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Managing Cardio–Renal–Metabolic Disease With SGLT2 Inhibitors
Do It Better: Special Considerations for Managing Cardio–Renal–Metabolic Disease With SGLT2 Inhibitors

Released: December 01, 2025

Jennifer B. Green
Jennifer B. Green, MD
Michelle Kittleson
Michelle Kittleson, MD, PhD
Jay H. Shubrook
Jay H. Shubrook, DO, FACOFP, FAAFP
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Key Takeaways
  • HCPs should be clear in their prescribing instructions, stating for which disease or condition an SGLT2 inhibitor is being used.
  • In patients with HFpEF who develop hypotension, HCPs should consider an alternative diagnosis like amyloidosis; in turn, therapy can be spaced out better to help patients with HFrEF and hypotension tolerate SGLT2 inhibitors.
  • HCPs may consider using GLP-1 receptor agonists in patients with peripheral arterial disease (PAD) and active foot wounds, but an SGLT2 inhibitor may be used in those with PAD and a history of amputation to address other adverse outcomes.

In this commentary, Jay H. Shubrook, DO, FACOFP, FAAFP; Michelle Kittleson, MD, PhD; and Jennifer B. Green, MD, answer questions posed by healthcare professionals (HCPs) during a live symposium titled “Do It Better: Effective Strategies for Implementing Evidence-Based, Patient-Centered Care in Cardio–Renal–Metabolic Disease” at FMX 2025. Learn about specific considerations for using SGLT2 inhibitors in treatment plans for patients with cardio–renal–metabolic disease, such as managing hypotension among those with heart failure with preserved ejection fraction (HFpEF) and addressing amputation risk among those with pulmonary arterial disease (PAD). 

What strategies do you employ to improve access to SGLT2 inhibitors?

Jay H. Shubrook, DO, FACOFP, FAAFP:
Access to therapy is a big barrier for patients and one that I think is important for HCPs to address. There are a couple of strategies that I employ to help patients access their therapy. In California, we write the “SIG” (or directions for patients) regarding the intended use of the prescribed agent. If writing a prescription for an SGLT2 inhibitor, I write in the SIG whether its use is for heart failure, diabetes, chronic kidney disease, or another condition. In doing so, it becomes easier to do the prior authorization, and much more likely patients will receive approval. Therefore, I suggest all HCPs be clear in their SIG so everybody will know for what disease or condition you are prescribing the therapy. Just like with GLP-1 receptor agonists, you have to write the indication in the SIG so the health insurance company knows what the purpose is.

How do you manage hypotension in patients with HFpEF?

Michelle Kittleson, MD, PhD:
I think of hypotension in 2 different ways. If a patient with HFpEF develops hypotension after adding an SGLT2 inhibitor to their treatment plan, that is a huge red flag. Typically, these patients have hypertension that promotes their HFpEF. So, you must consider an alternative diagnosis. For example, patients who develop symptomatic orthostatic hypotension when they start these agents could have amyloidosis brewing underneath. Think about that. Something doesn’t fit if your patient with HFpEF becomes hypotensive and does not tolerate SGLT2 inhibitors.

For those with heart failure with reduced ejection fraction (HFrEF), symptomatic hypotension is important to recognize, emphasis on symptomatic. The trick is having patients with HFrEF and symptomatic hypotension take their treatment before bedtime to minimize side effects. That is, lisinopril 2.5 mg may be preferable if twice-daily ARNI causes symptoms and sustained metoprolol instead of twice-daily carvedilol as metoprolol succinate can be taken once a day at night. Mineralocorticoid receptor antagonists and SGLT2 inhibitors are unlikely to significantly drop one’s blood pressure, but HCPs can prescribe these in a way that can help patients tolerate them and space their treatment out. Remember, we do not care about the number; we care about the symptoms. So, I generally tell patients to not check blood pressure unless they feel lightheaded, and we respect symptomatic orthostatic hypotension because it can lead to injury.

Should SGLT2 inhibitors be avoided or used with caution in patients with PAD due to amputation risk?

Jennifer B. Green, MD:
There were a lot of questions from HCPs about amputations in patients with PAD. First, in all the cardiovascular outcomes trials that were discussed, patients with PAD were eligible and enrolled. These patients also are at high risk for stroke, myocardial infarction, and cardiovascular death, which is underappreciated.

With respect to the risk for amputation, certainly in the CANVAS trial, a disproportionate risk of lower extremity amputation was reported with the use of canagliflozin compared with placebo. That has not been seen again in subsequent trials. However, if I had a patient with an open foot wound, I would not start an SGLT2 inhibitor at that time because that patient is at high risk for amputation. I do not want to muddy the waters or have them think that they ended up having an amputation because of the SGLT2 inhibitor. Therefore, I might use a GLP-1 receptor agonist for risk reduction in that patient instead.

For those who had a foot ulcer in the past and have had an amputation, especially an amputation below the knee—which I see a lot in my patients—frankly, that problem is solved. I would definitely start an SGLT2 inhibitor in patients who have had an amputation. The key is to ensure that these patients have good foot care: they are inspecting their feet regularly, identifying problems early should they occur, and receiving appropriate treatment from a podiatrist or other foot care specialist to mitigate the risk of progressive ulceration and need for amputation. But patients with PAD are at high risk for all of the other adverse outcomes, and HCPs should not fail to treat or address that risk because they think patients might have an amputation. 

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How often do you prescribe SGLT2 inhibitors for your patients with cardio–renal–metabolic disease? You can get involved in the discussion by answering the poll or posting a comment below.

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