Ethnic Disparities in the Risk Factors, Morbidity, and Mortality of Cardiovascular Disease in People With Diabetes.

Cardiovascular disease (CVD) is the leading cause of death in people with diabetes. Compared with European Americans, African Americans have more favorable lipid profiles, as indicated by higher high-density lipoprotein cholesterol, lower triglycerides, and less dense low-density lipoprotein particles. The less atherogenic lipid profile translates to lower incidence and prevalence of CVD in African Americans with diabetes, despite higher rates of hypertension and obesity. However, African Americans with CVD experience worse clinical outcomes, including higher mortality, compared with European Americans. This mini-review summarizes the epidemiology, pathophysiology, mechanisms, and management of CVD in people with diabetes, focusing on possible factors underlying the "African American CVD paradox" (lower CVD incidence/prevalence but worse outcomes). Although the reasons for the disparities in CVD outcomes remain to be fully elucidated, we present a critical appraisal of the roles of suboptimal control of risk factors, inequities in care delivery, several biological factors, and psychosocial stress. We identify gaps in current knowledge and propose areas for future investigation.

Plasma Sphingolipid Profile of Healthy Black and White Adults Differs Based on Their Parental History of Type 2 Diabetes.

CONTEXT: Ceramides and sphingolipids have been linked to type 2 diabetes (T2D). The Ceramides and Sphingolipids as Predictors of Incident Dysglycemia (CASPID) study is designed to determine the association of plasma sphingolipids with the pathophysiology of human T2D. OBJECTIVE: A comparison of plasma sphingolipids profiles in Black and White adults with (FH+) and without (FH-) family history of T2D. DESIGN: We recruited 100 Black and White FH- (54 Black, 46 White) and 140 FH+ (75 Black, 65 White) adults. Fasting plasma levels of 58 sphingolipid species, including 18 each from 3 major classes (ceramides, monohexosylceramides, and sphingomyelins, all with 18:1 sphingoid base) and 4 long-chain sphingoid base-containing species, were measured by liquid chromatography/mass spectrometry. RESULTS: Sphingomyelin was the most abundant sphingolipid in plasma (89% in FH-), and was significantly elevated in FH+ subjects (93%). Ceramides and monohexosylceramides comprised 5% and 6% of total sphingolipids in the plasma of FH- subjects, and were reduced significantly in FH+ subjects (3% and 4%, respectively). In FH+ subjects, most ceramide and monohexosylceramide species were decreased but sphingomyelin species were increased. The level of C18:1 species of all 3 classes was elevated in FH+ subjects. CONCLUSION: Elevated levels of sphingomyelin, the major sphingolipids of plasma, and oleic acid-containing sphingolipids in healthy FH+ subjects compared with healthy FH- subjects may reflect heritable elements linking sphingolipids and the development of T2D.

Ceramides and other sphingolipids as predictors of incident dysglycemia (CASPID): Design, methods, and baseline characteristics.

The Ceramides and other Sphingolipids as Predictors of Incident Dysglycemia (CASPID) study tests the overall hypothesis that sphingolipids are pathophysiologic mediators of transition from normal glucose regulation (NGR) to prediabetes, type 2 diabetes (T2DM), and associated complications. The CASPID study utilizes two longitudinal cohorts - the Pathobiology of Prediabetes in a Biracial Cohort (POP-ABC)/Pathobiology and Reversibility of Prediabetes in a Biracial Cohort (PROP-ABC) and the Diabetes Prevention Program (DPP)/DPP Outcomes Study (DPPOS). Normoglycemic POP-ABC/PROP-ABC were followed for 10 years for progression to prediabetes and offered lifestyle intervention to reverse prediabetes. The DPP/DPPOS participants had prediabetes at enrollment, were randomized to placebo, lifestyle intervention, or metformin treatment, and followed for 11 years for progression to T2DM. Using a case-control design, we analyze 76 targeted plasma sphingolipids as predictors of progression from NGR to prediabetes (Aim 1), prediabetes to T2DM (Aim 2), response to interventions (Aim 3), and development of diabetes complications (Aim 4). A sample size of 600 subjects provides >80% power to detect a 20% difference in sphingolipid profiles between comparison groups (alpha = 0.01). At enrollment, POP-ABC participants had a mean age of 47.7 ± 9.00 years, body mass index (BMI) 30.4 ± 6.10 kg/m2, fasting glucose 92.9 ± 6.90 mg/dL, and 2-h glucose 130 ± 28.8 mg/dL; DPP participants had a mean age of 51.9 ± 9.44 years, BMI 33.7 ± 6.33 kg/m2, fasting glucose 106 ± 7.88 mg/dL, and 2-h glucose 164 ± 16.9 mg/dL. Among normoglycemic participants, those with parental history of T2DM had significantly higher baseline levels of total sphingomyelins, and lower levels of total ceramides and sphingosine, compared with control subjects without familial diabetes history. As the first such study in longitudinal human cohorts, CASPID will elucidate the role of sphingolipids in the pathogenesis of dysglycemia and facilitate the discovery of novel predictive and prognostic biomarkers.

Update on Medical Management of Diabetes: Focus on Relevance for Orthopedic Surgeons.

Diabetes mellitus affects more than 30 million US adults and 537 million people worldwide and accounts for major complications, including more than 100,000 lower extremity amputations annually in the United States. Peripheral neuropathy, peripheral vascular disease, and foot ulcers are frequent findings in diabetes patients at risk for amputation. Suboptimal care of early foot lesions increases the risk of amputation. Studies have shown that these complications can be prevented in people with type 1 and type 2 diabetes by optimizing glycemic control and comorbid risk factors. This review focuses on evaluating and managing diabetes, which should interest orthopedic surgeons.

Diagnosis and Management of Prediabetes: A Review.

Importance: Prediabetes, an intermediate stage between normal glucose regulation and diabetes, affects 1 in 3 adults in the US and approximately 720 million individuals worldwide. Observations: Prediabetes is defined by a fasting glucose level of 100 to 125 mg/dL, a glucose level of 140 to 199 mg/dL measured 2 hours after a 75-g oral glucose load, or glycated hemoglobin level (HbA1C) of 5.7% to 6.4% or 6.0% to 6.4%. In the US, approximately 10% of people with prediabetes progress to having diabetes each year. A meta-analysis found that prediabetes at baseline was associated with increased mortality and increased cardiovascular event rates (excess absolute risk, 7.36 per 10 000 person-years for mortality and 8.75 per 10 000 person-years for cardiovascular disease during 6.6 years). Intensive lifestyle modification, consisting of calorie restriction, increased physical activity (≥150 min/wk), self-monitoring, and motivational support, decreased the incidence of diabetes by 6.2 cases per 100 person-years during a 3-year period. Metformin decreased the risk of diabetes among individuals with prediabetes by 3.2 cases per 100 person-years during 3 years. Metformin is most effective for women with prior gestational diabetes and for individuals younger than 60 years with body mass index of 35 or greater, fasting plasma glucose level of 110 mg/dL or higher, or HbA1c level of 6.0% or higher. Conclusions and Relevance: Prediabetes is associated with increased risk of diabetes, cardiovascular events, and mortality. First-line therapy for prediabetes is lifestyle modification that includes weight loss and exercise or metformin. Lifestyle modification is associated with a larger benefit than metformin.

Plasma FGF-21 and Sclerostin Levels, Glycemia, Adiposity, and Insulin Sensitivity in Normoglycemic Black and White Adults.

Increased circulating fibroblast growth factor (FGF)-21 and sclerostin levels have been reported in patients with type 2 diabetes (T2D). We assessed the association of FGF-21 and sclerostin with adiposity, glycemia, and glucoregulatory measures in healthy subjects. We studied 20 normoglycemic Black and White offspring of parents with T2D. Assessments included oral glucose tolerance test, insulin sensitivity (Si-clamp), insulin secretion (homeostasis model assessment index of b-cell function [HOMA-B]), and body fat (dual-energy X-ray absorptiometry). Fasting plasma FGF-21 and sclerostin levels were measured with enzyme-linked immunosorbent assays. The participants' mean (+SD) age was 50.4 ± 5.97 years; body mass index (BMI) 32.5 ± 5.86 kg/m2; fasting plasma glucose (FPG) 96.1 ± 5.21 mg/dL, and 2-hour postload glucose 116 ± 5.45 mg/dL. FGF-21 levels were similar in Black people vs White people (0.36 ± 0.15 ng/mL vs 0.39 ± 0.25 ng/mL), men vs women (0.45 ± 0.14 vs 0.44 ± 0.07 ng/mL), correlated positively with BMI (r = 0.23, P = .05) and waist circumference (r = 0.27, P = .04), and inversely with FPG (r = -0.26, P = .05). Sclerostin levels also were similar in Black people (33.5 ± 17.1 pmol/L) vs White people (34.2 ± 6.41 pmol/L), men vs women (35.3 ± 9.01 pmol/L vs 32.3 ± 15.8 pmol/L), and correlated inversely with FPG (r = -0.11 to -0.44) but not adiposity measures. The correlation coefficient between Si-clamp values and FGF-21 levels was -0.31 (P = .09) compared with 0.04 (P = .89) for sclerostin levels. FGF-21 and sclerostin levels were not correlated with each other or HOMA-B. Among healthy Black and White subjects, plasma FGF-21 and sclerostin showed differential associations with adiposity but concordant association with FPG levels.

Severe Hypoglycemia and Incident Heart Failure Among Adults With Type 2 Diabetes.

CONTEXT: The association of severe hypoglycemia on the incidence of heart failure (HF) is unclear. OBJECTIVE: We evaluated the association of severe hypoglycemia with incident HF among individuals with type 2 diabetes. METHODS: We included participants with type 2 diabetes from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study. Severe hypoglycemia episodes were assessed during the initial 24 months following randomization and defined using 2 methods: (1) symptomatic, severe hypoglycemic event requiring medical assistance (first definition); or (2) requiring any assistance (second definition). Participants without HF at baseline and during the first 24 months of the study were prospectively followed for incident HF hospitalization. Multivariable Cox regression was used to generate adjusted hazard ratios (HR) for the association of severe hypoglycemia and incident HF. RESULTS: Among 9208 participants (mean age 63 years, 38% female, 62% White), 365 had ≥ 1 episode of severe hypoglycemic. Over a median follow-up duration of 3 years, there were 249 incident HF events. After multivariable adjustment for relevant confounders, participants with severe hypoglycemia requiring medical assistance had a 68% higher relative risk of incident HF (HR 1.68; 95% CI, 1.06-2.66), as compared with individuals who never experienced any episode of hypoglycemia. Severe hypoglycemia requiring any assistance was also associated with a 49% higher relative risk of HF (HR 1.49; 95% CI, 1.01-2.21). CONCLUSION: In a large cohort of adults with type 2 diabetes, severe hypoglycemia was independently associated with greater risk of incident HF.

Association of bone mineral density with prediabetes risk among African-American and European-American adult offspring of parents with type 2 diabetes.

Introduction: Type 2 diabetes mellitus (T2DM) is associated with alterations in bone mineral density (BMD), but association between prediabetes and BMD is unclear. Methods: We analyzed BMD among the initially normoglycemic participants in the Pathobiology of Prediabetes in a Biracial Cohort (POP-ABC) study in relation to incident prediabetes during 5 years of follow-up. Results and Discussion: A total of 343 participants (193 Black, 150 White) underwent DEXA during Year 1 of POP-ABC and were followed quarterly for 5 years. The mean age was 44.2 ± 10.6 years; BMI was 30.2 ± 7.23 kg/m2. At baseline, the mean BMD was 1.176 ± 0.135 g/cm2 (1.230 ± 0.124 g/cm2 in men vs. 1.154 ± 0.134 g/cm2 in women, P<0.0001; 1.203 ± 0.114 g/cm2 in Black vs. 1.146 ± 0.150 g/cm2 in White participants, P=0.0003). During 5 years of follow-up, 101 participants developed prediabetes and 10 subjects developed T2DM (progressors); 232 were nonprogressors. Progressors to prediabetes had numerically higher baseline BMD and experienced lower 1-year decline in BMD (P<0.0001) compared with nonprogressors. From Kaplan-Meier analysis, the time to 50% prediabetes survival was 2.15 y among participants in the lowest quartile of baseline BMD, longer than those in higher quartiles (1.31 - 1.41 y). Values for BMD correlated inversely with age and adiponectin levels, and positively with BMI. In logistic regression analysis, BMD z score significantly predicted incident prediabetes: more negative BMD z scores were associated with decreased incident prediabetes (odds ratio 0.598 [95% confidence interval 0.407 - 0.877], P=0.0085), after controlling for age, BMI, change in BMI, ethnicity, blood glucose and adiponectin. Conclusions: Among initially normoglycemic individuals, higher baseline BMD was associated with higher risk of incident prediabetes during 5 years of follow-up.

Islet cell encapsulation - Application in diabetes treatment.

In this minireview, we briefly outline the hallmarks of diabetes, the distinction between type 1 and type 2 diabetes, the global incidence of diabetes, and its associated comorbidities. The main goal of the review is to highlight the great potential of encapsulated pancreatic islet transplantation to provide a cure for type 1 diabetes. Following a short overview of the different approaches to islet encapsulation, we provide a summary of the merits and demerits of each approach of the encapsulation technology. We then discuss various attempts to clinical translation with each model of encapsulation as well as the factors that have mitigated the full clinical realization of the promise of the encapsulation technology, the progress that has been made and the challenges that remain to be overcome. In particular, we pay significant attention to the emerging strategies to overcome these challenges. We believe that these strategies to enhance the performance of the encapsulated islet constructs discussed herein provide good platforms for additional work to achieve successful clinical translation of the encapsulated islet technology.

Cardiovascular outcomes of antidiabetes medications by race/ethnicity: A systematic review and meta-analysis.

BACKGROUND: The consistency of cardiovascular risk reduction by antidiabetes medications across racial and ethnic groups remains unclear. The aim of this study was to analyze racial/ethnic patterns in the results of cardiovascular outcomes trials of antidiabetes medications in people with type 2 diabetes. METHOD: PubMed and Cochrane library databases were searched from the inception dates to December 2020. Cardiovascular outcome trials in type 2 diabetes that randomized participants to antidiabetes medication or control treatment and reported results by race/ethnic groups or region were included. RESULTS: A total of 19 studies were included in this meta-analysis. Among White participants, treatment with antidiabetes medications significantly decreased the risk of composite cardiovascular outcomes when compared with placebo treatment (OR = 0.88, 95% CI 0.83-0.94, p < 0.05). Among Asian participants, antidiabetes medications also significantly decreased the risk of composite cardiovascular outcomes when compared with control treatment (OR = 0.80, 95% CI 0.74-0.86, p < 0.05). A similar pattern was found when analyzing the effects of antidiabetes medications vs. control treatment in other racial/ethnic groups comprising mostly Hispanics and Pacific Islanders (OR = 0.87, 95% CI 0.78-0.98, p < 0.05). However, among Black participants, treatment with antidiabetes medications resulted in nominal but non-significant decreases in the composite cardiovascular outcomes when compared with control treatment (OR = 0.84, 95% CI 0.62-1.14, p = 0.26). CONCLUSIONS: The present meta-analysis showed cardiovascular safety of antidiabetes medications in people with type 2 diabetes from all racial/ethnic groups studied; however, significant composite cardiovascular risk reductions were demonstrated only in White and Asian participants. To determine whether antidiabetes drugs confer consistent cardiovascular benefits in Black and other racial/ethnic participants requires more investigations in the future.

Association of plasma acylcarnitines with insulin sensitivity, insulin secretion, and prediabetes in a biracial cohort.

The ability to predict prediabetes, which affects ∼90 million adults in the US and ∼400 million adults worldwide, would be valuable to public health. Acylcarnitines, fatty acid metabolites, have been associated with type 2 diabetes risk in cross-sectional studies of mostly Caucasian subjects, but prospective studies on their link to prediabetes in diverse populations are lacking. Here, we determined the association of plasma acylcarnitines with incident prediabetes in African Americans and European Americans enrolled in a prospective study. We analyzed 45 acylcarnitines in baseline plasma samples from 70 adults (35 African-American, 35 European-American) with incident prediabetes (progressors) and 70 matched controls (non-progressors) during 5.5-year (mean 2.6 years) follow-up in the Pathobiology of Prediabetes in a Biracial Cohort (POP-ABC) study. Incident prediabetes (impaired fasting glucose/impaired glucose tolerance) was confirmed with OGTT. We measured acylcarnitines using tandem mass spectrometry, insulin sensitivity by hyperinsulinemic euglycemic clamp, and insulin secretion using intravenous glucose tolerance test. The results showed that progressors and non-progressors during POP-ABC study follow-up were concordant for 36 acylcarnitines and discordant for nine others. In logistic regression models, beta-hydroxy butyryl carnitine (C4-OH), 3-hydroxy-isovaleryl carnitine/malonyl carnitine (C5-OH/C3-DC), and octenoyl carnitine (C8:1) were the only significant predictors of incident prediabetes. The combined cut-off plasma levels of <0.03 micromol/L for C4-OH, <0.03 micromol/L for C5-OH/C3-DC, and >0.25 micromol/L for C8:1 acylcarnitines predicted incident prediabetes with 81.9% sensitivity and 65.2% specificity. Thus, circulating levels of one medium-chain and two short-chain acylcarnitines may be sensitive biomarkers for the risk of incident prediabetes among initially normoglycemic individuals with parental history of type 2 diabetes.

Trajectories of Body Weight and Fat Mass in Relation to Incident Prediabetes in a Biracial Cohort of Free-Living Adults.

OBJECTIVES: Obesity is a risk factor for type 2 diabetes (T2D), but prospective data relating adiposity measures to incident prediabetes are scant. METHODS: The Pathobiology of Prediabetes in A Biracial Cohort study followed normoglycemic African Americans (AA) and European Americans (EA) with parental history of T2D for the primary outcome of incident prediabetes (impaired fasting glucose and/or impaired glucose tolerance) for 5.5 years. Serial assessments included anthropometry and body fat composition. We analyzed weight, body mass index (BMI), waist, total, and abdominal fat mass in relation to incident prediabetes risk. RESULTS: Of the 376 subjects enrolled (217 AA, 159 EA; mean age 44.2 years, BMI 31.4 kg/m2), 343 (192 AA, 151 EA) had evaluable follow-up data. A total of 101 (52 AA, 49 EA) developed prediabetes during follow-up. Progressors to prediabetes had a mean baseline weight of 90.0 ± 20.4 kg versus 82.9 ± 21.7 kg among nonprogressors (P = 0.0036). During 5.5 (mean 2.62) years of follow-up, the weight change among nonprogressors was 0.63 ± 6.11 kg compared with 2.54 ± 6.91 kg among progressors (ANOVA P = 0.0072). Progressors also showed greater increases in total fat (P = 0.0015) and trunk fat (P = 0.0005) mass than nonprogressors. Adjusted for age and sex, the significant predictors of incident prediabetes were BMI (P = 0.0013), waist (P < 0.0001), total fat (P = 0.0025), and trunk fat (P < 0.0001) mass. CONCLUSIONS: Among obese free-living offspring of parents with T2D, long-term normoglycemic status was associated with a weight gain of ~0.2 kg/y, whereas progression to prediabetes was associated with a weight gain of ~1 kg/y.

Role of ceramides in the pathogenesis of diabetes mellitus and its complications.

Diabetes mellitus (DM) is a systemic metabolic disease that affects 463 million adults worldwide and is a leading cause of cardiovascular disease, blindness, nephropathy, peripheral neuropathy, and lower-limb amputation. Lipids have long been recognized as contributors to the pathogenesis and pathophysiology of DM and its complications, but recent discoveries have highlighted ceramides, a class of bioactive sphingolipids with cell signaling and second messenger capabilities, as particularly important contributors to insulin resistance and the underlying mechanisms of DM complications. Besides their association with insulin resistance and pathophysiology of type 2 diabetes, evidence is emerging that certain species of ceramides are mediators of cellular mechanisms involved in the initiation and progression of microvascular and macrovascular complications of DM. Advances in our understanding of these associations provide unique opportunities for exploring ceramide species as potential novel therapeutic targets and biomarkers. This review discusses the links between ceramides and the pathogenesis of DM and diabetic complications and identifies opportunities for novel discoveries and applications.

Glycemic Response to Oral Dexamethasone Predicts Incident Prediabetes in Normoglycemic Subjects With Parental Diabetes.

BACKGROUND: Prediabetes, an often unrecognized precursor of type 2 diabetes (T2DM), is associated with cardiometabolic complications. Here, we investigated the utility of dexamethasone challenge in predicting incident prediabetes among normoglycemic subjects with parental T2DM enrolled in the prospective Pathobiology of Prediabetes in a Biracial Cohort study. DESIGN AND METHODS: After documenting normoglycemic status with an oral glucose tolerance test (OGTT), participants ingested dexamethasone (2 mg) at 10:00 pm, and fasting plasma glucose (FPG-Dex) and cortisol were measured at 8:00 am the next day. Subjects were followed quarterly for 5 years, the primary outcome being incident prediabetes. Serial assessments included body composition, blood chemistry, OGTT, insulin sensitivity, and secretion. RESULTS: We analyzed data from 190 participants (107 Black, 83 white; mean age 44.7 ± 10.0 years; body mass index [BMI] 29.8 ± 6.8 kg/m2; fasting plasma glucose [FPG] 90.9 ± 5.7 mg/dL). Following dexamethasone ingestion, plasma cortisol was < 5 µg/dL; FPG-Dex levels displayed marked variability (81-145 mg/dL) as did delta FPG (-7 to +48 mg/dL). During 5 years of follow-up, 58 of 190 subjects (30.5%) progressed to prediabetes. FPG-Dex (116.8 ± 10.9 vs 106.9 ± 10.8 mg/dL, P < 0.0001) and delta FPG (23.4 ± 10.1 vs 17.0 ± 10.2 mg/dL, P < 0.0001) were higher in progressors than nonprogressors. FPG-Dex (P = 0.007) was an independent predictor of incident prediabetes in a multivariate model that included age, race, gender, BMI, waist circumference, FPG, insulin sensitivity, and secretion. In further analyses, an FPG-Dex level ≥ 107 mg/dL predicted incident prediabetes with 88% sensitivity and 49% specificity. CONCLUSIONS: The glycemic response to dexamethasone significantly predicted incident prediabetes among offspring of parents with T2DM, and may be a tool for uncovering latent risk of dysglycemia.

Efficacy of Ertugliflozin on Heart Failure-Related Events in Patients With Type 2 Diabetes Mellitus and Established Atherosclerotic Cardiovascular Disease: Results of the VERTIS CV Trial.

BACKGROUND: In patients with type 2 diabetes mellitus, sodium-glucose cotransporter 2 inhibitors reduce the risk of hospitalization for heart failure (HHF). We assessed the effect of ertugliflozin on HHF and related outcomes. METHODS: VERTIS CV (Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial), a double-blind, placebo-controlled trial, randomly assigned patients with type 2 diabetes mellitus and atherosclerotic cardiovascular (CV) disease to once-daily ertugliflozin 5 mg, 15 mg, or placebo. Prespecified secondary analyses compared ertugliflozin (pooled doses) versus placebo on time to first event of HHF and composite of HHF/CV death, overall and stratified by prespecified characteristics. Cox proportional hazards modeling was used with the Fine and Gray method to account for competing mortality risk, and Andersen-Gill modeling to analyze total (first+recurrent) HHF and total HHF/CV death events. RESULTS: A total of 8246 patients were randomly assigned to ertugliflozin (n=5499) or placebo (n=2747); n=1958 (23.7%) had a history of heart failure (HF) and n=5006 (60.7%) had pretrial ejection fraction (EF) available, including n=959 with EF ≤45%. Ertugliflozin did not significantly reduce first HHF/CV death (hazard ratio [HR], 0.88 [95% CI, 0.75-1.03]). Overall, ertugliflozin reduced risk for first HHF (HR, 0.70 [95% CI, 0.54-0.90]; P=0.006). Previous HF did not modify this effect (HF: HR, 0.63 [95% CI, 0.44-0.90]; no HF: HR, 0.79 [95% CI, 0.54-1.15]; P interaction=0.40). In patients with HF, the risk reduction for first HHF was similar for those with reduced EF ≤45% versus preserved EF >45% or unknown. However, in the overall population, the risk reduction tended to be greater for those with EF ≤45% (HR, 0.48 [95% CI, 0.30-0.76]) versus EF >45% (HR, 0.86 [95% CI, 0.58-1.29]). Effect on risk for first HHF was consistent across most subgroups, but greater benefit of ertugliflozin was observed in 3 populations: baseline estimated glomerular filtration rate <60 mL·min-1·1.73 m-2, albuminuria, and diuretic use (each P interaction <0.05). Ertugliflozin reduced total events of HHF (rate ratio, 0.70 [95% CI, 0.56-0.87]) and total HHF/CV death (rate ratio, 0.83 [95% CI, 0.72-0.96]). CONCLUSIONS: In patients with type 2 diabetes mellitus, ertugliflozin reduced the risk for first and total HHF and total HHF/CV death, adding further support for the use of sodium-glucose cotransporter 2 inhibitors in primary and secondary prevention of HHF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01986881.