SGLT2-Inhibitors: Real World Stories, UTI, GTI & Frail Patients - Part II

CME INDIA Presentation based on a case by Dr. Meena Chhabra, MD, Diabetologist, New Delhi and CME INDIA Discussion.

Link to Part – I:

SGLT2-Inhibitors: Real World Stories, UTI, GTI & Frail Patients

Part-2:

SGLT2-Inhibitors: Real World Stories, UTI, GTI & Frail Patients - Part II

Dr. A. K. Das, Diabetologist, Muzaffarpur:

Doesn’t sglt2i put the elderly population at risk of UTIs and life threatening urosepsis while preventing HF? Opinions please.

Dr. Abhijit Chatterjee, DM Card., Kolkata:

It is still possible to get the benefits of SGLT2i without having the risk of urosepsis.
Get a routine urine test done every month.
Every good treatment is beset with problems.
For example, the antagonists of the renin angiotensin aldosterone system have well known side effects. But that doesn’t deter us from making good use of them.
We do routine blood tests to make sure that they are not causing any mischief.

Dr. Awadhesh K. Singh, DM Endo., Kolkata:

Answer: No! It doesn’t increase UTI at any age and not particular in elderly – as it is unfortunately perceived by many. Yes, GTI is increased in all age but more commonly in reproductive age groups in both sex!

Dr. Raju Sharma, Sr. Physician, Jamshedpur:

Doubt if a routine monthly test will benefit.

Dr. Ambrish Mithal, DM Endo., Delhi:

I don’t quite agree. Either we put aside clinical observations completely. Even if it does not numerically increase the risk (of which I am not totally convinced) it definitely makes UTI harder to treat.
Clinical trials and real-world differences are always there.
See the GI side effects of GLP1 in clinical studies and in the real world. Is there a difference?
See the data on Alendronate and upper GI side effects in the FIT study. Compare with real life.
Being an Elderly woman is NOT a contraindication to SGLT2 I. But if someone has history or recent or recurrent UTI, I would not use it. Most Elderly ladies tolerate it well. But it has to be explained to the patient to report in case of any symptoms. At least that’s my practice.

Dr. N. K. Singh, Dhanbad:

Real world scenario really needs more dedicated studies, I think.
But it is something exciting that Frail patient do tolerate it well.
And fear of volume depletion is also very very remote.

Dr. Ambrish Mithal, DM Endo., Delhi:

The kind of population that some of us in large multispecialty hospitals see is very prone to all kinds of complications.
Of course, they do.
But we cannot dismiss clinical observations.
Where was the doubt about their efficacy in the frail?
I recently saw a 47 kg person with BP 100/60 losing weight on SGLT2 but physician insisting that it be continued.
It’s like not being worried about weight gain with pioglitazone and telling the patient it is all good fat. No problem. Continue to gain weight. It’s good for you.

Dr. Gaurabh Gupta, New Delhi:

This is the middle path right balance between EBM (Evidence based medicine) and clinical experience.
Which needs open mind and not obsession for one or the other.
Individual observations may differ based of patient population factors yet d approach is of prime importance.
Don’t give up clinical observation in era of EBM.

Dr. Awadhesh K. Singh, DM Endo., Kolkata:

Sorry – don’t agree! Clinical observations are anecdote until compiled and statistically calculated truthfully.

Dr. Ambrish Mithal, DM Endo., Delhi:

“Adverse Effect Profile and Effectiveness of Sodium Glucose Co-transporter 2 Inhibitors (SGLT2i) – A Prospective Real-world Setting Study – PubMed” https://pubmed.ncbi.nlm.nih.gov/31016153/
This is not a quality study just data compilation but gives us some idea.
Yes, it is. Everything has to be proven by evidence.
But pursuit of evidence arises from clinical observation.
What percentage of your patients tolerate 1.8 Victoza?

Dr. Vinay Dhandhania, Diabetologist, Ranchi:

10%.

Dr. Awadhesh K. Singh, DM Endo., Kolkata:

Just to share a unique fact: In EMPA-REG outcome trial UTI was less in EMPA arm vs PBO.
Numerically less I meant.

Second Trial: EMPEROR-REDUCED-Empa vs PBO.S/E higher in PBO vs Empa

Dr. Arbind Kr. Arya, Jamshedpur:

I too had to stop Sglt2i in quite a good no. Of my patients due to recurrent UTI, Phimosis, drastic weight loss etc.
Individualise approach & proper selection of patients, significant weight loss, making patients uncomfortable, cannot be ignored.

Dr. Awadhesh K. Singh, DM Endo., Kolkata:

We all have stopped – Debate is not GTI – debate is about UTI.

UTIs in type 2 diabetes patients receiving SGLT2 inhibitors versus control in randomized controlled trials.No increased UTI with SGLT2i vs Control, Meta-analysis of 77 studies.(Ref-1)
Jiali Liu et al
- In summary, the current RCT evidence showed that, SGLT2 inhibitors increase the risk of genital infections, and the effects may differ among SGLT2 inhibitors and trials with different follow up.
- The impact of SGLT2 inhibitors on the risk of UTIs remains uncertain; the upcoming major trials may provide important insights on this issue. When their results are available, an update meta-analysis is warranted. (2017)

Dr. Ambrish Mithal, DM Endo., Delhi:

I suppose, I am fully aware of the importance of clinical trials double blinded evidence-based medicine. I have taught a course on that. This group (CME INDIA) has a large number of physicians and it is important to be aware of what we are seeing in our clinics. About 90% of my type 2 DMs are on SGLT2 I. People need to be aware of what others are seeing. I am not making any recommendations or guidelines. Just sharing my experience.
There was a time when my patients used to travel to London and come back to tell me how come you didn’t put me on Actos? Why do you use old drugs like Amaryl? These days everyone is crazy about Ozempic. Time is a great teacher and one has to be alert and aware about every molecule. Let us see.
At least 90% have taken the drugs at some point or the other. In my experience discontinuation rates are not low. Others may have different experience.

Dr. Awadhesh K. Singh, DM Endo., Kolkata:

S/E are always more frequently observed in real world setting vs-controlled environment of RCT for obvious reasons. There is no question about that but my limited point is no data yet hinted that SGLT2i has too much increased frequency of UTI. There were 5 head-to-head studies of SGLT2i vs Gliptins and 4 studies vs SU – and there was no increase in UTI between SGLT2i vs Gliptins or SUs!
Please see another paper a real-world study by John Mathew where they demonstrated no increased S/E with Cana vs other drugs in hot climates! 😊
Mathew John paper (1):

Efficacy and safety of canagliflozin were evaluated in patients with T2DM living in hot climates using pooled data from placebo-controlled studies and data from an active–controlled study.

Canagliflozin 100 and 300 mg improved glycaemic control and lowered body weight and blood pressure in patients living in hot climates.

Canagliflozin was generally well tolerated in patients living in hot climates, with low incidences of volume depletion–related AEs.

Dr. Ambrish Mithal, DM Endo., Delhi:

Actually, I cannot make a firm comment about “frequency” of UTI without data. Because that requires a well-planned study with a large number of subjects, control arm etc. But yes, several people with severe or recurrent UTI benefit greatly from discontinuation of SGLT2
We need to do a systematic honest RW study, not company sponsored.

Dr. Manoj Chawla, Diabetologist, Mumbai:

I personally feel that incidence is higher than reported in RCTs (Also a lot more asymptomatic bacteriuria for patients using Sglt2i not requiring treatment usually). Also, if a drug increases patient distress- whether through UTI, GUI, Weight loss (Many patients don’t like that too) or just not feeling well after a particular drug, irrespective of the published evidence, you may have to change the treatment regimen. We are treating the patient, not the disease.

Dr. Awadhesh K. Singh, DM Endo., Kolkata:

Contrarily, I treat the disease of patients not the symptoms of the patients.
The saddest part of this story is – while the whole world had agreed and kept faith in SGLT2i as a first-line drug – here we are trying to know the GTI/UTI issue of SGLT2i after a nearly decade of use!!!

Dr. Manoj Chawla, Mumbai:

The sad part is that such a wonderful drug with so much documented benefit can’t be tolerated by a section of patients but that is the sad reality.

Dr. Shashank Joshi, DM Endo., Mumbai:

I agree with you, India needs a robust public and private sector pharmacovigilance for sure. Every drug which has effect has adverse events. Clearly, we have both in real world and RCT tended to report a minuscule fraction of what we need. There is a need for multicentric reportage of this so that we know the truth.
In fact, it’s only in last decade we have started collecting some prospective data and reporting it this needs to be strengthened and appreciated. Safety is as important as all other outcomes if not more.

Dr. Ambrish Mithal, DM Endo., Delhi:

I think SGLT2 I have taken off in a big way in India. I see nothing sad about their usage here. After prices have come down, they are part of most prescriptions. But we should- rather we MUST – discuss clinical use and experience in a forum like this.
We are still discussing side effects of pioglitazone (As an example).
So, it’s good to share experiences. Not everything is a recommendation or guideline.

Dr. Arvind Gupta, Jaipur:

Very interesting observations by the legends. Learned so much.

Dr. Vinod Mittal, Diabetologist, Delhi:

Agree completely. I think proper education and appropriate selection of the patient is very important.
In my clinical practice, I have hardly seen any UTI, yes GTI is there but again depends on how much time we spend with the patient in education regarding adverse effects.

Dr. Santosh Malpani, Diabetologist, Nanded:

As SGLT2i are prescribed, SU or insulin dose is usually reduced for fear of hypo. Which can result in increased glycemia which itself can be a factor for balanitis.
UTI assessment should be done in controlled diabetes on SGLT2i.

CME INDIA Learning Points

People with diabetes are at increased risk of genitourinary infections.
Vaginitis is twice as likely among women with diabetes than those without and balanitis is three times as likely in men with diabetes compared with those without.
The incidence of genital infection is higher among younger than older adults and the increased risk in people with diabetes is correspondingly greater.
The bacteriuria associated with glycosuria contribute to the higher risk of genitourinary infection in people with diabetes.
Increased adherence of Escherichia coli to uroepithelial cells and increased virulence of Candida albicans in individuals with suboptimal glycaemic control; and immune dysfunction associated with hyperglycaemia contribute to the higher risk of genitourinary infection in people with diabetes.
SGLT2 inhibitors add to the problem. UTIs associated with SGLT2s are described as mainly mild to moderate in intensity. They usually respond to standard treatment and are ‘rarely a cause of discontinuation.
Genital infections during treatment with SGLT2 inhibitors – mainly mycotic balanitis and vulvovaginitis – are significantly more common than with placebo.
GTIs are five times more likely than with other antidiabetic agents.
The overall incidence of genital infections with SGLT2 inhibitor therapy varies in different studies. (Usually 4–6 per cent compared with about one per cent with placebo and, more common among women (approximately 7–11 per cent) than men. Genitourinary tract infection was found in 20.6% cases by an Indian study. (3)
The risk of genital infection is increased in women with previous episodes and in uncircumcised men.
If already on SGLT2i, presence of urinary ketone is not a contraindication to use SGLT2i. Ketonuria on SGLT2i without Ketonemia is very common.
In 2022, when concept of diabetes treatment has totally changed from gluco-centric to cardio-renal-metabolic-centric and encouraging data for primary prevention with SGLT2-inhibitors is on the door, a judicious use of SGLT2-inhibitors is the need of hour. Many fears like Acute kidney injury, hypovolemia and frailty issues are now in backyard. We do encounter UTI and GTI issues, but again these can be easily handled. If needed, stopping temporarily and restarting at appropriate juncture with proper hygiene related information is the answer.

References:

Jiali Liu, Ling Li, Sheyu Li , Pengli Jia, Ke Deng, Wenwen Chen& Xin Sun.Effects of SGLT2 inhibitors on UTIs and genital infections in type 2 diabetes mellitus: a systematic review and meta-analysis Scientific Reports | 7: 2824 | DOI:10.1038/s41598-017-02733-w
John, M., Cerdas, S., Violante, R., Deerochanawong, C., Hassanein, M., Slee, A., Canovatchel, W. and Hamilton, G. (2016), Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus living in hot climates. Int J Clin Pract, 70: 775-785. https://doi.org/10.1111/ijcp.12868
Gill HK, Kaur P, Mahendru S, Mithal A. Adverse Effect Profile and Effectiveness of Sodium Glucose Co-transporter 2 Inhibitors (SGLT2i) – A Prospective Real-world Setting Study. Indian J Endocrinol Metab. 2019 Jan-Feb;23(1):50-55. doi: 10.4103/ijem.IJEM_566_18. PMID: 31016153; PMCID: PMC6446693.
Lin YH, Lin CH, Huang YY, Tai AS, Fu SC, Chen ST, Lin SH. Risk factors of first and recurrent genitourinary tract infection in patients with type 2 diabetes treated with SGLT2 inhibitors: A retrospective cohort study. Diabetes Res Clin Pract. 2022 Apr;186:109816. doi: 10.1016/j.diabres.2022.109816. Epub 2022 Mar 2. PMID: 35247527.
Geerlings S, et al. Genital and urinary tract infections in diabetes: impact of pharmacologically-induced glucosuria. Diabetes Res Clin Pract 2014;103:373–81
Vasilakou D, et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med 2013;159:262–74