Pain in Patients With Type 2 Diabetes-Related Polyneuropathy Is Associated With Vascular Events and Mortality

Abstract Purpose Type 2 diabetes–related polyneuropathy (DPN) is associated with increased vascular events and mortality, but determinants and outcomes of pain in DPN are poorly understood. We sought to examine the effect of neuropathic pain on vascular events and mortality in patients without DPN, DPN with pain (DPN + P), and DPN without pain (DPN-P). Methods A retrospective cohort study was conducted within a large health system of adult patients with type 2 diabetes from January 1, 2009 through December 31, 2016. Using an electronic algorithm, patients were classified as no DPN, DPN + P, or DPN-P. Primary outcomes included number of vascular events and time to mortality. Independent associations with DPN + P were evaluated using multivariable negative binomial and Cox proportional hazards regression models, adjusting for demographics, socioeconomic characteristics, and comorbidities. Results Of 43 945 patients with type 2 diabetes (age 64.6 ± 14.0 years; 52.1% female), 13 910 (31.7%) had DPN: 9104 DPN + P (65.4%) vs 4806 DPN-P (34.6%). Vascular events occurred in 4538 (15.1%) of no DPN patients, 2401 (26.4%) DPN + P, and 1006 (20.9%) DPN-P. After adjustment, DPN + P remained a significant predictor of number of vascular events (incidence rate ratio [IRR] = 1.55, 95% CI, 1.29-1.85), whereas no DPN was protective (IRR = 0.70, 95% CI, 0.60-0.82), as compared to DPN-P. Compared to DPN-P, DPN + P was also a significant predictor of mortality (hazard ratio = 1.42, 95% CI, 1.25-1.61). Conclusions Our study found a significant association between pain in DPN and an increased risk of vascular events and mortality. This observation warrants longitudinal study of the risk factors and natural history of pain in DPN.

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Retinopathy, Neuropathy, and Subsequent Cardiovascular Events in Patients with Type 2 Diabetes and Acute Coronary Syndrome in the ELIXA: The Importance of Disease Duration

Journal of Diabetes Research ◽

10.1155/2018/1631263 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 2

Author(s):

Jelena P. Seferovic ◽

Rhonda Bentley-Lewis ◽

Brian Claggett ◽

Rafael Diaz ◽

Hertzel C. Gerstein ◽

...

Keyword(s):

Type 2 Diabetes ◽

Acute Coronary Syndrome ◽

Proportional Hazards ◽

Clinical Markers ◽

Coronary Syndrome ◽

Proportional Hazards Regression ◽

Increased Risk ◽

Registration Number ◽

History Of

Introduction. We investigated the association of diabetic retinopathy and neuropathy with increased risk of recurrent cardiovascular (CV) events in 6068 patients with type 2 diabetes mellitus (T2DM) and recent acute coronary syndrome (ACS) enrolled in the Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA). Methods. History of retinopathy and neuropathy as well as duration of T2DM were self-reported at screening. Proportional hazards regression models were used to assess relationships between retinopathy, neuropathy, and recurrent CV events. Results. At screening, retinopathy and neuropathy were reported in 10.7% and 17.5% of patients, respectively, while 5.7% reported both. When adjusted for randomized treatment only, both retinopathy and neuropathy were associated with a primary composite outcome (CV death, nonfatal MI, stroke, or hospitalization for unstable angina) (retinopathy: HR 1.44, 95% CI 1.19–1.75; neuropathy: HR 1.33, 95% CI 1.12–1.57), CV composite (CV death, nonfatal MI, stroke, hospitalization for heart failure (HF)) (retinopathy: HR 1.57, 95% CI 1.31–1.88; neuropathy: HR 1.38, 95% CI 1.19–1.62), myocardial infarction (retinopathy: HR 1.38, 95% CI 1.08–1.76; neuropathy: HR 1.26, 95% CI 1.02–1.54), HF hospitalization (retinopathy: HR 2.03, 95% CI 1.48–2.78; neuropathy: HR 1.71, 95% CI 1.30–2.27), and all-cause mortality (retinopathy: HR 1.65, 95% CI 1.28–2.12; neuropathy: HR 1.43, 95% CI 1.14–1.78). When included in the same model, and adjusted for T2DM duration, there were no independent associations of either with CV outcomes, while T2DM duration remained strongly associated with all outcomes. Addition of demographic characteristics and CV risk factors did not further alter these relationships. Conclusions. In patients with T2DM and recent ACS, a history of retinopathy and/or neuropathy and longer T2DM duration could be considered clinical markers for high risk of recurrent CV events. This trial is registered with the ELIXA (Evaluation of Lixisenatide in Acute Coronary Syndrome), ClinicalTrials.gov registration number NCT01147250.

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High Betaine, a Trimethylamine N-Oxide Related Metabolite, Is Prospectively Associated with Low Future Risk of Type 2 Diabetes Mellitus in the PREVEND Study

Journal of Clinical Medicine ◽

10.3390/jcm8111813 ◽

2019 ◽

Vol 8 (11) ◽

pp. 1813 ◽

Cited By ~ 2

Author(s):

Erwin Garcia ◽

Maryse C. J. Osté ◽

Dennis W. Bennett ◽

Elias J. Jeyarajah ◽

Irina Shalaurova ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Regression ◽

Proportional Hazards Regression ◽

Study Results ◽

Future Risk

Background: Gut microbiota-related metabolites, trimethylamine-N-oxide (TMAO), choline, and betaine, have been shown to be associated with cardiovascular disease (CVD) risk. Moreover, lower plasma betaine concentrations have been reported in subjects with type 2 diabetes mellitus (T2DM). However, few studies have explored the association of betaine with incident T2DM, especially in the general population. The goals of this study were to evaluate the performance of a newly developed betaine assay and to prospectively explore the potential clinical associations of betaine and future risk of T2DM in a large population-based cohort. Methods: We developed a high-throughput, nuclear magnetic resonance (NMR) spectroscopy procedure for acquiring spectra that allow for the accurate quantification of plasma/serum betaine and TMAO. Assay performance for betaine quantification was assessed and Cox proportional hazards regression was employed to evaluate the association of betaine with incident T2DM in 4336 participants in the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study. Results: Betaine assay results were linear (y = 1.02X − 3.75) over a wide range of concentrations (26.0–1135 µM). The limit of blank (LOB), limit of detection (LOD) and limit of quantitation (LOQ) were 6.4, 8.9, and 13.2 µM, respectively. Coefficients of variation for intra- and inter-assay precision ranged from 1.5–4.3% and 2.5–5.5%, respectively. Deming regression analysis of results produced by NMR and liquid chromatography coupled to tandem mass spectrometry(LC-MS/MS) revealed an R2 value of 0.94 (Y = 1.08x – 1.89) and a small bias for higher values by NMR. The reference interval, in a cohort of apparently healthy adult participants (n = 501), was determined to be 23.8 to 74.7 µM (mean of 42.9 ± 12.6 µM). In the PREVEND study (n = 4336, excluding subjects with T2DM at baseline), higher betaine was associated with older age and lower body mass index, total cholesterol, triglycerides, and hsCRP. During a median follow-up of 7.3 (interquartile range (IQR), 5.9–7.7) years, 224 new T2DM cases were ascertained. Cox proportional hazards regression models revealed that the highest tertile of betaine was associated with a lower incidence of T2DM. Hazard ratio (HR) for the crude model was 0.61 (95% CI: 0.44–0.85, p = 0.004). The association remained significant even after adjusting for multiple clinical covariates and T2DM risk factors, including fasting glucose. HR for the fully-adjusted model was 0.50 (95% CI: 0.32–0.80, p = 0.003). Conclusions: The newly developed NMR-based betaine assay exhibits performance characteristics that are consistent with usage in the clinical laboratory. Betaine levels may be useful for assessing the risk of future T2DM.

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Time in range in relation to all-cause and cardiovascular mortality in patients with type 2 diabetes: a prospective cohort study

10.2337/figshare.12980045 ◽

2020 ◽

Author(s):

Jingyi Lu ◽

Chunfang Wang ◽

Yun Shen ◽

Lei Chen ◽

Lei Zhang ◽

...

Keyword(s):

Type 2 Diabetes ◽

Proportional Hazards ◽

Reference Group ◽

Surrogate Marker ◽

Cox Proportional Hazards ◽

Increased Risk ◽

Time In Range ◽

Different Levels ◽

Cvd Mortality

Objective: There is growing evidence linking time in range (TIR), an emerging metric for assessing glycemic control, to diabetes-related outcomes. We aimed to investigate the association between TIR and mortality in patients with type 2 diabetes. Research design and methods: A total of 6225 adult patients with type 2 diabetes were included from January 2005 to December 2015 from a single center in Shanghai, China. TIR was measured with continuous glucose monitoring at baseline, and the participants were stratified into 4 groups by TIR: >85%, 71-85%, 51-70%, and ≤50%. Cox proportional hazards regression models were used to estimate the association between different levels of TIR and the risks of all-cause and cardiovascular disease (CVD) mortality. Results: The mean age of the participants was 61.7 years at baseline. During a median follow-up of 6.9 years, 838 deaths were identified, 287 of which were due to CVD. The multivariable-adjusted hazard ratios associated with different levels of TIR (>85% [reference group], 71-85%, 51-70%, and ≤50%) were 1.00, 1.23 (95% CI, 0.98-1.55), 1.30 (95% CI, 1.04-1.63), and 1.83 (95% CI, 1.48-2.28) for all-cause mortality (P for trend <0.001), and 1.00, 1.35 (95% CI, 0.90-2.04), 1.47 (95% CI, 0.99-2.19), and 1.85 (95% CI, 1.25-2.72) for CVD mortality (P for trend =0.015), respectively. Conclusions: The present study indicated an association of lower TIR with an increased risk of all-cause and CVD mortality among patients with type 2 diabetes, supporting the validity of TIR as a surrogate marker of long-term adverse clinical outcomes.

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Levels of ankle–brachial index and the risk of diabetes mellitus complications

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2019-000977 ◽

2020 ◽

Vol 8 (1) ◽

pp. e000977

Author(s):

Lia Alves-Cabratosa ◽

Marc Comas-Cufí ◽

Anna Ponjoan ◽

Maria Garcia-Gil ◽

Ruth Martí-Lluch ◽

...

Keyword(s):

Type 2 Diabetes ◽

Proportional Hazards ◽

Microvascular Complications ◽

Ankle Brachial Index ◽

Cardiovascular Prevention ◽

Cox Proportional Hazards ◽

Cox Models ◽

Complications Of Diabetes ◽

Increased Risk

ObjectiveWe sought to compare the association of categorized ankle–brachial index (ABI) with mortality and complications of diabetes in persons with no symptoms of peripheral arterial disease (PAD) and in primary cardiovascular disease prevention.Research design and methodsThis is a retrospective cohort study of persons with type 2 diabetes aged 35–85 years, from 2006 to 2011. Data were obtained from the Sistema d'Informació per al Desenvolupament de la Investigació en Atenció Primària (SIDIAPQ). Participants had an ABI measurement that was classified into six categories. For each category of ABI, we assessed the incidence of mortality; macrovascular complications of diabetes: acute myocardial infarction (AMI), ischemic stroke, and a composite of these two; and microvascular complications of this metabolic condition: nephropathy, retinopathy, and neuropathy. We also estimated the HRs for these outcomes by ABI category using Cox proportional hazards models.ResultsData from 34 689 persons with type 2 diabetes were included. The mean age was 66.2; 51.5% were men; and the median follow-up was 6.0 years. The outcome with the highest incidence was nephropathy, with 24.4 cases per 1000 person-years in the reference category of 1.1≤ABI≤1.3. The incidences in this category for mortality and AMI were 15.4 and 4.1, respectively. In the Cox models, low ABI was associated with increased risk and was significant from ABI lower than 0.9; below this level, the risk kept increasing steeply. High ABI (over 1.3) was also associated with significant increased risk for most outcomes.ConclusionsThe studied categories of ABI were associated with different risks of type 2 diabetes complications in persons asymptomatic for PAD, who were in primary cardiovascular prevention. These findings could be useful to optimize preventive interventions according to the ABI category in this population.

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Risk of non-infectious uveitis or myasthenia gravis in patients on checkpoint inhibitors in a large healthcare claims database

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2020-317060 ◽

2020 ◽

pp. bjophthalmol-2020-317060 ◽

Cited By ~ 1

Author(s):

Tian Xia ◽

Alexander J Brucker ◽

Brendan McGeehan ◽

Brian L VanderBeek

Keyword(s):

Multivariate Analysis ◽

Myasthenia Gravis ◽

Index Date ◽

Proportional Hazards ◽

Checkpoint Inhibitors ◽

Cox Proportional Hazards ◽

Proportional Hazards Regression ◽

Increased Risk ◽

History Of ◽

Infectious Uveitis

AimTo determine if checkpoint inhibitors (CPIs) confer an increased risk of non-infectious uveitis or myasthenia gravis (MG) compared to patients on non-checkpoint inhibitor (N-CPI) chemotherapy.MethodsA retrospective cohort study was performed comparing patients in a large commercial and Medicare advantage database exposed to CPI compared to N-CPI. All patients who initiated a CPI (ipilimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, cemiplimab and durvalumab) were eligible. Date of earliest CPI in the exposure group and N-CPI chemotherapy in the comparator group was considered the index date. Exclusion occurred in both cohorts for any history of uveitis or MG diagnosis and having <1 year in the insurance plan prior to the index date, and <6 months in plan following the index date. Every exposed patient was matched up to 1:10 based on demographics and index year to patients on N-CPI chemotherapy. Multivariate Cox proportional hazards regression modelling was performed.ResultsFor evaluation of incidence of non-infectious uveitis, 26 (0.3%) of 8678 patients on CPI and 123 (0.2%) of 76 153 N-CPI comparators were found to have non-infectious uveitis. After multivariate analysis, CPIs showed an increased hazard for uveitis compared to N-CPI (HR=2.09; 95% CI 1.36 to 3.22, p=0.001). For the MG analysis, 11 (0.1%) of 9210 patients developed MG in the CPI group and 36 (0.04%) of 80 620 comparators. The CPI cohort had a higher hazard of developing MG (HR=2.60; 95% CI 1.34 to 5.07, p=0.005) compared to controls in multivariate analysis.ConclusionsExposure to CPI confers a higher risk for non-infectious uveitis and MG compared to N-CPI chemotherapy.

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Anemia and incidence of dementia in patients with new-onset type 2 diabetes: a nationwide population-based cohort study

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2020-001289 ◽

2020 ◽

Vol 8 (1) ◽

pp. e001289

Author(s):

Jae Woo Choi ◽

Tae Hyun Kim ◽

Euna Han

Keyword(s):

Type 2 Diabetes ◽

Proportional Hazards ◽

Population Based ◽

Primary Diagnosis ◽

Cox Proportional Hazards ◽

Onset Type ◽

Increased Risk ◽

New Onset ◽

Incidence Of Dementia

IntroductionThis study aimed to examine the association between anemia and the incidence of dementia in patients with new-onset type 2 diabetes.Research design and methodsThis study used the Korean National Health Insurance Service-Health Screening Cohort and included 32 590 participants aged ≥40 years who were diagnosed with new-onset type 2 diabetes between 2004 and 2007 and followed up until 2013. Anemia was defined according to the criteria provided by the WHO, hemoglobin <120 g/L for women and <130 g/L for men, and was measured from after diagnosis date of type 2 diabetes to 2007. Dementia was defined by the Classification of Diseases 10th revision code as primary diagnosis and was measured from after hemoglobin measurement to 2013. We calculated the adjusted HR (AHR) and 95% CI to assess the risk of dementia using multivariable Cox proportional hazards regression models.ResultsWe identified 1682 patients who developed dementia within a 7.5-year follow-up. Among patients with type 2 diabetes, patients with anemia were associated with an increased risk of dementia than those without anemia (AHR, 1.21; 95% CI 1.06 to 1.39). Patients with mild (AHR, 1.18; 95% CI 1.03 to 1.38) and moderate (AHR, 1.39; 95% CI 1.06 to 1.83) anemia were associated with an increased risk of dementia than those without anemia among patients with type 2 diabetes. Men (AHR, 1.47; 95% CI 1.16 to 1.83) and middle-aged adults (AHR, 1.31; 95% CI 1.03 to 1.75) with anemia were associated with an increased risk of dementia than their counterparts without anemia among patients with type 2 diabetes.ConclusionsOur findings suggest that anemia is significantly associated with an increased risk of dementia among patients with newly diagnosed type 2 diabetes.

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Risk of a post-colonoscopy colorectal cancer in patients with type 2 diabetes: a Danish population-based cohort study

BMJ Open Gastroenterology ◽

10.1136/bmjgast-2021-000786 ◽

2021 ◽

Vol 8 (1) ◽

pp. e000786

Author(s):

Frederikke Schønfeldt Troelsen ◽

Henrik Toft Sørensen ◽

Lars Pedersen ◽

Rune Erichsen

Keyword(s):

Colorectal Cancer ◽

Type 2 Diabetes ◽

Cohort Study ◽

Proportional Hazards ◽

Population Based ◽

Cox Proportional Hazards ◽

Increased Risk ◽

First Time

ObjectivePrevalent type 2 diabetes (T2D) is associated with an increased risk of colorectal cancer and could impair the quality of bowel preparation for colonoscopy. This may in turn increase the risk of overlooked precancerous polyps and subsequent risk of post-colonoscopy colorectal cancer (PCCRC). We investigated whether patients with T2D are at increased risk of PCCRC compared with patients without T2D.DesignWe conducted a population-based cohort study of patients with T2D and without T2D undergoing colonoscopy in Denmark (1995–2015). We investigated the risk of PCCRC by calculating >6 to 36 months cumulative incidence proportions (CIPs) treating death and colectomy as competing risks. Using Cox proportional-hazards regression analyses, we also computed HRs of PCCRC, comparing patients with T2D and non-T2D. According to the World Endoscopy Organization guidelines, we calculated PCCRC 3-year rates to estimate the proportions of T2D and non-T2D CRC patients experiencing PCCRC.ResultsWe identified 29 031 patients with T2D and 333 232 patients without T2D undergoing colonoscopy. We observed 250 PCCRCs among patients with T2D and 1658 PCCRCs among patients without T2D. The >6 to 36 months CIP after a first-time colonoscopy was 0.64% (95% CI 0.55% to 0.74%) for T2D and 0.36% (95% CI 0.34% to 0.38%) for patients without T2D. The HRs of PCCRC were 1.43 (95% CI 1.21 to 1.72) after a first-time colonoscopy and 1.18 (95% CI 0.75 to 1.85) after a second-time colonoscopy. The PCCRC 3-year rate was 7.9% for patients with T2D and 7.4% for patients without T2D.ConclusionT2D may be associated with an increased HR of PCCRC.

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Prenatal diethylstilbestrol exposure and risk of diabetes, gallbladder disease, and pancreatic disorders and malignancies

Journal of Developmental Origins of Health and Disease ◽

10.1017/s2040174420000872 ◽

2020 ◽

pp. 1-8

Author(s):

Rebecca Troisi ◽

Marianne Hyer ◽

Linda Titus ◽

Julie R. Palmer ◽

Elizabeth E. Hatch ◽

...

Keyword(s):

Type 2 Diabetes ◽

Pancreatic Cancer ◽

General Population ◽

Proportional Hazards ◽

Gallbladder Disease ◽

Incidence Rates ◽

Cox Proportional Hazards ◽

Increased Risk ◽

Pancreatic Disorders

Abstract Prenatal diethylstilbestrol (DES) exposure is associated with increased risk of hormonally mediated cancers and other medical conditions. We evaluated the association between DES and risk of pancreatic cancer and pancreatic disorders, type 2 diabetes, and gallbladder disease, which may be involved with this malignancy. Our analyses used follow-up data from the US National Cancer Institute DES Combined Cohort Study. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for age, sex, cohort, body mass index, smoking, and alcohol for the association between prenatal DES exposure and type 2 diabetes, gallbladder disease (mainly cholelithiasis), pancreatic disorders (mainly pancreatitis), and pancreatic cancer among 5667 exposed and 3315 unexposed individuals followed from 1990 to 2017. Standardized incidence rate (SIR) ratios for pancreatic cancer were based on age-, race-, and calendar year-specific general population cancer incidence rates. In women and men combined, the hazards for total pancreatic disorders and pancreatitis were greater in the prenatally DES exposed than the unexposed (HR = 11, 95% CI 2.6–51 and HR = 7.0, 95% CI 1.5–33, respectively). DES was not associated overall with gallbladder disease (HR = 1.2, 95% CI 0.88–1.5) or diabetes (HR = 1.1, 95% CI 0.9–1.2). In women, but not in men, DES exposure was associated with increased risk of pancreatic cancer compared with the unexposed (HR: 4.1, 95% CI 0.84–20) or general population (SIR: 1.9, 95% CI 1.0–3.2). Prenatal DES exposure may increase the risk of pancreatic disorders, including pancreatitis in women and men. The data suggested elevated pancreatic cancer risk in DES-exposed women, but not in exposed men.

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Safety of add-on sulfonylurea therapy in patients with type 2 diabetes using metformin: a population-based real-world study

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2021-002352 ◽

2021 ◽

Vol 9 (2) ◽

pp. e002352

Author(s):

Ingrid Hougen ◽

Reid H Whitlock ◽

Paul Komenda ◽

Claudio Rigatto ◽

Kristin K Clemens ◽

...

Keyword(s):

Type 2 Diabetes ◽

Real World ◽

Cardiovascular Events ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Dipeptidyl Peptidase 4 ◽

Increased Risk ◽

Dipeptidyl Peptidase 4 Inhibitors ◽

All Cause Mortality

IntroductionMetformin is the initial oral antihyperglycemic agent (OHA) of choice for most patients with type 2 diabetes (T2D). However, more than one agent is often required for optimal glucose control. As the choice of preferred second OHAs is less well defined, we sought to compare the real-world safety of sulfonylureas to other OHAs as add-on therapy to metformin in patients with T2D.Research design and methodsThis retrospective cohort study included adults in Manitoba, Canada with T2D from 2006 to 2017. Using a new-user design, we divided patients who started on metformin into two groups: add-on therapy with a sulfonylurea and add-on therapy with a different OHA. Outcomes included all-cause mortality, cardiovascular events, and major hypoglycemic episodes. We calculated propensity scores and applied inverse probability of treatment weights to each individual. We compared groups using Cox proportional hazards regression and explored differences in HRs between pre-2008 (acarbose, meglitinides, and thiazolidinediones) and post-2008 (dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, and sodium-glucose linked transporter-2 inhibitors) OHAs.ResultsOur cohort included 32 576 individuals (28 077 metformin plus sulfonylurea and 4499 metformin plus ‘other’). Patients newly prescribed a sulfonylurea in the setting of metformin had a higher risk of all-cause mortality (HR 1.44, 95% CI 1.12 to 1.84, p=0.005) and major hypoglycemic episodes (HR 2.78, 95% CI 1.66 to 4.66, p<0.001) than those prescribed an ‘other’ OHA. No differences in cardiovascular events were observed (HR 0.99, 95% CI 0.81 to 1.22, p=0.92). In subgroup analyses, mortality and cardiovascular event risk was higher in patients prescribed sulfonylureas versus post-2008 OHAs.ConclusionsSulfonylureas as add-on therapy to metformin are associated with increased risk of all-cause mortality and major hypoglycemic episodes compared with ‘other’ OHAs. Post hoc analysis suggests newer OHAs may be preferred to sulfonylureas as second-line therapy for glycemic control.

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