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Argirios Argiriou:
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What are the key side effects of SGLT2 inhibitors that we need to be aware of in primary care? During my 10-plus years of experience in prescribing SGLT2 inhibitors, the commonest side effects I've encountered are mycotic genital infections. Counseling about good personal hygiene is pivotal. If individuals do develop troublesome mycotic genital infections, they can be treated in the usual manner and tend not to have recurrence.

Initially, urinary tract infections were thought to be a challenge, but that hasn't been borne out in clinical studies or in my own clinical experience. However, if individuals do develop urinary tract infections, again, they can be treated in the usual manner and tend not to have recurrence.

We should also reinforce the importance of adequate hydration to prevent volume depletion. I usually recommend around 2-2.5 L of clear fluids daily, not including tea, coffee, or alcohol. Other osmotic symptoms, such as thirst, polyuria, lightheadedness, and fatigue, can also occur but usually dissipate with time.

An adverse effect of note is a rare association with diabetic ketoacidosis (DKA), with around 1 in 1000 or 1 in 10,000 at risk. However, the benefits do outweigh this risk. The challenge is that the DKA we sometimes see with SGLT2 inhibitor use is euglycemic DKA. Blood glucose levels are normal or near normal.

How do we make sense of this in primary care? We need to warn individuals of the signs and symptoms of DKA, which is quite challenging, as DKA presents very nonspecifically. However, I tell my patients that if you're significantly unwell, especially with a fever, you should get in touch for further assessment.

We need to assess the individuals, we should check blood glucose levels, and if we suspect DKA, we should test for blood ketones, even if blood glucose levels are normal or near normal, because of the possible euglycemic nature of the DKA. Importantly, there's no need to issue ketone testing strips to those on SGLT2 inhibitors, but we should have access to them in our respective clinical practices. (μεταξύ μας, πόσοι Έλληνες Ιατροί στην ΠΦΥ έχουν άμεση δυνατότητα μέτρησης των κετονών του αίματος ;  )

Thus, SGLT2 inhibitors should add to our ever-expanding list of sick-day guidance drugs — drugs to temporarily pause during any acute, potentially dehydrating illness. A useful mnemonic is SADMAN. We should counsel patients to temporarily pause the SADMAN drugs during any acute, dehydrating illness: S for SGLT2 inhibitor, A for ACE inhibitor, D for diuretic, M for metformin, A for ARB, and N for nonsteroidal. Importantly, we need to remind individuals to restart these drugs once they're eating and drinking normally and recovered from their illness.

Finally, there's a very rare association between SGLT2 inhibitor use and Fournier gangrene, or necrotizing fasciitis of the genitalia or perineum, which is challenging to quantify. I've never seen this with respect to SGLT2 inhibitors during my career to date. An important confounder is that type 2 diabetes itself is a risk factor for Fournier gangrene. Moreover, there was no significant imbalance seen in cases of Fournier gangrene in all major SGLT2 inhibitor trials to date.

How do we make sense of this in primary care? I've got to be honest: I don't explicitly mention Fournier gangrene, as I think this would present a huge barrier to starting or continuing therapy. However, I do reinforce the importance of good personal hygiene and advise individuals taking SGLT2 inhibitors to seek urgent medical attention if they experience any severe pain, tenderness, erythema, or swelling in the genital or perineal area, particularly if accompanied by a fever or malaise.

To finish with some resources you might find helpful, I've created several concise, patient-facing videos on YouTube and TikTok about SGLT2 inhibitors to help inform, educate, and counsel our patients about all aspects of their SGLT2 therapy, including benefits, side effects, and sick-day and driving guidance. You can find me @DrKevinFernando on YouTube and TikTok.

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