Semaglutide in Type 2 Diabetes and CKD: Katherine R. Tuttle, MD, FASN

Semaglutide (Ozempic; Novo Nordisk) is the preferred glucagon-like peptide 1 (GLP-1) agent for people with type 2 diabetes and chronic kidney disease (CKD) when the goal is treating the kidney disease itself, according to Katherine R. Tuttle, MD, FASN, executive director for research at Providence Health Care and professor of medicine at the University of Washington.

In an interview with The American Journal of Managed Care^®, Tuttle discussed the evidence behind semaglutide in this population, the first-line therapies recommended by guidelines, and how additional drugs are layered on over time.

Why Semaglutide Is Preferred in Diabetes-Related CKD

Tuttle pointed to the FLOW (NCT03819153) trial as the foundation of the evidence. “The FLOW trial was the one and only dedicated kidney outcome trial that showed clear benefit on major adverse kidney outcomes,” Tuttle said. Those outcomes included a loss of 50% or more of glomerular filtration rate (GFR), kidney failure, and death due to kidney or cardiovascular causes.

The risk reduction was large, Tuttle said, with a relative risk reduction of 24% on top of a high absolute risk rate of 15% in the placebo group. Semaglutide is also the only GLP-1 agent with a labeled indication for people with type 2 diabetes and CKD, covering preservation of kidney function and prevention of kidney failure and death.

“I really do think in that population it is the preferred agent,” Tuttle said.

Tuttle noted that patients already taking another GLP-1 agent to treat hyperglycemia, manage weight, or address atherosclerotic cardiovascular disease (ASCVD) do not need to change course. “That’s perfectly fine,” Tuttle said. Secondary outcomes from trials of the other agents align with FLOW, Tuttle added, but for treating CKD specifically, “we have to go by the labeled indication, which would be exclusively for semaglutide at this point.”

What Guidelines Recommend as First-Line Therapy

For now, Tuttle said, clinicians should look to clinical practice guidelines in nephrology, primarily from Kidney Disease: Improving Global Outcomes (KDIGO). These align with guidance from the American Diabetes Association and with a joint guideline on cardiovascular-kidney-metabolic syndrome.

Across those guidelines, a renin-angiotensin system inhibitor, in the form of either an ACE inhibitor or an angiotensin receptor blocker but not both, plus a sodium-glucose cotransporter 2 (SGLT2) inhibitor, is first-line therapy, Tuttle said. The recommendation rests on “an abundance of clinical trial evidence” showing benefit from that combination in reducing major kidney, cardiovascular, and mortality risks, particularly for the SGLT2 inhibitor class.

When albuminuria persists, the guidelines recommend adding another therapy from a kidney risk standpoint. That is where clinical decision-making comes in, Tuttle said, because combination trials are lacking. “We have not done trials with combinations yet, or they haven’t reported out yet,” Tuttle said. In KDIGO, these recommendations are called practice points, where expert opinion helps guide clinicians in the absence of trial evidence.

How Added Therapies Are Sequenced Over Time

For a person with concomitant heart failure and persistent albuminuria, finerenone could be a reasonable next choice. For a person with CKD and type 2 diabetes who needs additional weight loss or glycemic control, or who has ASCVD, a GLP-1 agent may be the better pick.

Tuttle recommended continual reassessment of albuminuria and GFR, along with conventional risk factors such as blood pressure, lipids, and A_1C. If albuminuria persists or other risk factors remain uncontrolled, the next drug is added. A patient who started finerenone could then receive a GLP-1 agent, and the reverse is also true.

“So we really now consider it four-pillared therapy that we tier and add sequentially based on severity of risk driving intensity of treatment,” Tuttle said.