the subjects randomized to the intensive BP control had a lower composite outcome of CV death, nonfatal MI, and nonfatal stroke over a 9-year follow-up period. In a meta-analysis of 40 trials evaluating the effect of 10 mm systolic BP (SBP) lowering on all-cause mortality and vascular outcomes in diabetics, there was a benefit of BP lowering in mortality, CV events, retinopathy, and albuminuria, but not on renal failure. In another meta-analysis including 69,000 patients, those with diabetes had less progression towards ESRD when their SBP was <140 but decreasing the SBP to <130 did not show further decrease in progression to ESRD. This is in contrast to patients without type 2 diabetes mellitus (T2DM) who show continued benefit to a SBP <130.

In the J-DOIT3 study, the risk of CV outcomes with a SBP >140 mm Hg depended on the patients’ overall CV risk (also based on smoking status, cholesterol, diabetes status, etc). If the 10-year CVD risk score is > 10% (high-risk individuals), then there appears to be benefit in decreasing the BP to <130.

One important thing to note is that the creatinine may increase as the BP is being lowered. In a post hoc analysis of the ACCORD trial, the group with intensive BP control had an up to 30% increase in creatinine; however, the intensive arm still conferred long-term benefit.

Take-home points:

• SBP <140 mm Hg in patients with diabetes does not protect the kidneys any more, but will reduce CV risk.
• In practice, the goal for patients with diabetes should be 130-140/90. Following that, determine their CV risk and decide if you should target SBP <130 in high-risk individuals.

Part 2. “Do Glycemic Control Goals in Diabetes Change with GFR? How to Assess It” by Dr. Katherine Tuttle:

Dr. Tuttle started her talk by emphasizing that most people with T2DM and CKD will die of CVD before reaching ESRD or getting a kidney transplant. Moreover, as soon as microalbuminuria appears, there is an increased risk of death. Any elevation in SCr is associated with a 20x increased annual risk of death, which is equivalent to stage 3 lung cancer.

Even though the incidence (new cases) of ESRD from T2DM has decreased, the prevalence (actual number of cases alive) of ESRD from T2DM continues to rise. We know from patients with type 1 diabetes (DCCT/EDIC) that young people with diabetes who began intensive treatment early in their life had a decrease in kidney disease and other diabetic complications. There is no question that if we treat people early in diabetes with lower BP goals and more intense glycemic therapy, they will benefit in the long term. But the risk equation changes when patients have had long-term diabetes and other related complications, particularly kidney disease. Is there, then, a benefit from more intensive glycemic control then?

When you evaluate the trials, there does NOT seem to be an improvement in outcomes with intensive A_1c lowering (6.4-6.9%). In fact, hypoglycemia and mortality were higher when A_1c was controlled to <7% in patients with long standing T2DM. Therefore, in patients with long term diabetes, there is no benefit and in fact there is potential harm in intensive glucose control. This also applies to any patients with diabetes with mild CKD or mild albuminuria. Also important is the fact that A1C and other markers of diabetes are not accurate in CKD. Continuous glucose monitoring is the most accurate way to monitor blood sugar in patients with diabetes.

More recently, there has been a major shift and improvement in outcomes of patients with diabetes with CKD, largely due to the advent of SGLT2 inhibitors and other glycemic agents.

When kidney function was evaluated in the EMPA-REG (see this NephJC post), empagliflozin caused an abrupt decline in GFR soon after treatment was initiated. However, GFR stabilized over time and there was renal benefit in the long term. In the CANVAS trial, CV risk reduction was seen in the CKD group taking canagliflozin. Additionally, the CKD group had a larger reduction in strokes when compared to the non-CKD population taking the drug.

Liraglutide (GLP-1 agonist) is also proving to be a hypoglycemic with renal benefits. In the LEADER trial, liraglutide reduced CV risk in all patients, and in the CKD subgroup. Interestingly, this benefit increased as GFR declined. In other words, the lower the GFR, the higher the CV risk reduction from liraglutide.

Take-home points:

• In patients with CKD, HbA_1C goals <7% increase the risk of hypoglycemia.
• Continuous glucose monitoring is the most accurate way to assess blood sugars in CKD.
• GLP-1 agonists and SGLT-2 inhibitors are effective for CV risk reduction in patients with CKD, and may even have GFR-preserving benefits.

Part 3. “How and When to Modify Oral Diabetes Medications as GFR Declines” by Dr. Mark Molitch: 

Dr. Molitch focused on the changes in insulin sensitivity as GFR declines. In order to prevent hypoglycemia in our patients, we should remember that as GFR declines, the insulin requirements to maintain euglycemia decline as well. These changes in insulin dosing should be made in AKI in addition to progressive CKD. Despite reductions in insulin doses, patients with CKD still have higher rates of hypoglycemia as compared to patients with diabetes without CKD.

Dr. Molitch recommends using glipizide and not the other sulfonylureas in patients with CKD.  This is due to reduced metabolite clearance of alternatives such as glyburide and glimepiride.

Nateglinide and repaglinide are short acting and taken with meals; therefore, they may have niche in patients who skip meals, making them avoid hypoglycemia. Nateglinide has a metabolite whose clearance is delayed in CKD, and should not be used for eGFR <60 mL/min.

With the awareness of metformin associated lactic acidosis (MALA) increasing (see this NephJC post), this question needed addressing. It should be stopped in patients with eGFR <30 mL/min, and used with caution in patients with eGFR between 30-60 mL/min. In acutely ill patients, the risk of MALA increases, so always hold metformin in these individuals.

Similar reductions apply to DDP4 and SLGT2 inhibitors with progressive loss of GFR.

Dr. Molitch ended with an interesting question: How do we manage insulin in ESRD? There are surprisingly very little data on this subject. We desperately need studies and trials to learn more about how to manage this unique scenario.

– Post prepared by Pascale Khairallah, AJKD Editorial Intern. Follow her @Khairallah_P.