Janet B. McGill

Diabetes is a highly prevalent, chronic condition requiring complex treatment strategies and close monitoring. Achievement of optimal glucose management reduces vascular complications of diabetes and the long-term burden of the disease. Attenuation of postprandial rise in glucose is a critical component of overall glycemic management and often the most difficult for people with insulin-treated diabetes to achieve. While postprandial glucose (PPG) elevations are a consequence of insufficient endogenous insulin secretion or exogenous insulin dose to cover ingested carbohydrates, a mismatch between the absorption of nutrients and peak insulin concentration is also a key factor in managing PPG. Type 2 diabetes is characterized by loss of first-phase insulin secretion, resulting in elevations in PPG and prolongation of hyperglycemia after eating. In type 1 diabetes and other forms of insulin-requiring diabetes, insulin administration must match carbohydrate and other nutrient intake in both quantity and timing. Continuous glucose monitoring (CGM) has provided insights into glucose patterns and the effectiveness of diabetes therapies in managing glucose levels at all times of the day. When CGM is used with an automated insulin delivery pump or connected insulin pen, prandial insulin dosing can be analyzed for more effective coaching and education. Based on the 2026 American Diabetes Association Standards of Care guidelines, delivery devices and method of insulin administration should be assessed regularly and individualized based on the needs of each person, considering options such as automated insulin delivery, inhaled insulin, or multiple daily injections. This manuscript reviews the causes and contributors of postprandial hyperglycemia and strategies for its management. In particular, use of lifestyle management, insulin dose adjustments, timing of premeal insulin doses, and insulin kinetics will be reviewed for precision management of postprandial hyperglycemia.

Aims: This prespecified analysis evaluated whether the safety and efficacy of finerenone and a sodium–glucose cotransporter 2 inhibitor (SGLT2i) combination vary by baseline glycated haemoglobin (HbA1c). Materials and Methods: Adults with type 2 diabetes and a urinary albumin‐to‐creatinine ratio (UACR) of 100 − < 5000 mg/g, estimated glomerular filtration rate (eGFR) 30–90 mL/min/1.73 m ² and HbA1c < 11% (< 97 mmol/mol) were randomised (1:1:1) to once‐daily finerenone, empagliflozin or combination. Primary outcome was UACR change from baseline at Day 180. Results: Baseline HbA1c was available for 781/800 CONFIDENCE participants; baseline HbA1c and eGFR mean values (standard deviation) were 7.3% (1.2%) and 54.2 mL/min/1.73 m ² (17.1 mL/min/1.73 m ² ). At Day 180, HbA1c decreased with combination therapy and empagliflozin (both least‐squares mean change −0.1% [95% confidence interval −0.2, −0.0]), with no change with finerenone. In total, 212, 190, 188 and 191 participants were included in HbA1c Quartiles 1 (HbA1c ≤ 6.4% [≤ 46 mmol/mol]), 2 (HbA1c > 6.4 and ≤ 7.1% [> 46 and ≤ 54 mmol/mol]), 3 (HbA1c > 7.1 and ≤ 7.9% [> 54 and ≤ 63 mmol/mol]) and 4 (HbA1c > 7.9% [> 63 mmol/mol]), respectively. Change from baseline in HbA1c at Day 180 was greatest in Quartile 4. At Day 180, combination therapy reduced UACR from baseline in all HbA1c quartiles to a greater extent than either monotherapy (mean [95% CI] –53% [−63, −42], −47% [−57, −34], −63% [−70, −54] and −55% [−65, −42], in Quartiles 1–4, respectively). Conclusion: Simultaneous initiation with finerenone and an SGLT2i reduced UACR compared with monotherapy and was well‐tolerated irrespective of HbA1c levels.

BACKGROUND: This secondary analysis of the CONFIDENCE (combination effect of fInerenone and empagliflozin in participants with chronic kidney disease and type 2 diabetes using a UACR endpoint) trial (REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05254002) assessed systolic blood pressure (SBP) changes with empagliflozin/finerenone combination therapy versus monotherapy in people with chronic kidney disease and type 2 diabetes across baseline SBP categories. We assessed SBP response predictors and whether early (day 30) SBP changes mediate urinary albumin-to-creatinine ratio reductions. METHODS: Participants (n=800) were stratified by baseline SBP (P =0.004) or empagliflozin (odds ratio, 1.45 [95% CI, 0.97–2.17]; P =0.07). The strongest predictor of response was baseline SBP (odds ratio, 2.04 per 10 mm Hg higher SBP; P P <0.0001) but not in the <130 mm Hg group. SBP reduction mediated <10% of the total urinary albumin-to-creatinine ratio reduction. Acute kidney injury and hyperkalemia incidences were similar across SBP subgroups. CONCLUSIONS: Combination therapy reduced SBP more than monotherapies in participants with SBP ≥130 mm Hg. Urinary albumin-to-creatinine ratio reduction appeared largely independent of SBP changes at day 30; though this secondary analysis was limited by reliance on clinic blood pressure measurement. Prospective studies with ambulatory blood pressure monitoring are required.

Key Points: We investigated the effect of empagliflozin, finerenone, and their combination on eGFR decline in people with type 2 diabetes and albuminuria. Acute declines in eGFR occurred more in those on combination therapy, on diuretics, and with higher eGFR; eGFR changes were reversible. Finerenone's additive effect to empagliflozin on urinary albumin-to-creatinine ratio lowering was nonhemodynamic; empagliflozin lowered urinary albumin-to-creatinine ratio in part driven by eGFR change. Background: eGFR decline is common with sodium-glucose cotransporter 2 inhibitors and renin–angiotensin system inhibitors, often prompting treatment interruption or cessation, limiting cardiorenal benefits. This mostly prespecified COmbinatioN effect of FInerenone anD EmpaglifloziN in Participants with chronic kidney disease and type 2 diabetes using a UACR Endpoint (CONFIDENCE) trial analysis investigated the effect of empagliflozin, finerenone, and their combination on change from baseline in eGFR and its determinants and the relationship of change in eGFR with albuminuria reduction in people with type 2 diabetes and CKD. Methods: Evaluable participants ( N =790) with type 2 diabetes, CKD, and albuminuria, receiving stable doses of renin–angiotensin system inhibitors, were randomized 1:1:1 to empagliflozin, finerenone, or both. The primary outcome was urinary albumin-to-creatinine ratio (UACR) change from baseline to day 180. We assessed mean eGFR change from baseline at day 14 (acute), determinants of acute eGFR decline, and acute eGFR change from baseline as a mediator of UACR reduction at day 180. Results: The mean acute eGFR decline was greater with combination therapy (−6.6 ml/min per 1.73 m ² ) than with finerenone (−2.1 ml/min per 1.73 m ² ) or empagliflozin (−4.8 ml/min per 1.73 m ² ) monotherapy; P < 0.001. Acute decline in eGFR was significantly more pronounced among participants with higher baseline eGFR and in those receiving diuretics at baseline ( P < 0.001 for both factors). Baseline values for systolic BP and UACR had no statistically significant effect on acute eGFR decline. Exploratory analysis showed that acute eGFR change mediated 28% of the effect of adding empagliflozin to finerenone on UACR reduction at day 180 but only 5.2% of the effect when adding finerenone to empagliflozin. AKI was uncommon in all treatment groups. Conclusions: Acute eGFR decline was significantly associated with combination therapy, higher baseline eGFR, and diuretic use at baseline. Clinical Trial registry name and registration number: ClinicalTrials.gov, NCT05254002.

Introduction: Concurrent initiation of finerenone and empagliflozin can lower albuminuria more than component therapies at Day 180 in participants with chronic kidney disease (CKD) and type 2 diabetes (T2D ). We evaluated baseline clinical characteristics and longitudinal changes in urinary albumin-to-creatinine ratio (UACR) across age and sex cohorts. Methods: In CONFIDENCE (NCT05254002), participants with T2D, CKD (estimated glomerular filtration rate [eGFR] 30–90 ml/min/1.73 m2), and albuminuria (UACR 100 to 74 years) and sex. Outcomes included % change in UACR from baseline over time and incidences of key adverse events. Results: Increasing age was associated with higher baseline prevalence of atherosclerotic cardiovascular disease and lower eGFR. Older age was a significant predictor of UACR reduction, with –10.2% (95% CI: –15.5, –4.6) incremental change per 10-year age increase at Day 180 (P for age effect = 0.001). Women exhibited an 18.6% (95% CI: 6.3, 29.2) greater UACR reduction at Day 180 than men (P for sex effect = 0.008). These effects were independent of treatment; there was no interaction between age (P-interaction = 0.28) or sex (P-interaction = 0.46) on combination therapy treatment effect. Safety outcomes were consistent across all demographics. Conclusions: The UACR-lowering response of finerenone and empagliflozin scaled linearly with age (10% per decade) and sex (∼20% more among women). The benefit of combination therapy was independent of age and sex.

Key Points: We assessed whether baseline urine albumin-creatinine ratio (UACR) and eGFR modify treatment effects on UACR reduction and safety in the CONFIDENCE trial. Higher baseline eGFR or UACR, age, female sex, and atherosclerotic cardiovascular disease were associated with greater albuminuria lowering at 6 months (180 days). Treatment effects on efficacy and safety were consistent, with no significant heterogeneity across baseline UACR or eGFR groups. Background: In the CONFIDENCE trial, simultaneous initiation of finerenone (10 or 20 mg) and empagliflozin (10 mg) was superior to either monotherapy in reducing albuminuria at 180 days in participants with type 2 diabetes and CKD. In this analysis, we evaluated whether baseline urine albumin-creatinine ratio (UACR) and eGFR were associated with the magnitude of UACR reduction, and whether baseline UACR and eGFR modify the effect of combination treatment. Methods: In this post hoc analysis of the CONFIDENCE trial ( n =796), linear mixed-effects models were used to evaluate the effects of baseline UACR and eGFR on the change in UACR from baseline using subgroups on the basis of clinically relevant thresholds of UACR (2 ). Logistic regression models were used to assess the odds of achieving UACR reductions at day 180. Results: At day 180, higher baseline eGFR (per 10 ml/min per 1.73 m ² ) was independently associated with a −7% (95% confidence interval [CI], −11 to −4) greater reduction in UACR ( P < 0.001), and higher baseline UACR (per log change of UACR) was independently associated with a −9% (95% CI, −14 to −3) greater reduction in UACR ( P < 0.001). However, the treatment effect of finerenone, empagliflozin, or their combination on changes in UACR levels was not modified by baseline levels of eGFR or UACR. Besides the use of combination therapy, independent predictors of >30% reduction in UACR were age (odds ratio [OR], 1.23 per 10 years [95% CI, 1.05 to 1.45]), female sex (OR, 1.95 [95% CI, 1.32 to 2.86]), and atherosclerotic cardiovascular disease (OR, 1.63 [95% CI, 1.13 to 2.35]). The safety end points showed no significant heterogeneity across UACR or eGFR. Conclusions: Overall, greater albuminuria lowering was seen with a higher baseline eGFR or UACR, older age, in female patients, and those with atherosclerotic cardiovascular disease, irrespective of the treatment. Albuminuria-lowering with combination therapy, finerenone, or empagliflozin treatment effects were independent of baseline eGFR or UACR. Clinical Trial registry name and registration number: ClinicalTrials.gov, NCT05254002; European Union Drug Regulating Authorities Clinical Trials Database 2021-003037-11.

Key Points: Finerenone plus empagliflozin was more effective in reducing urinary albumin-to-creatinine ratio than either drug alone in Asian participants of the CONFIDENCE trial. Except for hyperkalemia, adverse events and serious adverse events were less frequent in participants from Asia than in the overall CONFIDENCE trial population. The risk–benefit profile of the combination seems similarly favorable in people from Asia as in the overall CONFIDENCE trial population. Background: The COmbinatioN effect of FInerenone anD EmpaglifloziN in participants with CKD and type 2 diabetes using a urinary albumin-to-creatinine ratio (UACR) Endpoint (CONFIDENCE) trial compared simultaneous initiation of finerenone with empagliflozin versus either drug alone. We report a pre-specified participant-level exploratory analysis of outcomes in the subpopulation from Asia (India, Japan, the Republic of Korea, and Taiwan). Methods: Adults with CKD and type 2 diabetes with UACR between 100 and 5000 mg/g and on a renin–angiotensin system inhibitor were recruited. Participants were randomized 1:1:1 to 180 days of treatment with finerenone 10/20 mg once daily (and empagliflozin-matching placebo), empagliflozin 10 mg once daily (and finerenone-matching placebo), or a combination of both. The primary efficacy outcome was change from baseline in UACR at 180 days. Safety and tolerability were also assessed. Results: This analysis included 360 participants from Asia. At day 180, the reduction in UACR with combination therapy was 30% greater than that with finerenone alone (95% confidence interval [CI], 12% to 45%; P = 0.003) and 34% greater than that with empagliflozin alone (95% CI, 16% to 47%; P < 0.001). In general, adverse and serious adverse events were numerically less common in participants from Asia than in those from Europe/North America, except for hyperkalemia. Investigator-reported (10% versus 7%) and laboratory-assessed hyperkalemia (serum potassium >5.5 mmol/L; 19% versus 11%) were more frequent in participants from Asia; however, eGFR declines of >30% at day 30 were less frequent in Asia (3% versus 5%). Conclusions: Simultaneous initiation of finerenone and empagliflozin was effective and well tolerated among CONFIDENCE study participants from Asia, consistent with the overall population.

Chronic kidney disease (CKD) is a common comorbidity of both type 1 diabetes (T1D) and type 2 diabetes (T2D) and is associated with increased mortality, end-stage kidney disease and cardiovascular disease risk. Despite standard-of-care treatment with renin–angiotensin system inhibitors added to blood pressure and glycaemic control, people with CKD and T1D have a residual risk of CKD progression. Advances in therapeutic management have been limited over the past 3 decades, especially compared with CKD in T2D, for which new treatment options have emerged in the last 5 years. In this review article we discuss the similarities and differences between T1D and T2D populations with CKD, including epidemiology, pathophysiology and clinical findings. Additionally, we explore the use of albuminuria as a potential bridging biomarker to extrapolate clinical evidence from one population to the other. This concept could offer a promising strategy to narrow the gap in treatment availability between these populations and address the unmet therapeutic need in people with CKD and T1D. The FINE-ONE trial is investigating the non-steroidal mineralocorticoid receptor antagonist finerenone in a population with CKD and T1D using the change in urine albumin:creatinine ratio from baseline over 6 months as its primary endpoint and bridging biomarker. Similarities between the populations from FINE-ONE trial and FIDELITY (a pooled dataset of individuals with CKD and T2D included in two large phase 3 clinical trials of finerenone) may inform the translation of clinical evidence on finerenone from people with CKD and T2D to those with CKD and T1D.

Key Points: Frailty is associated with a higher risk of adverse outcomes in people with CKD and type 2 diabetes. Finerenone reduced the risk of kidney and cardiovascular outcomes irrespective of baseline frailty. Finerenone was well tolerated; the relative risk of adverse events remained consistent between treatment arms across the frailty subgroups. Background: Frailty is associated with a higher risk of adverse outcomes. It is believed that people with a higher frailty index (FI) may be less tolerant to new treatments, often leading to inappropriate prescribing. This post hoc analysis of FInerenone in chronic kiDney diseasE and type 2 diabetes: Combined FInerenone in reducing kiDnEy faiLure and dIsease prOgression in Diabetic Kidney Disease (FIDELIO-DKD) and FIGARO-DKD Trial program analysis, a prespecified, pooled analysis of the FIDELIO-DKD and FIGARO-DKD phase 3 clinical trials, investigated the efficacy and safety of finerenone versus placebo according to baseline FI. Methods: Between September 2015 and October 2018, 12,990 people with CKD and type 2 diabetes receiving the maximum tolerated dose of a renin-angiotensin system inhibitor were randomized to receive finerenone 10 or 20 mg once daily or placebo. Baseline FI was calculated using the Rockwood cumulative deficit approach including 30 clinical characteristics. Primary efficacy outcomes included a kidney (kidney failure, sustained decrease of ≥57% in eGFR, or kidney-related death) and a cardiovascular (CV) composite outcome (CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure). Changes in urine albumin-to-creatinine ratio and eGFR were measured across the study period. Results: Overall, kidney and CV event rates increased with increasing frailty. Finerenone reduced the risk of primary kidney and CV composite outcomes irrespective of baseline frailty (P interaction = 0.93 and 0.35, respectively). Compared with placebo, finerenone also demonstrated significant reductions in urine albumin-to-creatinine ratio across all frailty subgroups (P < 0.01 for all visits) and significant attenuation of eGFR decline from baseline to month 48 in the three most frail quartiles (>Q1 to ≤Q2, P = 0.001; >Q2 to ≤Q3, P < 0.001; >Q3, P < 0.001, respectively). The incidence of serious adverse events and hyperkalemia increased with increasing frailty in both treatment arms. Conclusions: Finerenone reduced the risk of CV and kidney events in people with CKD and type 2 diabetes versus placebo irrespective of baseline frailty status. Clinical Trial registry name and registration number: FIDELIO-DKD (NCT02540993) and FIGARO-DKD (NCT02545049).

Background: Breath acetone (BrACE) is an end product of ketone metabolism that is measurable by noninvasive breath ketone analyzers. We assessed the correlation between capillary blood β-hydroxybutyrate (BOHB) and BrACE in people with type 1 diabetes during 14 days of outpatient care with and without dapagliflozin treatment and during supervised insulin withdrawal studies with and without dapagliflozin. Methods: In this randomized crossover study, participants completed two 14-day outpatient periods with or without dapagliflozin 10 mg daily. Each 14-day unsupervised outpatient period was followed by a 1-day supervised insulin withdrawal study. Paired BOHB and BrACE measurements were obtained 3 times daily during outpatient periods, then hourly during supervised insulin withdrawal. The correlation between BrACE and BOHB was assessed by Spearman’s ρ. Results: Twenty people with type 1 diabetes completed the study. During outpatient periods, BrACE and BOHB were moderately correlated (n = 1425 paired readings; ρ = .41; 95% CI = 0.36 to 0.45; P < .0001). However, BrACE and BOHB were strongly correlated during insulin withdrawal (n = 246 paired values, ρ = .81; 95% CI = 0.77 to 0.85). In ROC analysis, BrACE > 5 ppm demonstrated optimal sensitivity (93%) and specificity (87%) for detecting capillary BOHB ≥ 1.5 mmol/L. No serious adverse events occurred. Conclusions: In adults with type 1 diabetes, measurement of breath acetone provides a noninvasive estimate of blood BOHB concentration. The correlation between BrACE and BOHB was suboptimal during unsupervised outpatient care, but was strong during supervised insulin withdrawal. Trial registration: clinicaltrials.gov (NCT05541484)