Quality of life, patient satisfaction, and cardiovascular outcomes of the randomised 2 x 3 factorial Copenhagen insulin and Metformin therapy (CIMT) trial - A detailed statistical analysis plan.

Background: The evidence on the effects of metformin and insulin in type 2 diabetes patients on quality of life, patient satisfaction, and cardiovascular outcomes is unclear. Methods: The Copenhagen Insulin and Metformin Therapy (CIMT) trial is an investigator-initiated multicentre, randomised, placebo-controlled trial with a 2 × 3 factorial design conducted at eight hospitals in Denmark. Participants with type 2 diabetes were randomised to metformin (n = 206) versus placebo (n = 206); in combination with open-label biphasic insulin aspart one to three times daily (n = 137) versus insulin aspart three times daily in combination with insulin detemir once daily (n = 138) versus insulin detemir once daily (n = 137).We present a detailed description of the methodology and statistical analysis of the clinical CIMT outcomes including a detailed description of tests of the assumptions behind the statistical analyses. The outcomes are quality of life (Short Form Health Survey (SF-36)), Diabetes Medication Satisfaction Questionnaire, and Insulin Treatment Satisfaction Questionnaire (assessed at entry and 18 months after randomisation) and cardiovascular outcomes including time to a composite of either myocardial infarction, stroke, peripheral amputation, coronary revascularisation, peripheral revascularisation, or death. Discussions: This statistical analysis plan ensure the highest possible quality of the subsequent post-hoc analyses. Trial registration: The protocol was approved by the Regional Committee on Biomedical Research Ethics (H-D-2007-112), the Danish Medicines Agency (EudraCT: 2007-006665-33 CIMT), and registered within ClinicalTrials.gov (NCT00657943, 8th of April 2008).

Clinical potential of treatment with semaglutide in type 2 diabetes patients.

Glucagon-like receptor agonists (GLP-1RAs) are included in current national and international guidelines as second-line treatment especially in patients with type 2 diabetes and concomitant cardiovascular disease (CVD). First-generation GLP-1RAs were two- or once-daily injectables, but longer-acting GLP-1RAs have now been developed for once-weekly administration - e.g., exenatide ER, dulaglutide and semaglutide. With semaglutide, the same prolongation principle as designed in liraglutide is used (spacer and fatty acid chain). However, the similarity to endogenous human GLP-1 is well preserved, sharing 94% homology. It is administered with a simple device and without resuspension before use. The efficacy and safety of semaglutide have been investigated in an extensive clinical development program including more than 9,000 patients with type 2 diabetes. Semaglutide has been compared head-to-head with a dipeptidyl peptidase-4 (DPP4)-inhibitor, GLP-1RAs and basal insulin. Further head-to-head studies are awaiting that compare semaglutide against a sodium-dependent-glucose transporter-2 (SGLT2)-inhibitor. In these studies, semaglutide was found to provide significant and clinically relevant reductions in HbA1c, fasting plasma glucose (FPG), glucose excursions, body weight and blood pressure. The reduction in glycaemic parameters was more pronounced than that in the comparator GLP-1RAs. The rate of hypoglycemia is very low during treatment with semaglutide if not combined with sulphonylureas or insulin. A cardiovascular outcome trial (CVOT) was performed before the approval of semaglutide, at the request of legal authorities. Not only non-inferiority was confirmed, but also superiority compared with placebo used in a population of patients with type 2 diabetes and CVD treated with oral antihyperglycaemic drugs (OADs) and/or insulin with regard to the primary composite endpoint: death from cardiovascular (CV) causes, nonfatal myocardial infarction or nonfatal stroke. The safety of treatment with semaglutide in patients with type 2 diabetes has been extensively investigated. Overall, gastrointestinal side effects dominate, as observed with other GLP-1RAs, and was observed in the same range as for comparator GLP-1RAs. As observed with other GLP-1RAs, side effects such as nausea and vomiting diminished over time during continuous treatment. Regarding microvascular complications, an unexpected increase in diabetes-related retinopathy was observed in the CVOT; Semaglutide Unabated Sustainability in Treatment of Type 2 diabetes' [SUSTAIN 6]), but not in other studies. The reason for this increase is not finally elucidated, but may be due to a nonspecific effect of a rapid decrease in glycaemic parameters in patients with preexisting retinopathy with high HbA1c at the start of the treatment. There is currently a warning in the Summary of Product Characteristics (SmPC) for semaglutide concerning treatment in patients with preexisting retinopathy. Further studies are needed to clarify this.

[Cholesterol-lowering treatment with PCSK9-inhibitors].

Monoclonal antibodies inhibiting proprotein convertase subtilisin-kexin type 9 constitute a new class of lipid-lowering drugs. Currently, evolocumab and alirocumab are marketed. A recent cardiovascular outcome study with evolocumab has shown a cardiovascular (CV) event reduction of 15% in high-risk individuals at very low levels of low-density lipoproteins. The adverse event profile up to two years is mild. Treatment is very costly, and data on CV endpoints are still limited. Treatment is restricted to patients at very high risk of getting CV diseases and on a maximal tolerated statin and ezetimibe treatment in addition to dietary intervention.

[Combination therapy of thyroxine and triiodothyronine in hypothyroid patients].

Decreased quality of life is described more often in hypothyroid patients, who are treated with a synthetic form of thyroxine (L-T4), than in euthyroid controls. A combination of L-T4 and a synthetic form of triiodothyronine (L-T3) has been suggested; however, previous meta-analyses on unselected patients did not find any effect. Recent studies demonstrate, that the overall hypothalamic-pituitary-thyroid-tissue homeostasis could be more complex than previously suggested. Polymorphisms in deiodinase and thyroid hormone transporter genes could theoretically explain, why a minor subgroup of hypothyroid patients seem to have an effect of L-T4/L-T3 combination therapy.

[Cross-sectoral collaboration in type 2 diabetes management in Denmark].

To optimize medical care, Danish guidelines for type 2 diabetes emphasize cross-sectoral collaboration. Risk stratification is recommended as a model of organizing care in terms of distributing tasks and responsibilities between primary and secondary healthcare sectors. Collaboration between the sectors is expected to be beneficial for patients and ensure rational utilization of resources. Challenges such as inter-sectoral communication, sharing of data and unambiguous responsibility underline the need for continuous optimization of the organization of cross-sectorial diabetes management.

Major adverse cardiovascular event reduction with GLP-1 and SGLT2 agents: evidence and clinical potential.

Treatment of patients with type 2 diabetes is directed against treating symptoms of hyperglycemia, minimizing the risk of hypoglycemia, and the risk of microvascular and macrovascular complications. The majority of patients with type 2 diabetes die from cardiovascular or cerebrovascular disease. Future therapies should therefore focus on reducing cardiovascular morbidity in this high-risk population. Glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose co-transporter 2 inhibitors (SGLT2-i) are two drug classes with proven antihyperglycemic effect in type 2 diabetes. However, these drugs seem to have other effects such as weight reduction, low risk of hypoglycemia, and blood pressure reduction. Emerging evidence suggests pleiotropic effects, which potentially could be important in reducing cardiovascular risk. Prompted by regulatory authorities demanding cardiovascular outcome trials (CVOTs) assessing the cardiovascular safety of new antihyperglycemic drug candidates, many CVOTs are ongoing and a few of these are finalized. Somewhat surprising recent CVOTs in both drug classes have shown promising data on cardiovascular morbidity and mortality in patients with a very high risk of cardiovascular events. It is uncertain whether this is a class effect of the two drug classes, and it is yet unproven whether long-term cardiovascular benefits of these drugs can be extrapolated to populations at lower risk of cardiovascular disease. The aim of the present review is to give an overview of our current knowledge of the GLP-1RA and SGLT2-i classes, with specific focus on mechanisms of action, effects on cardiovascular risk factors and cardiovascular morbidity and mortality from the CVOTs presently available. The clinical potential of these data is discussed.

Supportive and non-supportive interactions in families with a type 2 diabetes patient: an integrative review.

BACKGROUND: Type 2 diabetes and its management affect the patient and the close family potentially causing either psychological distress or increased sense of responsibility and collaboration in these families. Interactions between patient and family play an important role in maintaining lifestyle changes and diabetes self-management. The purpose of this integrative review was to summarise and assess published studies on the intra-family perspective of supportive and non-supportive interactions in families with a type 2 diabetes patient. METHODS: Included in the review were published qualitative and quantitative studies that examined the intra-family perspective on supportive and non-supportive interactions. We searched the literature from 2000 to 2016 and the search strategy comprised the following databases: Cochrane, PubMed, CINAHL, Web of Science, PsycINFO and Psyc-ARTICLES as well as hand searching of reference lists. Quality assessment, data extraction and analysis were undertaken on all included studies. RESULTS: We identified five eligible research papers. Employing content analysis three categories describing interactions were refined: Impact of practical action, impact of emotional involvement, and impact of communication content. Supportive interactions included encouraging communication and family collaboration in managing diet, medications, and blood glucose checking. Non-supportive interactions were visible irritation, nagging behaviour and refusing to share the burden of living with diabetes. CONCLUSION: The findings stress the importance of including both patient and family in clinical practice to target diabetes self-management adherence and well-being of the whole family. The majority of self-management occurs within the family environment. Therefore, the intra-family perspective of supportive and non-supportive interactions should be understood and addressed as the family members are interdependent and affected by each other. Future research assessing the impact of professional support and the family function will have the potential to improve the daily life and well-being of patients with type 2 diabetes as well as the whole family.

Hyperproinsulinemia in obesity and in type 2 diabetes and its relation to cardiovascular disease.

INTRODUCTION: Disproportionately elevated fasting levels of proinsulin immunoreactive material (PIM)relative to insulin immunoreactivity (IRI) are a well-established abnormality in type 2 diabetes. Thesignificance of this abnormality has been investigated and discussed in several studies. Areas covered: The present review focuses on the role of proinsulin and its conversion intermediates inthe development of type 2 diabetes, obesity and insulin resistance, and the potential role as a marker ofcardiovascular risk, including the most important studies in this field. Expert commentary: The composition of plasma PIM is heterogeneous comprising des(31,32)-proinsulin,intact proinsulin and small amounts of des(64,65)-proinsulin. Disproportionate hyperproinsulinemiaseems to occur early in the development and before the diagnosis of type 2 diabetes, and seemsassociated to disease progression. Obesity and insulin resistance does not influence fasting PIM/IRI levels in type 2 diabetes. Fasting PIM/IRI levels in type 2 diabetes are closely associated with the degree of impairment in insulin secretory capacity. Different type 2 diabetes alleles have been described associated with elevated PIM/IRI levels. Recent data suggests that proinsulin and its conversion intermediates may have a role as markers of increased risk of cardiovascular disease in glucose intolerance and type 2 diabetes.

Shared care management of patients with type 2 diabetes across the primary and secondary healthcare sectors: study protocol for a randomised controlled trial.

BACKGROUND: The prevalence of type 2 diabetes (T2D) is growing globally and hospital-based outpatient clinics are burdened with increasing numbers of patients. To ensure high quality treatment and care, it is necessary to structurally reorganise the management of patients with T2D. The objective of this study is to test if T2D patients (who are at intermediate risk of or are already having incipient diabetic complications) jointly managed by a hospital-based outpatient clinic and general practitioners (shared care programme) have a non-inferior outcome compared to an established programme in a specialised (hospital based) outpatient diabetes clinic. METHODS: The study is designed as a randomised controlled trial. The shared care model will be tested during a period of 3 years, with data collection at baseline and at 12, 24 and 36 months. All patients will be offered four medical visits a year; the shared care intervention consists of one annual comprehensive check-up at the outpatient clinic and three quarterly visits at the general practitioners' office. The control group will be followed with four quarterly visits at the outpatient clinic, including an annual comprehensive check-up. In the outpatient clinic, the patients will be treated by a specialised diabetes team, including an endocrinologist. On the basis of a predefined stratification model, we will recruit patients stratified to be at intermediate risk of or already having incipient diabetic complications. We plan to include 140 patients. The primary outcome is glycated haemoglobin. Other outcome measures include (1) the proportion of patients who meet the Danish standard indicators reflecting quality of care; (2) quality of life measured by Short Form 36; and (3) the functionality of the patients' families measured by Family Assessment Measure III. The experiences of the patients and families when participating in the shared care program will be explored by collecting dyadic interviews. DISCUSSION: This study will evaluate the quality of a shared care programme for patients with T2D, and provide evidence about advantages and disadvantages compared with a programme in a specialised outpatient clinic. The results may provide important information on how to organise the care for patients with T2D in the future. TRIAL REGISTRATION: This trial was registered with Clinicaltrials.gov on 21 October 2015, registration number: NCT02586545 .

Risk stratification by endocrinologists of patients with type 2 diabetes in a Danish specialised outpatient clinic: a cross-sectional study.

BACKGROUND: To target optimised medical care the Danish guidelines for diabetes recommend stratification of patients with type 2 diabetes (T2D) into three levels according to risk and complexity of treatment. The aim was to describe the T2D population in an outpatient clinic, measure the compliance of the endocrinologists' to perform risk stratification, and investigate the level of concordance between stratification performed by the endocrinologists and objective assessments. METHODS: A cross-sectional study with data collected from medical records and laboratory databases. The Danish risk stratification model contained the following criteria: HbA1c, blood pressure, metabolic complications, microvascular and macrovascular complications. Stratification levels encompassed: level 1 (uncomplicated), level 2 (intermediate risk) and level 3 (high risk). Objective assessments were conducted independently by two health professionals, and compared with the endocrinologists' assessments. In order to test the degree of concordance, we conducted Cohen's kappa, McNemar's test for marginal homogeneity, and Bowker's test for symmetry. RESULTS: Of 245 newly referred patients, 209 (85%) were stratified by the endocrinologists to level 1 (16%), level 2 (55%) and level 3 (29%). By objective assessments, 4% were stratified to level 1, 51% to level 2 and 45% to level 3. Of 419 long-term follow-up patients, 380 (91%) were stratified by the endocrinologists to level 1 (5%), level 2 (57%), level 3 (38%). By objective assessments, 3% were stratified to level 1, 58% to level 2 and 39% to level 3. The concordance rate between endocrinologists' and objective assessments was 63% among newly referred (kappa 0.39; fair agreement) and 67% for long-term follow-up (kappa 0.45; moderate agreement). Among newly referred patients, the endocrinologists stratified less patients at level 3 compared to objective assessments (p < 0.0001). There were no significant differences in marginal distribution within long-term follow-up patients. CONCLUSION: Type 2 diabetes patients, newly referred to or allocated for long-term follow-up in the out-patient clinic, were mainly intermediate and high-risk, complicated patients (96% and 95 %, respectively). Compliance of stratification by endocrinologists was high. The concordance between endocrinologists' and objective assessments was not strong. Our data suggest that clinician-support for stratification level categorisation might be needed.

PEGylated insulin Lispro (LY2605541): clinical overview of a new long-acting basal insulin analog in the treatment of Type 2 diabetes mellitus.

Neutral Protamine Hagedorn insulin with an intermediate action profile has been in use for many years for the treatment of Type 1 diabetes and as an option for Type 2 diabetes. It is efficacious in reducing blood sugars, but shows substantial variability and risk of hypoglycemia. Basal insulin analogs have been developed in recent years to overcome these issues. Three basal insulin analogs are currently in the market in Europe. PEGylated insulin lispro is a new second-generation basal insulin analog which most likely will undergo review in 2016 by the US FDA and EMA in Europe for possible approval for marketing. Phase III trials are finalized, but not yet published. Phase II studies suggest antiglycemic efficacy, possible with a preferential hepato-specific action, a low rate of hypoglycemia, minor weight loss and acceptable tolerability. The benefit-risk profile needs, however, to be established.

A randomized lifestyle intervention with 5-year follow-up in subjects with impaired glucose tolerance: pronounced short-term impact but long-term adherence problems.

AIMS: To compare data on cardiovascular risk factor changes in lipids, insulin, proinsulin, fibrinolysis, leptin and C-reactive protein, and on diabetes incidence, in relation to changes in lifestyle. METHODS: The study was a randomized lifestyle intervention trial conducted in northern Sweden between 1995 and 2000, in 168 individuals with impaired glucose tolerance (IGT) and body mass index above 27 at start. The intensive intervention group (n = 83) was subjected to a 1-month residential lifestyle programme. The usual care group (n = 85) participated in a health examination ending with a single counselling session. Follow-up was conducted at 1, 3 and 5 years. RESULTS: At 1-year follow-up, an extensive cardio-metabolic risk factor reduction was demonstrated in the intensive intervention group, along with a 70% decrease of progress to type 2 diabetes. At 5-year follow-up, most of these beneficial effects had disappeared. Reported physical activity and fibre intake as well as high-density lipoprotein cholesterol were still increased, and fasting insulin and proinsulin were lower. CONCLUSIONS: The intervention affected several important cardio-metabolic risk variables beneficially, and reduced the risk for type 2 diabetes, but the effects persisted only as long as the new lifestyle was maintained. Increased physical activity seemed to be the behaviour that was most easy to preserve.

Diabetic ketoacidosis in Denmark Incidence and mortality estimated from public health registries.

The aims of this study were to estimate incidence of diabetic ketoacidosis and mortality from diabetic ketoacidosis using data from public health registries. Four thousand eight hundred and seven admissions in the period 1996-2002 and 137 deaths in the period 1996-2000 with a diagnosis of diabetic ketoacidosis were identified from the Danish National Patient Registry and Danish Cause of Death Registry, respectively. Annual incidence of diabetic ketoacidosis in the general population was estimated to 12.9 per 100,000, being higher in males than in females (14.4 versus 11.4 per 100,000, p<0.0001). Twelve percent of all patients were classified as Type 2 diabetes, predominantly in patients >50 years. Overall mortality was 4%, being higher in patients >70 years than in patients < or =70 years (15% versus 2%, p<0.0001). One or more additional somatic diagnoses were stated on 77% of the death certificates, most often a diagnosis of cardiovascular (47%) or infectious (30%) diseases. Compared to previous studies, the incidence in the general population seems to have remained unaltered the past 25 years, but may have decreased in younger patients. Older patients with diabetic ketoacidosis differed from younger patients in having a higher mortality and a larger proportion of patients classified as Type 2 diabetes.

Treatment of diabetic ketoacidosis in adults in Denmark: a national survey.

The aims of this study were to investigate management routines of diabetic ketoacidosis (DKA) in adult patients in departments of internal medicine in Denmark and to relate current routines of treatment to available evidence. A questionnaire requesting information on management routines of DKA was sent to all departments of internal medicine in Denmark responsible of managing DKA. Fifty-nine departments (88%) returned the questionnaire and/or a copy of their management protocol. At 19 departments (32%), all patients with DKA were managed in an intensive care unit (ICU). Twenty-four different insulin regimens and 21 fluid protocols were identified. Routines of insulin therapy varied in terms of doses and routes of administration. Fifty-eight departments (97%) used isotonic saline for hydration. Potassium supplements were administered as a separate infusion of either isotonic potassium-sodium-chloride (83%) or isotonic potassium-chloride (10%). Recommended volumes to be administered during the first 8h of treatment varied significantly (median 4800ml, range 3750-7700ml). Use of bicarbonate was endorsed by 80%. This study shows significant variations in management routines of DKA in Denmark. In many cases, the treatment routines employed are not supported by evidence from clinical trials. We recommend implementation of national and/or European guidelines for management of DKA in adult patients.

[Diabetic ketoacidosis in an HIV-infected patient undergoing antiretroviral therapy]. / Diabetisk ketoacidose hos en hiv-positiv patient i antiretroviral behandling.

Following the introduction of highly active antiretroviral therapy (HAART), a number of metabolic and morphologic alterations, known as HIV-associated lipodystrophy syndrome (HALS), have been increasingly common in HIV-infected patients being treated with this therapy. The use of protease inhibitors (PI), in particular, has been associated with insulin resistance and hyperglycaemia, but only infrequently with diabetic ketoacidosis. We report a case of diabetic ketoacidosis in an HIV-infected woman after 1(1/2) years of a PI-containing regimen, demonstrating reduced beta cell function and insulin resistance.

Suppression of Beta-cell secretion by somatostatin does not fully reverse the disproportionate proinsulinemia of type 2 diabetes.

Disproportionate hyperproinsulinemia is a feature of beta-cell dysfunction in type 2 diabetes. It has been hypothesized that this abnormality represents an intrinsic abnormality of the beta-cell and/or may result from an increase in beta-cell secretory demand. To address this, six patients with type 2 diabetes and six age- and BMI-matched normal subjects received a combined 3-h insulin and somatostatin clamp to decrease beta-cell secretory demand. An arginine stimulation test was performed before and at the end of the clamp to measure beta-cell peptide release. In keeping with the reduction in secretory demand, C-peptide levels were suppressed by 60-80% during the clamp, as were proinsulin (PI) levels. The arginine-stimulated PI/C-peptide ratio decreased in the diabetic subjects from 4.4 +/- 1.5% before to 1.8 +/- 0.5% after the clamp (P < 0.01). This latter ratio was similar to that observed in the normal subjects before the somatostatin infusion (1.5 +/- 0.3%). In the normal subjects, after the clamp the PI/C-peptide ratio had decreased to 0.8 +/- 0.3% (P <0.01). Thus, the postclamp PI/C-peptide ratio in the subjects with type 2 diabetes was elevated compared with that in the normal subjects (P <0.05). Based on these observations, while relief of secretory demand on beta-cells by somatostatin decreases the disproportionate elevation in PI levels in patients with type 2 diabetes, the failure to normalize this measure suggests that an intrinsic abnormality of beta-cell function exists in subjects with type 2 diabetes that may be aggravated by increased secretory demand.