The Effect of Dapagliflozin on Albuminuria in DECLARE-TIMI 58

OBJECTIVESodium–glucose cotransporter 2 inhibitors (SGLT2i) improve albuminuria in patients with high cardiorenal risk. We report albuminuria change in the Dapagliflozin Effect on Cardiovascular Events (DECLARE-TIMI 58) cardiovascular outcome trial, which included populations with lower cardiorenal risk.RESEARCH DESIGN AND METHODSDECLARE-TIMI 58 randomized 17,160 patients with type 2 diabetes, creatinine clearance >60 mL/min, and either atherosclerotic cardiovascular disease (CVD; 40.6%) or risk-factors for CVD (59.4%) to dapagliflozin or placebo. Urinary albumin-to-creatinine ratio (UACR) was tested at baseline, 6 months, 12 months, and yearly thereafter. The change in UACR over time was measured as a continuous and categorical variable (≤15, >15 to <30, ≥30 to ≤300, and >300 mg/g) by treatment arm. The composite cardiorenal outcome was a ≥40% sustained decline in the estimated glomerular filtration rate (eGFR) to <60 mL/min/1.73 m², end-stage kidney disease, and cardiovascular or renal death; specific renal outcome included all except cardiovascular death.RESULTSBaseline UACR was available for 16,843 (98.15%) participants: 9,067 (53.83%) with ≤15 mg/g, 2,577 (15.30%) with >15 to <30 mg/g, 4,030 (23.93%) with 30–300 mg/g, and 1,169 (6.94%) with >300 mg/g. Measured as a continuous variable, UACR improved from baseline to 4.0 years with dapagliflozin, compared with placebo, across all UACR and eGFR categories (all P < 0.0001). Sustained confirmed ≥1 category improvement in UACR was more common in dapagliflozin versus placebo (hazard ratio 1.45 [95% CI 1.35–1.56], P < 0.0001). Cardiorenal outcome was reduced with dapagliflozin for subgroups of UACR ≥30 mg/g (P < 0.0125, P_interaction = 0.033), and the renal-specific outcome was reduced for all UACR subgroups (P < 0.05, P_interaction = 0.480).CONCLUSIONSIn DECLARE-TIMI 58, dapagliflozin demonstrated a favorable effect on UACR and renal-specific outcome across baseline UACR categories, including patients with normal albumin excretion. The results suggest a role for SGLT2i also in the primary prevention of diabetic kidney disease.     

Association of Oily and Nonoily Fish Consumption and Fish Oil Supplements With Incident Type 2 Diabetes: A Large Population-Based Prospective Study

OBJECTIVETo evaluate associations of oily and nonoily fish consumption and fish oil supplements with incident type 2 diabetes (T2D).RESEARCH DESIGN AND METHODSWe included 392,287 middle-aged and older participants (55.0% women) in the UK Biobank who were free of diabetes, major cardiovascular disease, and cancer and had information on habitual intake of major food groups and use of fish oil supplements at baseline (2006–2010). Of these, 163,706 participated in one to five rounds of 24-h dietary recalls during 2009–2012.RESULTSDuring a median 10.1 years of follow-up, 7,262 incident cases of T2D were identified. Compared with participants who reported never consumption of oily fish, the multivariable-adjusted hazard ratios of T2D were 0.84 (95% CI 0.78–0.91), 0.78 (0.72–0.85), and 0.78 (0.71–0.86) for those who reported <1 serving/week, weekly, and ≥2 servings/week of oily fish consumption, respectively (P-trend < 0.001). Consumption of nonoily fish was not associated with risk of T2D (P-trend = 0.45). Participants who reported regular fish oil use at baseline had a 9% (95% CI 4–14%) lower risk of T2D compared with nonusers. Baseline regular users of fish oil who also reported fish oil use during at least one of the 24-h dietary recalls had an 18% (8–27%) lower risk of T2D compared with constant nonusers.CONCLUSIONSOur findings suggest that consumption of oily fish but not nonoily fish was associated with a lower risk of T2D. Use of fish oil supplements, especially constant use over time, was also associated with a lower risk of T2D.     

Natriuretic Effect of Two Weeks of Dapagliflozin Treatment in Patients With Type 2 Diabetes and Preserved Kidney Function During Standardized Sodium Intake: Results of the DAPASALT Trial

OBJECTIVESodium–glucose cotransporter 2 (SGLT2) inhibitors reduce the risk for heart failure hospitalization potentially by inducing sodium excretion, osmotic diuresis, and plasma volume contraction. Few studies have investigated this hypothesis, but none have assessed cumulative sodium excretion with SGLT2 inhibition during standardized sodium intake in patients with type 2 diabetes.RESEARCH DESIGN AND METHODSThe DAPASALT trial was a mechanistic, nonrandomized, open-label study in patients with type 2 diabetes with preserved kidney function on a controlled standardized sodium diet (150 mmol/day). It evaluated the effects of dapagliflozin on sodium excretion, 24-h blood pressure, and extracellular, intracellular, and plasma volumes at the start of treatment (ST) (days 2–4), end of treatment (ET) (days 12–14), and follow-up (FU) (days 15–18).RESULTSFourteen patients were included in the efficacy analysis. Mean (SD) baseline sodium excretion (150 [32] mmol/24-h) did not significantly change during treatment (change at ST: −7.0 mmol/24-h [95% CI −22.4, 8.4]; change at ET: 2.1 mmol/24-h [−28.8, 33.0]). Mean baseline 24-h systolic blood pressure was 128 (10) mmHg and significantly reduced at ST (−6.1 mmHg [−9.1, −3.1]; P < 0.001) and ET (−7.2 mmHg [−10.0, −4.3]; P < 0.001). Dapagliflozin did not significantly alter plasma volume or intracellular volume, while extracellular volume changed at ST (−0.7 L [−1.3, −0.1]; P = 0.02). As expected, 24-h urinary glucose excretion significantly increased during dapagliflozin treatment and reversed during FU.CONCLUSIONSDuring standardized sodium intake, dapagliflozin reduced blood pressure without clear changes in urinary sodium excretion, suggesting that factors other than natriuresis and volume changes may contribute to the blood pressure–lowering effects.     

Coexistent Diabetes Is Associated With the Presence of Adverse Phenotypic Features in Patients With Hypertrophic Cardiomyopathy

OBJECTIVEType 2 diabetes mellitus (T2DM) is associated with worsened clinical outcomes in hypertrophic cardiomyopathy (HCM) patients. We sought to investigate whether HCM patients with T2DM comorbidity exhibit adverse cardiac alterations in myocardial energetics, function, perfusion, or tissue characteristics.RESEARCH DESIGN AND METHODSA total of 55 participants with concomitant HCM and T2DM (HCM-DM) (n = 20) or isolated HCM (n = 20) and healthy volunteers (HV) (n = 15) underwent ³¹P-MRS and cardiovascular MRI. The HCM groups were matched for HCM phenotype.RESULTSMean ± SD European Society of Cardiology sudden cardiac death risk scores were comparable between the HCM groups (HCM 2.2 ± 1.5%, HCM-DM 1.9 ± 1.2%; P = not significant), and sarcomeric mutations were equally common. HCM-DM patients had the highest median NT-proBNP levels (HV 42 ng/L [interquartile range 35–66], HCM 298 ng/L [157–837], HCM-DM 726 ng/L [213–8,695]; P < 0.0001). Left ventricular (LV) ejection fraction, mass, and wall thickness were similar between the HCM groups. HCM-DM patients displayed a greater degree of fibrosis burden with higher scar percentage and lower global longitudinal strain compared with HCM patients. PCr/ATP (the relative concentrations of phosphocreatine and ATP) was significantly lower in the HCM-DM group than in both HCM and HV (HV 2.17 ± 0.49, HCM 1.93 ± 0.38, HCM-DM 1.54 ± 0.27; P = 0.002). In a similar pattern, stress myocardial blood flow was significantly lower in the HCM-DM group than in both HCM and HV (HV 2.06 ± 0.42 mL/min/g, HCM 1.74 ± 0.44 mL/min/g, HCM-DM 1.39 ± 0.42 mL/min/g; P = 0.002).CONCLUSIONSWe show for the first time that HCM-DM patients display greater reductions in myocardial energetics, perfusion, and contractile function and higher myocardial scar burden and serum NT-proBNP levels compared with patients with isolated HCM despite similar LV mass and wall thickness and presence of sarcomeric mutations. These adverse phenotypic features may be important components of the adverse clinical manifestation attributable to a combined presence of HCM and T2DM.     

Comparative Effectiveness and Safety of Sodium–Glucose Cotransporter 2 Inhibitors Versus Glucagon-Like Peptide 1 Receptor Agonists in Older Adults

OBJECTIVEBoth sodium–glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1RA) demonstrated cardiovascular benefits in randomized controlled trials of patients with type 2 diabetes (T2D) generally <65 years old and mostly with cardiovascular disease. We aimed to evaluate the comparative effectiveness and safety of SGLT2i and GLP-1RA among real-world older adults.RESEARCH DESIGN AND METHODSUsing Medicare data (April 2013–December 2016), we identified 90,094 propensity score–matched (1:1) T2D patients ≥66 years old initiating SGLT2i or GLP-1RA. Primary outcomes were major adverse cardiovascular events (MACE) (i.e., myocardial infarction, stroke, or cardiovascular death) and hospitalization for heart failure (HHF). Other outcomes included diabetic ketoacidosis (DKA), genital infections, fractures, lower-limb amputations (LLA), acute kidney injury (AKI), severe urinary tract infections, and overall mortality. We estimated hazard ratios (HRs) and rate differences (RDs) per 1,000 person-years, controlling for 140 baseline covariates.RESULTSCompared with GLP-1RA, SGLT2i initiators had similar MACE risk (HR 0.98 [95% CI 0.87, 1.10]; RD −0.38 [95% CI −2.48, 1.72]) and reduced HHF risk (HR 0.68 [95% CI 0.57, 0.80]; RD −3.23 [95% CI −4.68, −1.77]), over a median follow-up of ∼6 months. They also had 0.7 more DKA events (RD 0.72 [95% CI 0.02, 1.41]), 0.9 more LLA (RD 0.90 [95% CI 0.10, 1.70]), 57.1 more genital infections (RD 57.08 [95% CI 53.45, 60.70]), and 7.1 fewer AKI events (RD −7.05 [95% CI −10.27, −3.83]) per 1,000 person-years.CONCLUSIONSAmong older adults, those taking SGLT2i had similar MACE risk, decreased HHF risk, and increased risk of DKA, LLA, and genital infections versus those taking GLP-1RA.     

Dihydropyrimidine dehydrogenase (DPYD) gene c.1627A>G A/G and G/G genotypes are risk factors for lymph node metastasis and distant metastasis of colorectal cancer

BackgroundDihydropyrimidine dehydrogenase (DPD) acts as the key enzyme catabolizing pyrimidines, and may affect the tumor progression. DPYD gene mutations affect DPD activity. The relationship between DPYD IVS14+1G>A, c.1627A>G, c.85T>C and lymph node metastasis (LNM) and distant metastasis (DM) of colorectal cancer (CRC) was investigated.MethodsA total of 537 CRC patients were enrolled in this study. DPYD polymorphisms were analyzed by polymerase chain reaction (PCR)‐Sanger sequencing. The relationship between DPYD genotypes and clinical features of patients, metastasis of CRC was analyzed.ResultsAbout DPYD c.1627A>G, A/A (57.7%) was the most common genotype, followed by A/G (35.6%), G/G (6.7%) genotypes. In c.85T>C, T/T, T/C, and C/C genotypes are accounted for 83.6%, 16.0%, and 0.4%, respectively. Logistic regression analysis revealed that DPYD c.1627A>G A/G and G/G genotypes in the dominant model (A/G + G/G vs. A/A) were significant risk factors for the LNM (p = 0.029, OR 1.506, 95% CI = 1.048–2.165) and DM (p = 0.039, OR 1.588, 95% CI = 1.041–2.423) of CRC. In addition, DPYD c.1627A>G polymorphism was more common in patients with abnormal serum carcinoembryonic antigen (CEA) (>5 ng/ml) (p = 0.003) or carbohydrate antigen 24–2 (CA24‐2) (>20 U/ml) level (p = 0.015).ConclusionsThe results suggested that DPYD c.1627A>G A/G, G/G genotypes are associated with increased risk of LNM and DM of CRC.     

Circulating and Dietary Trans Fatty Acids and Incident Type 2 Diabetes in Older Adults: The Cardiovascular Health Study

OBJECTIVE

To investigate the effects of trans fatty acids (TFAs) on type 2 diabetes mellitus (DM) by specific TFA subtype or method of assessment.

RESEARCH DESIGN AND METHODS

In the Cardiovascular Health Study, plasma phospholipid trans (t)-16:1n9, t-18:1, and cis (c)/t-, t/c-, and t/t-18:2 were measured in blood drawn from 2,919 adults aged 74 ± 5 years and free of prevalent DM in 1992. Dietary TFA was estimated among 4,207 adults free of prevalent DM when dietary questionnaires were initially administered in 1989 or 1996. Incident DM was defined through 2010 by medication use or blood glucose levels. Risks were assessed by Cox proportional hazards.

RESULTS

In biomarker analyses, 287 DM cases occurred during 30,825 person-years. Both t-16:1n9 (extreme quartile hazard ratio 1.59 [95% CI 1.04–2.42], P-trend = 0.04) and t-18:1 (1.91 [1.20–3.03], P-trend = 0.01) levels were associated with higher incident DM after adjustment for de novo lipogenesis fatty acids. In dietary analyses, 407 DM cases occurred during 50,105 person-years. Incident DM was positively associated with consumption of total TFAs (1.38 [1.03–1.86], P-trend = 0.02), t-18:1 (1.32 [1.00–1.76], P-trend = 0.04), and t-18:2 (1.41 [1.05–1.89], P-trend = 0.02). After further adjustment for other dietary habits, however, the associations of estimated dietary TFA with DM were attenuated, and only nonsignificant positive trends remained.

CONCLUSIONS

Among older adults, plasma phospholipid t-16:1n9 and t-18:1 levels were positively related to DM after adjustment for de novo lipogenesis fatty acids. Estimated dietary TFA was not significantly associated with DM. These findings highlight the need for further observational, interventional, and experimental studies of the effects TFA on DM.     

Type 2 Diabetes,Metabolic Traits,and Risk of Heart Failure: A Mendelian Randomization Study

OBJECTIVEThe aim of this study was to use Mendelian randomization (MR) techniques to estimate the causal relationships between genetic liability to type 2 diabetes (T2D), glycemic traits, and risk of heart failure (HF).RESEARCH DESIGN AND METHODSSummary-level data were obtained from genome-wide association studies of T2D, insulin resistance (IR), glycated hemoglobin, fasting insulin and glucose, and HF. MR was conducted using the inverse-variance weighted method. Sensitivity analyses included the MR-Egger method, weighted median and mode methods, and multivariable MR conditioning on potential mediators.RESULTSGenetic liability to T2D was causally related to higher risk of HF (odds ratio [OR] 1.13 per 1-log unit higher risk of T2D; 95% CI 1.11–1.14; P < 0.001); however, sensitivity analysis revealed evidence of directional pleiotropy. The relationship between T2D and HF was attenuated when adjusted for coronary disease, BMI, LDL cholesterol, and blood pressure in multivariable MR. Genetically instrumented higher IR was associated with higher risk of HF (OR 1.19 per 1-log unit higher risk of IR; 95% CI 1.00–1.41; P = 0.041). There were no notable associations identified between fasting insulin, glucose, or glycated hemoglobin and risk of HF. Genetic liability to HF was causally linked to higher risk of T2D (OR 1.49; 95% CI 1.01–2.19; P = 0.042), although again with evidence of pleiotropy.CONCLUSIONSThese findings suggest a possible causal role of T2D and IR in HF etiology, although the presence of both bidirectional effects and directional pleiotropy highlights potential sources of bias that must be considered.     

Effects of the SGLT2 Inhibitor Dapagliflozin on Energy Metabolism in Patients With Type 2 Diabetes: A Randomized,Double-Blind Crossover Trial

OBJECTIVESGTL2 inhibitors increase urinary glucose excretion and have beneficial effects on cardiovascular and renal outcomes. The underlying mechanism may involve caloric restriction-like metabolic effects due to urinary glucose loss. We investigated the effects of dapagliflozin on 24-h energy metabolism and insulin sensitivity in patients with type 2 diabetes.RESEARCH DESIGN AND METHODSThere were 26 patients with type 2 diabetes randomized to a 5-week double-blind, crossover study with a 6- to 8-week washout. Indirect calorimetry was used to measure 24-h energy metabolism and the respiratory exchange ratio (RER), both by whole-room calorimetry and by ventilated hood during a two-step euglycemic-hyperinsulinemic clamp. Results are presented as the differences in least squares mean (95% CI) between treatments.RESULTSEvaluable patients (n = 24) had a mean (SD) age of 64.2 (4.6) years, BMI of 28.1 (2.4) kg/m², and HbA_1c of 6.9% (0.7) (51.7 [6.8] mmol/mol). Rate of glucose disappearance was unaffected by dapagliflozin, whereas fasting endogenous glucose production (EGP) increased by dapagliflozin (+2.27 [1.39, 3.14] μmol/kg/min, P < 0.0001). Insulin-induced suppression of EGP (–1.71 [–2.75, –0.63] μmol/kg/min, P = 0.0036) and plasma free fatty acids (–21.93% [–39.31, –4.54], P = 0.016) was greater with dapagliflozin. Twenty-four-hour energy expenditure (–0.11 [–0.24, 0.03] MJ/day) remained unaffected by dapagliflozin, but dapagliflozin reduced the RER during daytime and nighttime, resulting in an increased day-to-nighttime difference in the RER (–0.010 [–0.017, –0.002], P = 0.016). Dapagliflozin treatment resulted in a negative 24-h energy and fat balance (–20.51 [–27.90, –13.12] g/day).CONCLUSIONSDapagliflozin treatment for 5 weeks resulted in major adjustments of metabolism mimicking caloric restriction, increased fat oxidation, improved hepatic and adipose insulin sensitivity, and improved 24-h energy metabolism.     

American Diabetes Association Framework for Glycemic Control in Older Adults: Implications for Risk of Hospitalization and Mortality

OBJECTIVEThe 2021 American Diabetes Association (ADA) guidelines recommend different A1C targets in older adults that are based on comorbid health status. We assessed risk of mortality and hospitalizations in older adults with diabetes across glycemic control (A1C <7%, 7 to <8%, ≥8%) and ADA-defined health status (healthy, complex/intermediate, very complex/poor) categories.RESEARCH DESIGN AND METHODSProspective cohort analysis of older adults aged 66–90 years with diagnosed diabetes in the Atherosclerosis Risk in Communities (ARIC) study.RESULTSOf the 1,841 participants (56% women, 29% Black), 32% were classified as healthy, 42% as complex/intermediate, and 27% as very complex/poor health. Over a median 6-year follow-up, there were 409 (22%) deaths and 4,130 hospitalizations (median [25th–75th percentile] 1 per person [0–3]). In the very complex/poor category, individuals with A1C ≥8% (vs. <7%) had higher mortality risk (hazard ratio 1.76 [95% CI 1.15–2.71]), even after adjustment for glucose-lowering medication use. Within the very complex/poor health category, individuals with A1C ≥8% (vs. <7%) had more hospitalizations (incidence rate ratio [IRR] 1.41 [95% CI 1.03–1.94]). In the complex/intermediate group, individuals with A1C ≥8% (vs. <7%) had more hospitalizations, even with adjustment for glucose-lowering medication use (IRR 1.64 [1.21–2.24]). Results were similar, but imprecise, when the analysis was restricted to insulin or sulfonylurea users (n = 663).CONCLUSIONSThere were substantial differences in mortality and hospitalizations across ADA health status categories, but older adults with A1C <7% were not at elevated risk, regardless of health status. Our results support the 2021 ADA guidelines and indicate that <7% is a reasonable treatment goal in some older adults with diabetes.     

Trends in Receipt of American Diabetes Association Guideline-Recommended Care Among U.S. Adults With Diabetes: NHANES 2005–2018

OBJECTIVETo characterize national trends and characteristics of adults with diabetes receiving American Diabetes Association (ADA) guideline-recommended care.RESEARCH DESIGN AND METHODSWe performed serial cross-sectional analyses of 4,069 adults aged ≥20 years with diabetes who participated in the 2005–2018 National Health and Nutrition Examination Survey (NHANES).RESULTSOverall, the proportion of U.S. adults with diabetes receiving ADA guideline-recommended care meeting all five criteria by self-report in the past year (having a primary doctor for diabetes and one or more visits for this doctor, HbA_1c testing, an eye examination, a foot examination, and cholesterol testing) increased from 25.0% in 2005–2006 to 34.1% in 2017–2018 (P-trend = 0.004). For participants with age ≥65 years, it increased from 29.3% in 2005–2006 to 44.2% in 2017–2018 (P-trend = 0.001), whereas for participants with age 40–64 and 20–39 years, it did not change significantly during the same time period: 25.2% to 25.8% (P-trend = 0.457) and 9.9% to 26.0% (P-trend = 0.401), respectively. Those who were not receiving ADA guideline-recommended care were more likely to be younger, of lower socioeconomic status, uninsured, newly diagnosed with diabetes, not on diabetes medication, and free of hypercholesterolemia.CONCLUSIONSReceipt of ADA guideline-recommended care increased only among adults with diabetes aged ≥65 years in the past decade. In 2017–2018, only one of three U.S. adults with diabetes reported receiving ADA guideline-recommended care, with even a lower receipt of care among those <65 years of age. Efforts are needed to improve health care delivery and equity in diabetes care. Insurance status is an important modifiable determinant of receiving ADA guideline-recommended care.     

Alcohol Abstinence and the Risk of Atrial Fibrillation in Patients With Newly Diagnosed Type 2 Diabetes Mellitus: A Nationwide Population-Based Study

OBJECTIVETo investigate the effects of alcohol abstinence on prevention of new-onset atrial fibrillation (AF) in patients with type 2 diabetes mellitus (T2DM).RESEARCH DESIGN AND METHODSA total of 1,112,682 patients newly diagnosed with T2DM between 2011 and 2014 were identified from the Korean National Health Insurance Service database. After excluding those with a history of AF, 175,100 patients were included. The primary outcome was new-onset AF.RESULTSDuring a mean follow-up of 4.0 years, AF occurred in 4,174 patients. Those with heavy alcohol consumption (alcohol intake ≥40 g/day) before T2DM diagnosis had a higher risk of AF (adjusted hazard ratio [aHR] 1.22; 95% CI 1.06–1.41) compared with patients with no alcohol consumption. After T2DM diagnosis, those with moderate to heavy alcohol consumption (alcohol intake ≥20 g/day) who abstained from alcohol had a lower risk of AF (aHR 0.81; 95% CI 0.68–0.97) compared with constant drinkers. Alcohol abstinence showed consistent trends toward lower incident AF in all subgroups and was statistically significant in men (aHR 0.80; 95% CI 0.67–0.96), those aged >65 years (aHR 0.69; 95% CI 0.52–0.91), those with CHA₂DS₂-VASc score <3 points (aHR 0.71; 95% CI 0.59–0.86), noninsulin users (aHR 0.77; 95% CI 0.63–0.94), and those with BMI <25 kg/m² (aHR 0.68; 95% CI 0.53–0.88).CONCLUSIONSIn patients with newly diagnosed T2DM, alcohol abstinence was associated with a low risk of AF development. Lifestyle modifications, such as alcohol abstinence, in patients newly diagnosed with T2DM should be recommended to reduce the risk of AF.     

Early Menopause and Cardiovascular Disease Risk in Women With or Without Type 2 Diabetes: A Pooled Analysis of 9,374 Postmenopausal Women

OBJECTIVEEarly menopause may be associated with higher cardiovascular disease (CVD) risk. Type 2 diabetes mellitus (T2DM), coupled with early menopause, may result in even greater CVD risk in women. We examined CVD risk in women with early compared with normal-age menopause, with and without T2DM overall, and by race/ethnicity.RESEARCH DESIGN AND METHODSWe pooled data from the Atherosclerosis Risk in Communities study, the Multi-Ethnic Study of Atherosclerosis, and the Jackson Heart Study. We included women with data on menopausal status, menopausal age, and T2DM, excluding pre- or perimenopausal women and those with prevalent CVD. Outcomes included incident coronary heart disease (CHD), stroke, heart failure (HF), and atherosclerotic cardiovascular disease (ASCVD) (CHD or stroke). We estimated the risk associated with early (<45 years) compared with normal-age menopause using Cox proportional hazards models. Covariates included age, race/ethnicity, education, BMI, blood pressure, cholesterol, smoking, alcohol consumption, antihypertensive medication, lipid-lowering medication, hormone therapy use, and pregnancy history.RESULTSWe included 9,374 postmenopausal women for a median follow-up of 15 years. We observed 1,068 CHD, 659 stroke, 1,412 HF, and 1,567 ASCVD events. T2DM significantly modified the effect of early menopause on CVD risk. Adjusted hazard ratios for early menopause and the outcomes were greater in women with T2DM versus those without (CHD 1.15 [95% CI 1.00, 1.33] vs. 1.09 [1.03, 1.15]; stroke 1.21 [1.04, 1.40] vs. 1.10 [1.04, 1.16]; ASCVD 1.29 [1.09, 1.51] vs. 1.10 [1.04, 1.17]; HF 1.18 [1.00, 1.39] vs. 1.09 [1.03, 1.16]). The modifying effect of T2DM on the association between early menopause and ASCVD was only statistically significant in Black compared with White women.CONCLUSIONSEarly menopause was associated with an increased risk for CVD in postmenopausal women. T2DM may further augment the risk, particularly in Black women.     

Immune Checkpoint Inhibitors and Risk of Type 1 Diabetes

OBJECTIVEType 1 diabetes mellitus (T1DM) is a rare, irreversible immune-related adverse event reported in patients receiving treatment with immune checkpoint inhibitors (ICI). However, clinical risk factors for ICI-induced T1DM (ICI-T1DM) and its impact on survival in patients remain unknown.RESEARCH DESIGN AND METHODSWe used Optum’s Clinformatics Data Mart database for assessment of the incidence and characteristics of T1DM in a large de-identified cohort of patients treated with ICI between 2017 and 2020. We applied Fine-Gray and cause-specific hazard models to study associations between patient/treatment characteristics and ICI-T1DM and applied the Cox model with ICI-T1DM as a time-varying covariate to assess the impact of ICI-T1DM on survival.RESULTSICI-T1DM was observed in 261 of 30,337 (0.86%) patients. Dual use of antibodies to cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) was associated with increasing risk of ICI-T1DM (hazard ratio [HR] 1.62; 95% CI 1.15–2.26) vs. anti–PD-L1 or anti–PD-1 alone. Younger age (HR 1.19 for every 5-year decrease; 95% CI 1.13–1.25) and preexisting non-T1DM diabetes (HR 4.48; 95% CI 3.45–5.83) were also associated with higher risk of ICI-T1DM. Conversely, prior use of immunosuppressive medications (HR 0.57; 95% CI 0.34–0.95) was associated with lower incidence of ICI-T1DM, but part of its protective effect may be due to the increased mortality rate. Development of ICI-T1DM does not seem to significantly impact patient survival.CONCLUSIONSThe risk of ICI-T1DM is associated with the type of ICI therapy, patient age, and preexisting non-T1DM diabetes. These data may help guide risk assessment and screening practices for patients during ICI therapy.     

Durability of Triple Combination Therapy Versus Stepwise Addition Therapy in Patients With New-Onset T2DM: 3-Year Follow-up of EDICT

OBJECTIVETo compare the long-term efficacy of initiating therapy with metformin/pioglitazone/exenatide in patients with new-onset type 2 diabetes mellitus (T2DM) versus sequential addition of metformin followed by glipizide and insulin.RESEARCH DESIGN AND METHODSDrug-naive patients (N = 318) with new-onset T2DM were randomly assigned to receive for 3 years either 1) combination therapy with metformin, pioglitazone, and exenatide (triple therapy) or 2) sequential addition of metformin followed by glipizide and insulin (conventional therapy) to maintain HbA_1c at <6.5% (48 mmol/mol). Insulin sensitivity and β-cell function were measured at baseline and 3 years. The primary outcome was the difference in HbA_1c between the groups at 3 years.RESULTSBaseline HbA_1c ± SEM values were 9.0% ± 0.2% and 8.9% ± 0.2% in the triple therapy and conventional therapy groups, respectively. The decrease in HbA_1c resulting from triple therapy was greater at 6 months than that produced by conventional therapy (0.30% [95% CI 0.21–0.39]; P = 0.001), and the HbA_1c reduction was maintained at 3 years in patients receiving triple therapy compared with conventional therapy (6.4% ± 0.1% and 6.9% ± 0.1%, respectively), despite intensification of antihyperglycemic therapy in the latter. Thus, the difference in HbA_1c between the two treatment groups at 3 years was 0.50% (95% CI 0.39–0.61; P < 0.0001). Triple therapy produced a threefold increase in insulin sensitivity and 30-fold increase in β-cell function. In conventional therapy, insulin sensitivity did not change and β-cell function increased by only 34% (both P < 0.0001 vs. triple therapy).CONCLUSIONSTriple therapy with agents that improve insulin sensitivity and β-cell function in patients with new-onset T2DM produces greater, more durable HbA_1c reduction than agents that lower glucose levels without correcting the underlying metabolic defects.     

Presence of Liver Steatosis Is Associated With Greater Diabetes Remission After Gastric Bypass Surgery

OBJECTIVEType 2 diabetes mellitus (T2DM) is characterized by insulin resistance (IR) and β-cell dysfunction. Ectopic fat accumulation in liver and muscle causes IR. Since bariatric and metabolic surgery significantly improves fatty liver disease, we hypothesized that coexistence of liver steatosis (i.e., when hepatic IR contributes in T2DM) would be associated with greater diabetes improvement after surgery.RESEARCH DESIGN AND METHODSA total of 519 patients with T2DM who underwent Roux-en-Y gastric bypass and simultaneous liver biopsy and had a minimum 5-year follow-up were analyzed to assess the independent association between biopsy-proven liver steatosis and postoperative long-term diabetes remission (glycated hemoglobin <6.5% [48 mmol/mol] off medications).RESULTSOf the 407 patients with biopsy-proven liver steatosis, long-term diabetes remission was achieved in 211 (52%) patients compared with remission in 44 out of 112 (39%) patients without steatosis (P = 0.027). In multivariable analysis, presence of liver steatosis was an independent predictor of long-term diabetes remission (odds ratio 1.96 [95% CI 1.04–3.72]; P = 0.038). Hepatocyte ballooning, lobular inflammation, or fibrosis at baseline did not predict diabetes remission.CONCLUSIONSThis study, for the first time, suggests that in patients with T2DM who are considering bariatric and metabolic surgery, coexistence of liver steatosis is associated with better long-term glycemic outcomes. Furthermore, our data suggest that there are distinct variants of T2DM in which metabolic responses to surgical weight loss are different. A subgroup of patients whose T2DM is characterized by the presence of hepatic steatosis (presumably associated with worse IR) experience better postoperative metabolic outcomes.     

Risk Factors for Incident Fracture in Older Adults With Type 2 Diabetes: The Framingham Heart Study

OBJECTIVETo identify risk factors for fracture in type 2 diabetes.RESEARCH DESIGN AND METHODSThis prospective study included members of the Framingham Original and Offspring Cohorts. Type 2 diabetes was defined as fasting plasma glucose >125 mg/dL or use of type 2 diabetes therapy. We used repeated-measures Cox proportional hazards regression to calculate hazard ratios (HRs) and 95% CIs for associations between potential predictors and incidence of fragility fracture.RESULTSParticipants included 793 individuals with type 2 diabetes. Mean ± SD age was 70 ± 10 years; 45% were women. A total of 106 incident fractures occurred over 1,437 observation follow-up intervals. Fracture incidence increased with age (adjusted HRs 1.00, 1.44 [95% CI 0.65, 3.16], and 2.40 [1.14, 5.04] for <60, 60–70, and >70 years, respectively; P_trend = 0.02), female sex (2.23 [1.26, 3.95]), HbA_1c (1.00, 2.10 [1.17, 3.75], and 1.29 [0.69, 2.41] for 4.45–6.46% [25–47 mmol/mol], 6.50–7.49% [48–58 mmol/mol], and 7.50–13.86% [58–128 mmol/mol]; P_trend =0.03), falls in past year (1.00, 1.87 [0.82, 4.28], and 3.29 [1.34, 8.09] for no falls, one fall, and two or more falls; P_trend =0.03), fracture history (2.05 [1.34, 3.12]), and lower grip strength (0.82 [0.69, 0.99] per 5-kg increase). Femoral neck bone mineral density, BMI, smoking, physical function, chronic diseases, medications, and physical function were not associated with fracture incidence.CONCLUSIONSPrior falls, fractures, low grip strength, and elevated HbA_1c are risk factors for fractures in older adults with type 2 diabetes. Evaluation of these factors may improve opportunities for early intervention and reduce fractures in this high-risk group.     

Efficacy and Safety of Dapagliflozin by Baseline Glycemic Status: A Prespecified Analysis From the DAPA-CKD Trial

OBJECTIVEThe Dapagliflozin and Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) study demonstrated risk reduction for kidney and cardiovascular outcomes with dapagliflozin versus placebo in participants with chronic kidney disease (CKD) with and without diabetes. We compared outcomes according to baseline glycemic status.RESEARCH DESIGN AND METHODSWe enrolled participants with CKD, estimated glomerular filtration rate (eGFR) 25–75 mL/min/1.73 m², and urinary albumin-to-creatinine ratio 200–5,000 mg/g. The primary composite end point was sustained eGFR decline ≥50%, end-stage kidney disease, or kidney or cardiovascular death.RESULTSOf 4,304 participants, 738 had normoglycemia, 660 had prediabetes, and 2,906 had type 2 diabetes. The effect of dapagliflozin on the primary outcome was consistent (P for interaction = 0.19) in normoglycemia (hazard ratio [HR] 0.62 [95% CI 0.39, 1.01]), prediabetes (HR 0.37 [0.21, 0.66]), and type 2 diabetes (HR 0.64 [0.52, 0.79]). We found no evidence for effect modification on any outcome. Adverse events were similar, with no major hypoglycemia or ketoacidosis in participants with normoglycemia or prediabetes.CONCLUSIONSDapagliflozin safely reduced kidney and cardiovascular events independent of baseline glycemic status.     

Effect of Dapagliflozin in DAPA-HF According to Background Glucose-Lowering Therapy

OBJECTIVETo determine whether the benefits of dapagliflozin in patients with heart failure and reduced ejection fraction (HFrEF) and type 2 diabetes in the Dapagliflozin And Prevention of Adverse-Outcomes in Heart Failure trial (DAPA-HF) varied by background glucose-lowering therapy (GLT).RESEARCH DESIGN AND METHODSWe examined the effect of study treatment by the use or not of GLT and by GLT classes and combinations. The primary outcome was a composite of worsening heart failure (hospitalization or urgent visit requiring intravenous therapy) or cardiovascular death.RESULTSIn the 2,139 type 2 diabetes patients, the effect of dapagliflozin on the primary outcome was consistent by GLT use or no use (hazard ratio 0.72 [95% CI 0.58–0.88] vs. 0.86 [0.60–1.23]; interaction P = 0.39) and across GLT classes.CONCLUSIONSIn DAPA-HF, dapagliflozin improved outcomes irrespective of use or no use of GLT or by GLT type used in patients with type 2 diabetes and HFrEF.