New drugs for type 2 diabetes mellitus:what is their place in therapy?

Oral therapy for type 2 diabetes mellitus, when used appropriately, can safely assist patients to achieve glycaemic targets in the short to medium term. However, the progressive nature of type 2 diabetes usually requires a combination of two or more oral agents in the longer term, often as a prelude to insulin therapy. Issues of safety and tolerability, notably weight gain, often limit the optimal application of anti-diabetic drugs such as sulforylureas and thiazolidinediones. Moreover, the impact of different drugs, even within a single class, on the risk of long-term vascular complications has come under scrutiny. For example, recent publication of evidence suggesting potential detrimental effects of rosiglitazone on myocardial events generated a heated debate and led to a reduction in use of this drug. In contrast, current evidence supports the view that pioglitazone has vasculoprotective properties. Both drugs are contraindicated in patients who are at risk of heart failure. An additional recently identified safety concern is an increased risk of fractures, especially in postmenopausal women. Several new drugs with glucose-lowering efficacy that may offer certain advantages have recently become available. These include (i) injectable glucagonlike peptide-1 (GLP-1) receptor agonists and oral dipeptidyl peptidase-4 (DPP-4) inhibitors; (ii) the amylin analogue pramlintide; and (iii) selective cannabinoid receptor-1 (CB1) antagonists. GLP-1 receptor agonists, such as exenatide, stimulate nutrient-induced insulin secretion and reduce inappropriate glucagon secretion while delaying gastric emptying and reducing appetite. These agents offer a low risk of hypoglycaemia combined with sustained weight loss. The DPP-4 inhibitors sitagliptin and vildagliptin are generally weight neutral, with less marked gastrointestinal adverse effects than the GLP-1 receptor agonists. Potential benefits of GLP-1 receptor stimulation on P cell neogenesis are under investigation. Pancreatitis has been reported in exenatide-treated patients. Pramlintide, an injected peptide used in combination with insulin, can reduce insulin dose and bodyweight. The CB1 receptor antagonist rimonabant promotes weight loss and has favourable effects on aspects of the metabolic syndrome, including the hyperglycaemia of type 2 diabetes. However, in 2007 the US FDA declined approval of rimonabant, requiring more data on adverse effects, notably depression. The future of dual peroxisome proliferator-activated receptor-alpha/gamma agonists, or glitazars, is presently uncertain following concerns about their safety. In conclusion, several new classes of drugs have recently become available in some countries that offer new options for treating type 2 diabetes. Beneficial or neutral effects on bodyweight are an attractive feature of the new drugs. However, the higher cost of these agents, coupled with an absence of long-term safety and clinical outcome data, need to be taken into consideration by clinicians and healthcare organizations.

Novel dipeptidyl peptidase IV resistant analogues of glucagon-like peptide-1(7-36)amide have preserved biological activities in vitro conferring improved glucose-lowering action in vivo

Although the incretin hormone glucagon-like peptide-1 (GLP-1) is a potent stimulator of insulin release, its rapid degradation in vivo by the enzyme dipeptidyl peptidase IV (DPP IV) greatly limits its potential for treatment of type 2 diabetes. Here, we report two novel Ala8-substituted analogues of GLP-1, (Abu8)GLP-1 and (Val8)GLP-1 which were completely resistant to inactivation by DPP IV or human plasma. (Abu8)GLP-1 and (Val8)GLP-1 exhibited moderate affinities (IC50: 4.76 and 81.1 nM, respectively) for the human GLP-1 receptor compared with native GLP-1 (IC50: 0.37 nM). (Abu8)GLP-1 and (Val8)GLP-1 dose-dependently stimulated cAMP in insulin-secreting BRIN BD11 cells with reduced potency compared with native GLP-1 (1.5- and 3.5-fold, respectively). Consistent with other mechanisms of action, the analogues showed similar, or in the case of (Val8)GLP-1 slightly impaired insulin releasing activity in BRIN BD11 cells. Using adult obese (ob/ob) mice, (Abu8 )GLP-1 had similar glucose-lowering potency to native GLP-1 whereas the action of (Val8)GLP-1 was enhanced by 37%. The in vivo insulin-releasing activities were similar. These data indicate that substitution of Ala8 in GLP-1 with Abu or Val confers resistance to DPP IV inactivation and that (Val8)GLP-1 is a particularly potent N-terminally modified GLP-1 analogue of possible use in type 2 diabetes.

Efficacy and safety of dapagliflozin monotherapy in people with Type 2 diabetes:a randomized double-blind placebo-controlled 102-week trial

Aims: To assess initial pharmacotherapy of Type 2 diabetes with the sodium-glucose cotransporter-2 inhibitor dapagliflozin. Methods: This double-blind, placebo-controlled trial, randomly allocated people with Type 2 diabetes aged 18-77 years and inadequate glycaemic control on diet and exercise [HbA1c 53-86 mmol/mol (7.0-10.0%)] to receive placebo (n = 75) or dapagliflozin monotherapy 2.5 mg (n = 65), 5 mg (n = 64) or 10 mg (n = 70) once daily in the morning. After 24 weeks, low-dose double-blind metformin 500 mg/day was added to the placebo group regimen (placebo+low-dose metformin group). Changes in HbA1c level, fasting plasma glucose and body weight, as well as adverse events, were assessed over 102 weeks. Results: Of the 274 participants randomized, 167 completed the study (60.9%). At 102 weeks, significant differences vs placebo+low-dose metformin with dapagliflozin 5 and 10 mg were observed for HbA1c (-5.8 mmol/mol [-0.53%], P = 0.018; and -4.8 mmol/mol [-0.44%], P = 0.048), respectively); and for FPG (-0.69 mmol/L, P = 0.044; and -1.12 mmol/l, P = 0.001, respectively). For body weight, the difference between the dapagliflozin 10-mg group and the placebo+low-dose metformin group was significant (-2.60 kg; P = 0.016). Hypoglycaemic events were uncommon, with rates of 5.3% for placebo+low-dose metformin group and 0-4.6% for the dapagliflozin groups. Genital infections and urinary tract infections were more common in the dapagliflozin groups than in the placebo+low-dose metformin group. Conclusions: Dapagliflozin as monotherapy in treatment-naïve people with early Type 2 diabetes improved glycaemic control and reduced weight without increasing hypoglycaemia over 102 weeks. Dapagliflozin may provide an alternative initial pharmacotherapy in such people.

The efficacy and safety of imeglimin as add-on therapy in patients with type 2 diabetes inadequately controlled with sitagliptin monotherapy

OBJECTIVE: This 12-week study assessed the efficacy and tolerability of imeglimin as add-on therapy to the dipeptidyl peptidase-4 inhibitor sitagliptin in patients with type 2 diabetes inadequately controlled with sitagliptin monotherapy. RESEARCH DESIGN AND METHODS: In a multicenter, randomized, double-blind, placebo-controlled, parallel-group study, imeglimin (1,500 mg b.i.d.) or placebo was added to sitagliptin (100 mg q.d.) over 12weeks in 170 patientswith type 2 diabetes (mean age 56.8 years; BMI 32.2 kg/m2) that was inadequately controlled with sitagliptin alone (A1C ≥7.5%) during a 12-week run-in period. The primary ef ficacy end point was the change in A1C from baseline versus placebo; secondary end points included corresponding changes in fasting plasma glucose (FPG) levels, strati fication by baseline A1C, and percentage of A1C responders. RESULTS: Imeglimin reduced A1C levels (least-squares mean difference) from baseline (8.5%) by 0.60% compared with an increase of 0.12% with placebo (between-group difference 0.72%, P < 0.001). The corresponding changes in FPG were -0.93 mmol/L with imeglimin vs. -0.11 mmol/L with placebo (P = 0.014). With imeglimin, the A1C level decreased by ≥0.5% in 54.3% of subjects vs. 21.6% with placebo (P < 0.001), and 19.8%of subjects receiving imeglimin achieved a decrease in A1C level of ≤7% compared with subjects receiving placebo (1.1%) (P = 0.004). Imeglimin was generally well tolerated, with a safety pro file comparable to placebo and no related treatment-emergent adverse events. CONCLUSIONS: Imeglimin demonstrated incremental efficacy benefits as add-on therapy to sitagliptin, with comparable tolerability to placebo, highlighting the potential for imeglimin to complement other oral antihyperglycemic therapies. © 2014 by the American Diabetes Association.

Metformin in patients with type 2 diabetes and kidney disease:a systematic review

IMPORTANCE: Metformin is widely viewed as the best initial pharmacological option to lower glucose concentrations in patients with type 2 diabetes mellitus. However, the drug is contraindicated in many individuals with impaired kidney function because of concerns of lactic acidosis. OBJECTIVE: To assess the risk of lactic acidosis associated with metformin use in individuals with impaired kidney function. EVIDENCE ACQUISITION: In July 2014, we searched the MEDLINE and Cochrane databases for English-language articles pertaining tometformin, kidney disease, and lactic acidosis in humans between 1950 and June 2014.We excluded reviews, letters, editorials, case reports, small case series, and manuscripts that did not directly pertain to the topic area or that met other exclusion criteria. Of an original 818 articles, 65 were included in this review, including pharmacokinetic/metabolic studies, large case series, retrospective studies, meta-analyses, and a clinical trial. RESULTS: Although metformin is renally cleared, drug levels generally remain within the therapeutic range and lactate concentrations are not substantially increased when used in patients with mild to moderate chronic kidney disease (estimated glomerular filtration rates, 30-60 mL/min per 1.73m2). The overall incidence of lactic acidosis in metformin users varies across studies from approximately 3 per 100 000 person-years to 10 per 100 000 person-years and is generally indistinguishable from the background rate in the overall population with diabetes. Data suggesting an increased risk of lactic acidosis in metformin-treated patients with chronic kidney disease are limited, and no randomized controlled trials have been conducted to test the safety ofmetformin in patients with significantly impaired kidney function. Population-based studies demonstrate that metformin may be prescribed counter to prevailing guidelines suggesting a renal risk in up to 1 in 4 patients with type 2 diabetes mellitus-use which, in most reports, has not been associated with increased rates of lactic acidosis. Observational studies suggest a potential benefit from metformin on macrovascular outcomes, even in patients with prevalent renal contraindications for its use. CONCLUSIONS AND RELEVANCE: Available evidence supports cautious expansion of metformin use in patients with mild to moderate chronic kidney disease, as defined by estimated glomerular filtration rate, with appropriate dosage reductions and careful follow-up of kidney function.

Factorizations of some Groups of Lie Type of Lie Rank 4

Еленка Генчева, Цанко Генчев В настоящата работа се разглеждат крайни прости групи G , които могат да се представят като произведение на две свои собствени неабелеви прости подгрупи A и B. Всяко такова представяне G = AB е прието да се нарича факторизация на G, а тъй като множителите A и B са избрани да бъдат прости подгрупи на G, то разглежданите факторизации са известни още като прости факторизации на G. Тук се предполага, че G е проста група от лиев тип и лиев ранг 4 над крайно поле GF (q). Ключови думи: крайни прости групи, групи от лиев тип, факторизации на групи.

Self-monitoring of blood glucose in Black Caribbean and South Asian Canadians with non-insulin treated Type 2 diabetes mellitus:a qualitative study of patients' perspectives

Background: To examine the views and current practice of SMBG among Black Caribbean and South Asian individuals with non-insulin treated Type 2 diabetes mellitus. Methods: Twelve participants completed semi-structured interviews that were guided by the Health Belief Model and analyzed using thematic network analysis. Results: The frequency of monitoring among participants varied from several times a day to once per week. Most participants expressed similar experiences regarding their views and practices of SMBG. Minor differences across gender and culture were observed. All participants understood the benefits, but not all viewed SMBG as beneficial to their personal diabetes management. SMBG can facilitate a better understanding and maintenance of self-care behaviours. However, it can trigger both positive and negative emotional responses, such as a sense of disappointment when high readings are not anticipated, resulting in emotional distress. Health care professionals play a key role in the way SMBG is perceived and used by patients. Conclusion: While the majority of participants value SMBG as a self-management tool, barriers exist that impede its practice, particularly its cost. How individuals cope with these barriers is integral to understanding why some patients adopt SMBG more than others. © 2013 Gucciardi et al.; licensee BioMed Central Ltd.

Short-term stability in refractive status despite large fluctuations in glucose levels in diabetes mellitus type 1 and 2

Purpose: This work investigates how short-term changes in blood glucose concentration affect the refractive components of the diabetic eye in patients with long-term Type 1 and Type 2 diabetes. Methods: Blood glucose concentration, refractive error components (mean spherical equivalent MSE, J0, J45), central corneal thickness (CCT), anterior chamber depth (ACD), crystalline lens thickness (LT), axial length (AL) and ocular aberrations were monitored at two-hourly intervals over a 12-hour period in: 20 T1DM patients (mean age ± SD) 38±14 years, baseline HbA1c 8.6±1.9%; 21 T2DM patients (mean age ± SD) 56±11 years, HbA1c 7.5±1.8%; and in 20 control subjects (mean age ± SD) 49±23 years, HbA1c 5.5±0.5%. The refractive and biometric results were compared with the corresponding changes in blood glucose concentration. Results: Blood glucose concentration at different times was found to vary significantly within (p<0.0005) and between groups (p<0.0005). However, the refractive error components and ocular aberrations were not found to alter significantly over the day in either the diabetic patients or the control subjects (p>0.05). Minor changes of marginal statistical or optical significance were observed in some biometric parameters. Similarly there were some marginally significant differences between the baseline biometric parameters of well-controlled and poorly-controlled diabetic subjects. Conclusion: This work suggests that normal, short-term fluctuations (of up to about 6 mM/l on a timescale of a few hours) in the blood glucose levels of diabetics are not usually associated with acute changes in refractive error or ocular wavefront aberrations. It is therefore possible that factors other than refractive error fluctuations are sometimes responsible for the transient visual problems often reported by diabetic patients. © 2012 Huntjens et al.

Sensor and software use for the glycaemic management of insulin-treated type 1 and type 2 diabetes patients

Lowering glucose levels, while avoiding hypoglycaemia, can be challenging in insulin-treated patients with diabetes. We evaluated the role of ambulatory glucose profile in optimising glycaemic control in this population. Insulin-treated patients with type 1 and type 2 diabetes were recruited into a prospective, multicentre, 100-day study and randomised to control (n = 28) or intervention (n = 59) groups. The intervention group used ambulatory glucose profile, generated by continuous glucose monitoring, to assess daily glucose levels, whereas the controls relied on capillary glucose testing. Patients were reviewed at days 30 and 45 by the health care professional to adjust insulin therapy. Comparing first and last 2 weeks of the study, ambulatory glucose profile-monitored type 2 diabetes patients (n = 28) showed increased time in euglycaemia (mean ± standard deviation) by 1.4 ± 3.5 h/day (p = 0.0427) associated with reduction in HbA1c from 77 ± 15 to 67 ± 13 mmol/mol (p = 0.0002) without increased hypoglycaemia. Type 1 diabetes patients (n = 25) showed reduction in hypoglycaemia from 1.4 ± 1.7 to 0.8 ± 0.8 h/day (p = 0.0472) associated with a marginal HbA1c decrease from 75 ± 10 to 72 ± 8 mmol/mol (p = 0.0508). Largely similar findings were observed comparing intervention and control groups at end of study. In conclusion, ambulatory glucose profile helps glycaemic management in insulin-treated diabetes patients by increasing time spent in euglycaemia and decreasing HbA1c in type 2 diabetes patients, while reducing hypoglycaemia in type 1 diabetes patients.

Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is a global epidemic that poses a major challenge to health-care systems. Improving metabolic control to approach normal glycaemia (where practical) greatly benefits long-term prognoses and justifies early, effective, sustained and safety-conscious intervention. Improvements in the understanding of the complex pathogenesis of T2DM have underpinned the development of glucose-lowering therapies with complementary mechanisms of action, which have expanded treatment options and facilitated individualized management strategies. Over the past decade, several new classes of glucose-lowering agents have been licensed, including glucagon-like peptide 1 receptor (GLP-1R) agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium/glucose cotransporter 2 (SGLT2) inhibitors. These agents can be used individually or in combination with well-established treatments such as biguanides, sulfonylureas and thiazolidinediones. Although novel agents have potential advantages including low risk of hypoglycaemia and help with weight control, long-term safety has yet to be established. In this Review, we assess the pharmacokinetics, pharmacodynamics and safety profiles, including cardiovascular safety, of currently available therapies for management of hyperglycaemia in patients with T2DM within the context of disease pathogenesis and natural history. In addition, we briefly describe treatment algorithms for patients with T2DM and lessons from present therapies to inform the development of future therapies.

Risk factors for type 2 diabetes mellitus and cardiovascular diseases in Hispanic adolescents

This cross-sectional study evaluated risk factors (RF) for type 2 diabetes (T2DM) and cardiovascular diseases (CVD) in 100 Hispanic adolescents(50 overweight, 50 non-overweight) aged 12-16 years, and their associations with body mass index (BMI), diet, physical activity (PA), gender, and birth weight (BW). The RF studied were fasting plasma glucose (FPG), insulin sensitivity (IS), total cholesterol (TC), triacylglycerols (TG), low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), acanthosis nigricans (AN), and blood pressure (BP). Dietary intakes were assessed using the Block Kids Questionnaire, fat-related intake behavior (FB) using the Fat-Related Diet Habits Questionnaire, and PA using the Modifiable Activity Questionnaire for Adolescents. Blood was collected after an overnight fast of 12 hours. All statistical analyses used SPSS 14.0. Overweight adolescents had presence of AN, higher BP, TC, TG, and LDL, and lower IS, ps < .001, as compared to non-overweight adolescents. Overweight adolescents were more likely to have 1 and 2 RF for T2DM and CVD as compared to having 0, ps < .001, and 2 RF as compared to having 1, p =.033. Adolescents with kilocalorie (Kcal) intake above requirements for age gender, and PA level were 4.6 times more likely to be overweight, p = .005. Overweight adolescents had worse FB, p = .011, and lower PA, p < .001. Adolescents with worse FB had higher BP, p = .016. Fiber below recommendations (14g/1,000 Kcal) was associated with being overweight, p = .012, and lower IS, p = .040. Adolescents with higher BW had higher FPG, p = .013. Our findings point to an association between being overweight and RF for T2DM and CVD, suggesting that overweight during adolescence may have serious health consequences for Hispanic adolescents. Also, our results indicate that Hispanic overweight adolescents eat more Kcal and less fiber than required, have worst FB, and less PA levels than their non-overweight counterparts. In addition, high BW and dietary habits of Hispanic adolescents, such as low fiber and FB, increase their risk for T2DM and CVD. We conclude that BMI can serve as a useful tool to identify Hispanic adolescents at risk for T2DM and CVD.

The relationship among serum levels of manganese superoxide dismutase and mitochondrial DNA 8-hydroxy-2'- deoxyguanosine, and dietary antioxidants intake in type 2 diabetes

Oxidative stress plays a key role in the development of Type 2 Diabetes (T2D). This cross-sectional study examined the relationship among serum levels of manganese superoxide dismutase (MnSOD), 8-hydroxy-2’-deoxyguanosine (8OHdG), dietary antioxidant intakes and glycemic control in African Americans (n=209) and Haitian Americans (n=234) with and without T2D. ^ African Americans had higher BMI (32.8 vs. 29.3 kg/m2), higher energy intake (2148 vs. 1770 kcal), and were more educated as compared to Haitian Americans; all variables were significant at p < .001. Serum levels of 8OHdG and MnSOD for African Americans (1691.0 ± 225.1 pg/ml, 2538.0 ± 1091.8 pg/ml; respectively) were significantly higher than for Haitian Americans (1626.2 ± 222.9, 2015.8 ± 656.3 pg/ml; respectively). 8OHdG was negatively correlated with MnSOD ( r = -.167, p < .001) in T2D. Having T2D was negatively correlated with MnSOD (r = -.337; p < .01) and positively correlated with 8OHdG (r = .500; p < .01). African Americans and Haitian Americans with T2D had fasting plasma glucose (FPG) levels of 143.0 ± 61.0 mg/dl and 157.6 ± 65.5 mg/dl, and A1C of 7.5 ± 1.8 % and 8.4 ± 2.4 %, respectively. African Americans and Haitian Americans without T2D had FPG levels of 95.8 ± 13.2 mg/dl and 98.7 ± 16.9 mg/dl, and A1C of 5.9 ± 0.4% and 6.0 ± 0.5%, respectively. Dietary intakes of vitamin C and vitamin D were negatively correlated with FPG (r = -.21; r = -.19, p < .05) respectively. Carotenoids negatively correlated with A1C (r = -.19, p < .05). Lower levels of MnSOD were associated with lower levels of zinc, r = .10, p < .05, and higher levels of carotenoids r = -.10, p < .05. Higher levels of 8OHdG were associated with lower levels of Vitamin D, r = -.14, p < .01, and carotenoids, r = -.09, p < .05. ^ The results demonstrate greater oxidative mtDNA damage in persons with T2D compared to those without T2D and in African Americans compared with Haitian Americans. The inverse relationship between dietary intake of antioxidants and oxidative stress implies a potential to reduce oxidative stress with diet. ^

Identification and expression modulation of a C-type lectin domain family 4 homologue that is highly expressed in monocytes/macrophages in rainbow trout (Oncorhynchus mykiss)

Peer reviewed

Identification and expression modulation of a C-type lectin domain family 4 homologue that is highly expressed in monocytes/macrophages in rainbow trout (Oncorhynchus mykiss)

Peer reviewed

Rôle de l'inositol polyphosphate 4-phosphatase de type II (Inpp4b) dans la différenciation et l'activité des ostéoclastes

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.