SGLT2i reduce atherothrombotic MACE, respiratory diseases, and burden of critical illness vs DPP4i in T2D patients in HK

09 Nov 2025
SGLT2i reduce atherothrombotic MACE, respiratory diseases, and burden of critical illness vs DPP4i in T2D patients in HK

In patients with type 2 diabetes (T2D), use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) is associated with a 36 percent reduction in risk of atherothrombotic major adverse cardiovascular events (MACE) vs dipeptidyl peptidase-4 inhibitors (DPP4i), a recent real-world territory-wide study in Hong Kong has shown.

The study, which involved 20,642 patients with T2D followed up for a median of 2.9 years, also showed a 29 percent reduction in risk of stroke and a 42 percent reduction in risk of MI with SGLT2i vs DPP4i. [J Am Heart Assoc 2025;14:e037207]

These findings, together with earlier territory-wide studies showing reduced obstructive airway disease (OAD) incidence and exacerbations, lower pneumonia incidence and mortality, as well as reduced intensive care unit (ICU) admission and related mortality with SGLT2i vs DPP4i in patients with T2D, may help inform clinical decisions on pharmacological management of this chronic condition, which is estimated to affect 10 percent of the population in Hong Kong. [JAMA Netw Open 2023;6:e2251177; J Clin Endocrinol Metab 2022;107:e1719-e1726; Crit Care Med 2023;51:1074-1085; Sci Rep 2024;14:10688]

Diabetes impacts well-being
This year’s World Diabetes Day (14 November 2025) focuses on diabetes and well-being in the workplace, highlighting challenges faced by patients in managing diabetes at work and the negative impact of these on their well-being. As 70 percent of patients with diabetes are of working age, and 75 percent have experienced diabetes-related anxiety, depression or another mental health condition, the impact on well-being is substantial. [https://worlddiabetesday.org/]

In Hong Kong, a cross-sectional study showed that patients with T2D managed in primary care (n=362; median T2D duration, 7.0 years) commonly (59.4 percent) experienced clinically significant diabetes-related distress, particularly in younger age groups. [Sci Rep 2024;14:10688]

Substantial economic burden
T2D is associated with reductions in productivity-adjusted life years (PALYs) of 17.0 percent in men and 27.8 percent in women in Hong Kong, according to a population-based modelling study conducted using data from 257,280 patients with T2D aged 20–64 years in 2019. These PALY losses were estimated to translate to gross domestic product losses of USD 15.3 billion in men and USD 14.5 billion in women. [Lancet Reg Health West Pac 2025;doi:10.1016/j.lanwpc.2025.101585]

High costs of managing complications
Complications of T2D incur high incremental healthcare costs. In a prospective cohort study involving 19,440 patients with T2D (mean duration of diabetes, 7.3 years) enrolled in Hong Kong’s JADE (Joint Asia Diabetes Evaluation) Register, who were observed for a median of 7 years, the mean annual healthcare costs (mainly due to inpatient care) were USD 2,990. However, overall healthcare costs in both inpatient and outpatient settings surged prominently in the year of occurrence of complications vs non-event years. [Diabetes Res Clin Pract 2025;219:111961]

Complications that incurred the highest incremental annual healthcare costs in the year of occurrence were lower extremity amputation (LEA) (USD 31,302), haemorrhagic stroke (USD 21,164), ischaemic stroke (USD 17,976), and end-stage renal disease (ESRD) (USD 14,774). Residual annual healthcare costs in post-event years were highest for ESRD (USD 10,020), LEA (USD 7,828), haemorrhagic stroke (USD 5,095), and cancer (USD 5,096).

These healthcare cost estimates may inform decision-makers on resource allocation aimed at reducing the burden of T2D and its complications.

SGLT2i lower risk of atherothrombotic MACE vs DPP4i in T2D
In patients with T2D, use of SGLT2i (including empagliflozin) is independently associated with significant reductions in atherothrombotic MACE, all-cause mortality, cardiovascular (CV) mortality, MI, stroke, and incident dialysis vs DPP4i, according to a recent territory-wide study conducted using the Hospital Authority’s (HA) electronic medical database. [J Am Heart Assoc 2025;14:e037207]

A total of 10,321 patients newly prescribed SGLT2i in 2015–2019 were propensity score (PS)–matched with 10,321 patients newly prescribed DPP4i during the same period for analysis. The cohort’s mean age was 59 years, and 63.7 percent were male.

After a median follow-up of 2.9 years, the primary outcome of atherothrombotic MACE (a composite of CV mortality, nonfatal stroke, and nonfatal MI) showed a significant 36 percent reduction among SGLT2i vs DPP4i users (4.4 vs 7.0 percent; hazard ratio [HR], 0.64; 95 percent confidence interval [CI], 0.57–0.72; p<0.001).



Subgroup analysis showed greater benefit of SGLT2i in patients with diabetes duration >7 vs ≤7 years (HR, 0.57 vs 0.73; pinteraction=0.035) and those with baseline estimated glomerular filtration rate (eGFR) ≤60 vs >60 mL/min/1.73 m2 (HR, 0.57 vs 0.76; pinteraction=0.019). SGLT2i’s effect was, however, not modified by presence of previous CV disease (CVD), diabetes control, age, or sex.

Reduced risks of stroke and MI
Significant risk reductions with SGLT2i vs DPP4i were observed for secondary outcomes, including:

  • All-cause mortality (HR, 0.44; 95 percent CI, 0.38–0.50; p<0.001);
  • CV mortality (HR, 0.53; 95 percent CI, 0.42–0.67; p<0.001);
  • Stroke (HR, 0.71; 95 percent CI, 0.60–0.83; p<0.001);
  • MI (HR, 0.58; 95 percent CI, 0.48–0.71; p<0.001); and
  • Incident dialysis (HR, 0.29; 95 percent CI, 0.21–0.40; p<0.001).
  

“In our study, the event curves for acute MI and stroke diverged between groups after 1–2 years of follow-up. It is likely that the protective effects of SGLT2i on atherosclerosis only emerge after an extended period of drug use and are detectable in a larger cohort,” reported the researchers from the University of Hong Kong (HKU), who also noted that SGLT2i’s pharmacological advantage on stroke and MI was more variable in previous randomized controlled trials (RCTs) that mostly used placebo as the comparator. [N Engl J Med 2015;373:2117-2128; N Engl J Med 2017;377:644-657; N Engl J Med 2019;380:347-357; N Engl J Med 2021;384:129-139; JAMA Cardiol 2021;6:148-158]

“Importantly, this benefit [on MI and stroke] was observed in patients with diabetes regardless of [presence or absence of] established CVD, lending evidence to extend recommendations for SGLT2i to all patients at risk of atherosclerotic CVD independent of glucose control,” they continued.

“In terms of renal outcomes, previous cohorts in patients with mean eGFR of 90 mL/min/1.73 m2 demonstrated halving of renal events over a mean follow-up of 14.9 months. Our observation period, which was longer for a cohort with a lower median eGFR of 81 mL/min/1.73 m2, resulted in a stronger renoprotective effect of 71 percent reduction in incident dialysis, highlighting the accretive benefits of long-term SGLT2i use,” they added.

However, the risk of unplanned coronary revascularization did not differ significantly between groups (HR, 0.88; 95 percent CI, 0.69–1.11; p=0.27).

Prioritize early use of SGLT2i
“We provide robust data to support the cerebrovascular and CV benefits of SGLT2i, beyond commonly reported anti–heart failure effects,” the researchers wrote. “The use of an active comparator in this study offered insights into the efficacy of SGLT2i in real-world practice, resembling the typical decision bifurcation faced by practicing clinicians.”

“We showed that SGLT2i were independently associated with reductions in atherothrombotic MACE, including stroke and MI, in a real-world setting compared with DPP4i. There is strong evidence for prioritizing early initiation of SGLT2i for treatment of T2D, in the absence of compelling contraindications,” they concluded.

Protective against obstructive airway disease and pneumonia too
SGLT2i were also associated with reductions in OAD incidence and exacerbations, as well as pneumonia incidence and mortality, vs DPP4i in retrospective studies of patients with T2D based on data retrieved from HA’s territory-wide electronic medical database.

Reduced OAD incidence and exacerbations
The study on OAD involved 30,385 patients with T2D who were prescribed SGLT2i or DPP4i in 2015–2018. The PS-matched non-OAD cohort (incidence analysis; mean age, 61.2 years; male, 56 percent) included 5,696 SGLT2i users and 22,784 DPP4i users, while the matched OAD cohort (exacerbation analysis; mean age, 62.2 years; male, 51 percent) included 381 SGLT2i users and 1,524 DPP4i users. [JAMA Netw Open 2023;6:e2251177]

SGLT2i use was associated with a lower risk of incident OAD (HR, 0.65; 95 percent CI, 0.54–0.79; p<0.001) and a lower rate of OAD exacerbations (rate ratio, 0.54; 95 percent CI, 0.36–0.83; p=0.01) vs DPP4i use, after a median follow-up of 2.2 years. The associations were consistent in subgroup analysis by sex.

“Previous studies reported that … diabetes was associated with higher risks of OAD and exacerbation events,” the researchers from HKU noted. [Diabetes Care 2010;33:55-60; Int Health 2020;12:246-252; J Allergy Clin Immunol Pract 2019;7:1868-1873] “Our findings suggest that SGLT2i may provide additional protective effects against OAD for patients with T2D, and further investigation is warranted.”

Lowered pneumonia incidence and mortality
In the study on pneumonia, 6,664 patients with T2D who were prescribed SGLT2i (including empagliflozin) in 2015–2018 were PS-matched with 26,656 patients prescribed DPP4i during the same period. [J Clin Endocrinol Metab 2022;107:e1719-e1726]

After a mean follow-up of 3.8 years, use of SGLT2i vs DPP4i was associated with significant reductions in pneumonia incidence (absolute rate difference, 4.05 per 1,000 person-years; 95 percent CI, 2.61–5.51) (incidence rate ratio, 0.71; 95 percent CI, 0.62–0.81; p<0.001) and mortality (HR, 0.57; 95 percent CI, 0.42–0.77; p<0.001).



“Patients with diabetes are at higher risks of pneumonia and pneumonia mortality,” the researchers from HKU wrote. [Diabetes Care 2010;33:55-60; N Engl J Med 2011;364:829-841] “[Our results showed that] compared with DPP4i, SGLT2i use was associated with reduced risks of pneumonia and pneumonia mortality in a real-world setting.”

SGLT2i reduce ICU admission and related mortality vs DPP4i in T2D
Benefits of SGLT2i extend to patients with T2D at the most severe end of the disease spectrum, with a retrospective territory-wide study in Hong Kong showing independent associations with lower rates of ICU admission and related mortality vs DPP4i across various disease categories. [Crit Care Med 2023;51:1074-1085]

The study, conducted using HA’s electronic medical database, involved 27,972 patients with T2D (mean age, 59 years; male, 62.3 percent) newly prescribed SGLT2i (including empagliflozin) or DPP4i in 2015–2019. The cohort comprised 10,308 SGLT2i users and 17,664 PS-matched DPP4i users, who were followed up for a median of 2.9 years.

Use of SGLT2i vs DPP4i was associated with significant reductions in coprimary outcomes of ICU admission (2.8 vs 3.7 percent; HR, 0.79; 95 percent CI, 0.69–0.91; p=0.001) and all-cause mortality (3.1 vs 7.5 percent; HR, 0.44; 95 percent CI, 0.38–0.49; p<0.001). The number needed to treat to prevent one mortality event was 22.


Mortality reduction was the greatest for renal causes (0.03 vs 0.14 percent; HR, 0.22; 95 percent CI, 0.07–0.73; p=0.014), followed by infectious causes (0.6 vs 2.3 percent; HR, 0.26; 95 percent CI, 0.20–0.34; p<0.001) and CV causes (1.0 vs 1.9 percent; HR, 0.58; 95 percent CI, 0.46–0.72; p<0.001).

Less severe critical illness, reduced sepsis admission
The severity of illness upon ICU admission was lower among SGLT2i vs DPP4i users (median Acute Physiology and Chronic Health Evaluation IV–predicted risk of death, 0.08 vs 0.14; p<0.001).

Notably, a 39 percent reduction in risk of ICU admission for sepsis was observed among SGLT2i vs DPP4i users (0.4 vs 0.8 percent; HR, 0.61; 95 percent CI, 0.43–0.85; p=0.004). According to the researchers from HKU, this risk reduction was striking, as sepsis accounts for ≤6 percent of infection-related hospitalizations and ≤12 percent of infection-related deaths in patients with diabetes. [Diabetes Care 2018;41:513-521]

Lower risks of emergency ICU admission (2.0 vs 2.8 percent; HR, 0.75; 95 percent CI, 0.64–0.89; p=0.001) and nonoperative ICU admission (1.5 vs 2.4 percent; HR, 0.66; 95 percent CI, 0.54–0.79; p<0.001) were also observed in SGLT2i vs DPP4i users. However, the ICU length of stay was similar between groups.