This randomized, double-blind, placebo-controlled, single and multiple ascending-dose study evaluated the pharmacodynamic effects and safety/tolerability of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes.
Patients (N = 116) discontinued their antihyperglycemic medications 2 weeks before randomization. Patients received canagliflozin 30, 100, 200, or 400 mg once daily or 300 mg twice daily, or placebo at 2 study centers in the United States and Germany, or canagliflozin 30 mg once daily or placebo at 1 study center in Korea, while maintaining an isocaloric diet for 2 weeks. On Days -1, 1, and 16, urinary glucose excretion (UGE), plasma glucose (PG), fasting PG (FPG), and insulin were measured. The renal threshold for glucose (RTG) was calculated from UGE, PG, and estimated glomerular filtration rate. Safety was evaluated based on adverse event (AE) reports, vital signs, electrocardiograms, clinical laboratory tests, and physical examinations.
Canagliflozin increased UGE dose-dependently (∼80-120 g/day with canagliflozin ≥100 mg), with increases maintained over the 14-day dosing period with each dose. Canagliflozin dose-dependently decreased RTG, with maximal reductions to ∼4-5 mM (72-90 mg/dL). Canagliflozin also reduced FPG and 24-hour mean PG; glucose reductions were seen on Day 1 and maintained over 2 weeks. Plasma insulin reductions with canagliflozin were consistent with observed PG reductions. Canagliflozin also reduced body weight. AEs were transient, mild to moderate in intensity, and balanced across groups; 1 canagliflozin-treated female reported an episode of vaginal candidiasis. Canagliflozin did not cause hypoglycemia, consistent with the RTG values remaining above the hypoglycemia threshold. At Day 16, there were no clinically meaningful changes in urine volume, urine electrolyte excretion, renal function, or routine laboratory test values.
Canagliflozin increased UGE and decreased RTG, leading to reductions in PG, insulin, and body weight, and was generally well tolerated in patients with type 2 diabetes.
The mechanisms of the improvement of glucose homeostasis through angiotensin receptor blockers are not fully elucidated in hypertensive patients. We investigated the effects of telmisartan on insulin signaling and glucose uptake in cultured myotubes and skeletal muscle from wild-type and muscle-specific peroxisome proliferator-activated receptor (PPAR) δ knockout (MCK-PPARδ(-/-)) mice. Telmisartan increased PPARδ expression and activated PPARδ transcriptional activity in cultured C2C12 myotubes. In palmitate-induced insulin-resistant C2C12 myotubes, telmisartan enhanced insulin-stimulated Akt and Akt substrate of 160 kDa (AS160) phosphorylation as well as Glut4 translocation to the plasma membrane. These effects were inhibited by antagonizing PPARδ or phosphatidylinositol-3 kinase, but not by PPARγ and PPARα inhibition. Palmitate reducing the insulin-stimulated glucose uptake in C2C12 myotubes could be restored by telmisartan. In vivo experiments showed that telmisartan treatment reversed high-fat diet-induced insulin resistance and glucose intolerance in wild-type mice but not in MCK-PPARδ(-/-) mice. The protein levels of PPARδ, phospho-Akt, phospho-AS160, and Glut4 translocation to the plasma membrane in the skeletal muscle on insulin stimulation were reduced by high-fat diet and were restored by telmisartan administration in wild-type mice. These effects were absent in MCK-PPARδ(-/-) mice. These findings implicate PPARδ as a potential therapeutic target in the treatment of hypertensive subjects with insulin resistance.
Metformin is the world's most commonly used oral glucose-lowering drug for type 2 diabetes, and this is mainly because it protects against diabetes-related mortality and all-cause mortality. Although it is an old drug, its mechanism of action has not yet been clarified and its pharmacokinetic pathway is still not fully understood. There is considerable inter-individual variability in the response to metformin, and this has led to many drug-drug interaction (DDI) studies of metformin. In this review, we describe both in vitro and human interaction studies of metformin both as a victim and as a perpetrator. We also clarify the importance of including pharmacodynamic end points in DDI studies of metformin and taking pharmacogenetic variation into account when performing these studies to avoid hidden pitfalls in the interpretation of DDIs with metformin. This evaluation of the literature has revealed holes in our knowledge and given clues as to where future DDI studies should be focused and performed.
Glucagon-like peptide 1 (GLP-1) is an intestinal hormone secreted after the ingestion of various nutrients. The main role of GLP-1 is to stimulate insulin secretion in a glucose-dependent manner. However, the expression of GLP-1 receptor was found to be expressed in a variety of tissues beyond pancreas such as lung, stomach, intestine, kidney, heart and brain. Beyond pancreas, a beneficial effect of GLP-1 on body weight reduction has been shown, suggesting its role for the treatment of obesity. In addition, GLP-1 has been demonstrated to reduce cardiovascular risk factors and to have a direct cardioprotective effect, fostering heart recovery after ischemic injury. Further, data from both experimental animal models and human studies have shown beneficial effect of GLP-1 on bone metabolism, either directly or indirectly on bone cells.
We review here the recent findings of the extra-pancreatic effects of GLP-1 focusing on both basic and clinical studies, thus opening future perspectives to the use of GLP-1 analogs for the treatment of disease beyond type 2 diabetes.
Finally, the GLP-1 has been demonstrated to have a beneficial effect on both vascular, degenerative diseases of central nervous system and psoriasis.
The responsibility of diabetes management and insulin therapy has definitively moved to primary care physicians. Within the primary care setting, there is a growing need for clear, evidence-based guidelines related to the management of insulin therapy. Straightforward algorithms regarding insulin initiation, titration, and follow-up management can help physicians effectively treat patients with type 2 diabetes mellitus. Once 2 oral diabetic drugs have failed in a patient whose disease duration is 7 to 10 years, use of insulin therapy with a basal insulin analog should be considered. For patients who receive maximal basal insulin doses without reaching fasting blood glucose and target glycated hemoglobin levels with basal insulin analogs, a mealtime-insulin intensification approach should be considered. The authors discuss how simplified insulin initiation and titration regimens allow primary care physicians and other health care professionals to care for patients with type 2 diabetes mellitus.
An emphysematous liver abscess is a fatal condition that often occurs in patients with uncontrolled diabetes mellitus. I herein describe two cases of Klebsiella pneumoniae-induced emphysematous liver abscesses complicated by septic pulmonary emboli in patients with poorly controlled diabetes mellitus. Both patients showed hemoglobin A1c levels of more than 10% and did not present with any abdominal symptoms on admission. However, they were diagnosed and successfully treated with percutaneous transhepatic abscess drainage and antibiotics. This fatal disease should be taken into consideration in patients with uncontrolled diabetes mellitus who suffer from prolonged fevers and uncharacteristic general malaise.
Brain natriuretic peptide (BNP/NPPB) is a member of the natriuretic family involved in the regulation of blood pressure and blood volume as well as lipolysis control in human fat cells. Thus BNP may play a role in energy metabolism and metabolic diseases. We therefore assessed the association between the BNP promoter T-381C polymorphism and risk of type 2 diabetes and metabolic and BNP expression traits in several population samples. In French population-based samples (n = 3216), we found that individuals bearing the -381CC genotype had lower (P = 0.005) fasting glucose levels than -381TC or -381TT individuals. Moreover, the -381CC genotype was less frequent in individuals with type 2 diabetes (n = 280, 13.6%) or with impaired fasting glucose (n = 248, 12.9%) compared with normoglycaemic individuals (n = 2485, 17.8%). The adjusted odds ratio (OR) (95% CI) of type 2 diabetes for -381CC individuals was 0.69 (0.47-1.00), P = 0.05, when compared with -381T allele bearers. We replicated this association in four additional case-control studies for type 2 diabetes. The overall OR (95% CI) of type 2 diabetes was 0.85 (0.76-0.96), P = 0.008, (under a recessive model) (3593 cases and 6646 controls in total). We also found that the -381C allele was associated with higher plasma BNP concentrations (P = 0.015, n = 634) and higher BNP promoter activity in reporter gene assays. Collectively, these data suggest that relatively high BNP expression may protect against type 2 diabetes in humans.
To assess the impact of a community pharmacy diabetes service model on patient outcomes in Type 2 diabetes.
The study utilized a multisite, control vs. intervention, repeated-measures design within four states in Australia. Fifty-six community pharmacies, 28 intervention and 28 control, were randomly selected from a representative sample of urban and rural areas. Intervention pharmacies delivered a diabetes service to patients with Type 2 diabetes, which comprised an ongoing cycle of assessment, management and review, provided at regular intervals over 6 months in the pharmacy. These services included support for self monitoring of blood glucose, education, adherence support, and reminders of checks for diabetes complications. Control pharmacists assessed patients at 0 and 6 months and delivered no intervention.
A total of 289 subjects (149 intervention and 140 control) completed the study. For the intervention subjects, the mean blood glucose level decreased over the 6-month study from 9.4 to 8.5 mmol/l (P < 0.01). Furthermore, significantly greater improvements in glycaemic control were seen in the intervention group compared with the control: the mean reduction in HbA(1c) in the intervention group was -0.97% (95% CI: -0.8, -1.14) compared with -0.27% (95% CI: -0.15, -0.39) in the control group. Improvements were also seen in blood pressure control and quality of life in the intervention group.
A pharmacy diabetes service model resulted in significant improvements in clinical and humanistic outcomes. Thus, community pharmacists can contribute significantly to improving care and health outcomes for patients with Type 2 diabetes. Future research should focus on clarifying the most effective elements of the service model.
Cardiovascular disease (CVD) burden remains the predominant cause of mortality and morbidity in the United States and in most of the developed world. The ongoing twin epidemics of obesity and type 2 diabetes mellitus provide a groundswell source for sustaining this trend for the foreseeable future (increasing the prevalence of CVD by 2-4 times), unless radical changes are made in public health policy. Oral hypoglycemic agents (OHAs) remain a mainstay for management of type 2 diabetes in most practice settings. Although these agents are primarily prescribed to achieve better glycemic control, it is important to evaluate what effects they have on cardiovascular risk and whether there are significant differences in effects among the different OHAs. This review presents the available data on the effects of the various OHAs on cardiovascular risk surrogates and actual events in retrospective and prospective study design settings.
The Enhanced Primary Care package, introduced in 1999, included an item number for multidisciplinary care plans. There has been little research into what is contained in care plans. This study investigated what general practitioners documented in care plans for their diabetic patients.
A retrospective audit of care plans was conducted as part of a larger audit that evaluated the impact of multidisciplinary care plans on the care of patients with type 2 diabetes. The subjects were GPs and their diabetic patients with care plans.
The care plans of 230 patients, identified by 26 GPs, were audited. Most GPs used a template to document care plans and the nature of the template influenced the content. There was limited information documented in care plans.
Simplification and consistency of care plan templates would assist the care planning process and encourage better documentation. Appropriate GP education is required to support this.