XI. STRATEGIES FOR IMPROVING DIABETES CARE D iabetes is a chronic illness that requires continuing medical care and patient self-management education to prevent acute complications and to reduce the risk of long-term complications. Diabetes care is complex and requires that many issues, beyond glycemic control, be addressed. A large body of evidence exists that supports a range of interventions to improve diabetes outcomes. These standards of care are intended to provide clinicians, patients, researchers, payors, and other interested individuals with the components of diabetes care, treatment goals, and tools to evaluate the quality of care. While individual preferences, comorbidities, and other patient factors may require modification of goals, targets that are desirable for most patients with diabetes are provided. These standards are not intended to preclude more extensive evaluation and management of the patient by other specialists as needed. For more detailed information, refer to Bode (Ed.): Medical Management of Type 1 Diabetes (1), Burant (Ed): Medical Management of Type 2 Diabetes (2), and Klingensmith (Ed): Intensive Diabetes Management (3). The recommendations included are diagnostic and therapeutic actions that are known or believed to favorably affect health outcomes of patients with diabetes. A grading system (Table 1), developed by the American Diabetes Association (ADA) and modeled after existing methods, was utilized to clarify and codify the evidence that forms the basis for the recommendations. The level of evidence that supports each recommendation is listed after each recommendation using the letters A, B, C, or E.

Standards of Medical Care in Diabetes

BackgroundThe cardiovascular effect of liraglutide, a glucagon-like peptide 1 analogue, when added to standard care in patients with type 2 diabetes, remains unknown. MethodsIn this double-blind trial, we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo. The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome, with a margin of 1.30 for the upper boundary of the 95% confidence interval of the hazard ratio. No adjustments for multiplicity were performed for the prespecified exploratory outcomes. ResultsA total of 9340 patients underwent randomization. The median follow-up was 3.8 years. The primary outcome occurred in significantly fewer patients in the liraglutide group (608 of 4668 patients [13.0%]) than in the placebo ...

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Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

BackgroundRegulatory guidance specifies the need to establish cardiovascular safety of new diabetes therapies in patients with type 2 diabetes in order to rule out excess cardiovascular risk. The cardiovascular effects of semaglutide, a glucagon-like peptide 1 analogue with an extended half-life of approximately 1 week, in type 2 diabetes are unknown. MethodsWe randomly assigned 3297 patients with type 2 diabetes who were on a standard-care regimen to receive once-weekly semaglutide (0.5 mg or 1.0 mg) or placebo for 104 weeks. The primary composite outcome was the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. We hypothesized that semaglutide would be noninferior to placebo for the primary outcome. The noninferiority margin was 1.8 for the upper boundary of the 95% confidence interval of the hazard ratio. ResultsAt baseline, 2735 of the patients (83.0%) had established cardiovascular disease, chronic kidney disease, or both. The primary outcome occurred in 10...

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Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes.

Obesity and type 2 diabetes are characterized by altered gut microbiota, inflammation, and gut barrier disruption. Microbial composition and the mechanisms of interaction with the host that affect gut barrier function during obesity and type 2 diabetes have not been elucidated. We recently isolated Akkermansia muciniphila, which is a mucin-degrading bacterium that resides in the mucus layer. The presence of this bacterium inversely correlates with body weight in rodents and humans. However, the precise physiological roles played by this bacterium during obesity and metabolic disorders are unknown. This study demonstrated that the abundance of A. muciniphila decreased in obese and type 2 diabetic mice. We also observed that prebiotic feeding normalized A. muciniphila abundance, which correlated with an improved metabolic profile. In addition, we demonstrated that A. muciniphila treatment reversed high-fat diet-induced metabolic disorders, including fat-mass gain, metabolic endotoxemia, adipose tissue inflammation, and insulin resistance. A. muciniphila administration increased the intestinal levels of endocannabinoids that control inflammation, the gut barrier, and gut peptide secretion. Finally, we demonstrated that all these effects required viable A. muciniphila because treatment with heat-killed cells did not improve the metabolic profile or the mucus layer thickness. In summary, this study provides substantial insight into the intricate mechanisms of bacterial (i.e., A. muciniphila) regulation of the cross-talk between the host and gut microbiota. These results also provide a rationale for the development of a treatment that uses this human mucus colonizer for the prevention or treatment of obesity and its associated metabolic disorders.

https://www.pnas.org/content/pnas/110/22/9066.full.pdf

Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity

Abstract Animal studies have shown that SGLT2 inhibition decreases oxidative stress, which may explain the cardiovascular protective effects observed following SGLT2 inhibition treatment. Thus, we investigated the effects of two and twelve weeks SGLT2 inhibition on DNA and RNA oxidation. Individuals with type 2 diabetes (n = 31) were randomized to two weeks of treatment with the SGLT2 inhibitor empagliflozin treatment (25 mg once daily) or placebo. The primary outcome was changes in DNA and RNA oxidation measured as urinary excretion of 8-oxo-7,8-dihydro-2’-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo), respectively. In another trial, individuals with type 2 diabetes (n = 35) were randomized to twelve weeks of dapagliflozin treatment (10 mg once daily) or placebo in a crossover study. Changes in urinary excretion of 8-oxodG and 8-oxoGuo were investigated as a posthoc analysis. Compared with placebo treatment, two weeks of empagliflozin treatment did not change urinary excretion of 8-oxodG (between-group difference: 0.3 nmol/24-hour (95% CI: −4.2 to 4.8)) or 8-oxoGuo (1.3 nmol/24-hour (95% CI: −4.7 to 7.3)). From a mean baseline 8-oxodG/creatinine urinary excretion of 1.34 nmol/mmol, dapagliflozin-treated individuals changed 8-oxodG/creatinine by −0.17 nmol/mmol (95% CI: −0.29 to −0.04) following twelve weeks of treatment, whereas placebo-treated individuals did not change 8-oxodG/creatinine (within-group effect: 0.10 nmol/mmol (95% CI: −0.02 to 0.22)) resulting in a significant between-group difference (p = 0.01). Urinary excretion of 8-oxoGuo was unaffected by dapagliflozin treatment. In conclusion, two weeks of empagliflozin treatment did not change DNA or RNA oxidation. However, a posthoc analysis revealed that longer-term dapagliflozin treatment decreased DNA oxidation. Clinicaltrials.gov: NCT02890745 and NCT02914691. Highlights Plasma ferritin correlated with DNA and RNA oxidation in individuals with T2D. Twelve weeks dapagliflozin treatment decreased DNA oxidation. Dapagliflozin and empagliflozin treatment did not change RNA oxidation. Lipid peroxidation was unaffected by two weeks empagliflozin treatment. Graphical Abstract

Effects of two- and twelve-weeks sodium-glucose cotransporter 2 inhibition on DNA and RNA oxidation: two randomized, placebo-controlled trials

100 years of glucagon and 100 more

Objective Bile acid diarrhoea (BAD) is debilitating yet treatable, but it remains underdiagnosed due to challenging diagnostics. We developed a blood test-based method to guide BAD diagnosis. Design We included serum from 50 treatment-naive patients with BAD diagnosed by gold standard 75selenium homotaurocholic acid test, 56 feature-matched controls and 37 patients with non-alcoholic fatty liver disease (NAFLD). Metabolomes were generated using mass spectrometry covering 1295 metabolites and compared between groups. Machine learning was used to develop a BAD Diagnostic Score (BDS). Results Metabolomes of patients with BAD significantly differed from controls and NAFLD. We detected 70 metabolites with a discriminatory performance in the discovery set with an area under receiver-operating curve metric above 0.80. Logistic regression modelling using concentrations of decanoylcarnitine, cholesterol ester (22:5), eicosatrienoic acid, L-alpha-lysophosphatidylinositol (18:0) and phosphatidylethanolamine (O-16:0/18:1) distinguished BAD from controls with a sensitivity of 0.78 (95% CI 0.64 to 0.89) and a specificity of 0.93 (95% CI 0.83 to 0.98). The model was independent of covariates (age, sex, body mass index) and distinguished BAD from NAFLD irrespective of fibrosis stage. BDS outperformed other blood test-based tests (7-alpha-hydroxy-4-cholesten-3-one and fibroblast growth factor 19) currently under development. Conclusions BDS derived from serum metabolites in a single-blood sample showed robust identification of patients with BAD with superior specificity and sensitivity compared with current blood test-based diagnostics.

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Serum lipidome unravels a diagnostic potential in bile acid diarrhoea

Clinicians are responsible for selecting a suitable second-line treatment for patients with type 2 diabetes mellitus when metformin monotherapy fails. New evidence could aid clinicians in deciding between one of the most commonly used second-line agents, glimepiride, and the recently approved dipeptidyl peptidase 4 inhibitor linagliptin.

Diabetes: Add-on to metformin in T2DM—linagliptin or glimepiride?

a-Linolenic acid (ALA; 18 : 3 n-3) is a plant-derived essential omega-3 (n-3) polyunsaturated fatty acid (PUFA). ALA must be obtained from the diet and is found in walnuts, rapeseed (canola) oils, flaxseeds and soya beans. ALA has been suggested to have cardiovascular benefit, albeit several, mainly observational studies have failed to demonstrate convincing results. At present, ALA supply for long-term cardioprotection is a highly controversial topic. In a recent meta-analysis of observational studies, ALA was shown to reduce the risk of cardiovascular disease (CVD). The clinical and methodological diversity among the studies included was ample and, consequently, heterogeneity was substantial. Nevertheless, the meta-analysis is comprehensive, methodologically sound and comprises 27 original studies with 251,049 individuals and 15,372 events. The work is of great value because it expands recent publications in the field by evaluating studies with dietary ALA as the exposure (N1⁄4 13), as well as studies using ALA biomarkers as exposure (N1⁄4 17). Importantly, the study is up-to-date owing to the inclusion of several recent investigations. The overall pooled relative risk (RR) was 0.86 (95% confidence interval (CI): 0.77–0.97; I1⁄4 71.3%). The association was significant for dietary ALA (pooled RR: 0.90 (95% CI: 0.81–0.99; I1⁄4 49.0%), and near-significant in the ALA biomarker studies (pooled RR: 0.80; 95% CI: 0.63–1.03; I1⁄4 79.8%). For elucidation of the potential explanation for the effects of ALA on CVD, the authors suggest that ALA may exert beneficial effects on low-density lipoprotein (LDL) cholesterol, thrombosis, arrhythmias, endothelial function and inflammatory factors. In general, there is considerable uncertainty regarding the mechanistic basis of the putative cardioprotective effects of ALA. To elucidate the potential pathways of the effects of ALA on CVD outcomes in the present as well as impending studies, we believe that one factor deserves allusion to. This factor, glucagon-like peptide-1 (GLP-1), is an incretin hormone secreted from intestinal L cells upon meal intake resulting in strong glucose-dependent insulin secretion from pancreatic b cells (the incretin effect). GLP-1 furthermore decreases postprandial glucagon levels, appetite sensation, food intake and gastric emptying, and, therefore, constitutes an important regulator of normal glucose homeostasis. Native GLP-1 is rapidly degraded to its inactive form, and thereby inactivated, by the ubiquitous enzyme dipeptidyl peptidase 4 (DPP-4). In the treatment of type 2 diabetes, this therapeutic limitation has been overcome by using DPP-4 inhibitors and stable GLP-1 receptor agonists with longer half-lifes. A large body of evidence suggests that GLP-1 exerts powerful cardioprotective effects. For instance, preclinical and clinical studies have shown that GLP-1 and GLP-1 analogues reduce ischemic reperfusion injury and infarct size, and, additionally, GLP-1 may exert long-term, beneficial effects on various cardiovascular parameters (such as blood pressure, heart failure, body weight, and lipid metabolism). The promising cardiovascular findings in patients treated with GLP-1 receptor agonists are currently under investigation in four large cardiovascular outcome studies (LEADER, EXCEL, ELIXA and REWIND). Likewise, the promising cardiovascular effects described for DPP-4 inhibitors are presently being evaluated in large cardiovascular outcome studies (TECOS, EXAMINE, SAVOR-TIMI and CAROLINA). In recent years, free fatty acids (FFAs) have been positioned as potent, endogenous signaling molecules in animal and human physiology. They activate G proteincoupled receptors (GPCRs), many of which are present on the L cells where they, among many functions, facilitate stimulation of GLP-1 secretion. Hirasawa et al. demonstrated that the activation of one of these GPCRs, GPR120, with long-chain FFAs promoted the secretion of GLP-1. This seminal study was conducted in vitro and in vivo and included receptor isolation from a human genomic DNA fragment. Interestingly, it was further demonstrated that when stimulating STC-1 cells, from a mouse GLP-1-secreting enteroendocrine cell line, with unsaturated long-chain FFAs, a dose-dependent stimulatory effect was demonstrated, with ALA exhibiting the greatest potency. Intriguingly, in a rat study also, long-term administration (four weeks) of ALA was shown to raise GLP-1 levels via GPR120 activation, indicating that daily ALA exposure is capable of augmenting basal levels of endogenous GLP-1.

Filip K. Knop

Papers

Effects of two- and twelve-weeks sodium-glucose cotransporter 2 inhibition on DNA and RNA oxidation: two randomized, placebo-controlled trials

100 years of glucagon and 100 more

Serum lipidome unravels a diagnostic potential in bile acid diarrhoea

Diabetes: Add-on to metformin in T2DM—linagliptin or glimepiride?

Cardiovascular effects of alpha-linolenic acid--a possible role of glucagon-like peptide-1.