Implications of the T2DM-CVD-CKD Link: What We've Learned

This transcript has been edited for clarity.

Jay H. Shubrook, DO: Hi. Today we're going to talk about the important link between diabetes, the kidney, and cardiovascular disease (CVD).

I'm Jay Shubrook, a family physician and diabetologist at Touro University. I am delighted to have with me Dr Katherine Tuttle, who is a professor of medicine at the University of Washington. Dr Tuttle is uniquely qualified to talk about this because she is both an endocrinologist and a nephrologist, and she serves on the board of directors of the Kidney Health Initiative. Welcome, Dr Tuttle.

Katherine R. Tuttle, MD: Thank you very much. It is a pleasure to join you this morning.

Shubrook: We have all of this exciting news about diabetes—there is so much going on. I learned about microvascular and macrovascular disease associated with diabetes, and I thought of them as separate things. With approval of some newer medicines, we have a lot of attention on CVD. It seems, though, that they are not separate and there might be a link between them. Please tell me more about the link between diabetic chronic kidney disease (CKD) and CVD.

Tuttle: We are taking a much more integrated view of not only diabetes, but diabetes as a package of vascular diseases that affect both the microcirculation and the macrocirculation.

To provide some biological rationale and epidemiologic evidence that will help us understand the results of clinical trials, I'll take a moment to talk about some observational data that our group published several years ago, looking at data from NHANES—the National Health and Nutrition Examination Survey. This is not longitudinal data but serial trends over time.

We were able to link the evidence of CKD, albuminuria, or low glomerular filtration rate (GFR) among diabetic patients in the NHANES data with clinical outcomes—most importantly, death and cardiovascular death. This study^[1] demonstrated that almost all of the excess all-cause and cardiovascular mortality risk in patients with diabetes occurred in the subset of patients with CKD, which is about half of people with type 2 diabetes.

Therefore, people with type 2 diabetes who have normal GFR and no albuminuria actually are at modestly increased risk for CVD compared with a nondiabetic population, but the risk escalates dramatically in people with albuminuria and low GFR. Albuminuria alone approximately quadruples the risk for cardiovascular death. Low GFR increases this risk six times; the combination of low GFR and albuminuria increases this risk 10 times.

These data show that patients who have evidence of CKD are at the highest risk for cardiovascular events leading to death. From the perspective of nephrology, this is important as well because we have traditionally focused on loss of kidney function leading to end-stage renal disease and have largely ignored the fatality risk of CKD, which is commonly mediated through CVD. Furthermore, among patients with type 2 diabetes who develop albuminuria or low GFR, 90% will die and not reach end-stage renal disease. About half of these deaths are attributed to CVD events.

The second leading cause of death is infections, which is another interesting issue—that's about a third of deaths. But still, CVD is the largest cause of death in people with diabetes and CKD.

We need to recognize that diabetes with CKD is a harbinger of death. If people survive to end-stage renal disease, you might say, "Congratulations—you made it." Not that we want patients to experience CKD progression but because there is a competing risk for death and end-stage renal disease. I think we are now beginning to recognize this fact, and it is critically important for day-to-day patient management as well as for how we design clinical trials and endpoints.

The new glucose-lowering agents are truly showing us how important it is to look at both risk outcomes. There is an opportunity to not only reduce risk for CV events and death, but to also prevent patients from progressing to kidney failure, which would really be the win—to both stay alive and stay healthy.

Shubrook: This reminds me why screening people is so important. I recently learned that very few patients with CKD know they have it. They do not know their albumin status; they do not know their GFR. If we are not screening, we are letting these people remain at risk, correct?

Tuttle: Yes. Awareness is low among both patients and healthcare professionals. For as long as I can remember, the American Diabetes Association (ADA) has recommended annual albuminuria screening. For at least the past 10 years, the ADA has recommended an annual GFR screening because the risk of developing CKD is so high, occurring in about half of patients with type 2 diabetes and a third of patients with type 1 diabetes.

Despite what we know and the recommendations, this is not being translated to daily practice. I don't think we've completely unpacked why that occurs. I believe it starts with awareness, detection, and intervention. I appreciate the chance to be on this webcast with you, because part of what we are doing right now is increasing awareness among healthcare professionals who hopefully will translate that knowledge to care of their patients. We can detect CKD early and intervene, which is an ideal opportunity to keep patients with diabetes healthy.

Shubrook: It's up to us to know that we have to screen our patients. Let's say that I screen a patient and the estimated GFR is found to be greater than 60, which is considered normal. How do I determine whether my patients are at risk so I know that I can start this next step?

Tuttle: It is important to screen for both albuminuria and GFR. The traditional view was that albuminuria occurred earlier and then GFR declined later. Now that view is being challenged. From a clinical perspective, it is important to measure both. In the patient with a GFR above 60, be sure to measure urine albumin.

I'm intentionally not saying order a microalbumin test. There is much confusion about what the term microalbumin means. It means a small amount of albumin in the urine. The truth is that many people have more than "microalbuminuria" and we're still calling it microalbuminuria. Microalbuminuria is a urine albumin to creatinine ratio of 30 to 300 mg/g. Macroalbuminuria is above 300 mg/g. Risks rise progressively as the level of albuminuria rises.

Many people with preserved GFR have albuminuria, and they are at much higher risk for both CKD and CVD. There is a large and growing group of patients with diabetes who have low GFR who do not have increased albuminuria. We don't fully understand the underlying reasons. It may be because of some of the therapies, such as renin-angiotensin system inhibitors, which are our go-to drugs for hypertension and diabetes. It may be from better glycemic control, which also reduces albuminuria.

What has been surprising and concerning is that, although clinical trials suggest that reduction of albuminuria predicts preservation of GFR in the short term, we are learning that it is really not preservation but a delay in time to CKD progression. Even though albuminuria can be reduced, it does not mean that patients are not at risk, especially with long-term diabetes. It is critical to assess GFR, too.

You mentioned a cut-off of 60 for GFR. This is an arbitrary dividing line, but the reason for reporting that way is related to the validity and accuracy of the estimating equations used to calculate GFR from serum creatinine. These equations lose accuracy above 60. There are many reasons for this issue, which have to do with technical methods of measuring creatinine and available data to derive equations for estimating GFR in the higher ranges.

For example, with an estimated GFR of 80, the serum creatinine could be measured the next day, and if it changed within the error of the measurement (eg, 0.1 mg/dL), the GFR estimate could then be 95. Such a numerical change does not reflect a difference in the patient—it's a technical issue. To avoid confusion, we say that an estimated GFR above 60 is "normal." Normal for actual GFR in adult life is approximately 100. A drop in actual GFR from 100 to 80 would be a harbinger of CKD progression, but early changes cannot be detected based on serum creatinine–based GFR.

There are methods to accurately measure GFR, but they are cumbersome in practice. Nevertheless, if estimated GFR is below 60, it is low in a clinically relevant sense.

Shubrook: What I've heard is that CKD is important. It is a microvascular complication. We know that many people with diabetes die from CVD. We may have underappreciated the link between CVD and CKD, making it more important to do annual screenings to look for urine albumin to creatinine ratio and assessment of GFR.

We'll talk next time about what to do in patients with CKD to improve both their diabetes and their kidney. Thank you so much for your time today. I look forward to talking to you again.

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