Plasma trimethylamine-N-oxide and related metabolites are associated with type 2 diabetes risk in the Prevención con Dieta Mediterránea (PREDIMED) trial

ABSTRACT Background The role of trimethylamine-N-oxide (TMAO) in type 2 diabetes (T2D) is currently partially understood and controversial. Objective The aim of this study was to investigate associations between TMAO and related metabolites with T2D risk in subjects at high risk of cardiovascular disease. Design This is a case-cohort design study within the Prevención con Dieta Mediterránea (PREDIMED) study, with 251 incident T2D cases and a random sample of 694 participants (641 noncases and 53 overlapping cases) without T2D at baseline (median follow-up: 3.8 y). We used liquid chromatography–tandem mass spectrometry to measure plasma TMAO, l-carnitine, betaine, lyso-phosphatidylcholine (LPC) and lyso-phosphatidylethanolamine (LPE) species, phosphocholine, α-glycerophosphocholine, and choline at baseline and after 1 y. We examined associations with the use of weighted Cox proportional hazard models, accounting for the weighted case-cohort design by the Barlow method. Results After adjustment for recognized T2D risk factors and multiple testing, individuals in the highest quartile of baseline TMAO and α-glycerophosphocholine had a lower risk of T2D [HR (95% CI): 0.52 (0.29, 0.89) and 0.46 (0.24, 0.89), respectively]. The HR (95% CI) comparing the extreme quartiles of betaine was 0.41 (0.23, 0.74). Similar trends were observed for C16:0 LPC, C18:1 LPC, C18:0 LPC, C20:4 LPC, C22:6 LPC, C18:1 LPC plasmalogen, and C16:0 LPE. After correcting for multiple comparisons, participants in the highest quartile of 1-y changes in oleic acid LPC plasmalogen concentrations had a lower T2D risk than the reference quartile. Conclusion Whether the associations between plasma TMAO and certain metabolite concentrations with T2D risk reflect its pathophysiology or represent an epiphenomenon needs to be elucidated. This trial is registered at http://www.controlled-trials.com as ISRCTN35739639.

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Association of Mean and Variability of HbA1c with Heart Failure in Patients with Type 2 Diabetes

Journal of Clinical Medicine ◽

10.3390/jcm10071401 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1401

Author(s):

You-Ting Lin ◽

Wei-Lun Huang ◽

Hung-Pin Wu ◽

Man-Ping Chang ◽

Ching-Chu Chen

Keyword(s):

Heart Failure ◽

Type 2 Diabetes ◽

Hba1c Level ◽

Care Program ◽

Good Glycemic Control ◽

Cox Proportional Hazard ◽

Hazard Ratios ◽

Cox Proportional Hazard Models ◽

Hba1c Variability

Heart failure (HF) is a common presentation in patients with type 2 diabetes mellitus (T2DM). Previous studies revealed that the HbA1c level is significantly associated with HF. However, little is known about the association between HbA1c variability and HF. We aimed to evaluate the association of mean and variability of HbA1c with HF in patients with T2DM. Using Diabetes Share Care Program data, patients with T2DM who had mean HbA1c (HbA1c-Mean), and HbA1c variability (tertiles of HbA1c-SD and HbA1c-adjSD) within 12–24 months during 2001–2008 were included. The cutoffs of HbA1c-Mean were set at <7%, 7–7.9%, and ≥8%. Hazard ratios (HRs) for HF during 2008–2018 were estimated using Cox proportional hazard models. A total of 3824 patients were included, of whom 315 patients developed HF during the observation period of 11.72 years. The associated risk of HF increased with tertiles of HbA1c variability and cutoffs of HbA1c-Mean. In mutually adjusted models, HbA1c-Mean showed a consistent dose-response association with HF, while the association of HbA1c variability with HF disappeared. Among patients with HbA1c-Mean <7%, the associated risk of HF in patients with HbA1c variability in tertile 3 was comparable to patients with HbA1c-Mean ≥8%. In conclusion, mean HbA1c was an independent predictor of HF and not explained by HbA1c variability. In addition to absolute HbA1c level, targeting on stability of HbA1c in patients with good glycemic control was also important for the development of HF in patients with T2DM.

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Plasma metabolites predict both insulin resistance and incident type 2 diabetes: a metabolomics approach within the Prevención con Dieta Mediterránea (PREDIMED) study

American Journal of Clinical Nutrition ◽

10.1093/ajcn/nqy262 ◽

2019 ◽

Vol 109 (3) ◽

pp. 626-634 ◽

Cited By ~ 12

Author(s):

Christopher Papandreou ◽

Mònica Bulló ◽

Miguel Ruiz-Canela ◽

Courtney Dennis ◽

Amy Deik ◽

...

Keyword(s):

Risk Factors ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Area Under The Curve ◽

Predictive Ability ◽

Plasma Metabolites ◽

Incident Type ◽

Dieta Mediterranea ◽

Dieta Mediterránea

ABSTRACT Background Insulin resistance is a complex metabolic disorder and is often associated with type 2 diabetes (T2D). Objectives The aim of this study was to test whether baseline metabolites can additionally improve the prediction of insulin resistance beyond classical risk factors. Furthermore, we examined whether a multimetabolite model predicting insulin resistance in nondiabetics can also predict incident T2D. Methods We used a case-cohort study nested within the Prevención con Dieta Mediterránea (PREDIMED) trial in subsets of 700, 500, and 256 participants without T2D at baseline and 1 and 3 y. Fasting plasma metabolites were semiquantitatively profiled with liquid chromatography–tandem mass spectrometry. We assessed associations between metabolite concentrations and the homeostasis model of insulin resistance (HOMA-IR) through the use of elastic net regression analysis. We subsequently examined associations between the baseline HOMA-IR–related multimetabolite model and T2D incidence through the use of weighted Cox proportional hazard models. Results We identified a set of baseline metabolites associated with HOMA-IR. One-year changes in metabolites were also significantly associated with HOMA-IR. The area under the curve was significantly greater for the model containing the classical risk factors and metabolites together compared with classical risk factors alone at baseline [0.81 (95% CI: 0.79, 0.84) compared with 0.69 (95% CI: 0.66, 0.73)] and during a 1-y period [0.69 (95% CI: 0.66, 0.72) compared with 0.57 (95% CI: 0.53, 0.62)]. The variance in HOMA-IR explained by the combination of metabolites and classical risk factors was also higher in all time periods. The estimated HRs for incident T2D in the multimetabolite score (model 3) predicting high HOMA-IR (median value or higher) or HOMA-IR (continuous) at baseline were 2.00 (95% CI: 1.58, 2.55) and 2.24 (95% CI: 1.72, 2.90), respectively, after adjustment for T2D risk factors. Conclusions The multimetabolite model identified in our study notably improved the predictive ability for HOMA-IR beyond classical risk factors and significantly predicted the risk of T2D.

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Abstract 3737: The Association Between Therapy With Insulin Glargine Versus Nph And The Risk Of Myocardial Infarction In Patients With Type 2 Diabetes

Circulation ◽

10.1161/circ.116.suppl_16.ii_849-c ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Mikhail Kosiborod ◽

Quanwu Zhang ◽

JoAnne Foody

Keyword(s):

Myocardial Infarction ◽

Type 2 Diabetes ◽

Insulin Glargine ◽

Lower Risk ◽

Administrative Database ◽

Medical Claim ◽

Cox Proportional Hazard ◽

Cox Proportional Hazard Models

Background: Prior studies have demonstrated that insulin glargine produces less hypoglycemia, as compared with NPH. Whether these results translate into better long-term cardiovascular outcomes in patients with Type 2 diabetes is unknown. Methods: Using a national managed care administrative database, we evaluated patients with Type 2 diabetes who were on oral antiglycemic agents within 6 months prior to initiating either insulin glargine (n=15,039) or NPH (n=5,666) and had at least 12 months of subsequent continuous plan enrollment during 03/2001–03/2005. Cox proportional hazard models were used to compare the rate of subsequent myocardial infarction (MI) events (defined by ICD-9 codes) following initiation of glargine vs NPH, after adjusting for demographic characteristics, comorbidities, other medications, insulin adherence and baseline Hemoglobin A1C (A1C). Results: Mean age was 56 years, 49% were women; mean duration of follow up was 24 months. Among patients who had available A1C (n=2514), those in glargine group had higher A1C at baseline vs. NPH (9.3 vs 8.9 respectively, p<0.0001). During the 1 st year following insulin initiation, 8.7% patients in NPH vs. 7.5% in glargine group had at least one medical claim for hypoglycemia (OR=1.17, 95% CI: 1.05–1.31). In unadjusted analysis, the rate of MI events was 4.4% in glargine group vs. 7.7% in the NPH group (p<0.0001). After multivariable adjustment, risk of MI events remained lower in glargine group (HR: 0.78, 95% CI: 0.64–0.95). Although hypoglycemic events were associated with higher MI risk (HR 1.3, 95% CI 1.18–1.44 for each quarter with a medical claim for hypoglycemia during 1 st year of follow up), the association between glargine use and lower risk of MI events remained significant even after adjusting for hypoglycemia (HR: 0.79, 95% CI 0.65–0.96). Conclusion: Initiation of insulin glargine in patients with Type 2 diabetes is associated with lower risk of subsequent MI events, as compared with NPH. Lower rate of hypoglycemia associated with glargine use does not completely account for this difference in outcomes. Further studies are needed to validate these results and provide insights into potential physiologic mechanisms.

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Total and subtypes of dietary fat intake and risk of type 2 diabetes mellitus in the Prevención con Dieta Mediterránea (PREDIMED) study

American Journal of Clinical Nutrition ◽

10.3945/ajcn.116.142034 ◽

2017 ◽

Vol 105 (3) ◽

pp. 723-735 ◽

Cited By ~ 36

Author(s):

Marta Guasch-Ferré ◽

Nerea Becerra-Tomás ◽

Miguel Ruiz-Canela ◽

Dolores Corella ◽

Helmut Schröder ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Dietary Fat ◽

Fat Intake ◽

Dietary Fat Intake ◽

Predimed Study ◽

Dieta Mediterranea ◽

Dieta Mediterránea

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Does metformin protect against osteoarthritis? An electronic health record cohort study

Primary Health Care Research & Development ◽

10.1017/s1463423617000287 ◽

2017 ◽

Vol 18 (06) ◽

pp. 623-628 ◽

Cited By ~ 8

Author(s):

Lauren A. Barnett ◽

Kelvin P. Jordan ◽

John J. Edwards ◽

Danielle A. van der Windt

Keyword(s):

Type 2 Diabetes ◽

Cohort Study ◽

Oral Treatment ◽

Baseline Period ◽

Cox Proportional Hazard ◽

Gamma Frailty ◽

Prior Record ◽

Cox Proportional Hazard Models ◽

General Practices

Background Obesity is a major risk factor for osteoarthritis (OA) whilst there is some evidence that diabetes also increases risk. Metformin is a common oral treatment for those with diabetes. Objective The aim is to investigate whether metformin reduces the risk of OA. Methods This was a cohort study set within the Consultations in Primary Care Archive, with 3217 patients with type 2 diabetes. Patients at 13 general practices with recorded type 2 diabetes in the baseline period (2002–2003) and no prior record of OA were identified. Exposure was a prescription for metformin. Outcome was an OA record during follow up. Cox proportional hazard models with Gamma frailty term were fitted: adjusted for age, gender, deprivation, and comorbidity. Results There was no association between prescribed metformin treatment at baseline and OA (adjusted HR: 1.02, 95% CI: 0.91, 1.15). A similar non- significant association was found when allowing exposure status of prescription of metformin to vary over time.

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