Sequential or Simultaneous Therapy in CKD: Which Approach Is Best?
Sequential or Simultaneous Therapy in CKD: Which Approach Is Best?
Article by Nancy A. Melville
Medscape
Preventing the substantial kidney and cardiovascular risks associated with diabetes and chronic kidney disease (CKD) increasingly required combinations of highly effective therapies. However, questions remained about whether treatment should begin with a sequential, stepwise approach or with an all-at-once simultaneous strategy.
During a debate at the American Diabetes Association (ADA) 2026 Scientific Sessions, experts outlined the pros and cons of each strategy but ultimately agreed that combination therapy was essential and should be dictated based on individual needs.
“Combination therapy in this population of people with diabetes and chronic kidney disease is the expectation,” stated Ian de Boer, MD, MS, director of the Kidney Research Institute, Division of Nephrology at the University of Washington in Seattle.
“We should be using combinations of lifestyle and pharmacotherapies in all of our patients, and we should do it in a way that’s personalized and iterative, so that we continually reevaluate, update, and accelerate it.”
The stakes are high because diabetes and CKD carry a multitude of risks, including stroke, heart failure, kidney failure, and death.
The good news, the speakers noted, is that an expanding array of therapies can address these risks through distinct mechanisms, potentially providing benefits beyond those achieved with any single agent.
The Case for Sequential Therapy: Choices A-Plenty, but Needs Are Nuanced
Key treatment options include GLP-1 receptor agonists (GLP-1 RAs), SGLT2 inhibitors, nonsteroidal mineralocorticoid receptor antagonists (ns-MRAs), renin-angiotensin system blockers, and statins.
However, “not every patient needs every tool,” de Boer said in arguing for a sequential therapy approach.
“This is not heart failure with reduced ejection fraction, where there are four pillars that all patients need,” he said. “It’s more nuanced in this population.”
“Some patients may need one, some need two, some need three, and the combinations may be different,” he added.
Eligibility criteria for individual drugs could depend on factors such as albuminuria, estimated glomerular filtration rates (eGFRs), and comorbidities. Responses could also vary among patients and change over time in the disease course.
When multiple drugs are administered simultaneously, clinicians could miss opportunities to determine how well a patient is responding to each medication, de Boer noted.
For instance, “a patient may have indications for drugs X and Y, but if you start them on drug X, there could be beneficial effects such that drug Y is in fact not needed,” he explained, adding that the reverse could also be true.
Identifying Adverse Events
The same concern applies to adverse events. When patients develop side effects after beginning several therapies at once, the source of a problem can be difficult to identify.
Acute reductions in eGFR are among the most common adverse effects associated with several of these medications. Such declines could generally be considered part of the hemodynamic process and as an acceptable risk in light of the drugs’ long-term benefits, de Boer explained.
However, “that only goes so far, and even nephrologists get scared when eGFR drops too much,” he cautioned.
In the recent CONFIDENCE trial, patients treated with a combination of the ns-MRA drug finerenone and the SGLT2 inhibitor empagliflozin experienced notably greater reductions in eGFR compared with either drug alone, de Boer added.
Treatment Burden and Adherence
De Boer also emphasized that adherence was critical to ensuring the sustained benefits of combination therapy.
He cited recent research showing higher risks for stroke, myocardial infarction, hospitalization, and death among patients with stage 3-4 CKD who discontinued treatment with SGLT2 inhibitors or GLP-1 RAs compared with those who did not discontinue treatment.
However, initiating several therapies at the same time could add to the treatment burden and potentially reduce adherence, he argued.
“ It is complicated for patients to start new drugs, and the more we burden them with at one time, the more it will potentially be difficult for them to follow through,” de Boer said.
The Case for a Simultaneous Strategy
Arguing for simultaneous initiation, Amy Mottl, MD, MPH, of The University of North Carolina in Chapel Hill, invoked the concept of metabolic memory.
Evidence from the DCCT/EDIC trial in type 1 diabetes underscores that the earlier patients receive intensified or optimized treatment, the greater and more durable the benefits for cardiovascular and mortality outcomes, she said.
Although A1c levels eventually converged after both groups received intensive insulin therapy, patients initially randomized to conventional therapy for a mean of approximately 6.5 years experienced higher rates of the development and progression of complications, including cardiovascular and kidney events, than who received intensified therapy from the outset.
Based on those and other findings, “I would argue that every day, week, and month that we have people with their risk factors controlled and on [guideline-directed medical therapy] matters,” Mottl said.
Adherence Greater With Simultaneous Treatment?
Although Mottl agreed that adherence is essential, she argued that evidence suggests it is actually easier to obtain with simultaneous therapy than with sequential treatment.
She cited the VERIFY trial, in which patients with CKD randomized to a sequential treatment regimen had a 62% chance of treatment failure by the end of the study, compared with only 44% among those who began combination therapy simultaneously.
Mottl also pointed to the recent TRIPLE-AXEL study, in which drug-naive patients with type 2 diabetes were randomized to either a triple combination therapy of once-daily metformin, dapagliflozin, and saxagliptin or a conventional stepwise add-on therapy initiated with metformin, followed by glimepiride and sitagliptin.
In that study, 39% of patients in the simultaneous therapy group achieved an A1c level below 6.5% without hypoglycemia, weight gain, or drug discontinuation compared with 17.1% in the stepwise group.
The collective evidence underscores that “simultaneous initiation of therapy is very well tolerated by the vast majority of people,” Mottl said.
She added that other studies had also shown benefits from simultaneous initiation in heart failure with reduced ejection fraction and in the primary prevention of atherosclerotic cardiovascular disease.
Patient Preferences
Patient preferences also favor simultaneous therapy in some cases, Mottl said. With sequential therapy, the treatment process can include dose titrations, regular laboratory testing, and follow-up visits every few months.
“It can be this process of test, prescribe, test, prescribe,” she said. “In my experience, a lot of patients really get frustrated.”
Patients often ask, “Why do you have to keep checking it? Is this bad for me? Is this a concern for me?” she said.
Clinicians should therefore educate and support patients, she added, emphasizing that the medications are safe and that earlier treatment could improve outcomes.
“Time is definitely nephrons,” Mottl said.
Because of the inconvenience associated with repeated treatment changes, many patients may prefer starting on multiple drugs from the outset, she suggested.
“I don’t have data for this, but I would argue that patients may be more willing to start on multiple drugs at once,” Mottl added. “Certainly not everybody, but many will.”
Such preferences further boost the argument for developing polypills to reduce treatment burden, Mottl added.
“My [impression is] that patients don’t really care how many medicines they take — they care about how many pills they take.”
Agreement That Swift Action Is Essential
In response, de Boer underscored that both sides agreed on most of the underlying principles.
“We don’t want to wait to improve outcomes,” he said. “We want to avoid inertia and do things quickly.”
He also agreed that “simultaneous initiation of multiple drugs [should be used] in circumstances that are appropriate, and that includes when they have different adverse-event profiles.”
Ultimately, “the main thing I do in the clinic right now is provide education and try to get patients to understand how we diagnose and stage chronic kidney disease, what the goals of therapy are, and what the advantages and disadvantages of our medications are,” he said.
De Boer reported consulting and/or other relationships with Boehringer Ingelheim International GmbH, Novo Nordisk, GlaxoSmithKline, Eli Lilly, Dexcom, and Roche. Mottl reported consulting and/or other relationships with AstraZeneca, Bayer AG, Otsuka America Pharmaceutical, and Vera Therapeutics.
