SGLT2 inhibitors and risk of genitourinary infections

The SGLT2 inhibitors dapagliflozin, canagliflozin and empagliflozin are now becoming established in the management of type 2 diabetes, but they are associated with an increased risk of genital and urinary tract infections, compounding the problem that people with diabetes are already at higher risk than the general population. This article examines the extent of these risks and how they may affect treatment adherence.

The first sodium-glucose co-transporter 2 (SGLT2) inhibitor, dapagliflozin, was introduced in the UK in 2012. Since then, dapagliflozin, canagliflozin and empagliflozin have become established in the management of type 2 diabetes and are now recommended as options for certain patients for first intensification (dual therapy) and second intensification (triple therapy), including in combination with insulin.1 They are also options as monotherapy (almost as a last resort) when metformin, a sulfonylurea, pioglitazone are unsuitable and if a dipeptidyl peptidase 4 (DPP-4) inhibitor (gliptin) would otherwise be prescribed.2

SGLT2 inhibitors are predominantly prescribed in primary care and the rate of increase in prescribing is matching that of the DPP-4 inhibitors at a similar phase of their life cycle (see Figure 1).3 Uptake is, however, currently relatively low: in 2015, GPs in England wrote 646,000 prescriptions for SGLT2 inhibitors out of a total of 35 million for “other antidiabetic drugs” (BNF category 6.1.2).4

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Figure 1. Prescribing volume of dipeptidylpeptidase (DPP-4) inhibitors and
sodium-glucose co-transporter 2 (SGLT2) inhibitors in primary care, England,
2007/8–2015/163

But that could change in light of evidence that the SGLT2 inhibitors may reduce mortality in patients with diabetes and cardiovascular disease. The recent EMPA-REG OUTCOME trial showed that, over a median follow-up of about three years, empagliflozin 10 or 25mg plus standard care significantly reduced the risk of the primary composite endpoint (cardiovascular death, myocardial infarction or nonfatal stroke) compared with placebo (10.5 vs 12.1 per cent; hazard ratio 0.86), as well as cardiovascular death (3.5–3.8 vs 5.9 per cent; hazard ratio 0.59–0.65) and all-cause mortality (5.6–5.8 vs 8.3 per cent; hazard ratio 0.67–0.70).5 Even aspiring to such a target would secure the future of SGLT2 inhibitors in clinical practice. Patients and GPs will therefore need to manage the most frequent adverse effects, notably genitourinary infections.

SGLT2 inhibition

SGLT2 is the major co-transporter for renal glucose reabsorption. Its inhibition by a gliflozin increases glucose excretion by 70–80g per day (and up to about 120g per day for canagliflozin 300mg daily). This is associated with an increase in urinary frequency due to the osmotic effect of glucose, and urine volume increases by around 400ml per day (about the same as the functional bladder volume in adults). These effects cause a fall in blood glucose and, secondary to a reduction in blood volume, a modest decrease in blood pressure.

Although direct comparisons are lacking, meta-analysis of clinical trials indicates there is little difference in efficacy between the SGLT2 inhibitors.6 Overall, the safety of SGLT2 inhibitors in clinical trials included in regulatory submissions was similar and the incidence of adverse events was comparable with placebo, with 2–6 per cent of patients stopping treatment as a result.7-9

Genitourinary infections and diabetes

People with diabetes are at increased risk of genitourinary infections. In a UK primary care population, the one-year incidence of urinary tract infection (UTI) was about 50 per cent greater among people with diabetes than among those without (46.9 vs 29.9 per 1000 person-years).10 Vaginitis is twice as likely among women with diabetes than those without (incidence 21.0 vs 10.3 per 1000 person-years; adjusted relative risk 1.81) and balanitis is three times as likely in men with diabetes compared with those without (incidence 8.4 vs 2.5 per 1000 person-years; adjusted relative risk 2.85).11 The incidence of genital infection is higher among younger than older adults and the increased risk in people with diabetes is correspondingly greater (see Table 1).12

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Table 1. Relative risk (95% CI) of vaginitis or balanitis according to age among people with type 2 diabetes compared with no diabetes (adjusted for index year and prior genital tract infection)12

Factors that contribute to the higher risk of genitourinary infection in people with diabetes include bacteriuria associated with glycosuria; 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.12 SGLT2 inhibitors add to the problem: in one phase 2 study, 12 per cent of 198 women with type 2 diabetes were positive for vaginal Candida spp. at baseline; after 12 weeks’ treatment with canagliflozin, 31 per cent of women who had been culture negative tested positive compared with 14 per cent of women who received placebo or the DPP-4 inhibitor sitagliptin and, of these, one-third to one-quarter were symptomatic.13

The impact of single episodes of urinary tract infection (UTI) or genital infection on quality of life has not been reported. Recurrent UTIs are associated with impaired quality of life, with measures demonstrating depression, anxiety and reduced social activity.14,15 Recurrent vulvovaginal candidiasis impairs quality of life across mental and physical health domains to an extent comparable with asthma or COPD and greater than headache/migraine.16,17

It is generally believed that the increased risk of genitourinary infections associated with SGLT2 inhibitors is secondary to glycosuria, presumably arising from residual urine in the lower urinary tract and on the genitalia. This is a class effect and, although direct comparisons are again lacking and data are sometimes difficult to compare,12 the risks appear to be similar for each agent.

Risk of urinary tract infections

SGLT2 inhibitors are associated with a small increase in the risk of UTI compared with placebo and most episodes are symptomatic.18 Reported figures for the incidence of UTIs in clinical trials vary but fall within the range 4–9 per cent, with a difference of 1.0–1.5 per cent above that reported with placebo.7-9 More women are affected than men; in phase 3 trials of canagliflozin, 88 per cent of UTI adverse effects were in women.18 The incidence is much higher among patients with a history of chronic or recurrent UTIs (27 per cent with empagliflozin, 24 per cent with placebo7). Data on whether recurrence is more frequent with SGLT2 inhibitors than with placebo are contradictory.8,18 Compared with other antidiabetic agents, SGLT2 inhibitors are associated with a 40 per cent higher risk of UTIs.19

UTIs associated with SGLT2s are described as mainly mild to moderate in intensity (see Table 2). They reportedly respond to standard treatment and are ‘rarely’ a cause of discontinuation.7-9 Severe events or events associated with hospital admission were reported in 0.1–0.4 per cent of patients in clinical trials; kidney infections and sepsis were ‘rare’. There were no differences in these outcomes between SGLT2 inhibitors and placebo.

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Table 2. Definitions of investigator-assessed intensity of adverse events used in clinical trials20

Risk of genital infections

Genital infections during treatment with SGLT2 inhibitors – mainly mycotic balanitis and vulvovaginitis – are significantly more common than with placebo7-9 and are five times more likely than with other antidiabetic agents.19 The overall incidence of genital infections with SGLT2 inhibitor therapy reported in clinical trials was 4–6 per cent compared with about one per cent with placebo but these events were more common among women (with rates of approximately 7–11 per cent) than men.

In a pooled population from canagliflozin clinical trials that included older patients and patients with renal impairment or high cardiovascular risk with a mean exposure to canagliflozin of 17 months, the incidence of genital infections was approximately 14–15 per cent with canagliflozin therapy vs 3 per cent with placebo in women and 7–9 per cent vs 1.6 per cent in men.20

It is usually said that most genital infections occur during early treatment but, as experience with canagliflozin shows, first episodes continue to be reported for many months (see Figure 2).20 Genital infections are described as mild to moderate in most cases, according to investigator assessment. The incidence of severe events or associated treatment discontinuation was 0.7–1.0 per cent among women and 0.5 per cent among men, though these figures are based on low sample sizes. The risk of genital infection is increased in women with previous episodes and in uncircumcised men.20 About 2 per cent of all women experienced recurrent infection with canagliflozin treatment compared with 0.3 per cent with placebo; of those who experienced an infection while taking canagliflozin, 18 per cent had two episodes and 3 per cent had three or more.20 In women, symptoms lasted for six to seven days after treatment for the infection was initiated. The majority of infections were treated with standard therapy, including self-treatment, while continuing to take an SGLT2 inhibitor. This involved topical therapy in about a third, oral therapy in 40 per cent and oral and topical therapy in a fifth of patients.20

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Figure 2. Time to first reported genital mycotic infection in (a) women and (b) men during treatment with the SGLT2 inhibitor canagliflozin compared with untreated subjects (note different y-axes)20

Adherence

Whether these adverse effects reduce adherence to SGLT2 inhibitors has not been reported, though it is hard to see how it would help. Adverse effects to antidiabetic medication do reduce adherence, though not to the same extent as simply forgetting a dose. In one US study, 17 per cent of patients missed doses due to adverse effects compared with 55 per cent who just forgot.21 In EMPA-REG OUTCOME, more than a quarter of the 7000 participants discontinued medication prematurely but this was a bigger problem with placebo than empagliflozin (29 vs 23 per cent).5 Adverse events accounted for discontinuation in 13 per cent of people assigned to placebo and 11.5 per cent of those treated with empagliflozin.

Conclusion

The SGLT2 inhibitors are becoming established in the treatment of type 2 diabetes and, if trial evidence of a reduction in mortality is realised in practice, they will play an increasingly important role. People with diabetes are at increased risk of UTI and genital infections and the risk is further increased by treatment with an SGLT2 inhibitor. Women, younger people and those with a history of infections are at higher risk. An individual’s history of genitourinary infection is therefore clearly something that will influence the decision to choose an SGLT2 inhibitor for intensification. Published reports describe most genitourinary events as mild to moderate in intensity, manageable with standard topical or oral therapy, and rarely causing treatment discontinuation. However, UTIs and genital infections significantly impair quality of life, at least when they are recurrent, and serious events were reported rarely in clinical trials.

References

1.NICE. Type 2 diabetes in adults: management. NG28. December 2015. www.nice.org.uk/guidance/ng28
2. NICE. Canagliflozin, dapagliflozin and empagliflozin as monotherapies for treating type 2 diabetes. TA390. May 2016. www.nice.org.uk/guidance/ta390
3. Health and Social Care Information Centre. Prescribing for diabetes, England 2005/06 to 2015/16. August 2016. http://content.digital.nhs.uk/catalogue/PUB21158
4. Health and Social Care Information Centre. Prescription cost analysis, England 2015. April 2016. https://www.gov.uk/government/statistics/prescription-cost-analysis-england-2015
5. Zinman B, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 Diabetes. N Engl J Med 2015;373:2117–28.
6. Shyangdan DS, Uthman OA, Waugh N. SGLT-2 receptor inhibitors for treating patients with type 2 diabetes mellitus: a systematic review and network meta-analysis. BMJ Open 2016;6:e009417. doi:10.1136/bmjopen-2015-009417.
7. European Medicines Agency. Jardiance (empagliflozin) public assessment report. March 2014.
8. European Medicines Agency. Forxiga (dapagliflozin) public assessment report. September 2012.
9. European Medicines Agency. Canagliflozin public assessment report. September 2013.
10.Hirji I, et al. Incidence of urinary tract infection among patients with type 2 diabetes in the UK General Practice Research Database (GPRD). J Diabetes Complications 2012;26:513–6.
11. Hirji I, et al. Incidence of genital infection among patients with type 2 diabetes in the UK General Practice Research Database. J Diabetes Complications 2012;26:501–5.
12. Geerlings S, et al. Genital and urinary tract infections in diabetes: impact of pharmacologically-induced glucosuria. Diabetes Res Clin Pract 2014;103:373–81.
13. Nyirjesy P, et al. Evaluation of vulvovaginal symptoms and Candida colonization in women with type 2 diabetes mellitus treated with canagliflozin, a sodium glucose co-transporter 2 inhibitor. Curr Med Res Opin 2012;28:1173–8.
14. Bermingham SL, Ashe JF. Systematic review of the impact of urinary tract infections on health-related quality of life. BJU Int 2012;110(11, pt C):E830–6. doi: 10.1111/j.1464-410X.2012.11337.x.
15. Renard J, et al. Recurrent lower urinary tract infections have a detrimental effect on patient quality of life: a prospective, observational study. Infect Dis Ther 2015;4(1):125–35.
16. Zhu YX, et al. Health-related quality of life as measured with the Short-Form 36 (SF-36) questionnaire in patients with recurrent vulvovaginal candidiasis. Health Qual Life Outcomes 2016;14:65.
17. Aballéa S, et al. Subjective health status and health-related quality of life among women with recurrent vulvovaginal candidosis (RVVC) in Europe and the USA. Health Qual Life Outcomes 2013;11:169. doi:10.1186/1477-7525-11-169.
18. Usiskin K, et al. Safety and tolerability of canagliflozin in patients with Type 2 diabetes mellitus: pooled analysis of Phase 3 study results. Postgrad Med 2014;126:16–34.
19. 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.
20. Nyirjesy P, et al. Genital mycotic infections with canagliflozin, a sodium glucose cotransporter 2 inhibitor, in patients with Type 2 diabetes mellitus: a pooled analysis of clinical studies. Curr Med Res Opin 2014;30:1109–19.
21. Larkin AT, et al. Determinants of adherence to diabetes treatment. J Diabetes 2015;7:864–71.

Declaration of interests

None to declare.

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