11:45 AM

466 - SGLT2i Side-Effects, Emotional Health Screening, “The Doctor”

Take 3 – Practical Practice Pointers©

Question From a Colleague

1) What Side Effects of SGLT2i Medications Should We Worry About?


Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are rapidly changing diabetes and heart failure management algorithms. As these medications are prescribed more and more, we need a solid grounding in the side effects of these medications. A colleague and I were discussing that it is hard to know which of the side effects to worry about.

A search for systematic reviews of adverse events from SGLT2i medications resulted in 34 systematic reviews/meta-analyses…published in 2022 alone! I chose one that looked at long term side effects, one that examined the risk of diabetic ketoacidosis, and one that rigorously compared SGLT2is with other second-line diabetes agents.

Each review was performed using high quality systematic review methods. We will only review the adverse events data here as we have covered recommendations for SGLT2i medications most recently in Take 3 #435.

A review looking at longer-term risks of SGLT2i medications vs. placebo or other diabetes medications found 39 trials and 112K patients who were on the medications for at least 52 weeks. The evidence overall was considered high quality, despite a high risk of attrition bias (losing patients to follow up).  The risks of adverse events with SGLT2i medications were:

·         Genital yeast infections, relative risk (RR) 4.00 (95% confidence interval (CI) 3.1 to 5.15) vs. placebo

·         Genital yeast infections, RR 5.38 (90% CI 3.86 to 7.49) vs. other hypoglycemics

·         Diabetic Ketoacidosis (DKA), RR 2.37 (95% CI 1.39 to 4.02) vs. placebo

·         Urinary Tract Infection (UTI) – no difference

·         Fractures – no difference.

Risk of DKA was examined in a systematic review that included 7 RCTs (with >42K patients) and 5 cohort studies (with around 320K patients) – all of which were considered to have a low risk of bias.  The risk of DKA with SGLT2i was:

·         In RCTs: 0.6 to 2.2 events per 1,000 person years(p-y) with SGLT2i vs 0.1 to 0.3 per 1,000 p-y with control (RR 2.46, 95% CI 1.16 to 5.21)

·         The rate was a little higher in each group in the cohort studies.

Finally, a systematic review and network meta-analysis examined the effects of all second-line diabetes agents vs. each other, placebo, and usual care. The review included 38 studies with 227,497 patients. Most included studies were of low risk of bias.

In the basic meta-analysis, the risks of adverse events with SGLT2i medications vs. usual care were:

·         Risk of amputation (RR 1.21, 95% CI 1.01 to 1.46, number needed to harm (NNH) 200)

·         Genital infection (RR 3.67, 95% CI 3.15 to 4.28, NNH 22)

·         Volume depletion (RR 1.16, 95% CI 1.06 to 1.27, NNH 66)

·         Ketoacidosis (RR 2.06, 95% CI 1.34 to 3.19, NNH 250)

·         However, there was an overall lower risk of serious adverse events (RR 0.92, 95% CI 0.89 to 0.96, NNH 24)

The network meta-analysis performed on this data found very similar relative risks.

John’s Comments:

 Remember that we need absolute risks instead of just relative risks to understand how many of these events we will see in practice. For the first review, we must dig a little to find the rate of genital yeast infections in the control groups (it varied between 0.5 and 5% in the studies) to know how much of a difference the SGLT2i medications cause (E.g., a RR of 4.0 times the baseline risk of 0.5 to 5% means a risk of 2 to 20% over the 52 weeks or more of follow up).

The authors of the last review give us numbers needed to harm, which help, and these numbers apply to the average of 3.2 years of follow up in the studies.The risk of amputation in this review is concerning, but should be weighed against the cardiovascular and kidney benefits.

The second review reveals that the expected rate of DKA is somewhere between 6 and 50 cases per 10000 patients per year – a low rate to be sure, but worth watching for, as studies often see a lower adverse event rate than is seen in practice. Previous systematic reviews have occasionally shown other adverse events, but these are more recent and should comprise better data.


·         Alexander JT, Staab EM, Wan W, et al. Longer-term Benefits and Risks of Sodium-Glucose Cotransporter-2 Inhibitors in Type 2 Diabetes: a Systematic Review and Meta-analysis. J GEN INTERN MED. 2022;37(2):439-448. Link

·         Colacci M, Fralick J, Odutayo A, Fralick M. Sodium-Glucose Cotransporter-2 Inhibitors and Risk of Diabetic Ketoacidosis Among Adults With Type 2 Diabetes: A Systematic Review and Meta-Analysis. Canadian Journal of Diabetes. 2022;46(1):10-15.e2. Link

·         Sim R, Chong CW, Loganadan NK, et al. Comparative effectiveness of cardiovascular, renal and safety outcomes of second‐line antidiabetic drugs use in people with type 2 diabetes: A systematic review and network meta‐analysis of randomised controlled trials. Diabet Med. 2022;39(3). Link


A Twofer of DRAFT Recommendations From the USPSTF

2)  Screening for Anxiety, Depression, and Suicide Risk in Adults

Major depressive disorder (MDD) is a common mental/emotional health disorder that if left untreated, can be associated with an increased risk of cardiovascular events, exacerbation of comorbid conditions, or increased mortality. In 2019, 8% of adults experienced at least one major depressive episode; 5.3% of adults experienced a major depressive episode with severe impairment.  Suicide is the 10th-leading cause of death in adults (45,390 deaths; 2017 data) and risk is directly linked to emotional health.

Anxiety disorders including generalized anxiety disorder (GAD), social anxiety disorder, panic disorder, separation anxiety disorder, phobias, selective mutism, and anxiety not otherwise specified have a past-year prevalence of 3%.  These disorders are often unrecognized in primary care settings and can result in years-long delays in treatment.   Comorbid major depression is reported in 39 percent of individuals with current GAD and 62 percent of individuals with lifetime GAD.

The USPSTF recently published two draft recommendations regarding the screening of adults for emotional health concerns.  For suicide risk and MDD, these are updates of previous recommendations from 2014 (suicide) and 2016 (MDD).  This marks their first recommendation specifically for anxiety. 

Recommendations include:

·         For adults < 64, screen for anxiety (B recommendation)

·         For adults > 65, the current evidence is insufficient to assess the balance of benefits and harms of screening for anxiety (I recommendation)

·         For all adults, screen for depression (B recommendation)

·         For all adults, the current evidence is insufficient to assess the balance of benefits and harms of screening for suicide risk (I recommendation)

The Task Force notes there is little evidence regarding the optimal interval for screening for depression or anxiety.  In the absence of data, a pragmatic approach might include using clinical judgment in consideration of risk factors, comorbid conditions, and life events to determine if additional screening of patients at increased risk is warranted.

It should be noted that the Task Force indicates there is no direct evidence on benefits of screening for anxiety in primary care or comparable settings on health outcomes such as quality of life, functioning, or remission in screened vs. unscreened adults.

Mark’s Comments:

Certainly, with the prevalence of mental/emotional health concerns increasing during COVID and now with the additive impact of the economic downturn, this guidance is very timely.  However, as noted above, direct evidence regarding the benefits of screening for anxiety does not presently exist, so the Task Force instead looked to indirect evidence to make their level B recommendation.  This could potentially result in overprescribing for this condition.  One positive that emerged from the pandemic is the greater availability of telehealth for these conditions, so there hope for increased access to psychotherapy as a greater option in conjunction with or instead of medication.


USPSTF.  Screening for Anxiety in Adults.  Draft Recommendation Statement.  September 20, 2022.  Link

USPSTF.  Screening for Depression and Suicide Risk in Adults.  Draft Recommendation Statement.  September 20, 2022.  Link

From PeerARTxMed ( www.PeerRxMed.org )

3)  How Can “The Doctor” from the 1800’s Speak to Us Today?

“Every now and then one paints a picture that seems to have opened a door and serves as a stepping stone to other things.”  ― Pablo Picasso

There are certain classic paintings which have captured some important “deeper meaning” for our work in the medical profession and withstood the test of time.  One such image is the painting titled “The Doctor,” created by Sir Luke Fildes in 1891.  

The painting was commissioned in 1890 with the subject left to the artist’s discretion.  Per Fildes’ son and biographer L.V. Fildes, the artist chose to recall a personal tragedy of his own, when in 1877 his first son, Philip, had died in their home at the age of one from typhoid.  He shares, “The character and bearing of their doctor throughout the time of their anxiety made a deep impression on my parents.  Dr. Murray became a symbol of professional devotion which would one day inspire the painting ….”

Likely you have viewed this picture many times before, and perhaps have even formed an opinion or a certain set of emotions around it.   Take a few moments to examine it with “fresh eyes,” paying particular attention to any specific details that you are drawn to.  As you do, consider these questions: 

·         What do you notice?  What emotions does it stir for you?     

·         As you look, are you reminded of any particular patients or circumstances? 

·         How does this image capture some important values of our healing profession?

·         Are there parts of it that you find yourself pushing against or feeling dissonance?

·         What might a painting with a similar theme look like today?


Click here for a larger version: "The Doctor"

While it would be easy to dismiss this painting as a product of a bygone era, perhaps there are ways it can still speak to us today.  If “the Doctor” could speak with you, what do you think he might say?  What would you want to say to him?

This week, consider sharing some of your impressions with your PeerRxMed partner.  Perhaps this could be a catalyst for discussion at your upcoming PRx90 (“up to 90 minutes every 90 days”) meeting time.   Afterall, we’ve inherited “The Doctor” as part of our collective professional history.  Let’s make that inheritance a dialogue that we can continue to learn from  ….


Mark and John

Carilion Clinic Department of Family and Community Medicine

Feel free to forward Take 3 to your colleagues. Glad to add them to the distribution list.

Email: mhgreenawald@carilionclinic.org