Ertugliflozin and incident obstructive sleep apnea: an analysis from the VERTIS CV trial.

PURPOSE: The sodium-glucose transporter 2 inhibitor (SGLT2i) empagliflozin may reduce the incidence of obstructive sleep apnea (OSA) in patients with type 2 diabetes (T2D) and cardiovascular (CV) disease. This analysis of VERTIS CV, the CV outcome trial for the SGLT2i ertugliflozin conducted in a similar group of patients, explored the effects of ertugliflozin on reported incident OSA. METHODS: In VERTIS CV, patients ≥ 40 years with T2D and atherosclerotic CV disease (ASCVD) were randomized to ertugliflozin 5 or 15 mg or placebo. The primary endpoint was the composite of major adverse CV events. This exploratory analysis evaluated the impact of ertugliflozin (5 and 15 mg pooled) on incident OSA. Patients with prevalent OSA were excluded. Incident OSA events were based on investigator-reported events using the MedDRA SMQ term "sleep apnea syndrome." A multivariable Cox proportional hazards regression model was constructed to assess the association between ertugliflozin and incident OSA. RESULTS: Of 8246 patients enrolled, 7697 (93.3%) were without baseline OSA (placebo, n = 2561; ertugliflozin, n = 5136; mean age 64.4 years; BMI 31.7 kg/m2; HbA1c, 8.2%; 69.2% male; 88.3% White). The OSA incidence rate was 1.44 per 1000 person-years versus 2.61 per 1000 person-years among patients treated with ertugliflozin versus placebo, respectively, corresponding to a 48% relative risk reduction (HR 0.52; 95% CI 0.28-0.96; P = 0.04). CONCLUSIONS: In VERTIS CV, ertugliflozin reduced by nearly half the incidence of OSA in patients with T2D and ASCVD. These data contribute to the literature that SGLT2is may have a significant beneficial impact on OSA. CLINICALTRIALS: gov identifier: NCT01986881.

Lessons Learned From Major Clinical Outcomes Trials Involving Sodium-Glucose Cotransporter 2 Inhibitors.

Diabetes is a known risk factor for the development of cardiovascular and chronic kidney disease. Sodium-glucose cotransporter 2 inhibitors are glucose-lowering medications that have been demonstrated to improve clinical cardiovascular and renal outcomes. This article reviews recent large clinical trials involving these medications and explains their impact on type 2 diabetes treatment guidelines.

Effect of obesity on sleep apnea pathogenesis differs in women versus men: multiple mediation analyses in the retrospective SNOOzzzE cohort.

There are multiple mechanisms underlying obstructive sleep apnea (OSA) development. However, how classic OSA risk factors such as body mass index (BMI) and sex portend to OSA development has not been fully described. Thus we sought to evaluate how obesity leads to OSA and assess how these mechanisms differ between men and women. The San Diego Multi-Outcome OSA Endophenotype (SNOOzzzE) cohort includes 3,319 consecutive adults who underwent a clinical in-laboratory polysomnography at the University of California, San Diego, sleep clinic between January 2017 and December 2019. Using routine polysomnography signals, we determined OSA endotypes. We then performed mediation analyses stratified by sex to determine how BMI influenced the apnea-hypopnea index (AHI) using OSA pathophysiological traits as mediators, adjusting for age, race, and ethnicity. We included 2,146 patients of whom 919 (43%) were women and 1,227 (57%) were obese [body mass index (BMI) > 30 kg/m2]. BMI was significantly associated with AHI in both women and men. In men, the adjusted effect of BMI on AHI was partially mediated by a reduction in upper airway stiffness (ßstandardized = 0.124), a reduction in circulatory delay (ßstandardized = 0.063), and an increase in arousal threshold (ßstandardized = 0.029; Pboot-strapped,all < 0.05). In women, the adjusted effect of BMI on AHI was partially mediated by a reduction in upper airway stiffness (ßstandardized = 0.05) and circulatory delay (ßstandardized = 0.037; Pboot-strapped,all < 0.05). BMI-related OSA pathogenesis differs by sex. An increase in upper airway collapsibility is consistent with prior studies. A reduction in circulatory delay may lead to shorter and thus more events per hour (higher AHI), while the relationship between arousal threshold and OSA is likely complex.NEW & NOTEWORTHY Our data provide important insights into obesity-related obstructive sleep apnea (OSA) pathogenesis, thereby validating, and extending, prior research findings. This is the largest sample size study to examine the relationships between obesity and gender on OSA pathogenesis. The influence of obesity on sleep apnea severity is mediated by different mechanistic traits (endotypes).

Role of metformin in the management of type 2 diabetes: recent advances.

Metformin is one of the oldest antidiabetic medications, commonly used in the management of type 2 diabetes. Its mechanism of action is based on reducing glucose production in the liver, decreasing insulin resistance, and increasing insulin sensitivity. The drug has been studied extensively and has been shown to be effective in lowering blood glucose levels without increasing the risk of hypoglycemia. It has been used for the treatment of obesity, gestational diabetes, and polycystic ovary syndrome. According to current guidelines, metformin can be used as the first­line agent in the management of diabetes; however, in individuals with type 2 diabetes who would benefit from cardio­renal protection, newer agents, such as sodium­glucose cotransporter­2 inhibitors and glucagon­like peptide­1 receptor agonists, are favored as the first­line therapy. The novel classes of antidiabetic medications have demonstrated significant positive effects on glycemia with added benefits in patients with obesity, renal disease, heart failure, and cardiovascular disease. The emergence of these more effective agents has significantly altered the way diabetes is managed, thus prompting re­evaluation of metformin as the initial therapy for all patients with diabetes.

Polysomnographic predictors of incident diabetes and pre-diabetes: an analysis of the DREAM study.

STUDY OBJECTIVES: We sought to evaluate sleep measures that better predict incident diabetes and prediabetes in a large cohort of veterans. METHODS: This secondary analysis included 650 patients without baseline diabetes from a multisite observational veterans' cohort. Participants underwent obstructive sleep apnea evaluation via laboratory-based polysomnography between 2000 and 2004 with follow-up through 2012. The primary outcomes were prediabetes and diabetes defined by fasting blood glucose, hemoglobin A1c, or use of glucose-lowering medication at study initiation. Exposure variables included respiratory event frequency, arousals, and oxygen desaturation. Cox models adjusted for body mass index, age, race, sex, change in body mass index, and continuous positive airway pressure device utilization. RESULTS: The adjusted analysis revealed that time spent with oxygen saturation less than 90 [hazards ratio (HR) 1.009], confidence interval (CI) 1.001-1.017, P = .02), respiratory arousals (HR 1.009, CI 1.003-1.015, P < 0.01) and total arousals (HR 1.006 CI 1.001-1.011 P = .02) were associated with an increased incidence of diabetes. Increases in mean nocturnal oxygen saturation were associated with decreased incidence of diabetes (HR 0.914 CI 0.857-0.975, P < .01) and prediabetes (HR 0.914 CI 0.857-0.975, P < .01). No significant relationships were demonstrated for apnea-hypopnea index (AHI), measures related to central apnea, Cheyne-Stokes respiration, periodic limb movements, or Epworth Sleepiness Scale score. CONCLUSIONS: There was no significant association of incident prediabetes or diabetes with AHI, the gold standard of sleep apnea severity. This study suggests that hypoxia may be a better predictor of glycemic outcomes than AHI in an obstructive sleep apnea population and may provide clues to the underlying mechanism(s) that link sleep-disordered breathing and its metabolic consequences. CITATION: Wojeck BS, Inzucchi SE, Qin L, Yaggi HK. Polysomnographic predictors of incident diabetes and pre-diabetes: an analysis of the DREAM study. J Clin Sleep Med. 2023;19(4):703-710.

Polysomnographic Phenotypes of Obstructive Sleep Apnea and Incident Type 2 Diabetes: Results from the DREAM Study.

Rationale: Obstructive sleep apnea (OSA) is associated with cardiovascular disease and incident type 2 diabetes (T2DM). Seven OSA phenotypes, labeled on the basis of their most distinguishing polysomnographic features, have been shown to be differentially associated with incident cardiovascular disease. However, little is known about the relevance of polysomnographic phenotypes for the risk of T2DM. Objectives: To assess whether polysomnographic phenotypes are associated with incident T2DM and to compare the predictive value of baseline polysomnographic phenotypes with the Apnea-Hypopnea Index (AHI) for T2DM. Methods: The study included 840 individuals without baseline diabetes from a multisite observational U.S. veteran cohort who underwent OSA evaluation between 2000 and 2004, with follow-up through 2012. The primary outcome was incident T2DM, defined as no diagnosis at baseline and a new physician diagnosis confirmed by fasting blood glucose >126 mg/dL during follow-up. Relationships between the seven polysomnographic phenotypes (1. mild, 2. periodic limb movements of sleep [PLMS], 3. non-rapid eye movement and poor sleep, 4. rapid eye movement and hypoxia, 5. hypopnea and hypoxia, 6. arousal and poor sleep, and 7. combined severe) and incident T2DM were investigated using Cox proportional hazards regression and competing risk regression models with and without adjustment for baseline covariates. Likelihood ratio tests were conducted to compare the predictive value of the phenotypes with the AHI. Results: During a median follow-up period of 61 months, 122 (14.5%) patients developed incident T2DM. After adjustment for baseline sociodemographics, fasting blood glucose, body mass index, comorbidities, and behavioral risk factors, hazard ratios among persons with "hypopnea and hypoxia" and "PLMS" phenotypes as compared with persons with "mild" phenotype were 3.18 (95% confidence interval [CI], 1.53-6.61] and 2.26 (95% CI, 1.06-4.83) for incident T2DM, respectively. Mild OSA (5 ⩽ AHI < 15) (vs. no OSA) was directly associated with incident T2DM in both unadjusted and multivariable-adjusted regression models. The addition of polysomnographic phenotypes, but not AHI, to known T2DM risk factors greatly improved the predictive value of the computed prediction model. Conclusions: Polysomnographic phenotypes "hypopnea and hypoxia" and "PLMS" independently predict risk of T2DM among a predominantly male veteran population. Polysomnographic phenotypes improved T2DM risk prediction comared with the use of AHI.

The Impact of Empagliflozin on Obstructive Sleep Apnea and Cardiovascular and Renal Outcomes: An Exploratory Analysis of the EMPA-REG OUTCOME Trial.

OBJECTIVE: To explore the effects of empagliflozin on the incidence of obstructive sleep apnea (OSA) and its effects on metabolic, cardiovascular (CV), and renal outcomes among participants with or without OSA in the EMPA-REG OUTCOME trial. RESEARCH DESIGN AND METHODS: Participants with diabetes and CV disease were randomized to empagliflozin (10 and 25 mg) or placebo daily in addition to standard of care. OSA was assessed by investigator report using Medical Dictionary for Regulatory Activities version 18.0, and CV outcomes were independently adjudicated. Analyses were performed using multivariable-adjusted Cox regression models. RESULTS: OSA was reported in 391 of 7,020 (5.6%) participants at baseline. Those with OSA were more likely to be male (83% vs. 71%) and to have moderate to severe obesity (BMI ≥35 kg/m2; 55% vs. 18%). Over a median of 3.1 years, empagliflozin had similar placebo-adjusted reductions in HbA1c, waist circumference, and systolic blood pressure, regardless of OSA status, but a larger effect on weight (adjusted mean ± SE difference at week 52: OSA vs. no OSA -2.9 ± 0.5 vs. -1.9 ± 0.1 kg). Incidence of 3-point major adverse CV events, CV death, heart failure hospitalization, and incident or worsening nephropathy in the placebo group was 1.2- to 2.0-fold higher for those with baseline OSA compared with those without. Empagliflozin significantly reduced the risk for outcomes regardless of OSA status (P-interaction all >0.05). Fifty patients reported a new diagnosis of OSA through 7 days after medication discontinuation, and this occurred less often with empagliflozin treatment (hazard ratio 0.48 [95% CI 0.27, 0.83]). CONCLUSIONS: In EMPA-REG OUTCOME, participants with OSA had greater comorbidity and higher frequency of CV and renal events. Empagliflozin had favorable effects on risk factors and CV and renal outcomes regardless of preexisting OSA and may also reduce the risk for new-onset OSA.