Impact of type 2 diabetes and the metabolic syndrome on myocardial structure and microvasculature of men with coronary artery disease

Background

Type 2 diabetes (T2D) is strongly associated with cardiovascular risk and requires medications that improve glycemic control and other cardiovascular risk factors. The authors aimed to assess the relative effectiveness of pioglitazone (Pio), metformin (Met) and any sulfonylurea (SU) combinations in non-insulin-treated T2D patients who were failing previous hypoglycemic therapy.

Methods

Over a 1-year period, two multicenter, open-labeled, controlled, 1-year, prospective, observational studies evaluated patients with T2D (n = 4585) from routine clinical practice in Spain and Greece with the same protocol. Patients were eligible if they had been prescribed Pio + SU, Pio + Met or SU + Met serving as a control cohort, once they had failed with previous therapy. Anthropometric measurements, lipid and glycemic profiles, blood pressure, and the proportions of patients at microvascular and macrovascular risk were assessed.

Results

All study treatment combinations rendered progressive 6-month and 12-month lipid, glycemic, and blood pressure improvements. Pio combinations, especially Pio + Met, were associated with increases in HDL-cholesterol and decreases in triglycerides and in the atherogenic index of plasma. The proportion of patients at high risk decreased after 12 months in all study cohorts. Minor weight changes (gain or loss) and no treatment-related fractures occurred during the study. The safety profile was good and proved similar among treatments, except for more hypoglycemic episodes in patients receiving SU and for the occurrence of edema in patients using Pio combinations. Serious cardiovascular events were rarely reported.

Conclusions

In patients with T2D failing prior hypoglycemic therapies, Pio combinations with SU or Met (especially Pio + Met) improved blood lipid and glycemic profiles, decreasing the proportion of patients with a high microvascular or macrovascular risk. The combination of Pio with SU or Met may therefore be recommended for T2D second-line therapy in the routine clinical practice, particularly in patients with dyslipidemia.     

The signal transduction pathway of PKC/NF-κB/c-fos may be involved in the influence of high glucose on the cardiomyocytes of neonatal rats

Background

Our aim was to compare the effects of a Paleolithic ('Old Stone Age') diet and a diabetes diet as generally recommended on risk factors for cardiovascular disease in patients with type 2 diabetes not treated with insulin.

Methods

In a randomized cross-over study, 13 patients with type 2 diabetes, 3 women and 10 men, were instructed to eat a Paleolithic diet based on lean meat, fish, fruits, vegetables, root vegetables, eggs and nuts; and a Diabetes diet designed in accordance with dietary guidelines during two consecutive 3-month periods. Outcome variables included changes in weight, waist circumference, serum lipids, C-reactive protein, blood pressure, glycated haemoglobin (HbA1c), and areas under the curve for plasma glucose and plasma insulin in the 75 g oral glucose tolerance test. Dietary intake was evaluated by use of 4-day weighed food records.

Results

Study participants had on average a diabetes duration of 9 years, a mean HbA1c of 6,6% units by Mono-S standard and were usually treated with metformin alone (3 subjects) or metformin in combination with a sulfonylurea (3 subjects) or a thiazolidinedione (3 subjects). Mean average dose of metformin was 1031 mg per day. Compared to the diabetes diet, the Paleolithic diet resulted in lower mean values of HbA1c (-0.4% units, p = 0.01), triacylglycerol (-0.4 mmol/L, p = 0.003), diastolic blood pressure (-4 mmHg, p = 0.03), weight (-3 kg, p = 0.01), BMI (-1 kg/m², p = 0.04) and waist circumference (-4 cm, p = 0.02), and higher mean values of high density lipoprotein cholesterol (+0.08 mmol/L, p = 0.03). The Paleolithic diet was mainly lower in cereals and dairy products, and higher in fruits, vegetables, meat and eggs, as compared with the Diabetes diet. Further, the Paleolithic diet was lower in total energy, energy density, carbohydrate, dietary glycemic load, saturated fatty acids and calcium, and higher in unsaturated fatty acids, dietary cholesterol and several vitamins. Dietary GI was slightly lower in the Paleolithic diet (GI = 50) than in the Diabetic diet (GI = 55).

Conclusion

Over a 3-month study period, a Paleolithic diet improved glycemic control and several cardiovascular risk factors compared to a Diabetes diet in patients with type 2 diabetes.

Trial registration

ClinicalTrials.gov NCT00435240.     

Cost-effectiveness of second-line antihyperglycemic therapy in patients with type 2 diabetes mellitus inadequately controlled on metformin

Background:

Metformin is widely accepted as first-line pharmacotherapy for patients with type 2 diabetes mellitus when glycemic control cannot be achieved by lifestyle interventions alone. However, uncertainty exists regarding the optimal second-line therapy for patients whose diabetes is inadequately controlled by metformin monotherapy. Increased use of newer, more costly agents, along with the rising incidence of type 2 diabetes, carries significant budgetary implications for health care systems. We conducted this analysis to determine the relative costs, benefits and cost-effectiveness of options for second-line treatment of type 2 diabetes.

Methods:

We used the United Kingdom Prospective Diabetes Study Outcomes Model to forecast diabetes-related complications, quality-adjusted life-years and costs of alternative second-line therapies available in Canada for adults with type 2 diabetes inadequately controlled by metformin. We obtained clinical data from a systematic review and mixed treatment comparison meta-analysis, and we obtained information on costs and utilities from published sources. We performed extensive sensitivity analyses to test the robustness of results to variation in inputs and assumptions.

Results:

Sulphonylureas, when added to metformin, were associated with the most favourable cost-effectiveness estimate, with an incremental cost of $12 757 per quality-adjusted life-year gained, relative to continued metformin monotherapy. Treatment with other agents, including thiazolidinediones and dipeptidyl peptidase-4 inhibitors, had unfavourable cost-effectiveness estimates compared with sulphonylureas. These results were robust to extensive sensitivity analyses.

Interpretation:

For most patients with type 2 diabetes that is inadequately controlled with metformin monotherapy, the addition of a sulphonylurea represents the most cost-effective second-line therapy.Type 2 diabetes mellitus is a progressive disease typically treated in a stepwise fashion, beginning with lifestyle modification, followed by the addition of one or more oral antihyperglycemic drugs and, finally, administration of exogenous insulin. Metformin monotherapy is widely recommended as first-line pharmacotherapy,^1,2 given its favourable effects in controlling blood glucose and body weight, low risk of hypoglycemia, low cost and association with mortality benefit.³ Multiple second-line treatment strategies are available for patients in whom glycemic control has become inadequate. These approaches are typically used in addition to continued metformin therapy.^4,5 Numerous second-line agents are available in Canada, including older oral agents, such as sulphonylureas, and more recently introduced agents, such as thiazolidinediones and dipeptidyl peptidase-4 inhibitors.The large number of choices for second-line therapy has increased uncertainty regarding the optimal treatment pathway. Recent clinical practice guidelines, including those produced by the Canadian Diabetes Association¹ and by the American Diabetes Association and the European Association for the Study of Diabetes,² have suggested selecting from among several agents on the basis of their respective advantages and disadvantages. There has been a considerable increase in the use of newer, more costly oral antihyperglycemic agents, which has resulted in substantial increases in associated costs to patients and both public and private drug plans in Canada.⁴ In light of current therapeutic uncertainty, the large proportion of patients requiring second-line therapy over time^3,6 and the increasing prevalence of type 2 diabetes,⁷ the utilization and cost of second-line therapy are likely to continue to grow.Informed decisions regarding optimal prescribing and reimbursement of second-line agents by public and private health care payers requires information about clinical benefits, costs and cost-effectiveness.⁸ As part of a larger initiative to determine optimal prescribing of antihyperglycemic agents, we sought to determine the incremental cost-effectiveness of treatment with alternative second-line agents added to metformin in patients with type 2 diabetes no longer adequately controlled by metformin monotherapy.     

Comparison of GLP-1 Analogues versus Sitagliptin in the Management of Type 2 Diabetes: Systematic Review and Meta-Analysis of Head-to-Head Studies

Background

Incretin–based therapies which include glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors are recommended by several practice guidelines as second-line agents for add-on therapy to metformin in patients with type 2 diabetes (T2DM) who do not achieve glycemic control with metformin plus lifestyle interventions alone. The purpose of this study is to perform a systematic review with meta-analysis of existing head to head studies to compare the efficacy and safety of GLP-1 analogues with DPP-4 inhibitors.

Methods

We performed a systematic review and meta-analysis of head-to-head studies to compare GLP-1 analogues with DPP-4 inhibitors in the management of type 2 diabetes. A random effects model was selected to perform the meta-analyses, results were expressed as weighted mean differences for continuous outcomes and relative risks for dichotomous outcomes, both with 95% confidence intervals, and with I² values and P values as markers of heterogeneity.

Results

Four head-to-head randomized controlled studies with 1755 patients were included. Compared to sitagliptin, GLP-1 analogues are more effective in reducing HbA1C (weight mean difference −0.41%, 95% CI −0.51 to −0.31) and body weight (weight mean difference −1.55 kg, 95% CI −1.98 to −1.12). Conversely, GLP-1 analogues are associated with a higher incidence of gastrointestinal adverse events compared to sitagliptin: nausea (relative risk 3.14, 95% CI 2.15 to 4.59), vomiting (relative risk 2.60, 95% CI 1.48 to 4.56), diarrhea (relative risk 1.82, 95% CI 1.24 to 2.69), and constipation (relative risk 2.50, 95% CI 1.33 to 4.70).

Conclusions

The result of this meta-analysis demonstrates that compared to sitagliptin, GLP-1 analogues are more effective for glycemic control and weight loss, but have similar efficacy in reducing blood pressure and lipid parameters, however, GLP-1 analogues are associated with a higher incidence of gastrointestinal adverse events and a similar incidence of hypoglycemia compared to sitagliptin.     

Safety and tolerability of sitagliptin in clinical studies: a pooled analysis of data from 10,246 patients with type 2 diabetes

Background

In a previous pooled analysis of 12 double-blind clinical studies that included data on 6,139 patients with type 2 diabetes, treatment with sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, was shown to be generally well tolerated compared with treatment with control agents. As clinical development of sitagliptin continues, additional studies have been completed, and more patients have been exposed to sitagliptin. The purpose of the present analysis is to update the safety and tolerability assessment of sitagliptin by pooling data from 19 double-blind clinical studies.

Methods

The present analysis included data from 10,246 patients with type 2 diabetes who received either sitagliptin 100 mg/day (N = 5,429; sitagliptin group) or a comparator agent (placebo or an active comparator) (N = 4,817; non-exposed group). The 19 studies from which this pooled population was drawn represent the double-blind, randomized studies that included patients treated with the usual clinical dose of sitagliptin (100 mg/day) for between 12 weeks and 2 years and for which results were available as of July 2009. These 19 studies assessed sitagliptin taken as monotherapy, initial combination therapy with metformin or pioglitazone, or as add-on combination therapy with other antihyperglycemic agents (metformin, pioglitazone, a sulfonylurea ± metformin, insulin ± metformin, or rosiglitazone + metformin). Patients in the non-exposed group were taking placebo, metformin, pioglitazone, a sulfonylurea ± metformin, insulin ± metformin, or rosiglitazone + metformin. The analysis used patient-level data from each study to evaluate between-group differences in the exposure-adjusted incidence rates of adverse events.

Results

Summary measures of overall adverse events were similar in the sitagliptin and non-exposed groups, except for an increased incidence of drug-related adverse events in the non-exposed group. Incidence rates of specific adverse events were also generally similar between the two groups, except for increased incidence rates of hypoglycemia, related to the greater use of a sulfonylurea, and diarrhea, related to the greater use of metformin, in the non-exposed group and constipation in the sitagliptin group. Treatment with sitagliptin was not associated with an increased risk of major adverse cardiovascular events.

Conclusions

In this updated pooled safety analysis of data from 10,246 patients with type 2 diabetes, sitagliptin 100 mg/day was generally well tolerated in clinical trials of up to 2 years in duration.     

Lay media reporting of rosiglitazone risk: extent, messaging and quality of reporting

Background

Both insulin and thiazolidinediones (TZDs) are effective in the treatment of hyperglycaemia and amelioration of insulin resistance in type 2 diabetes but have side effects including weight gain and fluid retention. The use of TZDs has been further hampered by the risk of adverse cardiovascular events including heart failure. The present study evaluated the effect of pioglitazone or insulin glargine on cardiac function and size as well as on surrogate markers of fluid retention such as weight, haemoglobin and natriuretic peptides.

Methods

Thirty patients with inadequate glycaemic control on metformin and sulfonylurea were randomised to receive add-on therapy with insulin glargine or pioglitazone for 26 weeks. Echocardiographic data and blood samples were collected from the two groups before the start of the treatment and after 26 weeks. Left ventricular end-diastolic and left atrial end-systolic volumes were quantified, weight measured and blood samples analyzed.

Results

After 26 weeks of treatment, the changes in HbA1c, weight and haemoglobin were similar between the two groups. HDL increased significantly in the pioglitazone group. While there was an increase in natriuretic peptides in the pioglitazone group (NT-proBNP 11.4 ± 19.6 to 22.8 ± 44.0, p = 0.046), the difference between the treatment groups was not significant. Left ventricular end-diastolic volume increased by 11% and left atrial end-systolic volume by 17% in the pioglitazone group (Both, p < 0.05, between treatment groups). There was a borderline significant increase in ejection fraction in the pioglitazone group.

Conclusion

This randomised pilot-study showed that six-month treatment with pioglitazone induced significant increases in natriuretic peptides and alterations of cardiac size. These changes were not observed with insulin glargine, which also is known to induce fluid retention. Larger randomised trials are warranted to confirm these findings.     

Elevated plasma free fatty acids increase cardiovascular risk by inducing plasma biomarkers of endothelial activation, myeloperoxidase and PAI-1 in healthy subjects

Background

Although there is a growing body of evidence showing that patients with type 2 diabetes mellitus (T2DM) have poor glycemic control in general, it is not clear whether T2DM patients with pre-existing cardiovascular diseases (CVD) are more or less likely to have good glycemic control than patients without pre-existing CVD. Our aim was to examine the degree of glycemic control among T2DM patients in Europe with and without pre-existing CVD.

Methods

This is a matched cohort study based on a multi-center, observational study with retrospective medical chart reviews of T2DM patients in Spain, France, United Kingdom, Norway, Finland, Germany, and Poland. Included patients were aged >= 30 years at time of diagnosis of T2DM, had added a SU or a PPARγ agonist to failing metformin monotherapy (index date) and had pre-existing CVD (cases). A control cohort with T2DM without pre-existing CVD was identified using 1:1 propensity score matching. With difference-in-difference approach, logistic and linear regression analyses were applied to identify differences in glycemic control by CVD during the follow up period, after controlling for baseline demographics, clinical information, and concurrent anti-hyperglycemic medication use.

Results

The percentage of case patients with adequate glycemic control relative to control patients during the 1st, 2nd, 3rd, and 4th years after the index date was 19.9 vs. 26.5, 16.8 vs. 26.5, 18.8 vs. 28.3, and 16.8 vs. 23.5 respectively. Cases were significantly less likely to have adequate glycemic control (odds ratio: 0.62; 95% confidence interval: 0.46-0.82) than controls after adjusting for baseline differences, secular trend, and other potential confounding covariates.

Conclusions

T2DM patients with pre-existing CVD tended to have poorer glycemic control than those without pre-existing CVD, all other factors being equal. It suggests that clinicians may need to pay more attention to glycemic control among T2DM patients with CVD.     

Effect of streptozotocin-induced diabetes on myocardial blood flow reserve assessed by myocardial contrast echocardiography in rats

Background

Hypertension and type 2 diabetes are common co-morbidities. Preliminary studies suggest that thiazolidinediones reduce blood pressure (BP). We therefore used ambulatory BP to quantify BP lowering at 6–12 months with rosiglitazone used in combination with metformin or sulfonylureas compared to metformin and sulfonylureas in people with type 2 diabetes.

Methods

Participants (n = 759) in the multicentre RECORD study were studied. Those taking metformin were randomized (open label) to add-on rosiglitazone or sulfonylureas, and those on sulfonylurea to add-on rosiglitazone or metformin.

Results

24-Hour ambulatory BP was measured at baseline, 6 months and 12 months. At 6 and 12 months, reductions in 24-hour ambulatory systolic BP (sBP) were greater with rosiglitazone versus metformin (difference at 6 months 2.7 [95% CI 0.5–4.9] mmHg, p = 0.015; 12 months 2.5 [95% CI 0.2–4.8] mmHg, p = 0.031). Corresponding changes for ambulatory diastolic BP (dBP) were comparable (6 months 2.7 [95% CI 1.4–4.0] mmHg, p < 0.001; 12 months 3.1 [95% CI 1.8–4.5] mmHg, p < 0.001). Similar differences were observed for rosiglitazone versus sulfonylureas at 12 months (sBP 2.7 [95% CI 0.5–4.9] mmHg, p = 0.016; dBP 2.1 [95% CI 0.7–3.4] mmHg, p = 0.003), but differences were smaller and/or not statistically significant at 6 months (sBP 1.5 [95% CI -0.6 to 3.6] mmHg, p = NS; dBP 1.3 [95% CI 0.0–2.5] mmHg, p = 0.049). Changes in BP were not accompanied by compensatory increases in heart rate, did not correlate with basal insulin sensitivity estimates and were not explained by changes in antihypertensive therapy between the various strata.

Conclusion

When added to metformin or a sulfonylurea, 12-month treatment with rosiglitazone reduces ambulatory BP to a greater extent than when metformin and a sulfonylurea are combined.

Trial registration

NCT00379769 http://clinicaltrials.gov/     

A randomized, double-blind, placebo-controlled trial to assess safety and tolerability during treatment of type 2 diabetes with usual diabetes therapy and either Cycloset™ or placebo

Background

Cycloset? is a quick-release formulation of bromocriptine mesylate, a dopamine agonist, which in animal models of insulin resistance and type 2 diabetes acts centrally to reduce resistance to insulin- mediated suppression of hepatic glucose output and tissue glucose disposal. In such animals, bromocriptine also reduces hepatic triglyceride synthesis and free fatty acid mobilization, manifesting decreases in both plasma triglycerides and free fatty acids. In clinical trials, morning administration of Cycloset? either as monotherapy or adjunctive therapy to sulfonylurea or insulin reduces HbA1c levels relative to placebo by 0.55–1.2. Cycloset? therapy also reduces plasma triglycerides and free fatty acid by approximately 25% and 20%, respectively, among those also receiving sulfonylurea therapies. The effects of once-daily morning Cycloset? therapy on glycemic control and plasma lipids are demonstrable throughout the diurnal portion of the day (7 a.m. to 7 p.m.) across postprandial time points.

Methods/Design

3,095 individuals were randomized in a 2:1 ratio into a one year trial aimed to assess the safety and efficacy of Cycloset? compared to placebo among individuals receiving a variety of treatments for type 2 diabetes. Eligibility criteria for this randomized placebo controlled trial included: age 30–80, HbA1c ≤ 10%, diabetes therapeutic regimen consisting of diet or no more than two hypoglycemic agents or insulin with or without one additional oral agent (usual diabetes therapy; UDT). The primary safety endpoint will test the hypothesis that the rate of all-cause serious adverse events after one year of usual diabetes therapy (UDT) plus Cycloset? is not greater than that for UDT plus placebo by more than an acceptable margin defined as a hazard ratio of 1.5 with a secondary endpoint analysis of the difference in the rate of serious cardiovascular events, (myocardial infarction, stroke, coronary revascularization or hospitalization for or angina or congestive heart failure). Efficacy analyses will evaluate effects of Cycloset? versus placebo on change from baseline in HbA1c, fasting glucose, body weight, waist circumference, blood pressure and plasma lipids.

Discussion

This study will extend the current data on Cycloset? safety, tolerability and efficacy in individuals with type 2 diabetes to include its effects in combination with thiazolodinediones, insulin secretagogues, metformin, alpha-glucosidase inhibitors and exogenous insulin regimens.

Trial registration

clinical trials.gov NCT00377676     

Comparative Efficacy and Safety of Antidiabetic Drug Regimens Added to Metformin Monotherapy in Patients with Type 2 Diabetes: A Network Meta-Analysis

Introduction

When first line therapy with metformin is insufficient for patients with type 2 diabetes (T2D), the optimal adjunctive therapy is unclear. We assessed the efficacy and safety of adjunctive antidiabetic agents in patients with inadequately controlled T2D on metformin alone.

Materials and Methods

A search of MEDLINE and CENTRAL, clinicaltrials.gov, regulatory websites was performed. We included randomized controlled trials of 3–12 months duration, evaluating Food and Drug Administration or European Union approved agents (noninsulin and long acting, once daily basal insulins) in patients experiencing inadequate glycemic control with metformin monotherapy (≥1500 mg daily or maximally tolerated dose for ≥4 weeks). Random-effects network meta-analyses were used to compare the weighted mean difference for changes from baseline in HbA1c, body weight (BW) and systolic blood pressure (SBP), and the risk of developing hypoglycemia, urinary (UTI) and genital tract infection (GTI).

Results

Sixty-two trials evaluating 25 agents were included. All agents significantly reduced HbA1c vs. placebo; albeit not to the same extent (range, 0.43% for miglitol to 1.29% for glibenclamide). Glargine, sulfonylureas (SUs) and nateglinide were associated with increased hypoglycemia risk vs. placebo (range, 4.00–11.67). Sodium glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 analogs, miglitol and empagliflozin/linagliptin significantly reduced BW (range, 1.15–2.26kg) whereas SUs, thiazolindinediones, glargine and alogliptin/pioglitazone caused weight gain (range, 1.19–2.44kg). SGLT2 inhibitors, empagliflozin/linagliptin, liraglutide and sitagliptin decreased SBP (range, 1.88–5.43mmHg). No therapy increased UTI risk vs. placebo; however, SGLT2 inhibitors were associated with an increased risk of GTI (range, 2.16–8.03).

Conclusions

Adding different AHAs to metformin was associated with varying effects on HbA1c, BW, SBP, hypoglycemia, UTI and GTI which should impact clinician choice when selecting adjunctive therapy.     

Ablation of prion protein immunoreactivity by heating in saturated calcium hydroxide

Background

Depression is common among diabetic subjects. We conducted the present study to estimate the prevalence of depression in subjects with type 2 diabetes (T2D) in Greece.

Methods

The study sample consisted of 320 T2D subjects without overt macrovascular disease attending the diabetes outpatient clinic of our hospital, from June 2007 to December 2007. Depressive symptoms were measured using the 21-item Beck Depression Inventory, modified for use in diabetic subjects.

Results

Of the study subjects 107 (33.4%) reported elevated depressive symptoms. More women than men with diabetes reported symptoms of depression (48.4% vs. 12.7%, P < 0.001). In the female study group, depressive symptoms were correlated with HbA_1c (P = 0.04), and duration of diabetes (P = 0.004). In the male study group, univariate linear regression analysis showed no significant relationships between depressive symptoms and the testing variables.

Conclusion

The prevalence of depression in Greek T2D subjects is high. Diabetic female subjects showed increased levels of depressive symptoms compared with male subjects. Independent risk factors of depressive symptoms in diabetic female subjects were diabetes duration and glycemic control.     

Initiation of insulin therapy in elderly patients taking oral antidiabetes drugs

Background

We sought to estimate the rate of initiation of insulin therapy among elderly patients using oral anti-diabetes drugs and to identify the factors associated with this initiation.

Methods

We conducted a population-based cohort study involving people aged 66 or more years who were newly dispensed an oral antidiabetes drug. Individuals who had received acarbose or a thiazolidinedione were excluded. The rate of insulin initiation was calculated by use of the Kaplan–Meier method. Factors associated with insulin initiation were identified by multivariable Cox regression analyses.

Results

In this cohort of 69 674 new users of oral antidiabetes drugs, insulin was initiated at rate of 9.7 cases per 1000 patient-years. Patients who had initially received an insulin secretagogue (rather than metformin), who were prescribed an oral antidiabetes drug by an endocrinologist or an internist, who received higher initial doses of an oral antidiabetes drug, who received oral corticosteroids, used glucometer strips, or were admitted to hospital in the year before initiation of oral antidiabetes therapy, or who received 16 or more medications were more likely than those without these characteristics to have insulin therapy initiated. In contrast, patients who received thiazides or who used up to 12 medications (v. none) were less likely to have insulin therapy initiated.

Interpretation

Several factors related to drugs and health services are associated with the initiation of insulin therapy in elderly patients receiving oral antidiabetes drugs. It is unclear whether these factors predict secondary failure of oral antidiabetes drugs or instead reflect better management of type 2 diabetes.Type 2 diabetes is a progressive disease that requires ongoing increases in doses and complexity of hypo-glycemic pharmacotherapy.¹ Although insulin may be the first agent prescribed to patients with type 2 diabetes who have marked hyperglycemia, oral antidiabetes drugs are usually the first pharmacologic treatment. In general, these drugs are first prescribed as monotherapy; however, combination therapy with 2 oral antidiabetes drugs with different mechanisms may also be a first-line option.^2–4 Unfortunately, oral antidiabetes drugs have limited efficacy for long-term glucose lowering^1,5 and, therefore, many patients may require insulin to achieve better metabolic control.⁶There are several factors that may account for the need to initiate insulin therapy in patients taking oral antidiabetes drugs, including progressive β-cell failure,⁷ deterioration of insulin sensitivity because of glucose toxicity or the development of resistance to the oral antidiabetes drug.^8,9 Disease severity, a younger age at diagnosis^1,10 and poor adherence to treatment may also lead to poor metabolic control in patients with diabetes.¹¹Our study included an outpatient population of elderly patients, all of whom were new users of an oral antidiabetes drug. We sought to estimate the rate of initiation of insulin therapy and to identify factors associated with initiation of insulin therapy.     

A long-term "memory" of HIF induction in response to chronic mild decreased oxygen after oxygen normalization

Background

Cardiovascular diseases (CVD) are the leading cause of death and the third cause of disability in Europe. Prevention programmes should include interventions aimed at a reduction of medical risk factors (hypertension, hypercholesterol, hyperglycemia, overweight and obesity) as well as behavioural risk factors (sedentary lifestyle, high fat intake and low fruit and vegetable intake, smoking). The aim of this study is to investigate the effects of a multifaceted, multidisciplinary electronic prevention programme on cardiovascular risk factors.

Methods/Design

In a randomized controlled trial, one group will receive a maximal intervention (= intervention group). The intervention group will be compared to the control group receiving a minimal intervention. An inclusion of 350 patients in total, with a follow-up of 3 years is foreseen. The inclusion criteria are age between 25–65 and insured by the Onderlinge Ziekenkas, insuring for guaranteed income in case of illness for self-employed. The maximal intervention group receives several prevention consultations by their general practitioner (GP) using a new type of cardiovascular risk calculator with personalised feedback on behavioural risk factors. These patients receive a follow-up with intensive support of health behaviour change via different methods, i.e. a tailored website and personal advice of a multidisciplinary team (psychologist, physiotherapist and dietician). The aim of this strategy is to reduce cardiovascular risk factors according to the guidelines. The primary outcome measures will be cardiovascular risk factors. The secondary outcome measures are cardiovascular events, quality of life, costs and incremental cost effectiveness ratios. The control group receives prevention consultations using a new type of cardiovascular risk calculator and general feedback.

Discussion

This trial incorporates interventions by GPs and other health professionals aiming at a reduction of medical and behavioural cardiovascular risk factors. An assessment of clinical, psychological and economical outcome measures will be performed.

Trial registration

ISRCTN23940498     

Extremely short duration high intensity interval training substantially improves insulin action in young healthy males

Background

Impaired glucose tolerance (IGT) is a prediabetic state. If IGT can be prevented from progressing to overt diabetes, hyperglycemia-related complications can be avoided. The purpose of the present study was to examine whether pioglitazone (ACTOS^®) can prevent progression of IGT to type 2 diabetes mellitus (T2DM) in a prospective randomized, double blind, placebo controlled trial.

Methods/Design

602 IGT subjects were identified with OGTT (2-hour plasma glucose = 140–199 mg/dl). In addition, IGT subjects were required to have FPG = 95–125 mg/dl and at least one other high risk characteristic. Prior to randomization all subjects had measurement of ankle-arm blood pressure, systolic/diastolic blood pressure, HbA_1C, lipid profile and a subset had frequently sampled intravenous glucose tolerance test (FSIVGTT), DEXA, and ultrasound determination of carotid intima-media thickness (IMT). Following this, subjects were randomized to receive pioglitazone (45 mg/day) or placebo, and returned every 2–3 months for FPG determination and annually for OGTT. Repeat carotid IMT measurement was performed at 18 months and study end. Recruitment took place over 24 months, and subjects were followed for an additional 24 months. At study end (48 months) or at time of diagnosis of diabetes the OGTT, FSIVGTT, DEXA, carotid IMT, and all other measurements were repeated. Primary endpoint is conversion of IGT to T2DM based upon FPG ≥ 126 or 2-hour PG ≥ 200 mg/dl. Secondary endpoints include whether pioglitazone can: (i) improve glycemic control (ii) enhance insulin sensitivity, (iii) augment beta cell function, (iv) improve risk factors for cardiovascular disease, (v) cause regression/slow progression of carotid IMT, (vi) revert newly diagnosed diabetes to normal glucose tolerance.

Conclusion

ACT NOW is designed to determine if pioglitazone can prevent/delay progression to diabetes in high risk IGT subjects, and to define the mechanisms (improved insulin sensitivity and/or enhanced beta cell function) via which pioglitazone exerts its beneficial effect on glucose metabolism to prevent/delay onset of T2DM.

Trial Registration

clinical trials.gov identifier: NCT00220961     

Impact of Glucose-Lowering Agents on the Risk of Cancer in Type 2 Diabetic Patients. The Barcelona Case-Control Study

Background

The aim of the present study is to evaluate the impact of glucose-lowering agents in the risk of cancer in a large type 2 diabetic population.

Methods

A nested case-control study was conducted within a defined cohort (275,164 type 2 diabetic patients attending 16 Primary Health Care Centers of Barcelona). Cases (n = 1,040) comprised those subjects with any cancer diagnosed between 2008 and 2010, registered at the Cancer Registry of Hospital Vall d''Hebron (Barcelona). Three control subjects for each case (n = 3,120) were matched by age, sex, diabetes duration, and geographical area. The treatments analyzed (within 3 years prior to cancer diagnosis) were: insulin glargine, insulin detemir, human insulin, fast-acting insulin and analogues, metformin, sulfonylureas, repaglinide, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, and alpha glucosidase inhibitors. Conditional logistic regressions were used to calculate the risk of cancer associated with the use of each drug adjusted by age, BMI, dose and duration of treatment, alcohol use, smoking habit, and diabetes duration.

Results

No differences were observed between case and control subjects for the proportion, dose or duration of exposure to each treatment. None of the types of insulin and oral agents analyzed showed a significant increase in the risk of cancer. Moreover, no cancer risk was observed when glargine was used alone or in combination with metformin.

Conclusions

Our results suggest that diabetes treatment does not influence the risk of cancer associated with type 2 diabetes. Therefore, an eventual increase of cancer should not be a reason for biasing the selection of any glucose-lowering treatment in type 2 diabetic population.     

Impact of Baseline BMI on Glycemic Control and Weight Change with Metformin Monotherapy in Chinese Type 2 Diabetes Patients: Phase IV Open-Label Trial

Background

Differences exist between treatment recommendations regarding the choice of metformin as first-line therapy for type 2 diabetes patients according to body mass index (BMI). This study compared the efficacy of metformin monotherapy among normal-weight, overweight, and obese patients with newly diagnosed type 2 diabetes.

Methods

In this prospective, multicenter, open-label study in China, patients aged 23–77 years were enrolled 1∶1:1 according to baseline BMI: normal-weight (BMI 18.5−23.9 kg/m²; n = 125); overweight (BMI 24.0−27.9 kg/m²; n = 122) or obese (BMI ≥28 kg/m²; n = 124). Extended-release metformin was administered for 16 weeks (500 mg/day, up-titrated weekly to a maximum 2,000 mg/day). The primary efficacy endpoint was the effect of baseline BMI on glycemic control with metformin monotherapy, measured as the change from baseline in glycosylated hemoglobin (HbA_1c) at week 16 compared among BMI groups using ANCOVA. Other endpoints included comparisons of metformin’s effects on fasting plasma glucose (FPG), lipid levels and body weight.

Results

Mean HbA_1c decreases at week 16, adjusted for baseline values, were –1.84%, –1.78% and –1.78% in normal-weight, overweight and obese patients, (P = 0.664); body weight decreased by 2.4%, 3.9% and 3.5%, respectively. FPG levels decreased similarly over time in all BMI groups (P = 0.461) and changes from baseline in high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) did not differ significantly among BMI groups at week 16 (P = 0.143 and 0.451, respectively).

Conclusions

Baseline BMI had no impact on glycemic control, weight change or other efficacy measures with metformin monotherapy. These data suggest that normal-weight type 2 diabetes patients would derive the same benefits from first-line treatment with metformin as overweight and obese patients, and are not at increased risk of excess weight loss.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00778622","term_id":"NCT00778622"}}NCT00778622     

Uncoupling protein 2 G(-866)A polymorphism: a new gene polymorphism associated with C-reactive protein in type 2 diabetic patients C-reactive protein in type 2 diabetic patients

Objective

To evaluate glycemic variability associated with two different premixed insulin analogue formulations when used in a twice-daily regimen.

Patients and Methods

Subjects comprised type 2 diabetic patients aged 20-79 years, treated with twice daily premixed insulin or insulin analogue formulations. All subjects were hospitalized for 6 days and randomized to receive either Humalog Mix 25 (Mix 25) or Humalog Mix 50 (Mix 50). They were then crossed over to the other arm between day 3 and day 4 of the study. Continuous glucose monitoring (CGM) was performed on all subjects to examine the differences in glycemic variability.

Results

Eleven type 2 diabetic patients were enrolled. No significant difference was found in 24-hour mean glucose values and their SDs, pre-meal glucose values, increases from pre-meal to peak glucose values, or time to peak glucose levels between either group. However, the mean glucose values observed during 0-8 hrs were significantly lower with Mix 25 compared to Mix 50 (128 vs. 147 mg/dL; p = 0.024).

Conclusions

The twice-daily Mix 25 regimen provided superior overnight glycemic control compared to the Mix 50 regimen in Japanese patients with type 2 diabetes. However, both twice-daily regimens with either Mix 25 or Mix 50 provided inadequate post-lunch glycemic control.

Trial Registration

Current Controlled Trials UMIN000001327     

Impact of Walking on Glycemic Control and Other Cardiovascular Risk Factors in Type 2 Diabetes: A Meta-Analysis

Background

Walking is the most popular and most preferred exercise among type 2 diabetes patients, yet compelling evidence regarding its beneficial effects on cardiovascular risk factors is still lacking. The aim of this meta-analysis of randomized controlled trials (RCTs) was to evaluate the association between walking and glycemic control and other cardiovascular risk factors in type 2 diabetes patients.

Methods

Three databases were searched up to August 2014. English-language RCTs were eligible for inclusion if they had assessed the walking effects (duration ≥8 weeks) on glycemic control or other cardiovascular risk factors among type 2 diabetes patients. Data were pooled using a random-effects model. Subgroup analyses based on supervision status and meta-regression analyses of variables regarding characteristics of participants and walking were performed to investigate their association with glycemic control.

Results

Eighteen studies involving 20 RCTs (866 participants) were included. Walking significantly decreased glycosylated haemoglobin A1c (HbA1c) by 0.50% (95% confidence intervals [CI]: −0.78% to −0.21%). Supervised walking was associated with a pronounced decrease in HbA1c (WMD −0.58%, 95% CI: −0.93% to −0.23%), whereas non-supervised walking was not. Further subgroup analysis suggested non-supervised walking using motivational strategies is also effective in decreasing HbA1c (WMD −0.53%, 95% CI: −1.05% to −0.02%). Effects of covariates on HbA1c change were generally unclear. For other cardiovascular risk factors, walking significantly reduced body mass index (BMI) and lowered diastolic blood pressure (DBP), but non-significantly lowered systolic blood pressure (SBP), or changed high-density or low-density lipoprotein cholesterol levels.

Conclusions

This meta-analysis supports that walking decreases HbA1c among type 2 diabetes patients. Supervision or the use of motivational strategies should be suggested when prescribed walking to ensure optimal glycemic control. Walking also reduces BMI and lowers DBP, however, it remains insufficient regarding the association of walking with lowered SBP or improved lipoprotein profiles.

Trial Registration

PROSPERO CRD42014009515     

The Effect of Glucagon-Like Peptide 1 Receptor Agonists on Weight Loss in Type 2 Diabetes: A Systematic Review and Mixed Treatment Comparison Meta-Analysis

Aims

To determine the effects of glucagon-like peptide-1 receptor agonists compared with placebo and other anti-diabetic agents on weight loss in overweight or obese patients with type 2 diabetes mellitus.

Methods

Electronic searches were conducted for randomised controlled trials that compared a glucagon-like peptide-1 receptor agonist therapy at a clinically relevant dose with a comparator treatment (other type 2 diabetes treatment or placebo) in adults with type 2 diabetes and a mean body mass index ≥ 25kg/m². Pair-wise meta-analyses and mixed treatment comparisons were conducted to examine the difference in weight change at six months between the glucagon-like peptide-1 receptor agonists and each comparator.

Results

In the mixed treatment comparison (27 trials), the glucagon-like peptide-1 receptor agonists were the most successful in terms of weight loss; exenatide 2mg/week: -1.62kg (95% CrI: -2.95kg, -0.30kg), exenatide 20μg: -1.37kg (95% CI: -222kg, -0.52kg), liraglutide 1.2mg: -1.01kg (95%CrI: -2.41kg, 0.38kg) and liraglutide 1.8mg: -1.51 kg (95% CI: -2.67kg, -0.37kg) compared with placebo. There were no differences between the GLP-1 receptor agonists in terms of weight loss.

Conclusions

This review provides evidence that glucagon-like peptide-1 receptor agonist therapies are associated with weight loss in overweight or obese patients with type 2 diabetes with no difference in weight loss seen between the different types of GLP-1 receptor agonists assessed.     

Early myocardial dysfunction in streptozotocin-induced diabetic mice: a study using in vivo magnetic resonance imaging (MRI)

Background

Low income individuals with diabetes are at particularly high risk for poor health outcomes. While specialized diabetes care may help reduce this risk, it is not currently known whether there are significant clinical differences across income groups at the time of referral. The objective of this study is to determine if the clinical profiles and medication use of patients referred for diabetes care differ across income quintiles.

Methods

This cross-sectional study was conducted using a Canadian, urban, Diabetes Education Centre (DEC) database. Clinical information on the 4687 patients referred to the DEC from May 2000 – January 2002 was examined. These data were merged with 2001 Canadian census data on income. Potential differences in continuous clinical parameters across income quintiles were examined using regression models. Differences in medication use were examined using Chi square analyses.

Results

Multivariate regression analysis indicated that income was negatively associated with BMI (p < 0.0005) and age (p = 0.023) at time of referral. The highest income quintiles were found to have lower serum triglycerides (p = 0.011) and higher HDL-c (p = 0.008) at time of referral. No significant differences were found in HBA1C, LDL-c or duration of diabetes. The Chi square analysis of medication use revealed that despite no significant differences in HBA1C, the lowest income quintiles used more metformin (p = 0.001) and sulfonylureas (p < 0.0005) than the wealthy. Use of other therapies were similar across income groups, including lipid lowering medications. High income patients were more likely to be treated with diet alone (p < 0.0005).

Conclusion

Our findings demonstrate that low income patients present to diabetes clinic older, heavier and with a more atherogenic lipid profile than do high income patients. Overall medication use was higher among the lower income group suggesting that differences in clinical profiles are not the result of under-treatment, thus invoking lifestyle factors as potential contributors to these findings.