Effects of DPP-4 inhibitors, GLP-1 receptor agonists, SGLT-2 inhibitors and sulphonylureas on mortality, cardiovascular and renal outcomes in type 2 diabetes: A network meta-analyses-driven approach.

AIMS: The aim of our meta-analyses was to compare the effects of glucose-lowering drugs on mortality, cardiovascular and renal endpoints for a range of type 2 diabetes (T2D) subgroups defined by their specific cardiovascular risk profile. METHODS: Meta-analyses comparing drugs within the classes of GLP-1RAs and SGLT-2 inhibitors were performed and compared to sulphonylureas and DPP-4 inhibitors with available cardiovascular outcome trials. The comparison between the different classes of glucose-lowering drugs included analyses of T2D populations with low risk and high risk for cardiovascular disease including populations with established cardiovascular disease and/or kidney disease. Outcomes included mortality, major cardiovascular adverse events (MACE), hospitalisation for heart failure (HHF) and a composite renal endpoint as applied in the underlying clinical trials. RESULTS: SGLT-2 inhibitors and GLP-1RAs showed beneficial effects on mortality and MACE compared to the classes of DPP-4 inhibitors and sulphonylureas. SGLT-2 inhibitors were shown to be the most effective treatment in terms of HHF and kidney disease. Metformin was used as background therapy for the vast majority of participants in all included studies. Overall, the absolute effects of SGLT-2 inhibitors and GLP-1RAs on these important outcomes were evident for patients with established or at high risk for cardiovascular disease but limited for the low-risk subgroup. CONCLUSIONS: The findings from our analyses substantiate the relevance of treatment with SGLT-2 inhibitors or GLP-1RAs as an add-on to metformin in patients with T2D and a high risk for cardiovascular disease, and furthermore, support the recommendation for SGLT-2 inhibitor treatment in patients with T2D and heart failure or established kidney disease.

Glucometabolic changes influence hospitalization and outcome in patients with COVID-19: An observational cohort study.

AIMS: The aim was to report the prevalence of diabetes status in patients hospitalized with COVID-19 and assess the association between the glucometabolic status at admission and 90-day mortality. METHODS: Consecutive patients hospitalized with COVID-19 were included in the study. All participants included had an HbA1c measurement 60 days prior to or within 7 days after admission. We studied the association between diabetes status, the glycemic gap (difference between admission and habitual status), admission plasma-glucose, and mortality using Cox proportional hazards regression. RESULTS: Of 674 patients included, 114 (17%) had normal glucose level, 287 (43%) had pre-diabetes, 74 (11%) had new-onset, and 199 (30%) had diagnosed diabetes. No association between diabetes status, plasma-glucose at admission, and mortality was found. Compared to the 2nd quartile (reference) of glycemic-gap, those with the highest glycemic gap had increased mortality (3rd (HR 2.38 [1.29-4.38], p = 0.005) and 4th quartile (HR 2.48 [1.37-4.52], p = 0.002). CONCLUSION: Abnormal glucose metabolism was highly prevalent among patients hospitalized with COVID-19. Diabetes status per se or admission plasma-glucose was not associated with a poorer outcome. However, a high glycemic gap was associated with increased risk of mortality, suggesting that, irrespective of diabetes status, glycemic stress serves as an important prognostic marker for mortality.

Prediabetes Defined by First Measured HbA1c Predicts Higher Cardiovascular Risk Compared With HbA1c in the Diabetes Range: A Cohort Study of Nationwide Registries.

OBJECTIVE: To assess the risk of major adverse cardiovascular events (MACE), all-cause mortality, and initiation of medical treatment in subjects with prediabetes according to first-time measured HbA1c. RESEARCH DESIGN AND METHODS: Through registry databases, we identified 326,305 Danish patients with a first HbA1c between 40 and 51 mmol/mol (5.8-6.8%) from 2011 to 2017. After exclusion of patients with prior disease, 84,678 patients were followed 12 months after first HbA1c measurement. Cox regression models were used to estimate hazard ratios (HRs) of MACE and standardized absolute risks. Cumulative incidences were used to analyze initiation of glucose-lowering, antihypertensive, cholesterol-lowering, and antithrombotic medication. RESULTS: The 12-month risk of MACE and all-cause mortality increased gradually with increasing HbA1c until 47 mmol/mol (6.5%). In comparisons of subjects with HbA1c 40-41 mmol/mol (5.8-5.9%), subjects with HbA1c 46-47 mmol/mol (6.4-6.5%) had a 0.79% (95% CI 0.33-1.24) higher standardized absolute risk and an HR of 2.21 (95% CI 1.67-2.92) of MACE. Patients with HbA1c 48-49 mmol/mol (6.5-6.6%) had a 0.09% (95% CI -0.35 to 0.52) lower absolute risk and an HR of 1.33 (95% CI 0.87-2.05) of MACE. Initiation of medication was significantly lower among patients with HbA1c of 46-47 mmol/mol (6.4-6.5%) than among patients with HbA1c of 48-49 mmol/mol (6.5-6.6%). CONCLUSIONS: In the Danish population screened for diabetes with HbA1c, the highest risk of MACE and all-cause mortality was found in subjects with HbA1c just below the diagnostic threshold for diabetes. Our results highlight the need for increased focus on the treatment of cardiovascular risk factors for subjects with prediabetes.

Study rationale and design of the EANITIATE study (EmpAgliflozin compared to NPH Insulin for sTeroId diAbeTEs) - a randomized, controlled, multicenter trial of safety and efficacy of treatment with empagliflozin compared with NPH-insulin in patients with newly onset diabetes following initiation of glucocorticoid treatment.

BACKGROUND: A well-known metabolic side effect from treatment with glucocorticoids is glucocorticoid-induced diabetes mellitus (GIDM). Guidelines on the management of GIDM in hospitalized patients (in the non-critical care setting), recommend initiation of insulin therapy. The scientific basis and evidence for superiority of insulin therapy over other glucose lowering therapies is however poor and associated with episodes of both hypo- and hyperglycaemia. There is an unmet need for an easier, safe and convenient therapy for glucocorticoid-induced diabetes. METHODS: EANITIATE is a Danish, open, prospective, multicenter, randomized (1:1), parallel group study in patients with new-onset diabetes following treatment with glucocorticoids (> 20 mg equivalent prednisolone dose/day) with blinded endpoint evaluation (PROBE design). Included patients are randomized to either a Sodium-Glucose-Cotransporter 2 (SGLT2) inhibitor or neutral protamin Hagedorn (NPH) insulin and followed for 30 days. Blinded continuous glucose monitoring (CGM) will provide data for the primary endpoint (mean daily blood glucose) and on glucose fluctuations in the two treatment arms. Secondary endpoints are patient related outcomes, hypoglycaemia, means and measures of variation for all values and for time specific glucose values. This is a non-inferiority study with the intent to demonstrate that treatment with empagliflozin is not inferior to treatment with NPH insulin when it comes to glycemic control and side effects. DISCUSSION: This novel approach to management of glucocorticoid-induced hyperglycemia has not been tested before and if SGLT2 inhibition with empaglifozin compared to NPH-insulin is a safe, effective and resource sparing treatment for GIDM, it has the potential to improve the situation for affected patients and have health economic benefits. TRIAL REGISTRATION: www.clinicaltrialsregister.eu no.: 2018-002640-82. Prospectively registered November 20th. 2018. Date of first patient enrolled: June 4th. 2019. This protocol article is based on the EANITATE protocol version 1.3, dated 29. January 2018.

A systematic review and meta-analysis of nutrition therapy compared with dietary advice in patients with type 2 diabetes.

Background: Despite recommendations, many patients with type 2 diabetes receive dietary advice from nurses or doctors instead of individualized nutrition therapy (INT) that is provided by a dietitian.Objective: We performed a meta-analysis to compare the effect of INT that is provided by a registered dietitian with the effect of dietary advice that is provided by other healthcare professionals.Design: A systematic review was conducted of Cochrane library databases, EMBASE, CINAHL, and MEDLINE in the period 2004-2017 for guidelines, reviews, and randomized controlled trials (RCTs) that assessed the outcomes glycated hemoglobin (HbA1c), weight, body mass index (BMI; in kg/m2), and LDL cholesterol. Risk of bias and the quality of evidence were assessed according to the Grading of Recommendations Assessment, Development and Evaluation guidelines.Results: We identified 5 RCTs comprising 912 participants in total. In the first year of intervention (at 6 or 12 mo), nutrition therapy compared with dietary advice was followed by a 0.45% (95% CI: 0.36%, 0.53%) lower mean difference in HbA1c, a 0.55 (95% CI: 0.02, 1.1) lower BMI, a 2.1-kg (95% CI: 1.2-, 2.9-kg) lower weight, and a 0.17-mmol/L (95% CI: 0.11-, 0.23-mmol/L) lower LDL cholesterol. No longer-term data were available. Some of the included studies had a potential bias, and therefore, the quality of the evidence was low or moderate. In addition, it was necessary to pool primary and secondary outcomes.Conclusions: INT that is provided by a dietitian compared with dietary advice that is provided by other health professionals leads to a greater effect on HbA1c, weight, and LDL cholesterol. Because of the potential bias, we recommend considering nutrition therapy that is provided by a dietitian as part of lifestyle intervention in type 2 diabetes, but further randomized studies are warranted.

Systematic review and meta-analysis of dietary carbohydrate restriction in patients with type 2 diabetes.

OBJECTIVE: Nutrition therapy is an integral part of self-management education in patients with type 2 diabetes. Carbohydrates with a low glycemic index are recommended, but the ideal amount of carbohydrate in the diet is unclear. We performed a meta-analysis comparing diets containing low to moderate amounts of carbohydrate (LCD) (energy percentage below 45%) to diets containing high amounts of carbohydrate (HCD) in subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS: We systematically reviewed Cochrane library databases, EMBASE, and MEDLINE in the period 2004-2014 for guidelines, meta-analyses, and randomized trials assessing the outcomes HbA1c, BMI, weight, LDL cholesterol, quality of life (QoL), and attrition. RESULTS: We identified 10 randomized trials comprising 1376 participants in total. In the first year of intervention, LCD was followed by a 0.34% lower HbA1c (3.7 mmol/mol) compared with HCD (95% CI 0.06 (0.7 mmol/mol), 0.63 (6.9 mmol/mol)). The greater the carbohydrate restriction, the greater the glucose-lowering effect (R=-0.85, p<0.01). At 1 year or later, however, HbA1c was similar in the 2 diet groups. The effect of the 2 types of diet on BMI/body weight, LDL cholesterol, QoL, and attrition rate was similar throughout interventions. LIMITATIONS: Glucose-lowering medication, the nutrition therapy, the amount of carbohydrate in the diet, glycemic index, fat and protein intake, baseline HbA1c, and adherence to the prescribed diets could all have affected the outcomes. CONCLUSIONS: Low to moderate carbohydrate diets have greater effect on glycemic control in type 2 diabetes compared with high-carbohydrate diets in the first year of intervention. The greater the carbohydrate restriction, the greater glucose lowering, a relationship that has not been demonstrated earlier. Apart from this lowering of HbA1c over the short term, there is no superiority of low-carbohydrate diets in terms of glycemic control, weight, or LDL cholesterol.

Metformin versus placebo in combination with insulin analogues in patients with type 2 diabetes mellitus-the randomised, blinded Copenhagen Insulin and Metformin Therapy (CIMT) trial.

OBJECTIVE: To assess the effect of metformin versus placebo both in combination with insulin analogue treatment on changes in carotid intima-media thickness (IMT) in patients with type 2 diabetes. DESIGN AND SETTING: Investigator-initiated, randomised, placebo-controlled trial with a 2 × 3 factorial design conducted at eight hospitals in Denmark. PARTICIPANTS AND INTERVENTIONS: 412 participants with type 2 diabetes (glycated haemoglobin (HbA1c) ≥ 7.5% (≥ 58 mmol/mol); body mass index >25 kg/m2) were in addition to open-labelled insulin treatment randomly assigned 1:1 to 18 months blinded metformin (1 g twice daily) versus placebo, aiming at an HbA1c ≤ 7.0% (≤ 53 mmol/mol). OUTCOMES: The primary outcome was change in the mean carotid IMT (a marker of subclinical cardiovascular disease). HbA1c, insulin dose, weight and hypoglycaemic and serious adverse events were other prespecified outcomes. RESULTS: Change in the mean carotid IMT did not differ significantly between the groups (between-group difference 0.012 mm (95% CI -0.003 to 0.026), p=0.11). HbA1c was more reduced in the metformin group (between-group difference -0.42% (95% CI -0.62% to -0.23%), p<0.001)), despite the significantly lower insulin dose at end of trial in the metformin group (1.04 IU/kg (95% CI 0.94 to 1.15)) compared with placebo (1.36 IU/kg (95% CI 1.23 to 1.51), p<0.001). The metformin group gained less weight (between-group difference -2.6 kg (95% CI -3.3 to -1.8), p<0.001). The groups did not differ with regard to number of patients with severe or non-severe hypoglycaemic or other serious adverse events, but the metformin group had more non-severe hypoglycaemic episodes (4347 vs 3161, p<0.001). CONCLUSIONS: Metformin in combination with insulin did not reduce carotid IMT despite larger reduction in HbA1c, less weight gain, and smaller insulin dose compared with placebo plus insulin. However, the trial only reached 46% of the planned sample size and lack of power may therefore have affected our results. TRIAL REGISTRATION NUMBER: NCT00657943; Results.

Effects of biphasic, basal-bolus or basal insulin analogue treatments on carotid intima-media thickness in patients with type 2 diabetes mellitus: the randomised Copenhagen Insulin and Metformin Therapy (CIMT) trial.

OBJECTIVE: To assess the effect of 3 insulin analogue regimens on change in carotid intima-media thickness (IMT) in patients with type 2 diabetes. DESIGN AND SETTING: Investigator-initiated, randomised, placebo-controlled trial with a 2 × 3 factorial design, conducted at 8 hospitals in Denmark. PARTICIPANTS AND INTERVENTIONS: Participants with type 2 diabetes (glycated haemoglobin (HbA1c) ≥ 7.5% (≥ 58 mmol/mol), body mass index >25 kg/m(2)) were, in addition to metformin versus placebo, randomised to 18 months open-label biphasic insulin aspart 1-3 times daily (n=137) versus insulin aspart 3 times daily in combination with insulin detemir once daily (n=138) versus insulin detemir alone once daily (n=137), aiming at HbA1c ≤ 7.0% (≤ 53 mmol/mol). OUTCOMES: Primary outcome was change in mean carotid IMT (a marker of subclinical cardiovascular disease). HbA1c, insulin dose, weight, and hypoglycaemic and serious adverse events were other prespecified outcomes. RESULTS: Carotid IMT change did not differ between groups (biphasic -0.009 mm (95% CI -0.022 to 0.004), aspart+detemir 0.000 mm (95% CI -0.013 to 0.013), detemir -0.012 mm (95% CI -0.025 to 0.000)). HbA1c was more reduced with biphasic (-1.0% (95% CI -1.2 to -0.8)) compared with the aspart+detemir (-0.4% (95% CI -0.6 to -0.3)) and detemir (-0.3% (95% CI -0.4 to -0.1)) groups (p<0.001). Weight gain was higher in the biphasic (3.3 kg (95% CI 2.7 to 4.0) and aspart+detemir (3.2 kg (95% CI 2.6 to 3.9)) compared with the detemir group (1.9 kg (95% CI 1.3 to 2.6)). Insulin dose was higher with detemir (1.6 IU/kg/day (95% CI 1.4 to 1.8)) compared with biphasic (1.0 IU/kg/day (95% CI 0.9 to 1.1)) and aspart+detemir (1.1 IU/kg/day (95% CI 1.0 to 1.3)) (p<0.001). Number of participants with severe hypoglycaemia and serious adverse events did not differ. CONCLUSIONS: Carotid IMT change did not differ between 3 insulin regimens despite differences in HbA1c, weight gain and insulin doses. The trial only reached 46% of planned sample size and lack of power may therefore have affected our results. TRIAL REGISTRATION NUMBER: NCT00657943.

Human Achilles tendon glycation and function in diabetes.

Diabetic patients have an increased risk of foot ulcers, and glycation of collagen may increase tissue stiffness. We hypothesized that the level of glycemic control (glycation) may affect Achilles tendon stiffness, which can influence gait pattern. We therefore investigated the relationship between collagen glycation, Achilles tendon stiffness parameters, and plantar pressure in poorly (n = 22) and well (n = 22) controlled diabetic patients, including healthy age-matched (45-70 yr) controls (n = 11). There were no differences in any of the outcome parameters (collagen cross-linking or tendon stiffness) between patients with well-controlled and poorly controlled diabetes. The overall effect of diabetes was explored by collapsing the diabetes groups (DB) compared with the controls. Skin collagen cross-linking lysylpyridinoline, hydroxylysylpyridinoline (136%, 80%, P < 0.01) and pentosidine concentrations (55%, P < 0.05) were markedly greater in DB. Furthermore, Achilles tendon material stiffness was higher in DB (54%, P < 0.01). Notably, DB also demonstrated higher forefoot/rearfoot peak-plantar-pressure ratio (33%, P < 0.01). Overall, Achilles tendon material stiffness and skin connective tissue cross-linking were greater in diabetic patients compared with controls. The higher foot pressure indicates that material stiffness of tendon and other tissue (e.g., skin and joint capsule) may influence foot gait. The difference in foot pressure distribution may contribute to the development of foot ulcers in diabetic patients.

Trends in leisure time physical activity, smoking, body mass index and alcohol consumption in Danish adults with and without diabetes: a repeat cross-sectional national survey covering the years 2000 to 2010.

AIMS: In recent decades there has been an increased focus on non-pharmacological treatment of diabetes. The aim of this study was to investigate trends in leisure time physical activity (PA), smoking, body mass index (BMI), and alcohol consumption reported in 2000, 2005 and 2010 by Danish subjects with diabetes. METHODS: Data comprised level of leisure time PA (inactive; moderate active; medium active; high active); smoking; BMI; and alcohol consumption, provided by The Danish Health and Morbidity Surveys. Participants older than 45 years with or without diabetes were included from cross-sectional analyses from 2000, 2005 and 2010. RESULTS: In participants with diabetes, leisure time PA levels increased from 2000 to 2010: The percentage of those that were physically active increased from 53.5% to 78.2% (p<0.001; women) and from 67.8% to 79.1% (p=0.01; men). The prevalence of daily smokers was reduced from 27.2% to 16.4%, p=0.015, in women with diabetes. In men with diabetes, BMI increased from 27.2 ± 4.0 to 28.6 ± 5.1 kgm(-2), p=0.003, and men who exceeded the maximum recommendation for alcohol consumption increased from 9.4% to 19.0%, p=0.007. The leisure time PA level was reduced in participants with diabetes compared to participants without diabetes throughout the study. CONCLUSIONS: The percentage of physically active Danish participants older than 45 years with diabetes increased from 2000 to 2010, and the most beneficial trends in life style were observed among the women. These trends may have serious implications for cardiovascular risk in Danish patients with diabetes.

[Organization of treatment and control of type 2 diabetic patients]. / Organisation af behandling og opfølgning af patienter med type 2-diabetes.

The organization of treatment and control of type 2 diabetic patients in Denmark has undergone a major development within the last decade. From being based on local hospital guidelines, treatment and control have moved towards a more organized collaboration between primary and secondary care based on common national guidelines. Quality indicators from primary and secondary care are collected routinely, and gradually an increasingly precise depiction is documented in the National Indicator Project.

The effects and costs of a group-based education programme for self-management of patients with Type 2 diabetes. A community-based study.

The worldwide epidemic of Type 2 diabetes necessitates evidence-based self-management education programmes. The purpose of this study was to investigate the effects and costs of an empowerment-based structured diabetes self-management education programme in an unselected group of patients with Type 2 diabetes. Seven hundred and two patients undergoing treatment by general practitioners (GPs) were included. The education comprised three modules over a 12-month period. It was based on the empowerment philosophy. The education followed a written curriculum, and the educators were given special training in its use. Glycemic control (HbA1c) was found to improve from 7.34 ± 1.34 to 6.88 ± 1.09%, P < 0.001 and body weight decreased from 90.9 ± 19.3 to 87.1 ± 18.1 kg, P < 0.001, following the education programme. Moreover, significant improvements were found in terms of fasting blood glucose, blood pressure, female waist circumference, lipid profile, quality of life, physical activity and the patients' knowledge of diabetes whilst the number of visits to GPs declined. This study supports the use of an empowerment vision as a basis for an interdisciplinary group-based education programme with individuals with Type 2 diabetes. Moreover, the costs of implementing this education programme were found to be minimal.

Hyperinsulinaemia is associated with increased long-term mortality following acute myocardial infarction in non-diabetic patients.

AIMS: To study the impact of disturbances in glucose metabolism on total mortality in non-diabetic patients with acute myocardial infarction. METHODS AND RESULTS: Four hundred and ninety four patients with a verified myocardial infarction and no history of diabetes were studied. The study population comprised a subgroup of patients screened for participation in the Trandolapril Cardiac Evaluation (TRACE) study. At baseline, fasting insulin, fasting glucose, glycosylated haemoglobin (HbA1c), and urinary albumin excretion were measured. Survival status was determined after 6-8 years. Patients with hyperinsulinaemia were more obese and more frequently suffered from hypertension, previous myocardial infarction and congestive heart failure. In a univariate regression analysis, values in the upper quartile of insulin, glucose, HbA1c, and urinary albumin were associated with an excess mortality risk (RR=1.8 (1.2-2.7), p=0.002; RR=1.6 (1.2-2.1), p=0.001; RR= 1.9 (1.3-2.9), p=0.001; RR=1.6 (1.2-2.1), p=0.02 respectively). However, only a high insulin level remained significant in a multivariable analysis (RR=1.54 (1.03-2.31), p=0.04) including baseline variables, left ventricular systolic function and in-hospital complications. CONCLUSIONS: High fasting plasma insulin is an independent risk factor of all-cause mortality in non-diabetic patients with acute myocardial infarction. This justifies future intervention studies aiming at reducing insulin resistance and using fasting insulin as the target variable.