Oral Blood Glucose Lowering Drugs Research Articles

A web-based program to improve treatment adherence in patients with type 2 diabetes: Development and study protocol

BackgroundMany patients with type 2 diabetes mellitus (T2DM) sub-optimally adhere to core treatment recommendations, such as healthy diets, sufficient physical activity and pharmacological support. This paper describes the development of the web-based computer-tailored program My Diabetes Profile (MDP), incorporating identified success factors of web-based interventions, and the protocol for testing the effectiveness of this program in a randomized multicentre trial. MethodsFormative research - including the input of a program committee, qualitative and quantitative studies with patients and health professionals and a literature search - yielded input for the development of the MDP program. MDP provides video and text tailored advice, based on determinants and salient beliefs derived from the I-Change Model, on decreasing unhealthy snack intake, increasing physical activity, and improving adherence to both oral blood glucose lowering drugs and self-administered insulin therapy. Patients with T2DM recruited by practice nurses and diabetes nurses across the Netherlands fill in online questionnaires at baseline and six-months follow-up. Participants are randomized on patient level to the intervention group (access to the MDP program) or control group (receiving care as usual). DiscussionThe formative research using co-creation principles proved essential in the development of the MDP program and involved various disciplines in T2DM management including target group representatives. Co-creation revealed clearly that patients needed short and attractive messages. Consequently, a mix of video and short text messages were chosen for the ultimate program format. Pilot testing was useful to further shape the program to needs of patients and professionals.Trial registration: Dutch Trial Register NTR6840; Archived program website: http://www.webcitation.org/6xXz01S7X

Sodium-Glucose Transporter Inhibitors and Diabetic Nephropathy in Humans and Animal Model

Diabetic nephropathy as the leading cause for end stage renal disease and replacement therapy is increasing every year. Treatment of T2DM with the present oral blood glucose lowering drugs and insulin is challenging, with an enormous number of patients are able to achieve the target glycaemic control (HbA1C<6.5%). Despite the use of new Insulin compounds and different recommended combination of oral anti-diabetic drugs, the benefits of these recommendations are offset by side effects such as weight gain and recurrent hypoglycaemia. Therefore, the need for new agents that control blood glucose strictly and have other proactive cellular pathways is challenging. The sodium glucose transporter protein 2 (SGLT2) inhibitors, are recently being widely used. The main therapeutic effect of these new drugs, SGLT2 inhibitors (SGLT2-I), is lowering the blood glucose levels via inhibitory effect on the transport of glucose and sodium in the proximal tubular cells by sodium glucose transport 1. SGLT2-I reduce plasma sodium level by natriuretic and diuresis, with decreasing blood pressure and body weight. These new medications can be used as first and second lines of treatment especially in patients with normal glomerular filtration rate, with or without cardiovascular complications. The most effective combination of SGLT2I is Metformin especially in albuminuria and slowing the progression of diabetic nephropathy especially if initiated in early stages of DM. The new class of medication (SGLT2I) are less effective in patients with moderate CKD (eGFR<45 ml/min). This review will focus on the new pathways such autophagy as a new pathway where SGLT2 are involved with protective effects.

Management of the hormonal syndrome of neuroendocrine tumors.

Gastroenteropancreatic neuroendocrine tumors (GEP/NET) are unusual and rare neoplasms that present many clinical challenges. They characteristically synthesize store and secrete a variety of peptides and neuroamines which can lead to the development of distinct clinical syndrome, however many are clinically silent until late presentation with mass effects. Management strategies include surgery cure and cytoreduction with the use of somatostatin analogues. Somatostatin have a broad range of biological actions that include inhibition of exocrine and endocrine secretions, gut motility, cell proliferation, cell survival and angiogenesis. Five somatostatin receptors (SSTR1-SSTR5) have been cloned and characterized. Somatostatin analogues include octreotide and lanreotide are effective medical tools in the treatment and present selectivity for SSTR2 and SSTR5. During treatment is seen disapperance of flushing, normalization of bowel movements and reduction of serotonin and 5-hydroxyindole acetic acid (5-HIAA) secretion. Telotristat represents a novel approach by specifically inhibiting serotonin synthesis and as such, is a promising potential new treatment for patients with carcinoid syndrome. To pancreatic functionig neuroendocrine tumors belongs insulinoma, gastrinoma, glucagonoma and VIP-oma. Medical management in patients with insulinoma include diazoxide which suppresses insulin release. Also mTOR inhibitors may inhibit insulin secretion. Treatment of gastrinoma include both proton pump inhibitors (PPIs) and histamine H2 – receptor antagonists. In patients with glucagonomas hyperglycaemia can be controlled using insulin and oral blood glucose lowering drugs. In malignant glucagonomas smatostatin analogues are effective in controlling necrolytic migratory erythemia. Severe cases of the VIP-oma syndrome require supplementation of fluid losses. Octreotide reduce tumoral VIP secretion and control secretory diarrhoea.

Commentary: metformin use is associated with reduced gastric cancer risk.

Type 2 diabetes mellitus has been associated with increased all cancer incidence, including gastric cancer. Both hyperinsulinaemia and inflammatory changes secondary to adiposity have been suggested as important underlying mechanisms. 2 The debate of possible advantage or disadvantage of metformin, and other blood glucose lowering drugs, with regard to cancer risk is of great importance given the widespread use of these drugs. Recently, use of incretins was reported to cause no increased risk of pancreatic cancer. Metformin is generally considered the first-line drug for treating type 2 diabetes, and is one of the most commonly prescribed drugs worldwide. Previous population-based reports have suggested a preventive effect of metformin for liver, colorectal, pancreas, oesophageal and stomach cancers, although the available evidence is inconclusive. 5 The anti-carcinogenic effects of metformin have been attributed to several mechanisms, including activation of LKB1/AMPK pathway, induction of cell cycle arrest and/ or apoptosis, and activation of the immune system. Kim et al. report data from a Korean nationwide retrospective cohort study of type 2 diabetic patients. This interesting article, which is a valuable addition to the existing literature, reports a reduction in gastric cancer incidence among patients using metformin during more than 3 years, as compared to type 2 diabetic patients on other oral blood glucose lowering drugs. The relative risk of gastric cancer development among metformin users was reduced up to 43% (HR 0.57; 95% CI 0.37–0.87) after 3 years or more of metformin use. The nationwide data from a national insurance claim database support the validity of the association between metformin use and reduced gastric cancer incidence. However, duration of diabetes, and the need for switching to second-line oral therapies, are still important possible confounders for the reported association. Therefore, results of large randomised controlled trials are needed to finally elucidate this issue. In addition, with regard to clinical implications, and specifically the development of preventive medical strategies for gastric cancer, the preventive effect of metformin use will most certainly still be inferior to the importance of Helicobacter pylori eradication.

Safety and Efficacy of Gliclazide as Treatment for Type 2 Diabetes: A Systematic Review and Meta-Analysis of Randomized Trials

Objective and DesignGliclazide has been associated with a low risk of hypoglycemic episodes and beneficial long-term cardiovascular safety in observational cohorts. The aim of this study was to assess in a systematic review and meta-analysis of randomized controlled trials the safety and efficacy of gliclazide compared to other oral glucose-lowering agents (PROSPERO2013:CRD42013004156)Data SourcesMedline, EMBASE, Clinicaltrials.gov, Trialregister.nl, Clinicaltrialsregister.eu and the Cochrane database.SelectionIncluded were randomized studies of at least 12 weeks duration with the following outcomes: HbA1c change, incidence of severe hypoglycemia, weight change, cardiovascular events and/or mortality when comparing gliclazide with other oral blood glucose lowering drugs. Bias was assessed with the Cochrane risk of bias tool. The inverse variance random effects model was used.ResultsNineteen trials were included; 3,083 patients treated with gliclazide and 3,155 patients treated with other oral blood glucose lowering drugs. There was a considerable amount of heterogeneity between and bias in studies. Compared to other glucose lowering agents except metformin, gliclazide was slightly more effective (−0.13% (95%CI: −0.25, −0.02, I2 55%)). One out of 2,387 gliclazide users experienced a severe hypoglycemic event, whilst also using insulin. There were 25 confirmed non-severe hypoglycemic events (2.2%) in 1,152 gliclazide users and 22 events (1.8%) in 1,163 patients in the comparator group (risk ratio 1.09 (95% CI: 0.20, 5.78, I2 77%)). Few studies reported differences in weight and none were designed to evaluate cardiovascular outcomes.ConclusionsThe methodological quality of randomized trials comparing gliclazide to other oral glucose lowering agents was poor and effect estimates on weight were limited by publication bias. The number of severe hypoglycemic episodes was extremely low, and gliclazide appears at least equally effective compared to other glucose lowering agents. None of the trials were designed for evaluating cardiovascular outcomes, which warrants attention in future randomized trials.

Antidiabetic therapy in real practice: indicators for adherence and treatment cost

BackgroundType 2 diabetes has become a disease with a high economic and social impact. The ARNO Observatory is a clinical data warehouse consisting of a network of local health care units (ASL) scattered throughout the Italian territory which collects data on health care consumption for about 10.5 million people. The purpose of this study was to evaluate the use of antidiabetic drugs with particular reference to type of treatment. The analyses were carried out on a sample of 169,375 patients treated with oral blood glucose-lowering drugs in 2008 from a total population of 4,040,624 health care beneficiaries at 12 local health care units in the ARNO Observatory.MethodsPatients were considered “on treatment with oral blood glucose-lowering drugs” if they had received at least one prescription of an antidiabetic drug (Anatomical Therapeutic Chemical code A10B) during 2008. The patients were divided into three treatment groups, ie, monotherapy, fixed-combination drugs, and dual therapy. The following indicators were assessed: number of patients treated with an oral antidiabetic drug, mean number of hospitalizations, mean number of specialist examinations, and mean expenditure per treated patient. Adherence was assessed using the medication possession ratio indicator (MPR).ResultsPatients treated with oral blood glucose-lowering drugs comprised 4.2% of the investigated population, and had an average age of 68.9 years. The mean annual number of hospitalizations was lower in the dual therapy group (298 versus 328 per 1000 patients in the sample), while the average number of specialist examinations was lower in the fixed-combination group (30.1 versus 35.1). Patients on monotherapy showed a better percentage of adherence for glimepiride (70.5%) and pioglitazone (70.4%), whereas the best adherence in the fixed-combination therapy group was recorded for metformin + pioglitazone (75.5%). The average annual cost per diabetic patient was €2388, with differences between the monotherapy (€2321), fixed-combination (€2270), and dual therapy (€2465) groups. Fixed combination therapy involved a lower mean expenditure for insulin, other drugs, and specialist and diagnostic care. Thiazolidinediones (such as pioglitazone) showed the lowest average annual cost per patient among the monotherapies, with a marked decrease in costs for hospitalization, specialist care, and diagnostics.ConclusionThe results of our study should be extended to other regional/national reference local health care units in order to define and compare average standard costs per pathology throughout the wide sample considered in this research work. Appropriate drug prescribing is of critical importance in order to achieve therapeutic objectives and to optimize the use of resources in modern health care systems.

Frequency of Monitoring Diabetes in Primary Care: What Do Well-Controlled Patients Prefer?

ObjectiveTo describe the preferences and the associated patients’ characteristics of well-controlled type 2 diabetes patients for the diabetes monitoring frequency in primary care. MethodsCross-sectional study with 233 participating general practitioners across the Netherlands. Eligible patients were between 40 and 80 years, diagnosed with type 2 diabetes for more than 1 year not on insulin, and with glycated hemoglobin (A1C) ≤7.5%, systolic blood pressure ≤145 mm Hg and total cholesterol ≤5.2 mmol/L. Participants were asked whether they had a preference for 3-monthly or 6-monthly monitoring or no preference. ResultsFrom 2215 patients, 747 patients (33.7%) preferred 3-monthly and 677 (30.6%) 6-monthly monitoring by either the general practitioner or the practice nurse. The former group consisted of less smokers, felt less healthy, reported more diabetes-related distress, had the highest reported frequency of hyperglycemic episodes and used more oral blood glucose lowering drugs compared to the other patients. Those preferring 6-monthly monitoring were least satisfied with diabetes treatment, reported the lowest frequency of hyperglycemic episodes and used less oral blood glucose lowering drugs compared to the other patients. ConclusionA preference for more frequent monitoring was associated with a worse disease status, whereas a preference for less frequent monitoring tended to be associated with the opposite. Patients seem to have logical preferences that need to be accounted for in diabetes care.

Alpha-glucosidase inhibitors 2012 – cardiovascular considerations and trial evaluation

Alpha-glucosidase inhibitors have been available for clinical use for about 20 years. They have shown reasonably good efficacy comparable to other oral blood glucose lowering drugs and in some parts of the world are the most commonly prescribed oral diabetes medication, especially in Asian countries. Unlike as has been observed with some other blood glucose lowering agents, however, no adverse signals of potential cardiovascular harm have emerged in relation to their use. On the contrary, significant beneficial cardiovascular outcome results have been observed in the post-hoc analyses of randomised placebo-controlled trials with the alpha-glucosidase inhibitor acarbose. Targeting mainly postprandial hyperglycaemia, alpha-glucosidase inhibitors favourably affect several cardiovascular risk factors, such as obesity, hypertension and high glycaemic variability with little to no risk for hypoglycaemia. Furthermore, acarbose favourably affects endothelial dysfunction and carotid intima media thickening in humans and, in animal models, improves cardiac interstitial fibrosis and hypertrophy of cardiomyocytes. The ultimate determination of the cardiovascular effects of alpha-glucosidase inhibitors in terms of clinical outcomes awaits the results of ongoing long-term, randomised, placebo-controlled trials.

Educational needs of diabetic patients whom referred to the diabetes center

Diabetes is one of the most common metabolic disorders that threat to community health. Complications of this disease include eye damage, nephropathy, cardiovascular disease, neuropathy and.. According to statistics, every 5 Iranians one or has diabetes or high risk for it. If diabetes and non-observance of essential points, such as permanent control blood sugar, complications, focuses on large and often irreparable effects and high cost to the patient and the country is imposed. According to the Ministry of Health annual cost of USD 900 billion in diabetic patients is therapeutic. MethodsThe study of a cross-sectional descriptive study to review the training needs diabetic patients referred to the Diabetes Centre of Hamedan city in Iran. The study of all diabetic patients was referred to Hamadan, the census method for 6 months were studied. Information gathering tool was a questionnaire form. ResultsThe results showed that 22.5% age range were in the 41-50 year. 45.7% with symptoms and 20.2% random were aware of their illness. Only 8.9 patients to exercise, 43.4% patients to ocular complications of diabetes knowledge were weak. 31.8% had eye complications. Only 48.5% of patients in most of the performance always enjoyed feeding .63% at least once with acute complications (hypoglycaemia, Hyperglycemias’), were about 59% of the complications was repeated.69.3% of patients awareness of day care unfit legs.40% were aware of the oral blood glucose lowering drugs. ConclusionFastest and most effective way to achieve public access to justice training. Training style health and lifestyle of the most important tasks community health nurses is considered that individuals can decide the right to personal behaviour so that awareness and the education level of public health community, and ultimately performance will automatically increase significantly. Basic education and treatment of the diabetic patients and diabetic patients must participate in training sessions and learn the important need to learn how to live with their disease.

Comparing Adverse Event Rates of Oral Blood Glucose-Lowering Drugs Reported by Patients and Healthcare Providers

Non-serious symptomatic adverse drug events (ADEs) affect the real benefit-risk ratio of a drug. Currently, such ADEs are quantified in different ways, often using reports from a healthcare provider or patients, resulting in large variations in estimated rates. Several studies showed that patients report bothersome or symptomatic ADEs more frequently than providers, but no comparisons to an external reference or gold standard have been made. We conducted a literature review to assess the agreement and concurrent validity of healthcare provider- and patient-oriented methods for quantifying symptomatic ADEs of oral blood glucose-lowering drugs in patients with type 2 diabetes mellitus. We systematically searched MEDLINE and EMBASE databases for observational studies reporting on rates of ADEs in patients treated for type 2 diabetes that were published between 1999 and 2011. We included nine observational studies reporting absolute rates of symptomatic ADEs in patients receiving monotherapy. We calculated 95% confidence intervals and assessed agreement between rates observed with different methods. We assessed concurrent validity using the range noted in the Summary of Product Characteristics (SPC) as the gold standard. A comparison of rates reported by patients and providers was only possible using three studies of metformin that assessed mainly gastrointestinal (GI) ADEs. Provider-oriented methods by means of medical record review gave lower rates for abdominal pain (0.6-3.7%), dyspepsia (1.3-2.8%) and constipation (0.6-1.0%) than a patient questionnaire method (8.5%, 11.9% and 20.7%, respectively). For diarrhoea, the patient-reported rate (5.2%) was in agreement with the provider-based rates (1.6-7.6%). The majority of the rates reported by providers and patients were not corresponding with the ranges in the SPC. For GI ADEs the rates were all lower, whereas for lactic acidosis and hypoglycaemia the rates were higher. Although it has repeatedly been proposed that patients' reports on safety should be incorporated with providers' reports, especially for symptomatic ADEs, the number of observational studies using patient-oriented methods for assessing ADEs other than hypoglycaemia are limited. Provider-based measurement tended to underestimate symptomatic ADEs. Patient-oriented methods seemed to give ADE rates that were closer to the rates reported in the SPC.

Diabetes in Mozambique: Prevalence, management and healthcare challenges

Aim The growing trend towards and deficient management of diabetes in Africa are important public-health challenges requiring surveillance. For this reason, this study aimed to assess the prevalence and awareness of diabetes in urban and rural Mozambique, and to describe its management. Methods In 2005, a representative sample of the national Mozambican adult population ( n = 2343) was evaluated, according to the STEPwise approach to chronic disease risk factor surveillance (STEPS). Twelve-hour fasting blood glucose (FBG) was measured, using fingertip capillary whole blood, to estimate the prevalence of impaired fasting glucose (IFG; FBG ≥ 5.6 mmol/L and less than 6.1 mmol/L) and diabetes (FBG ≥ 6.1 mmol/L, or treatment with insulin and/or oral blood glucose-lowering drugs). Patients’ awareness and management of diabetes were assessed by questionnaire. Results The prevalence of diabetes and IFG was 2.9% [95% confidence interval (95%CI): 1.8–4.0] and 2.5% (95%CI: 1.3–3.7), respectively. Diabetes was more frequent among urban dwellers (OR = 2.92, 95%CI: 1.45–5.86), mostly due to urban–rural differences in age, education, body mass index (BMI) and waist circumference (adjusted OR = 2.27, 95%CI: 0.83–6.26). In all, 13% of those with diabetes were aware of their condition, 10.9% had undergone glycaemia determination during the previous year, and 9% were being treated with oral blood glucose-lowering drugs and 3% with insulin. Conclusion Diabetes prevalence is low in Mozambique, but most diabetic patients were neither aware of their condition nor being treated pharmacologically, thus posing serious challenges to the provision of adequate care in an already disadvantageous context.

Use of statins in patients receiving oral blood glucose-lowering drugs.

Objectives: The aim was to study the prevalence of co-medication of statins in patients receiving oral blood glucose-lowering drugs by age and gender. Method: Treatment with oral antidiabetics was used as a surrogate endpoint for the presence of type 2 diabetes. Data on patients with at least one prescription of oral antidiabetics in the period 2004-2006 were retrieved from the Norwegian Prescription Database (NorPD). Information on dispensation of statins in the same calendar year was also obtained. Long-term users of oral antidiabetics were defined as patients filling a prescription of these drugs the year prior to the year of observation. Results: In 2006, a total of 76 288 users of oral blood glucose-lowering drugs were registered as long-term users. 57.0% men and 49.7% women of long-term users received a statin. 15 646 patients were new users of oral antidiabetics in 2006. 45.5% men and 34.9% women of new users received a statin. The proportion of statin users increased with age and was higher in men than in women in all age groups. An absolute increase of 3% from 2005 to 2006 was observed in the proportion of use of statins in both long-term users and new users of oral antidiabetics. Conclusions: In 2006, 54% of long-term users and 40% of new users of oral blood glucose-lowering drugs also received statins; these proportions were an increase from 2005. Men were more likely to receive statins than women which can reflect that, in the general population, the overall cardiovascular risk in men is higher than in women

Road traffic accident risk in patients with diabetes mellitus receiving blood glucose‐lowering drugs. Prospective follow‐up study

To investigate, at a national level, whether patients using insulin or oral glucose-lowering agents had an increased risk of road traffic accidents compared with non-users. All Norwegians aged 18-69 years (3.1 million) were followed from April 2004 until September 2006. Information on drug prescriptions, road traffic accidents and emigration/death was obtained from the following population-based registries: the Prescription Database, the Road Accident Registry and the Central Population Registry. The exposure period was the time from the first prescription of insulin or oral glucose-lowering agent during the study period. The incidence of accidents in the exposed person-time was compared with the incidence of accidents in the unexposed person-time by standardized incidence ratio (SIR). During the study period, 20 494 road traffic accidents with personal injuries were registered in Norway. One hundred and eighty-three accidents were registered for insulin users not taking oral glucose-lowering agents and 219 for users of oral blood glucose-lowering drugs without insulin. The SIR (95% confidence interval) for all ages and both genders combined were: insulin 1.4 (1.2-1.6), oral glucose-lowering agents 1.2 (1.0-1.3) and users of drugs for peptic ulcer and gastro-oesophageal reflux disease (negative comparators) 1.3 (1.2-1.4). The highest SIRs were found among the youngest insulin users (18-34 years old). A slightly increased risk of being involved in a road traffic accident was observed for drivers prescribed insulin, while no increased risk was observed for drivers prescribed oral glucose-lowering agents. The increased risk observed for insulin users was similar to that observed for users of drugs for peptic ulcer and gastro-oesophageal reflux disease.

Theoretical study of molecular structure, p Ka, lipophilicity, solubility, absorption, and polar surface area of some hypoglycemic agents

The methods of theoretical chemistry have been used to elucidate molecular properties of the hypoglycemic sulfonylureas and glinides (acetohexamide, tofazamide, tolbutamide, chlorpropamide, gliclazide, glimepiride, glipizide, glibenclamide, nateglinide, and repaglinide). The geometries and energies of these drugs have been computed using HF/6-31G(d) and Becke3LYP/6-31G(d) methods. The equilibrium structure of the sulfonylureas investigated in the isolated state is determined by the formation of suitable intramolecular hydrogen bonds within the sulfonamide moiety. This specific interaction gives rise to the unique overall shape of individual drug conformers. Values of these dihedral angles for individual drugs are different. Generally, the ab initio SCF and DFT optimized structures in the gas phase fit well one another. Water has a remarkable effect on the geometry of the drugs studied. The p K a values of sulfonylurea moiety are in the range of 5.2–6.2 and these drugs are characterized as weak organic acids. Repaglinide and nateglinide are oral blood glucose-lowering drugs of the glinide class containing acidic carboxylic group. The p K a values of this carboxylic acid moiety are in the range of 3.5–4.0. Computed partition coefficients (XLOGP2 method) for drugs studied varied between 1.8 and 5.9. Thus these compounds are described as lipophilic drugs. Although the sulfonylurea and glinidine derivatives studied are only slightly soluble in water, their computed solubilities from interval between 0.001 and 4 g/L are sufficient for fast adsorption.

Analisi di costo-efficacia di exenatide versus insulina glargine nel trattamento dei pazienti diabetici di tipo 2 in fallimento secondario al doppio ipoglicemizzante orale

The objective of this economic evaluation was to compare efficacy and costs of exenatide or insulin glargine in the treatment of patients with type 2 diabetes mellitus who have poor glycemic control despite taking oral blood glucose-lowering drugs. We built a model in which two cohorts of patients received exenatide or insulin glargine. The patients were followed for one year. The economic evaluation was conducted from the perspective of the Italian National Health Service. We considered Quality-Adjusted Life-Years (QALYs) and direct medical costs (pharmacological treatment, complications etc.). Benefits and costs were not discounted. Costs were assessed in 2007 Euros. Sensitivity and threshold analysis on key clinical and economic parameters were performed. For the two cohorts QALYs (per patient) with exenatide were 0.75 and for insulin glargine were 0.74. The expected cost (per patient) was € 2,757.37 with exenatide and € 2,837.05 with insulin glargine. This study suggests that, compared with insulin glargine, exenatide is dominant in the treatment of patients with type 2 diabetes mellitus who have poor glycemic control despite taking oral blood glucose-lowering drugs.

Exenatide versus Insulin Glargine in Patients with Suboptimally Controlled Type 2 Diabetes

Physicians may use either insulin or exenatide injections for patients with type 2 diabetes mellitus who have poor glycemic control despite taking oral blood glucose-lowering drugs. To compare effects of exenatide and insulin glargine on glycemic control in patients with type 2 diabetes mellitus that is suboptimally controlled with metformin and a sulfonylurea. 26-week multicenter, open-label, randomized, controlled trial. 82 outpatient study centers in 13 countries. 551 patients with type 2 diabetes and inadequate glycemic control (defined as hemoglobin A1c level ranging from 7.0% to 10.0%) despite combination metformin and sulfonylurea therapy. Exenatide, 10 microg twice daily, or insulin glargine, 1 daily dose titrated to maintain fasting blood glucose levels of less than 5.6 mmol/L (<100 mg/dL). Hemoglobin A1c level, fasting plasma glucose level, body weight, 7-point self-monitored blood glucose, standardized test-meal challenge, safety, and tolerability. Baseline mean hemoglobin A1c level was 8.2% for patients receiving exenatide and 8.3% for those receiving insulin glargine. At week 26, both exenatide and insulin glargine reduced hemoglobin A1c levels by 1.11% (difference, 0.017 percentage point [95% CI, -0.123 to 0.157 percentage point]). Exenatide reduced postprandial glucose excursions more than insulin glargine, while insulin glargine reduced fasting glucose concentrations more than exenatide. Body weight decreased 2.3 kg with exenatide and increased 1.8 kg with insulin glargine (difference, -4.1 kg [CI, -4.6 to -3.5 kg]). Rates of symptomatic hypoglycemia were similar, but nocturnal hypoglycemia occurred less frequently with exenatide (0.9 event/patient-year versus 2.4 events/patient-year; difference, -1.6 events/patient-year [CI, -2.3 to -0.9 event/patient year]). Gastrointestinal symptoms were more common in the exenatide group than in the insulin glargine group, including nausea (57.1% vs. 8.6%), vomiting (17.4% vs. 3.7%) and diarrhea (8.5% vs. 3.0%). The trial was open-label and did not assess clinical complications related to diabetes. Of the 551 participants, 19.4% of those receiving exenatide and 9.7% of those receiving insulin glargine withdrew from the study. Only 21.6% of the insulin glargine group and 8.6% of the exenatide group achieved the target level for fasting plasma glucose of less than 5.6 mmol/L (<100 mg/dL). Exenatide and insulin glargine achieved similar improvements in overall glycemic control in patients with type 2 diabetes that was suboptimally controlled with oral combination therapy. Exenatide was associated with weight reduction and had a higher incidence of gastrointestinal adverse effects than insulin glargine.

The Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive)

The PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) assesses the effect of pioglitazone, a peroxisome proliferator-activated receptor agonist, with anti-inflammatory and vascular properties, on the secondary prevention of macrovascular events in type 2 diabetes. PROactive is an on-going randomized, double-blind outcome study in patients with type 2 diabetes managed with diet and/or oral blood glucose-lowering drugs (combination of oral agents with insulin is permitted) who have a history of macrovascular disease. Patients are randomized to receive pioglitazone (forced titration from 15 to 30 to 45 mg, depending on tolerability) or placebo in addition to existing therapy. The primary end point is the time from randomization to occurrence of a new macrovascular event or death. Follow-up is estimated to span 4 years. A total of 5238 patients have been randomized from 19 countries. At entry into the study, patients enrolled are a mean age of 61.8 years, with type 2 diabetes for a mean of 9.5 years; 60.9 and 61.5% are taking metformin or a sulfonylurea, respectively; and 33.6% are using insulin in addition to oral glucose-lowering drugs. The majority of patients are men (66.1%). Patients are required to meet one or more of entry criteria, as follows: >6 months' history of myocardial infarction (46.7%); coronary artery revascularization (30.8%), stroke (18.8%), or acute coronary syndrome for >3 months (13.7%); other evidence of coronary artery disease (48.1%); or peripheral arterial occlusive disease (19.9%). One-half (48.5%) of the patients have two or more of these risk factors. Three-quarters (75.4%) have hypertension, and 58.8% are current or previous smokers. The cohort of patients enrolled in PROactive is a typical type 2 diabetic population at high risk of further macrovascular events. The characteristics of this population are ideal for assessing the ability of pioglitazone to reduce the cardiovascular risk of patients with type 2 diabetes.