Dapagliflozin in Myocardial Infarction without Diabetes or Heart Failure.

BACKGROUND: In patients with acute myocardial infarction (MI), therapies that could further reduce the risk of adverse cardiovascular and metabolic outcomes are needed. METHODS: In this international registry-based, randomized, double-blind trial, patients without prior diabetes or chronic heart failure, presenting with acute MI and impaired left ventricular systolic function, were randomly assigned 10 mg of dapagliflozin or placebo, given once daily. The primary outcome was the hierarchical composite of death, hospitalization for heart failure, nonfatal MI, atrial fibrillation/flutter, type 2 diabetes mellitus, New York Heart Association Functional Classification at the last visit, and body weight decrease of 5% or greater at the last visit using the win ratio analysis method. The key secondary outcome was the same hierarchical composite excluding the body weight component. RESULTS: We enrolled 4017 patients of whom 2019 were assigned to dapagliflozin and 1998 to placebo. The analysis of the primary hierarchical composite outcome resulted in significantly more wins for dapagliflozin than for placebo (win ratio, 1.34; 95% confidence interval [CI], 1.20 to 1.50; P<0.001). The win ratio outcome, which was adopted in a change of analysis during trial performance because of low event accrual, was mainly driven by the added cardiometabolic outcomes. The composite of time to cardiovascular death/hospitalization for heart failure occurred in 50/2019 (2.5%) patients assigned to dapagliflozin and 52/1998 (2.6%) patients assigned to placebo (hazard ratio, 0.95; 95% CI, 0.64 to 1.40). The rates of other cardiovascular events were low, with differences between the groups not reaching nominal statistical significance. No safety concerns were identified. CONCLUSIONS: In patients with acute MI as noted above, after approximately 1 year of treatment with dapagliflozin there were significant benefits with regard to improvement in cardiometabolic outcomes but no impact on the composite of cardiovascular death or hospitalization for heart failure compared with placebo. (Funded by AstraZeneca; ClinicalTrial.gov number, NCT04564742.)

Rationale and design of the DAPA-MI trial: Dapagliflozin in patients without diabetes mellitus with acute myocardial infarction.

BACKGROUND: Therapies that could further prevent the development of heart failure (HF) and other cardiovascular and metabolic events in patients with recent myocardial infarction (MI) represent a large and unmet medical need. METHODS: DAPA-MI is a multicenter, parallel-group, registry-based, randomized, double-blind, placebo-controlled phase 3 trial in patients without known diabetes or established HF, presenting with MI and impaired left ventricular systolic function or Q-wave MI. The trial evaluated the effect of dapagliflozin 10 mg vs placebo, given once daily in addition to standard of care therapy, on death, hospitalization for HF (HHF), and other cardiometabolic outcomes. The primary objective of the trial was to determine, using the win-ratio method, if dapagliflozin is superior to placebo by comparing the hierarchical composite outcome of death, HHF, nonfatal MI, atrial fibrillation/flutter, new onset of type 2 diabetes mellitus, HF symptoms as measured by New York Heart Association Functional Classification at last visit, and body weight decrease ≥5% at last visit. Assuming a true win-ratio of 1.20 between dapagliflozin and placebo, 4,000 patients provide a statistical power of 80% for the test of the primary composite outcome. A registry-based randomized controlled trial framework allowed for recruitment, randomization, blinding, and pragmatic data collection of baseline demographics, medications, and clinical outcomes using existing national clinical registries (in Sweden and the UK) integrated with the trial database. CONCLUSIONS: The trial explores opportunities to improve further the outcome of patients with impaired LV function after MI. The innovative trial design of DAPA-MI, incorporating national clinical registry data, has facilitated efficient patient recruitment as well as outcome ascertainment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT04564742.

Effect of insulin degludec versus insulin glargine U100 on time in range: SWITCH PRO, a crossover study of basal insulin-treated adults with type 2 diabetes and risk factors for hypoglycaemia.

AIMS: To compare time in range (TIR) with use of insulin degludec U100 (degludec) versus insulin glargine U100 (glargine U100) in people with type 2 diabetes. MATERIALS AND METHODS: We conducted a randomized, crossover, multicentre trial comparing degludec and glargine U100 in basal insulin-treated adults with type 2 diabetes and ≥1 hypoglycaemia risk factor. There were two treatment periods, each with 16-week titration and 2-week maintenance phases (with evaluation of glucose using blinded professional continuous glucose monitoring). The once-weekly titration (target: 3.9-5.0 mmol/L) was based on pre-breakfast self-measured blood glucose. The primary endpoint was percentage of TIR (3.9─10.0 mmol/L). Secondary endpoints included overall and nocturnal percentage of time in tight glycaemic range (3.9-7.8 mmol/L), and mean glycated haemoglobin (HbA1c) and glucose levels. RESULTS: At baseline, participants (n = 498) had a mean (SD) age of 62.8 (9.8) years, a diabetes duration of 15.1 (7.7) years and an HbA1c level of 59.6 (11.0) mmol/mol (7.6 [1.0]%). Noninferiority and superiority were confirmed for degludec versus glargine U100 for the primary endpoint, with a mean TIR of 72.1% for degludec versus 70.7% for glargine U100 (estimated treatment difference [ETD] 1.43% [95% confidence interval (CI): 0.12, 2.74; P = 0.03] or 20.6 min/d). Overall time in tight glycaemic range favoured degludec versus glargine U100 (ETD 1.5% [95% CI: 0.15, 2.89] or 21.9 min/d). Degludec also reduced nocturnal time below range (TBR; <3.9 mmol/L) compared with glargine U100 (ETD -0.88% [95% CI: -1.34, -0.42] or 12.7 min/night; post hoc) and significantly fewer nocturnal hypoglycaemic episodes of <3.0 mmol/L were observed. CONCLUSIONS: Degludec, compared with glargine U100, provided more TIR and time in tight glycaemic range, and reduced nocturnal TBR in insulin-treated people with type 2 diabetes.

Heredity of type 2 diabetes confers increased susceptibility to oxidative stress and inflammation.

INTRODUCTION AND OBJECTIVE: Heredity of type 2 diabetes mellitus (T2DM) is associated with greater risk for developing T2DM. Thus, individuals who have a first-degree relative with T2DM (FDRT) provide a natural model to study factors of susceptibility towards development of T2DM, which are poorly understood. Emerging key players in T2DM pathophysiology such as adverse oxidative stress and inflammatory responses could be among possible mechanisms that predispose FDRTs to develop T2DM. Here, we aimed to examine the role of oxidative stress and inflammatory responses as mediators of this excess risk by studying dynamic postprandial responses in FDRTs. RESEARCH DESIGN AND METHODS: In this open-label case-control study, we recruited normoglycemic men with (n=9) or without (n=9) a family history of T2DM. We assessed plasma glucose, insulin, lipid profile, cytokines and F2-isoprostanes, expression levels of oxidative and inflammatory genes/proteins in circulating mononuclear cells (MNC), myotubes and adipocytes at baseline (fasting state), and after consumption of a carbohydrate-rich liquid meal or insulin stimulation. RESULTS: Postprandial glucose and insulin responses were not different between groups. Expression of oxidant transcription factor NRF2 protein (p<0.05 for myotubes) and gene (pgroup=0.002, ptime×group=0.016), along with its target genes TXNRD1 (pgroup=0.004, ptime×group=0.007), GPX3 (pgroup=0.011, ptime×group=0.019) and SOD-1 (pgroup=0.046 and ptime×group=0.191) was upregulated in FDRT-derived MNC after meal ingestion or insulin stimulation. Synergistically, expression of target genes of inflammatory transcription factor nuclear factor kappa B such as tumor necrosis factor alpha (pgroup=0.001, ptime×group=0.007) was greater in FDRT-derived MNC than in non-FDRT-derived MNC after meal ingestion or insulin stimulation. CONCLUSIONS: Our findings shed light on how heredity of T2DM confers increased susceptibility to oxidative stress and inflammation. This could provide early insights into the underlying mechanisms and future risk of FDRTs for developing T2DM and its associated complications.

Family Members: The Forgotten Players in the Diabetes Care Team (The TALK-HYPO Study).

INTRODUCTION: The objective of this study was to establish the burden of hypoglycemia on family members of people with diabetes (PWDs) and to gain an understanding of how conversations about hypoglycemia can contribute to diabetes care. METHODS: This was a multinational cross-sectional study of family members of people with type 1 or type 2 diabetes taking insulin and/or secretagogues for ≥ 12 months who voluntarily completed an online questionnaire. RESULTS: Overall, 4300 family members of PWDs (type 1 [29%], type 2 [46%], unknown [25%]) were surveyed. Two in three family members (66%) reported thinking about the hypoglycemia of the PWD at least monthly, and 64% felt worried or anxious about the PWD's risk for hypoglycemia. There was general agreement among family members that more conversations about hypoglycemia would have a positive impact on the PWD's life (76%). CONCLUSIONS: Hypoglycemia can present a burden on the lives of family members of PWDs. Conversations about hypoglycemia, facilitated by a healthcare professional, may reduce this burden and hypoglycemia risk. FUNDING: Novo Nordisk A/S.

Two-Hour Postprandial Lipoprotein Particle Concentration Differs Between Lean and Obese Individuals.

The concentrations of lipoprotein particles [high-density lipoproteins (HDLs), low-density lipoproteins (LDLs), very-low-density lipoproteins (VLDLs), and chylomicrons] are associated with the risk of cardiovascular diseases. Most studies have examined these associations in the fasting state. Previous studies have shown lipoprotein particle concentration change following meal, and these changes are different in individuals with obesity. In this study, we aimed to assess whether various meal compositions lead to adverse short-term (2-h) postprandial lipoproteinemia in obese insulin resistant (obese-IR) subjects as compared to lean insulin sensitive (lean-IS) subjects. In a randomized crossover trial, nine lean-IS and nine obese-IR Chinese men aged 22-35 years were challenged with isoenergetic and isovolumic meals rich in protein (HP), fat (HF), or carbohydrate (HC). Plasma samples were collected after a 10-h fast, as well as 1-h and 2-h post-meal and analyzed using nuclear magnetic resonance. Plasma concentration of large VLDLs and chylomicron particles was higher and increased more after all meals in obese-IR compared to lean-IS subjects. The HP meal decreased small LDL particle concentration in obese-IR subjects, and increased small HDL particle concentration in all subjects. The HF meal led to a decrease in small HDL concentration in all subjects. In conclusion, obese-IR subjects revealed a detrimental response to meal challenges even as early as 2-h after meal intake.

Genes Involved in Oxidative Stress Pathways Are Differentially Expressed in Circulating Mononuclear Cells Derived From Obese Insulin-Resistant and Lean Insulin-Sensitive Individuals Following a Single Mixed-Meal Challenge.

Background: Oxidative stress induced by nutritional overload has been linked to the pathogenesis of insulin resistance, which is associated with metabolic syndrome, obesity, type 2 diabetes and diabetic vascular complications. Postprandial changes in expression of oxidative stress pathway genes in obese vs. lean individuals, following intake of different types of meals varying in macronutrient composition have not been characterized to date. Here we aimed to test whether/how oxidative stress responses in obese vs. lean individuals are modulated by meal composition. Methods: High-carbohydrate (HC), high-fat (HF), or high-protein (HP) liquid mixed meals were administered to study subjects (lean insulin-sensitive, n = 9 and obese insulin-resistant, n = 9). Plasma levels of glucose and insulin, lipid profile, urinary F2-isoprostanes (F2-IsoP), and expression levels of genes of oxidative stress pathways were assessed in mononuclear cells (MNC) derived from fresh peripheral blood, at baseline and up to 6-h postprandial states. Differences in these parameters were compared between insulin-sensitive/resistant groups undergoing aforementioned meal challenges. Results: Obese individuals exhibited increased pro-oxidant (i.e., CYBB and CYBA) and anti-oxidant (i.e., TXN RD1) gene expression in the postprandial state, compared with lean subjects, regardless of meal type (P interaction for group × time < 0.05). By contrast, lean subjects had higher expression of NCF-4 gene (pro-oxidant) after HC meal and SOD1 gene (anti-oxidant) after HC and HF meals (P interaction for group × meal < 0.05). There was an increase in postprandial level of urinary F2-IsoP in the obese (P < 0.05) but not lean group. Conclusions: These findings may represent an adaptive oxidative response to mitigate increased stress induced by acute nutritional excess. Further, the results suggest an increased predisposition of obese subjects to oxidative stress. Chronic nutritional excess resulting in increases in body weight and adiposity might lead to decompensation leading to worsening insulin resistance and its sequel. Insights from this study could impact on nutritional recommendations for obese subjects at high-risk of cardiovascular diseases.

Plasma Protein and MicroRNA Biomarkers of Insulin Resistance: A Network-Based Integrative -Omics Analysis.

Although insulin resistance (IR) is a key pathophysiologic condition underlying various metabolic disorders, impaired cellular glucose uptake is one of many manifestations of metabolic derangements in the human body. To study the systems-wide molecular changes associated with obesity-dependent IR, we integrated information on plasma proteins and microRNAs in eight obese insulin-resistant (OIR, HOMA-IR > 2.5) and nine lean insulin-sensitive (LIS, HOMA-IR < 1.0) normoglycemic males. Of 374 circulating miRNAs we profiled, 65 species increased and 73 species decreased in the OIR compared to the LIS subjects, suggesting that the overall balance of the miRNA secretome is shifted in the OIR subjects. We also observed that 40 plasma proteins increased and 4 plasma proteins decreased in the OIR subjects compared to the LIS subjects, and most proteins are involved in metabolic and endocytic functions. We used an integrative -omics analysis framework called iOmicsPASS to link differentially regulated miRNAs with their target genes on the TargetScan map and the human protein interactome. Combined with tissue of origin information, the integrative analysis allowed us to nominate obesity-dependent and obesity-independent protein markers, along with potential sites of post-transcriptional regulation by some of the miRNAs. We also observed the changes in each -omics platform that are not linked by the TargetScan map, suggesting that proteins and microRNAs provide orthogonal information for the progression of OIR. In summary, our integrative analysis provides a network of elevated plasma markers of OIR and a global shift of microRNA secretome composition in the blood plasma.

A high carbohydrate, but not fat or protein meal attenuates postprandial ghrelin, PYY and GLP-1 responses in Chinese men.

It is known that the macronutrient content of a meal has different impacts on the postprandial satiety and appetite hormonal responses. Whether obesity interacts with such nutrient-dependent responses is not well characterized. We examined the postprandial appetite and satiety hormonal responses after a high-protein (HP), high-carbohydrate (HC), or high-fat (HF) mixed meal. This was a randomized cross-over study of 9 lean insulin-sensitive (mean±SEM HOMA-IR 0.83±0.10) and 9 obese insulin-resistant (HOMA-IR 4.34±0.41) young (age 21-40 years), normoglycaemic Chinese men. We measured fasting and postprandial plasma concentration of glucose, insulin, active glucagon-like peptide-1 (GLP-1), total peptide-YY (PYY), and acyl-ghrelin in response to HP, HF, or HC meals. Overall postprandial plasma insulin response was more robust in the lean compared to obese subjects. The postprandial GLP-1 response after HF or HP meal was higher than HC meal in both lean and obese subjects. In obese subjects, HF meal induced higher response in postprandial PYY compared to HC meal. HP and HF meals also suppressed ghrelin greater compared to HC meal in the obese than lean subjects. In conclusion, a high-protein or high-fat meal induces a more favorable postprandial satiety and appetite hormonal response than a high-carbohydrate meal in obese insulin-resistant subjects.

Meal rich in carbohydrate, but not protein or fat, reveals adverse immunometabolic responses associated with obesity.

BACKGROUND: Obesity-related insulin resistance is linked to inflammation. Immunometabolic function differs between lean and obese subjects, but whether macronutrient composition of ingested meals affects these responses is not well known. We examined the effects of a single meal rich in fat, protein, or carbohydrate on immunometabolic responses. METHODS: Nine lean insulin sensitive (LIS) men and 9 obese insulin resistant (OIR) men ingested high-carbohydrate (HC), high-fat (HF) or high-protein (HP) mixed meals in random order. We assessed plasma glucose, insulin, and cytokine responses and cytokine gene expression in circulating mononuclear cells (MNC) at fasting and postprandial states (up to 6-h). RESULTS: Expression of NF-κB and TNFα genes were greater; whereas that of TGFß and IL-6 genes were lower, in the OIR compared to the LIS individuals. The differences were significantly greater after the HC meal, but not after the HP or HF meal. Similar results were obtained for plasma concentrations of TNFα and IL-6. CONCLUSIONS: Our findings indicate that a single HC meal has a distinct adverse effect on immunometabolic responses in the OIR individuals. The cumulative effect of such adverse responses to meals rich in carbohydrate may predispose the OIR individuals to a higher risk of cardiovascular disease.

Metabolic gene expression profile in circulating mononuclear cells reflects obesity-associated metabolic inflexibility.

BACKGROUND: Obesity is associated with an impaired ability to switch from fatty acid to glucose oxidation during the fasted to fed transition, particularly in skeletal muscle. However, whether such metabolic inflexibility is reflected at the gene transcription level in circulatory mononuclear cells (MNC) is not known. METHODS: The whole-body respiratory quotient (RQ) and transcriptional regulation of genes involved in carbohydrate and lipid metabolism in MNC were measured during fasting and in response (up to 6 h) to high-carbohydrate and high-fat meals in nine lean insulin-sensitive and nine obese insulin-resistant men. RESULTS: Compared to lean subjects, obese subjects had an impaired ability to increase RQ and switch from fatty acid to glucose oxidation following the high-carbohydrate meal (interaction term P < 0.05). This was accompanied by an impaired induction of genes involved in oxidative metabolism of glucose in MNC, such as phosphofructokinase (PFK), pyruvate dehydrogenase kinase 4 (PDK4), peroxisome proliferator-activated receptor alpha (PPARα) and uncoupling protein 3 (UCP3) and increased expression of genes involved in fatty acid metabolism, such as fatty acid translocase (FAT/CD36) and fatty acid synthase (FASN) (P < 0.05). On the contrary, there were no differences in the gene expression profiles between lean and obese subjects following the high-fat meal. CONCLUSIONS: Postprandial expression profiles of genes involved in glucose and fatty acid metabolism in the MNC reflect the differing metabolic flexibility phenotypes of our cohort of lean and obese individuals. These differences in metabolic flexibility between the lean and obese are elicited by an acute meal challenge that is rich in carbohydrate but not fat.

Ethnic Differences in the Role of Adipocytokines Linking Abdominal Adiposity and Insulin Sensitivity Among Asians.

CONTEXT: Among Asian ethnic groups, Chinese or Malays are more insulin sensitive than South Asians, in particular in lean individuals. We have further reported that body fat partitioning did not explain this ethnic difference in insulin sensitivity. OBJECTIVE: We examined whether adipocytokines might explain the ethnic differences in the relationship between obesity and insulin resistance among the three major ethnic groups in Singapore. DESIGN AND PARTICIPANTS: This was a cross-sectional study of 101 Chinese, 82 Malays, and 81 South Asian men. Insulin sensitivity index (ISI) was measured using hyperinsulinemic euglycemic clamp. Visceral (VAT) and subcutaneous adipose tissue (SAT) volumes were quantified using magnetic resonance imaging. MAIN OUTCOME MEASURES: Plasma total and high-molecular-weight adiponectin, leptin, visfatin, apelin, IL-6, fibroblast growth factor 21 (FGF21), retinol binding protein-4 (RBP 4), and resistin were measured using enzyme-linked immunoassays. RESULTS: Principle component (PC) analysis on the adipocytokines identified three PCs, which explained 49.5% of the total variance. Adiponectin loaded negatively, and leptin and FGF21 loaded positively onto PC1. Visfatin, resistin, and apelin all loaded positively onto PC2. IL-6 loaded positively and RBP-4 negatively onto PC3. Only PC1 was negatively associated with ISI in all ethnic groups. In the path analysis, SAT and VAT were negatively associated with ISI in Chinese and Malays without significant mediatory role of PC1. In South Asians, the relationship between VAT and ISI was mediated partly through PC1, whereas the relationship between SAT and ISI was mediated mainly through PC1. CONCLUSIONS: The relationships between abdominal obesity, adipocytokines and insulin sensitivity differ between ethnic groups. Adiponectin, leptin, and FGF21 play a mediating role in the relationship between abdominal adiposity and insulin resistance in South Asians, but not in Malays or Chinese.

Determinants of incident prediabetes and type 2 diabetes in a 7-year cohort in a developing country: The Isfahan Cohort Study.

BACKGROUND: This study aimed to identify determinants of new onset type-2 diabetes (T2D) and prediabetes in a region with high rate of T2D but scarcity of evidence. METHODS: Participants free of T2D were identified in a population-based study of adults older than 35 years living in the rural and urban areas of three districts in Iran in 2001 and were re-examined after 7 years. Biochemical measurements, anthropometric data, blood pressure, smoking status and dietary intake were determined at both measurement points through identical protocols and procedures. Data analysis was done using multivariate ordered logistic regressions. RESULTS: Incidence rate of prediabetes and T2D was 32.3 (95%CI, 29.7-35.1) and 18.9 (17.1-20.9) per 1000 person-year, respectively. Odds of progression to prediabetes and T2D were increased with ageing, living in rural area (OR = 1.28), unhealthy diet (OR = 1.32), overweight (OR = 1.45), obesity (OR = 1.97), waist gain (OR = 1.37), high waist-to-hip ratio (OR = 1.35), hypertension (OR = 1.35), and hypertriglyceridemia (OR = 1.50); but reduced with higher education (OR = 0.76) and weight loss (OR = 0.67) in the adjusted models. In those with prediabetes at baseline, parental history of T2D (OR = 2.26), obesity (OR = 2.59), high waist circumference (OR = 2.03), and hypertriglyceridemia (OR = 1.94) were associated with developing T2D. No factor was found to be associated with regression from prediabetes to normoglycemia in adjusted models. CONCLUSIONS: Current data endorses proposed statistical projections for the future trend of diabetes, and highlights the potential role of obesity specifically visceral type.