Post-initiation predictors of discontinuation of the sodium-glucose cotransporter-2 inhibitors: A comparative cohort study from the United Kingdom

Aims

To assess post-initiation predictors of discontinuation of sodium-glucose cotransporter-2 (SGLT2) inhibitors compared to dipeptidyl-peptidase-4 (DPP-4) inhibitors in the United Kingdom.

Materials and Methods

We conducted a comparative population-based retrospective cohort study using primary care data from the UK Clinical Practice Research Datalink (CPRD) with linked data to hospital and death records. We included new metformin users who initiated either SGLT2 inhibitors or DPP-4 inhibitors between January 2013 and October 2019. The main outcome was treatment discontinuation, defined as the first 90-day gap after the estimated treatment end date. We used a series of extended Cox models to assess which time-dependent predictors were associated with treatment discontinuation. To test if the hazard ratio of discontinuation for each predictor was statistically different between SGLT2 and DPP-4 inhibitors, an exposure-predictor interaction term was added to each model.

Results

There were 2550 new users of SGLT2 inhibitors and 8195 new users of DPP-4 inhibitors. Approximately 69% of SGLT2 inhibitor and 74% of DPP-4 inhibitor users had discontinued treatment by the end of follow-up. Occurrence of fractures after treatment initiation was a significant predictor of discontinuation of SGLT2 inhibitors (hazard ratio [HR] 4.13, 95% confidence interval [CI] 2.12-8.06) but not DPP-4 inhibitors (HR 0.93, 95% CI 0.79-1.11). The rate of treatment discontinuation was significantly higher for those with low estimated glomerular filtration rate and minimal contact with the healthcare system. Efficacy endpoints, such as heart failure and glycated haemoglobin level, were not associated with treatment discontinuation.

Conclusions

Our findings reflect some discrepancy between the available evidence and prescribing behaviour for SGLT2 inhibitors.     

Use of dipeptidyl peptidase-4 inhibitors and risk of splanchnic vein thrombosis: A Danish nationwide new-user active comparator cohort study

Use of dipeptidyl peptidase-4 (DPP-4) inhibitors, on the basis of spontaneous adverse event reports, has recently been suspected of causing splanchnic vein thrombosis. Here, we report the results of a population-based new-user active comparator cohort study addressing this hypothesis, comparing DPP-4 inhibitor initiators (n = 75 042) with initiators of glucagon-like-peptide-1 receptor agonists (GLP-1RAs) or sodium-glucose co-transporter-2 (SGLT2) inhibitors (n = 38 718). We estimated the hazard ratio (HR) associating DPP-4 inhibitor use with risk of splanchnic vein thrombosis using Cox regression. In a crude analysis, the incidence rate of splanchnic vein thrombosis was 0.22/1000 person-years among DPP-4 inhibitor initiators, compared to 0.17 among GLP-1RA/SGLT2 inhibitor initiators, corresponding to an unadjusted absolute incidence rate difference of 0.05 (95% confidence interval [CI] –0.04 to 0.14) and an HR of 1.29 (95% CI 0.78 to 2.15). Adjusting for potential confounders using stabilized inverse probability of treatment weighing, we obtained an absolute incidence rate difference of 0.03/1000 person-years (95% CI –0.07 to 0.14) and an HR of 1.18 (95% CI 0.62 to 2.26). No evidence of increased risk of splanchnic vein thrombosis was found in supplementary analyses, including an absence of any dose–response patterns. As such, we found no association between DPP-4 inhibitor use and splanchnic vein thrombosis risk.     

Risk of sepsis and pneumonia in patients initiated on SGLT2 inhibitors and DPP-4 inhibitors

AimThe organ protective effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors may be beneficial against infectious complications. This real-world study aims to compare the risk of pneumonia and sepsis between SGLT2 inhibitors and dipeptidyl peptidase 4 (DPP-4) inhibitors in patients with type 2 diabetes.MethodsUsing a territory-wide clinical registry in Hong Kong (Clinical Data Analysis and Reporting System [CDARS]), we included patients initiated on SGLT2 inhibitors or DPP-4 inhibitors between January 01, 2015 and December 31, 2019 through 1:2 propensity score matching. The primary outcomes were incident events of pneumonia, sepsis and the related mortality. Cox proportional hazards analysis was used to compare the risk of incident pneumonia and sepsis for SGLT2 inhibitors versus DPP-4 inhibitors.ResultsAfter propensity score matching, 10,706 new users of SGLT2 inhibitors and 18,281 new users of DPP-4 inhibitors were included. The mean age of all eligible subjects were 60 years (SD 11.07) and 61.1% were male. There were 309 pneumonia events [incidence rate per 1000 person-years (IR) = 11.38] among SGLT2 inhibitors users and 961 events (IR = 20.45) among DPP-4 inhibitors users, with lower risk of pneumonia among SGLT2 inhibitors users (adjusted HR 0.63 [95%CI 0.55–0.72], p<0.001). Similarly, SGLT2 inhibitors users had lower incidence of sepsis [164 (IR=6.00) vs. 610 (IR=12.88) events] as well as associated risk of incident sepsis (HR 0.52 [95% CI 0.44–0.62], p<0.001), compared to DPP-4 inhibitors users. Outcome analyses showed that SGLT2 inhibitors were associated with lower risk of pneumonia-related death (HR 0.41 [95%CI 0.29–0.58], p<0.001), sepsis-related death (HR 0.39 [95%CI 0.18–0.84], p<0.05), and infection-related death (HR 0.43 [95%CI 0.32–0.57], p<0.001), compared to DPP-4 inhibitors users. Results were consistent when stratified by age, sex, pre-existing cardiovascular disease, and type of SGLT2 inhibitors.ConclusionWe provide real-world evidence that irrespective of age, sex, prior-existing cardiovascular disease, or type of SGLT2 inhibitors used, patients with type 2 diabetes initiated on SGLT2 inhibitors have lower incidence of pneumonia and sepsis as well as mortality risk associated with pneumonia, sepsis, and infectious diseases, compared with those initiated on DPP-4 inhibitors.     

Comparative risk of genital infections associated with sodium-glucose co-transporter-2 inhibitors

The extent to which sodium-glucose co-transporter-2 (SGLT2) inhibitors increase the risk of genital infections in routine clinical care, compared with other antidiabetic medications, is not clear, or whether the increased risk is consistent across gender or age subgroups, within individual SGLT2 agents, or if it is more pronounced at a particular time after treatment initiation. We conducted a retrospective cohort study using two US commercial claims databases (2013-2017). In the primary analysis, 1:1 propensity score-matched cohorts of female and male subjects with type 2 diabetes mellitus initiating SGLT2 versus dipeptidyl peptidase-4 inhibitors were created. The outcome was a composite of genital candidal infections, vaginitis or vulvovaginitis in women, and genital candidal infections, balanitis, balanoposthitis, phimosis or paraphimosis in men. Among propensity score-matched cohorts of 129 994 women and 156 074 men, the adjusted hazard ratio (HR) and excess risk per 1000 person-years for SGLT2 versus DPP-4 inhibitors was 2.81 (95% confidence interval [CI], 2.64, 2.99) and 87.4 (95% CI, 79.1, 96.2) respectively for women, and was 2.68 (95% CI, 2.31, 3.11) and 11.9 (95% CI, 9.3-15.0) for men. Findings were similar in the SGLT2 inhibitor versus GLP-1 agonist comparison, more pronounced in the subgroup of patients aged ≥60 (HR, 4.45 [95% CI, 3.83-5.17] in women and 3.30 [95% CI, 2.56-4.25] in men), and no meaningful difference across individual SGLT2 inhibitors was identified. This increase in risk was evident in the first month of treatment initiation and remained elevated throughout the course of therapy. SGLT2 inhibitors were associated with an approximately 3-fold increase in risk of genital infections.     

Dipeptidyl peptidase-4 (DPP-4) inhibitor and mortality in coronavirus disease 2019 (COVID-19) – A systematic review,meta-analysis,and meta-regression

Background and aimsThis study aims to synthesize evidence on dipeptidyl peptidase-4 (DPP-4) inhibitor and mortality in COVID-19 patients and factors affecting it.MethodsWe performed a systematic literature search from PubMed, Scopus, and Embase databases from inception of databases up until 7 March 2021. Studies that met all of the following criteria were included: 1) observational studies or randomized controlled trials that report COVID-19 patients, 2) reporting DPP-4 inhibitor use, 3) mortality, and 4) mortality based on DPP-4 inhibitor use. The exposure was DPP-4 inhibitor, defined as DPP-4 inhibitor use that started prior to COVID-19 hospitalization. The control group was patients with no exposure to DPP-4 inhibitor. The outcome was mortality. The pooled effect estimate was reported as risk ratio (RR).ResultsThere were 4,477 patients from 9 studies in this systematic review and meta-analysis. 31% of (15%, 46%) the patients use DPP-4 inhibitor. Mortality occurs in 23% (15%, 31%) of the patients. DPP-4 inhibitor was associated with lower mortality in patients with COVID-19 (RR 0.76 [0.60, 0.97], p = 0.030, I2: 44.5%, p = 0.072). Meta-regression analysis showed that the association between DPP-4 inhibitor and mortality was significantly affected by metformin (RR 1.02 [1.00, 1.04], p = 0.048) and angiotensin converting enzyme inhibitor or angiotensin receptor blocker (ACEI/ARB) use (RR 1.04 [1.01, 1.07], p = 0.006), but not age (p = 0.759), sex (reference: male, p = 0.148), and hypertension (p = 0.218).ConclusionDPP-4 inhibitor use was associated with lower mortality in COVID-19 patients, and the association was weaker in patients who were also taking metformin and/or ACE inhibitors.     

Exposure to dipeptidyl-peptidase-4 inhibitors and COVID-19 among people with type 2 diabetes: A case-control study

Because other coronaviruses enter the cells by binding to dipeptidyl-peptidase-4 (DPP-4), it has been speculated that DPP-4 inhibitors (DPP-4is) may exert an activity against severe acute respiratory syndrome coronavirus 2. In the absence of clinical trial results, we analysed epidemiological data to support or discard such a hypothesis. We retrieved information on exposure to DPP-4is among patients with type 2 diabetes (T2D) hospitalized for COVID-19 at an outbreak hospital in Italy. As a reference, we retrieved information on exposure to DPP-4is among matched patients with T2D in the same region. Of 403 hospitalized COVID-19 patients, 85 had T2D. The rate of exposure to DPP-4is was similar between T2D patients with COVID-19 (10.6%) and 14 857 matched patients in the region (8.8%), or 793 matched patients in the local outpatient clinic (15.4%), 8284 matched patients hospitalized for other reasons (8.5%), and when comparing 71 patients hospitalized for COVID-19 pneumonia (11.3%) with 351 matched patients with pneumonia of another aetiology (10.3%). T2D patients with COVID-19 who were on DPP-4is had a similar disease outcome as those who were not. In summary, we found no evidence that DPP-4is might affect hospitalization for COVID-19.     

DPP-4 inhibition and COVID-19: From initial concerns to recent expectations

Dipeptidyl peptidase-4 inhibitors (DPP-4is) have gained a key place in the management of type 2 diabetes mellitus (T2DM) essentially because of their good safety profile even in the frail population. DPP-4, originally known as ‘T-cell antigen CD26’, is expressed in many immune cells and regulates their functions, so the initial concern over the use of DPP-4is was the possible increased susceptibility to infections. Furthermore, because of the high affinity between human DPP-4 and the spike (S) receptor-binding domain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it was suspected that this virus, responsible for coronavirus disease 2019 (COVID-19), might be able to use the DPP-4 enzyme as a functional receptor to gain entry into the host. However, DPP-4is also exert anti-inflammatory effects, which could be beneficial in patients exposed to cytokine storms due to COVID-19. Yet, when observational (mostly retrospective) studies compared clinical outcomes in DPP-4i users vs non-users among diabetes patients with COVID-19, the overall results regarding the risk of progression towards more severe forms of the disease and mortality were heterogeneous, thereby precluding any definite conclusions. Nevertheless, new expectations have arisen following recent reports of significant reductions in admissions to intensive care units and mortality in DPP-4i users. However, given the limitations inherent in such observational studies, any available results should be considered, at best, as hypothetical and only suggestive of potentially substantial benefits with DPP-4is in diabetes patients with COVID-19. While the safe use of DPP-4is in COVID-19 patients appears to be an acceptable hypothesis, all such positive findings still need to be confirmed in randomized controlled trials (a few of which are currently ongoing) before any recommendations can be made for clinical practice.     

When metformin is not enough: Pros and cons of SGLT2 and DPP‐4 inhibitors as a second line therapy

The newer oral therapies for type 2 diabetes mellitus, dipeptidyl peptidase‐4 (DPP‐4) inhibitors and sodium glucose cotransporter 2 (SGLT2) inhibitors, have advantages over older agents. Dipeptidyl peptidase‐4 inhibitors are weight neutral and have few adverse effects. Sodium glucose cotransporter 2 inhibitors have additional benefits: weight loss, blood pressure reduction, cardiovascular risk reduction, and renoprotective effects. Sodium glucose cotransporter 2 inhibitors have increased risk of urogenital infections and possible risk of “euglycaemic” diabetic ketoacidosis. It is important to balance the benefits over the older‐oral therapies as these agents are more expensive; yet some analyses suggest that they are within the limits of what is considered cost‐effective in health care. We discuss the relative merits and drawbacks of these 2 classes and consider their roles in the treatment of type 2 diabetes mellitus. We suggest a number of patient profiles where early use of these agents could be used. We favour the use of SGLT2 inhibitors over DPP‐4 inhibitors as add on therapy to metformin when glycaemic targets have not been achieved given their similar glycaemic efficacy and the additional benefits of SGLT2 inhibitors. We particularly favour SGLT2 inhibitors in those where additional weight loss and blood pressure reductions are desired, and in patients with heart failure or cardiovascular disease. Care should be taken to warn patients about genital fungal infections and to avoid use in people with risk factors for SGLT2 associated ketoacidosis. We favour DPP‐4 inhibitors in those where side effects of other agents are of concern, the frail elderly population, and those with renal disease precluding SGTL2 inhibitor use.     

Comparable COVID-19 outcomes with current use of GLP-1 receptor agonists,DPP-4 inhibitors or SGLT-2 inhibitors among patients with diabetes who tested positive for SARS-CoV-2

Incretin-based therapies, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 inhibitors (DPP-4i), have been hypothesized to exert beneficial effects on COVID-19 outcomes due to anti-inflammatory properties. In this population-based cohort study, we retrieved data from nationwide registries on all individuals diagnosed with severe acute respiratory syndrome coronavirus 2 infection up to 1 November 2020. For individuals with diabetes, we examined the impact of use of GLP-1 RAs (n = 370) and DPP-4i (n = 284) compared with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) (n = 342) on risk of hospital admission and severe outcomes. Relative risks (RRs) were calculated after applying propensity score weighted methods to control for confounding. Current users of GLP-1 RAs had an adjusted RR of 0.89 (95% confidence interval 0.34-2.33), while users of DPP-4i had an adjusted RR of 2.42 (95% confidence interval 0.99-5.89) for 30-day mortality compared with SGLT-2i use. Further, use of GLP-1 RAs or DPP-4i compared with SGLT-2i was not associated with decreased risk of hospital admission. Thus, use of incretin-based therapies in individuals with diabetes and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was not associated with improved clinical outcomes.     

Association between sodium glucose co-transporter 2 inhibitors and incident glaucoma in patients with type 2 diabetes: A multi-institutional cohort study in Taiwan

PurposeType 2 diabetes (T2D) is an important risk factor for glaucoma, and sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to protect the optic nerves. We therefore aimed to evaluate the association between SGLT2 inhibitors and incident glaucoma.MethodsThis retrospective cohort study analyzed the largest multi-institutional electronic medical records database in Taiwan, containing data of over a million individuals. We included T2D patients newly prescribed SGLT2 inhibitors or glucagon-like peptide-1 receptor agonists (GLP-1 RAs) from 2016 to 2018. Our primary outcome was incident glaucoma diagnosis between initiation of SGLT2 inhibitors or GLP-1 RAs, and 31st March 2021. After applying inverse probability of treatment weighting (IPTW) to increase homogeneity between the two treatment groups, we estimated hazard ratios (HR) with 95% confidence intervals (CI) for the risk of glaucoma, based on Cox proportional hazards regression models.ResultsWe included 9,927 and 1,065 T2D patients who had been newly prescribed SGLT2 inhibitors or GLP-1 RAs, respectively. Lower risk of incident glaucoma was observed in patients receiving SGLT2 inhibitors (7.9 events per 1,000 person-years), compared to those receiving GLP-1 RAs (10.0 events per 1,000 person-years), with an HR of 0.81 (95% CI: 0.69–0.95). Multiple sensitivity analyses and a negative control outcome analysis confirmed the robustness of our main findings.ConclusionThis study suggests that T2D patients newly prescribed SGLT2 inhibitors have a reduced risk of incident glaucoma, compared to those prescribed GLP-1 RAs, in clinical practice. Future prospective studies are suggested to confirm this association.     

Favourable effect of the sodium-glucose co-transporter-2 inhibitor canagliflozin plus the dipeptidyl peptidase-4 inhibitor teneligliptin in combination on glycaemic fluctuation: An open-label,prospective, randomized,parallel-group comparison trial (the CALMER study)

This multicentre, prospective, randomized, open-label, blinded-endpoint, parallel-group, short-term (4–5 weeks) controlled trial was conducted to investigate the superiority of the effect of reducing mean amplitude of glycaemic excursions (MAGE) during meal tolerance tests (MTTs) for the combination of dipeptidyl peptidase-4 (DPP-4) inhibitor and sodium-glucose co-transporter-2 (SGLT2) inhibitor compared with SGLT2 inhibitor monotherapy. Ninety-nine patients with type 2 diabetes who were taking teneligliptin (20 mg/d) were randomized to one of the following two groups: those who switched to 100 mg/d of canagliflozin (SWITCH group) or those who added 100 mg/d of canagliflozin (COMB group). MAGE in the COMB group was significantly decreased compared with that in the SWITCH group (COMB 117.5 ± 39.8 to 92.2 ± 28.0 mg/dL vs SWITCH 110.7 ± 29.8 to 104.2 ± 27.6 mg/dL; P<0.01). Mean blood glucose decreased significantly during MTTs in both groups, although the extent of the reduction was significantly greater in the COMB group (COMB 142.3 ± 28.7 to 119.5 ± 25.1 mg/dL vs SWITCH 146.4 ± 25.5 to 135.5 ± 22.4 mg/dL; P < 0.01). SGLT2 inhibitor combined with DPP-4 inhibitor therapy strongly reduced glycaemic fluctuation compared with SGLT2 inhibitor monotherapy.     

Sodium-glucose co-transporter-2 inhibitors and atrial fibrillation in the cardiovascular and renal outcome trials

Dapagliflozin is a sodium-glucose co-transporter-2 (SGLT2) inhibitor that has recently been shown to reduce the incidence of reported episodes of atrial fibrillation (AF)/atrial flutter in the DECLARE-TIMI 58 trial. This raises the question regarding whether SGLT2 inhibitors can reduce the incidence of AF in a high-risk population. We searched for trials comparing SGLT2 inhibitors to placebo in high-risk individuals with or without diabetes (ie, cardiovascular and renal outcome trials) and that reported the incidence of AF as a serious adverse event. The EMPA-REG OUTCOME trial, CANVAS, CANVAS-R, the DECLARE-TIMI 58 trial, CREDENCE, DAPA-HF, VERTIS-CV and DAPA-CKD were included. The incidence of AF, reported as a serious adverse event, was 0.9% in individuals who received an SGLT2 inhibitor compared to 1.1% in those who received placebo. Pooled results showed a significantly lower incidence of AF in individuals with and without diabetes (relative risk 0.79, 95% confidence interval 0.67,0.93). This review suggests that there is a significantly lower risk of incident AF for individuals on SGLT2 inhibitors versus placebo. While there was a statistically significant lower incidence of AF, reported as a serious adverse event, more research is needed to evaluate its clinical significance.     

Dipeptidyl Peptidase-4 Inhibitors,Peripheral Arterial Disease,and Lower Extremity Amputation Risk in Diabetic Patients

Background

Recent studies have elucidated the vascular protective effects of dipeptidyl peptidase-4 (DPP-4) inhibitors. However, to date, no large-scale studies have been carried out to determine the impact of DPP-4 inhibitors on the occurrence of peripheral arterial disease, and lower extremity amputation risk in patients with type 2 diabetes mellitus.

Factors influencing on development of COVID-19 pneumonia and association with oral anti-diabetic drugs in hospitalized patients with diabetes mellitus

BackgroundDiabetes mellitus (DM) increases mortality and morbidity in patients with coronavirus disease (COVID-19). In this study, it was aimed to assess factors influencing on COVID-19 pneumonia in hospitalized patients with diabetes and association with oral anti-diabetic drugs.Materials and methodsThis cross-sectional study included 432 patients with type 2 diabetes mellitus diagnosed with COVID-19. Data regarding clinical characteristics, demographic characteristics, intensive care unit (ICU) rate in patients admitted to ICU, laboratory results on day 1 and 7, thoracic computed tomography (CT) findings and oral anti-diabetic drugs used were extracted from medical records. In all patients, 75-days mortality was recorded. Data were assessed independently.ResultsThere was pneumonia in 386 (89.4%) of 432 patients with diabetes. The risk for pneumonia was markedly higher in patients on DPP-4 inhibitors; however, there was no significant among other oral anti-diabetic groups and subgroups. In addition, elevated CRP was linked to the increased risk for pneumonia. Only patients in the pneumonia group had SGLT-2 inhibitor use. During follow-up, 91 patients died. In Cox regression analysis, low Glasgow Coma Scale score, and increased lactate dehydrogenase levels were identified as significant independent risk factors for mortality.ConclusionThe study indicated that DPP-4 inhibitor used and elevated CRP level were associated with pneumonia development. Only patients in the pneumonia group had SGLT-2 inhibitor use. No oral anti-diabetics was found to be associated with COVID-19 related death.     

Dypeptidylpeptidase-4 inhibitors and the cardiovascular system: How to manage the fil rouge

Dypeptidylpeptidase-4 (DPP-4) inhibitors are a therapeutic option for improving glucose control in patients with type 2 diabetes. They can be prescribed at different stages of the natural history of the disease because of their low risk for hypoglycemia and associated weight gain. For all new drugs for diabetes, the US Food and Drug Administration requires the demonstration of the cardiovascular (CV) safety profile through pooled analyses of phase 3 studies or specifically designed trials.A significant superiority over placebo has been observed with a sodium-dependent glucose transporter-2 inhibitor, empagliflozin, and two glucagon-like peptide-1 receptor agonists, liraglutide and semaglutide, thus suggesting cardioprotective effects for some antidiabetic drugs.The neutral results of CV safety trials on DPP-4 inhibitors have been disappointing, appearing to contradict the data from pooled analyses and meta-analyses of early trials. The main aim of this review is to find a possible interpretation for the differences between the results of these early trials and the CV safety studies with DPP-4 inhibitors. We conclude that the hypothesis of additional beneficial effects by DPP-4 inhibitors (beyond the improvement of glucose control), on the CV system in low-risk patients in primary prevention, needs to be verified with specifically designed studies.     

Estimated lifetime benefit of novel pharmacological therapies in patients with type 2 diabetes and chronic kidney disease: A joint analysis of randomized controlled clinical trials

Aim

To estimate the lifetime benefit of a combination treatment of sodium-glucose co-transporter 2 (SGLT2) inhibitors and mineralocorticoid-receptor antagonists (MRA) in patients with type 2 diabetes and chronic kidney disease (CKD).

Materials and Methods

The cumulative effect of combination treatment was derived from trial-level estimates of the effect of an SGLT2 inhibitor (canagliflozin) and MRA (finerenone) from the CREDENCE (N = 4401) and FIDELIO (N = 5734) trials, respectively. The cumulative effect was applied to the control group of patients with type 2 diabetes in the DAPA-CKD trial (N = 1451) to estimate long-term gains in event-free and overall survival. The analysis was repeated in an observational study. The primary outcome was a composite endpoint of doubling of serum creatinine, end-stage kidney disease or death because of kidney failure.

Results

The hazard ratio of combination treatment for the primary outcome was 0.50 [95% confidence interval (CI): 0.44, 0.57]. At age 50 years, the estimated event-free survival from the primary outcome was 16.7 years (95% CI: 18.1, 21.0) with combination treatment versus 10.0 years (95% CI: 6.8, 12.3) with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers resulting in an incremental gain of 6.7 years (95% CI: 5.5, 7.9). In an observational study, the estimated gain in event-free survival regarding primary outcome was 6.3 years (95% CI: 5.2, 7.3). In a conservative scenario, assuming low adherence (70% of the observed adherence) and less pronounced efficacy (70% of the observed efficacy with 2% yearly decline) of combination therapy, gain in event-free survival regarding primary outcome was 2.5 years (95% CI: 2.0, 2.9).

Conclusions

Combined disease-modifying treatment with an SGLT2 inhibitor and MRA in patients with type 2 diabetes and CKD may substantially increase the number of years free from kidney failure and mortality.     

钠葡萄糖协同转运子2抑制剂:糖尿病治疗的新选择

钠葡萄糖协同转运子2(SGLT2)是几乎仅在近曲小管表达的跨膜蛋白,介导了90%滤过葡萄糖的重吸收,SGLT2抑制剂可特异性抑制肾小管对滤过葡萄糖的重吸收,增加尿糖排泄,发挥降糖作用.SGLT2抑制剂还具有促进体重下降,间接改善肥胖的作用.根皮苷作为人类最早发现的SGLT2抑制剂,研究较为局限,随着T-1095、serglilozin、dapagliflozin等新型SGLT2抑制剂的开发,SCLT2抑制剂在治疗糖尿病上的有效性和安全性得到了进一步论证,为糖尿病治疗提供了新选择.     

Dipeptidyl peptidase‐4 inhibitors moderate the risk of genitourinary tract infections associated with sodium‐glucose co‐transporter‐2 inhibitors

Genitourinary tract infections (GUTIs) are the most common adverse event (AE) occurring during therapy with sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors. We evaluated whether dipeptidyl peptidase‐4 inhibitors moderate the risk of GUTI during SGLT2 inhibitor therapy, using two approaches. First, we screened the literature for randomized controlled trials (RCTs) directly comparing the frequency of GUTIs in patients receiving DPP‐4 inhibitor/SGLT2 inhibitor combination therapy vs those receiving an SGLT2 inhibitor only. In the five trials we retrieved, the pooled risk ratio for genital tract infections (GTIs) in patients on DPP‐4 inhibitor/SGLT2 inhibitor combination therapy vs those on SGLT2 inhibitors alone was 0.51 (95% confidence interval [CI] 0.28‐0.92). Second, we found that within the Food and Drug Administration AE Reporting System, the frequency of GUTIs among reports listing both SGLT2 and DPP‐4 inhibitors as suspect or concomitant drugs was significantly lower than among reports listing SGLT2 inhibitors without DPP‐4 inhibitors, with a proportional reporting ratio of 0.74 (95% CI 0.61‐0.90). In conclusion, in RCTs and in a large pharmacovigilance database, combination therapy with a DPP‐4 inhibitor appears to reduce the frequency of G(U)TIs associated with SGLT2 inhibitors.