Per-Henrik Groop, MD, DMSc


October 03, 2017

Today I have an important message to all clinicians who treat patients with diabetes, especially patients with type 2 diabetes: Cardiovascular disease (CVD) and renal disease are inextricably linked.

If you see a patient in your clinic with CVD, I urge you to watch out for kidney disease. If you have a patient with kidney disease, watch out for CVD. It will be there because they are linked.

Patients with kidney disease have a lot of consequences, such as hypertension, endothelial dysfunction, insulin resistance, anemia, inactivation of renin, and the tendency for aldosterone system activation of the sympathetic nervous system. These are all risk factors for CVD. No question—CVD and renal disease go together.

Consequences 'Grim' for Diabetic Kidney Disease

If you screen for renal disease in patients with type 2 diabetes, roughly every second patient will have albuminuria, and about 22% to 24% will have a reduced estimated glomerular filtration rate (eGFR), meaning that the eGFR is below 60 mL/min.

We use 60 mL/min as a cutoff for chronic kidney disease because it is 2 standard deviations below the average. It's  just like how you use 2.5 standard deviations below the average for the diagnosis of osteoporosis. So, a patient with eGFR below 60 mL/min will have chronic kidney disease, and if the patient also has diabetes, we call it diabetic kidney disease.

The consequences of diabetic kidney disease are grim because these patients have manyfold increased risks for premature death and cardiovascular events, they have an increased risk of ending up on dialysis, and they also have double the risk for severe hypoglycemia.

A patient with type 2 diabetes and renal disease will probably also have CVD and therefore an increased risk of dying due to the CVD, ending up on dialysis because of the diabetic kidney disease, or facing cardiovascular events.

Difficulties in Achieving Optimal Glycemic Control

What should you do? What is the basic reason for the complications in any patient with diabetes? Hyperglycemia. We need to make sure we try to achieve optimal glycemic control.

Many studies show that optimal glycemic control reduces the risk for microvascular complications. You have probably heard that glycemic control is not important for macrovascular disease. That is not entirely true. A UK Prospective Diabetes Study (UKPDS)[1] in newly diagnosed diabetic patients showed that after 10 years, a 0.9% reduction in A1c had a wonderful effect on the microvascular side but not on the macrovascular side. But after another 10 years in the UKPDS group studies, although all the A1c levels merged, you could see an effect on the macrovascular side.[2]

Optimal glycemic control reduces the risks for microalbuminuria, macroalbuminuria, and dialysis. Why is it so difficult to achieve optimal glycemic control in patients with type 2 diabetes? The reason is that patients with diabetic kidney disease have a many-times increased risk for severe hyperglycemia due to more insulin circulating in the blood and less compensatory gluconeogenesis.

What do I mean? Half of the insulin secreted by the pancreas is excreted by the kidneys, and half is extracted by the liver. If you have renal impairment, the kidneys are not excreting insulin to the full extent, so you will have more circulating insulin, and patients run the risk for hypoglycemia.

Also, because of the renal impairment, these patients do not produce glucose in the kidneys as a person without kidney disease or diabetes is doing. During the night, kidneys produce about 30% of new glucose. In renal impairment, you do not see that compensatory gluconeogenesis.

Any patient with type 2 diabetes and renal impairment will have more insulin circulating and less compensatory gluconeogenesis, and they run the risk for severe hypoglycemia. These are the reasons why it is so extremely difficult to achieve good glycemic control.

Consider the Newer Agents

What should we do? By their mode of action, we know that insulin, sulfonylureas, and glinides cause hypoglycemia. But the newer drugs—dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose co-transporter-2 (SGLT2) inhibitors, and glucagon-like peptide-1 (GLP-1) agonists—do not cause hypoglycemia. These medications should be utilized in these patients to achieve good glycemic control.

What can the newer medications achieve? The EMP-REG OUTCOMES trial[3] showed that by using the SGLT2 inhibitor empagliflozin in type 2 diabetes, you can prevent cardiovascular death dramatically, reduce hospitalization for heart failure, and reduce all-cause mortality.

This is absolutely wonderful news. EMP-REG OUTCOME also had prespecified renal outcomes and showed that renal events were prevented to some extent. That's good news if you use empagliflozin: Not only might you reduce cardiovascular death and hospitalization for heart failure, but you also might reduce renal events.

The LEADER trial,[4] employing the GLP-1 agonist liraglutide, showed exactly the same thing—that you can reduce CVD and the progression of kidney disease or the onset of new kidney disease. Wonderful news.

Hope for the Future

The caveat is that we do not yet have studies specifically on the effects of [the newer agents] in renal disease. EMP-REG OUTCOMES and LEADER tested whether these drugs [were associated with] CVD. Not only were they found not to cause CVD, they also reduced the risk for CVD. Although these trials had prespecified outcomes for renal events, these wonderful data cannot directly be used for an indication to use these new medications to prevent kidney disease.

I hope that in a few years I can sit here and tell you the good news, that these agents are indicated for prevention of kidney disease. We do not have data yet to support that as an indication for these medications.

On the other hand, in clinical practice, if you have a patient with established CVD and renal disease, consider using the newer medications because they do not cause hypoglycemia, seem to reduce CVD and cardiovascular death, and seem to have a positive effect on kidney disease.

Dear colleagues, one important take-home message is that diabetic kidney disease is common, the consequences are grim, and we have to take action. The good news is that newer medications are beneficial in terms of CVD and cardiovascular death, and I do hope that we will also show that they are beneficial in preventing diabetic kidney disease.


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