Daily Endocrinology Research Analysis
Three high-impact endocrinology studies stood out today. An individual participant-level meta-analysis shows empagliflozin robustly reduces both acute and chronic kidney outcomes across broad populations, irrespective of the initial eGFR dip. A large perioperative cohort links pre-operative SGLT2 inhibitor use to lower 30-day mortality and complications, and a long-term Swedish cohort suggests baseline uric acid predicts future complications in young-onset type 1 diabetes.
Summary
Three high-impact endocrinology studies stood out today. An individual participant-level meta-analysis shows empagliflozin robustly reduces both acute and chronic kidney outcomes across broad populations, irrespective of the initial eGFR dip. A large perioperative cohort links pre-operative SGLT2 inhibitor use to lower 30-day mortality and complications, and a long-term Swedish cohort suggests baseline uric acid predicts future complications in young-onset type 1 diabetes.
Research Themes
- Broad kidney protection with SGLT2 inhibition across populations
- Perioperative safety and outcomes with SGLT2 inhibitors
- Uric acid as a prognostic biomarker in type 1 diabetes
Selected Articles
1. Effects of empagliflozin on conventional and exploratory acute and chronic kidney outcomes: an individual participant-level meta-analysis.
Across four large RCTs (n=23,340), empagliflozin reduced AKI markers, CKD progression, and kidney failure and markedly slowed chronic eGFR decline. Benefits were consistent regardless of predicted acute eGFR dip, diabetes or heart failure status, baseline kidney function, or albuminuria.
Impact: This IPD meta-analysis resolves concerns about the initial eGFR dip and demonstrates broad renal protection, supporting wider use of SGLT2 inhibitors across CKD spectra.
Clinical Implications: Clinicians should not withhold SGLT2 inhibitors due to acute eGFR dips; empagliflozin provides consistent kidney protection across albuminuria levels and comorbidities, favoring early initiation in CKD with or without diabetes.
Key Findings
- 20% lower risk of ≥50% creatinine rise and 27% fewer acute kidney injury adverse events versus placebo.
- 30% lower risk of chronic kidney disease progression and 34% lower risk of kidney failure.
- Chronic eGFR decline slowed by 64%, including a 64% reduction in off-treatment dip-free slope.
- Benefits were independent of predicted acute eGFR dip size, diabetes or heart failure status, baseline eGFR, and albuminuria.
Methodological Strengths
- Individual participant-level meta-analysis across four large placebo-controlled RCTs.
- Consistent effects across prespecified subgroups with multiple complementary kidney endpoints.
Limitations
- Analyses limited to empagliflozin trials supplied by a single sponsor; generalizability to all SGLT2 inhibitors inferred but not proven.
- Some exploratory outcomes (e.g., dip-free slope) were post-hoc and available in a subset.
Future Directions: Head-to-head SGLT2 inhibitor comparisons and pragmatic implementation studies in low-albuminuria CKD, advanced CKD, and perioperative settings; mechanistic work to explain dip-independent benefits.
BACKGROUND: Uncertainty remains about effects of sodium-glucose co-transporter-2 (SGLT2) inhibition on kidney outcomes in individuals with slowly progressive chronic kidney disease (eg, low albuminuria) and those at risk of large acute estimated glomerular filtration rate (eGFR) dips on initiation of such treatment. We aimed to explore the effects of empagliflozin on a range of kidney outcomes in these population subtypes. METHODS: In this meta-analysis, we used individual-level data from 23 340 participants in four large placebo-controlled trials (EMPA-REG OUTCOME, EMPEROR-Reduced, EMPEROR-Preserved, and EMPA-KIDNEY) to assess the effects of empagliflozin on conventional and exploratory acute and chronic kidney outcomes. We then assessed whether effects varied by predicted size of the acute eGFR dip on treatment initiation or among other key population subtypes using tests for heterogeneity and trend. The individual-level data were requested from Boehringer Ingelheim (Ingelheim, Germany). FINDINGS: Compared with placebo, allocation to empagliflozin reduced the risk of a marker of acute kidney injury (a ≥50% increase in serum creatinine in consecutive follow-up samples) by 20% (hazard ratio 0·80 [95% CI 0·72-0·88]; 1573 outcomes), acute kidney injury adverse events by 27% (0·73 [0·63-0·85]; 694 outcomes), a categorical chronic kidney disease progression outcome by 30% (0·70 [0·63-0·78]; 1403 outcomes), and kidney failure by 34% (0·66 [0·55-0·79]; 490 outcomes). Empagliflozin slowed a chronic annual rate of eGFR decline by 64% (95% CI 59-69) and off-treatment dip-free slope-a post-hoc outcome using randomisation and off-treatment eGFR values available in a subset of 10 630 participants-by 64% (54-73). These kidney benefits were similar in subgroups divided by predicted size of acute eGFR dip, and were present irrespective of diabetes or heart failure status, level of kidney function, or albuminuria. INTERPRETATION: SGLT2 inhibition reduces risk of acute and chronic kidney outcomes irrespective of the size of the acute dip in eGFR. Kidney benefits are evident irrespective of diabetes status, heart failure status, primary cause of kidney disease, and markers of severity of these diseases. FUNDING: None.
2. Association between pre-operative sodium-glucose cotransporter-2 inhibitor use and postoperative outcomes: a propensity score-matched analysis of the TriNetX database.
In 98,118 propensity-matched pairs of surgical patients with type 2 diabetes, pre-operative SGLT2 inhibitor use was associated with lower 30-day mortality and fewer cardiovascular events, AKI, and DKA. Benefits were particularly evident in women, those with obesity or proteinuria, and in cardiovascular surgery.
Impact: This large real-world analysis challenges prior perioperative safety concerns and suggests potential protective effects of SGLT2 inhibitors around surgery.
Clinical Implications: For surgical patients with type 2 diabetes, routine cessation of SGLT2 inhibitors solely due to DKA concerns may warrant re-evaluation; individualized risk–benefit assessment and prospective trials are needed.
Key Findings
- 30-day all-cause mortality was 39% lower with pre-operative SGLT2 inhibitor use (RR 0.61, 95% CI 0.55–0.67).
- Reduced risks of major adverse cardiovascular events (RR 0.89), acute kidney injury (RR 0.71), and diabetic ketoacidosis (RR 0.31).
- Stronger mortality reductions in females, individuals with obesity or proteinuria, and those undergoing cardiovascular surgery.
Methodological Strengths
- Nationwide propensity score-matched cohort with very large sample size (98,118 matched pairs).
- Multiple clinically relevant endpoints with consistent directionality across subgroups.
Limitations
- Retrospective observational design susceptible to residual confounding and exposure misclassification.
- Medication timing relative to surgery and perioperative management protocols may vary and are not fully captured.
Future Directions: Randomized perioperative trials and pragmatic studies to define optimal timing, continuation vs. withholding strategies, and patient subgroups who benefit most.
INTRODUCTION: While sodium-glucose cotransporter-2 inhibitors offer cardiovascular and renal benefits, their peri-operative safety and effect profile remain unclear. This study aimed to evaluate the association between pre-operative sodium-glucose cotransporter-2 inhibitor use and postoperative adverse events in patients with type 2 diabetes mellitus. METHODS: This nationwide propensity-score matched cohort study utilised the TriNetX database to analyse data from patients with type 2 diabetes mellitus who underwent surgery in the USA. Patients were categorised based on whether they had received a prescription for sodium-glucose cotransporter-2 inhibitors 90 days before surgery. The primary outcome was 30-day all-cause mortality. Secondary outcomes included the incidence of major adverse cardiovascular events; acute kidney injury; and diabetic ketoacidosis. RESULTS: In 98,118 matched pairs, 30-day all-cause mortality was significantly lower in patients in the sodium-glucose cotransporter-2 inhibitor group compared with those in the control group (RR 0.61, 95%CI 0.55-0.67, p < 0.001). Patients receiving sodium-glucose cotransporter-2 inhibitor treatment also showed lower risks of major adverse cardiovascular events (RR 0.89, 95%CI 0.86-0.91); acute kidney injury (RR 0.71, 95%CI 0.69-0.74); and diabetic ketoacidosis (RR 0.31, 95%CI 0.18-0.540) (p < 0.001 for all comparisons). Subgroup analyses revealed a more pronounced reduction in mortality among females, patients living with obesity or proteinuria, and those undergoing cardiovascular surgery. DISCUSSION: Our study showed a significantly reduced risk of postoperative mortality and morbidity associated with pre-operative sodium-glucose cotransporter-2 inhibitor use in patients with type 2 diabetes mellitus, including a notably lower rate of diabetic ketoacidosis, contrary to previous concerns. Randomised controlled trials are warranted to validate these findings. Medicines called sodium‐glucose cotransporter‐2 (SGLT2) inhibitors can help the heart and kidneys. But doctors aren't sure if these medicines are safe for people with type 2 diabetes who are having surgery. This study looked at whether taking these medicines before surgery affects health problems afterward. Researchers used a large database of people with type 2 diabetes in the USA who had surgery. They compared people who took SGLT2 inhibitors within 90 days before surgery with people who did not take them. They checked if patients died within 30 days after surgery and looked at heart problems, kidney injury, and diabetic ketoacidosis (which is a dangerous problem when blood sugar gets too high). Out of 98,118 matched pairs of patients, people taking SGLT2 inhibitors were less likely to die within 30 days. They also had fewer heart problems, kidney injuries, and cases of diabetic ketoacidosis. The benefit was even greater in women, people with obesity, people with protein in their urine, and those who had heart surgery. The study showed that patients with type 2 diabetes who took SGLT2 inhibitors before surgery had better outcomes, including lower death rates and fewer health problems. This is surprising because some earlier studies worried these medicines might increase risks. More detailed trials are needed to confirm these results.
3. Uric acid and future complications in young individuals with type 1 diabetes: results from the Diabetes Incidence Study in Sweden (DISS) and the National Diabetes Registry of Sweden (NDR).
In young-onset type 1 diabetes, higher baseline uric acid at diagnosis was associated with increased long-term risk of both macrovascular and microvascular complications over a median 19 years. Risk rose approximately 1% per 1 μmol/L increase, with the highest UA quartile conferring more than threefold higher risk.
Impact: Identifies uric acid as a potential early prognostic biomarker at diagnosis for young-onset type 1 diabetes, enabling risk stratification decades before complications emerge.
Clinical Implications: Baseline uric acid could inform early risk stratification and targeted prevention in young individuals with type 1 diabetes; interventional studies are needed to test whether UA lowering modifies outcomes.
Key Findings
- Baseline UA was higher in those who later developed complications (209.2 ± 68.9 vs 171.7 ± 50.2 μmol/L; p<0.001).
- Each 1 μmol/L increase in UA increased the odds of complications by about 1%.
- Participants in the highest UA quartile had over threefold higher risk of future diabetes-related complications (adjusted).
- Median follow-up was 19.0 years, leveraging national registry linkage for outcomes.
Methodological Strengths
- Nationwide cohort with long median follow-up and registry-based outcome ascertainment.
- Matched analysis controlling for key baseline variables (age at diagnosis, sex, HbA1c).
Limitations
- Sample size for complication cases was modest (n=94), potentially limiting precision.
- Residual confounding and incomplete covariate data (e.g., lifestyle factors) may remain.
Future Directions: Prospective validation and interventional trials to test UA lowering; integration of UA into multi-marker risk scores for type 1 diabetes complications.
AIMS/HYPOTHESIS: The aim of this work was to investigate whether baseline uric acid (UA) is associated with future complications among young individuals with newly diagnosed type 1 diabetes. METHODS: UA levels were analysed in individuals, aged 15-34 years with newly diagnosed type 1 diabetes, from the nationwide Diabetes Incidence Study in Sweden (DISS) cohort to assess the relationship with macro- and microvascular complications later in life. Information on complications was obtained by record linkage to the National Diabetes Registry of Sweden and the National Patient Registry of Sweden. Individuals who developed complications during follow-up (n = 94) were matched for year and age at diagnosis (±2 years), sex and HbA RESULTS: Plasma UA levels at the time of diabetes diagnosis were significantly higher in individuals who later developed diabetes-related complications compared with those who did not, after a median follow-up of 19.0 years (IQR 16.3-21.0): 209.2 ± 68.9 vs 171.7 ± 50.2 µmol/l (p<0.001). The odds of developing complications were 1% higher for every 1 μmol/l rise in baseline UA, and individuals within the highest quartile of UA were more than three times more likely to develop diabetes-related complications later in life after adjusting for age, HbA CONCLUSIONS/INTERPRETATION: This study indicates that higher baseline UA levels at the time of type 1 diabetes diagnosis may be linked to both macrovascular and microvascular complications later in life.