Mechanisms of action of metformin with special reference to cardiovascular protection.

Management guidelines continue to identify metformin as initial pharmacologic antidiabetic therapy of choice for people with type 2 diabetes without contraindications, despite recent randomized trials that have demonstrated significant improvements in cardiovascular outcomes with newer classes of antidiabetic therapies. The purpose of this review is to summarize the current state of knowledge of metformin's therapeutic actions on blood glucose and cardiovascular clinical evidence and to consider the mechanisms that underlie them. The effects of metformin on glycaemia occur mainly in the liver, but metformin-stimulated glucose disposal by the gut has emerged as an increasingly import site of action of metformin. Additionally, metformin induces increased secretion of GLP-1 from intestinal L-cells. Clinical cardiovascular protection with metformin is supported by three randomized outcomes trials (in newly diagnosed and late stage insulin-treated type 2 diabetes patients) and a wealth of observational data. Initial evidence suggests that cotreatment with metformin may enhance the impact of newer incretin-based therapies on cardiovascular outcomes, an important observation as metformin can be combined with any other antidiabetic agent. Multiple potential mechanisms support the concept of cardiovascular protection with metformin beyond those provided by reduced blood glucose, including weight loss, improvements in haemostatic function, reduced inflammation, and oxidative stress, and inhibition of key steps in the process of atherosclerosis. Accordingly, metformin remains well placed to support improvements in cardiovascular outcomes, from diagnosis and throughout the course of type 2 diabetes, even in this new age of improved outcomes in type 2 diabetes.

Prediabetes management in the Middle East, Africa and Russia: Current status and call for action.

Most data on the burden of diabetes and prediabetes are from countries where local infrastructure can support reliable estimates of the burden of non-communicable diseases. Countries in the Middle East and Africa, together with Russia, have a total population of almost 2 billion, but have been relatively overlooked by authors in this field. We reviewed the prevalence and drivers of prediabetes and diabetes across this large region. A large, and variable, burden of dysglycaemia exists, especially in Middle Eastern and North African countries, associated with high levels of obesity and sedentariness, with a generally lower prevalence in most other parts of Africa. The design and size of studies are highly variable, and more research to quantify the scale of the problem is needed. Local barriers to care relating to issues concerned with gender, consanguinity, lack of understanding of diabetes, lack of understanding of obesity as a health issue, and limited resource at a national level for tracking and intervention for diabetes and other non-communicable diseases. Lifestyle interventions with proven local cost-effectiveness, enhanced access to pharmacologic intervention, and societal interventions to promote better diet and more activity will be an important element in strategies to combat these adverse trends.

Type 2 diabetes mellitus management and body mass index: experiences with initiating insulin detemir in the a1chieve study.

INTRODUCTION: This sub-analysis of the A1chieve study aimed to examine the safety and efficacy of insulin detemir (IDet) initiation over 24 weeks in relation to baseline body mass index (BMI) in people with type 2 diabetes mellitus (T2DM). METHODS: A1chieve was a 24-week non-interventional study to assess the safety and efficacy of insulin analogs in routine practice. This sub-analysis included insulin-naïve patients who initiated IDet therapy based on their physicians' decision. Patients were stratified according to baseline BMI (Group I, <25.0 kg/m(2); Group II, 25.0 to <30.0 kg/m(2); Group III, 30.0 to <35.0 kg/m(2); Group IV ≥35.0 kg/m(2)). Safety and efficacy variables were assessed over 24 weeks. RESULTS: Overall, 10,650 insulin-naïve patients were included (3,045 patients in Group I, 4,186 patients in Group II, 2,365 patients in Group III, and 1,054 patients in Group IV). Four serious adverse drug reactions (SADRs) were reported. From baseline to Week 24, there was no statistically significant difference in the proportion of patients reporting overall hypoglycemia in Group I (4.0% vs. 4.4%), while a significant decrease in Group II (4.8% vs. 4.0%, p = 0.0335) and significant increases in Groups III and IV (3.3% vs. 5.4% and 3.4% vs. 7.0%, respectively, p < 0.001) were noted. The mean body weight increased from baseline to Week 24 in Group I (60.7 ± 8.4 vs. 61.8 ± 8.5 kg) and reduced in Groups II, III, and IV (74.5 ± 9.2 vs. 74.2 ± 9.2 kg, 87.4 ± 10.3 vs. 86.0 ± 9.8 kg, and 102.2 ± 14.3 vs. 100.1 ± 14.2 kg, respectively; all p < 0.001). Significant improvements were noted in glycemic parameters, systolic blood pressure, and lipids over 24 weeks, irrespective of baseline BMI status. CONCLUSION: IDet therapy was associated with improved glycemic control and a low number of SADRs. Greater weight loss was observed with higher BMI.

Safety and effectiveness of biphasic insulin aspart 30 in people with type 2 diabetes switching from basal-bolus insulin regimens in the A1chieve study.

AIMS: Biphasic insulin aspart 30 allows fewer daily injections versus basal-bolus insulin regimens, which may improve adherence and treatment outcome. This sub-analysis of the observational A1chieve study assessed clinical safety and effectiveness of biphasic insulin aspart 30 in people with type 2 diabetes previously receiving basal-bolus insulin regimens. METHODS: A1chieve was an international, open-label, 24-week study in people with type 2 diabetes starting/switching to biphasic insulin aspart 30, insulin detemir or insulin aspart. This sub-analysis assessed patients switching from insulin glargine- or neutral protamine Hagedorn insulin-based basal-bolus insulin regimens to biphasic insulin aspart 30. RESULTS: 1024 patients were included. At 24 weeks, glycated haemoglobin and fasting plasma glucose were significantly reduced from baseline in both cohorts (all p<0.001). The proportion reporting any hypoglycaemia, major hypoglycaemia or nocturnal hypoglycaemia was significantly reduced after 24 weeks (all p<0.05). No serious adverse drug reactions were reported. Both cohorts had significantly improved health-related quality of life (HRQoL; p<0.001). CONCLUSIONS: 24 weeks after switching from basal-bolus insulin regimens to biphasic insulin aspart 30, glycaemic control and HRQoL were significantly improved, and hypoglycaemia was significantly reduced. This suggests that people with type 2 diabetes inadequately controlled on basal-bolus insulin regimens can consider biphasic insulin aspart 30.

Insulin detemir in the management of type 2 diabetes in non-Western countries: safety and effectiveness data from the A1chieve observational study.

AIMS: This subgroup analysis of the A1chieve study examined data from 15,545 people who started treatment with insulin detemir ± oral glucose-lowering drugs in routine clinical care. METHODS: A1chieve was a 24-week, international, prospective, non-interventional study of people with type 2 diabetes from non-Western nations starting treatment with basal insulin detemir, bolus insulin aspart or biphasic insulin aspart 30, alone or in combination, to evaluate their safety and effectiveness in routine clinical practice. RESULTS: HbA1c for the global cohort improved after 24 weeks from 9.5 ± 1.6% by -2.0 ± 1.6% [80 ± 17 by -22 ± 17 mmol/mol] (-2.1 ± 1.6% [-23 ± 17 mmol/mol] for insulin-naïve participants; -1.6 ± 1.7% [-17 ± 19 mmol/mol] for prior insulin users). Fasting plasma glucose and postprandial plasma glucose were also significantly reduced (p<0.001), irrespective of prior therapy or geographical region. The incidence of major hypoglycaemia decreased significantly over 24 weeks in both the insulin-naïve and insulin-experienced groups (p<0.0001). Mean body weight decreased overall by -0.4 ± 4.0 kg and blood pressure, lipid profiles, and self-reported quality of life improved over 24 weeks for all people starting treatment with insulin detemir. CONCLUSION: People with type 2 diabetes in poor glycaemic control starting treatment with insulin detemir reported significant improvements in glycaemic control with improved treatment tolerability, irrespective of prior treatment and geographical region, after 24 weeks.

Safety and effectiveness of biphasic insulin aspart 30 in different age-groups: a1chieve sub-analysis.

INTRODUCTION: Effective management of type 2 diabetes requires sustained glycemic control over many years, which can be particularly challenging for elderly people. This sub-analysis of the A1chieve study evaluated the clinical safety and effectiveness of biphasic insulin aspart 30 in 3 age-groups (≤40, >40-65, and >65 years) of previously insulin-experienced and insulin-naïve people with type 2 diabetes. METHODS: A1chieve was an international, multicenter, prospective, open-label, non-interventional, 24-week study in people with type 2 diabetes who had been receiving anti-diabetes medication before starting, or switching to, therapy with biphasic insulin aspart 30, insulin detemir or insulin aspart (alone or in combination) in routine clinical practice. This sub-analysis evaluated clinical safety and effectiveness of biphasic insulin aspart 30 (±oral glucose-lowering drugs) in different age-groups. RESULTS: Data on 40,122 participants were included. In all age-groups, the proportion of participants experiencing any hypoglycemia, major hypoglycemia or nocturnal hypoglycemia was significantly reduced from baseline, except for the following in insulin-naïve patients: a significant increase in any hypoglycemia in patients aged >65 years; no change in any hypoglycemia, major hypoglycemia, and nocturnal hypoglycemia in patients aged >40-65, ≤40, and >65 years, respectively. Significant improvements at 24 weeks vs. baseline were observed in insulin-experienced and insulin-naïve participants for: glycated hemoglobin (change from baseline ranged from -1.8% to -2.4%); fasting plasma glucose (from -3.0 to -4.3 mmol/l); post-breakfast post-prandial plasma glucose (from -4.1 to -6.5 mmol/l); and health-related quality of life (HRQoL). Sixteen serious adverse drug reactions were reported. CONCLUSION: After 24-week treatment with biphasic insulin aspart 30, all age-groups of insulin-experienced and insulin-naïve patients experienced significantly improved glycemic control and HRQoL; incidence of hypoglycemia was generally reduced. The tolerability and effectiveness of biphasic insulin aspart 30 may benefit all age-groups.

Comparison of National/Regional Diabetes Guidelines for the Management of Blood Glucose Control in non-Western Countries.

INTRODUCTION: Development of higher standards for diabetes care is a core element of coping with the global diabetes epidemic. Diabetes guidelines are part of the approach to raising standards. The epidemic is greatest in countries with recent rises in income from a low base. The objective of the current study was to investigate the availability and nature of locally produced diabetes guidelines in such countries. METHODS: Searches were conducted using Medline, Google, and health ministry and diabetes association websites. RESULTS: Guidelines were identified in 33 of 75 countries outside North America, western Europe, and Australasia. In 25 of these 33 countries, management strategies for type 1 diabetes were included. National guidelines relied heavily on pre-existing national and international guidelines, with reference to American Diabetes Association standards of medical care and/or other consensus statements by 55%, International Diabetes Federation by 36%, European Association for the Study of Diabetes by 12%, and American Association of Clinical Endocrinologists by 9%. The identified guidelines were generally evidence-based, though there was some use of secondary evidence reviews, including other guidelines, rather than original literature reviews and evidence synthesis. In type 1 diabetes guidelines, the option of different insulin regimens (mostly meal-time + basal or premix regimens) was recommended depending on patient need. Type 2 diabetes guidelines either recommended a glycosylated hemoglobin target of <7.0% (<53 mmol/mol) (70% of guidelines) or <6.5% (<47 mmol/mol) (30% of guidelines) as the ideal glycemic target. Most guidelines recommended a target fasting plasma glucose that fell within the range of 3.8-7.2 mmol/L. Most guidelines also set a 2-h post-prandial glucose target value within the range of 4.0-8.3 mmol/L. CONCLUSION: While only a first step in achieving a high quality of disease management, national guidelines of quality and with fair consistency of recommendations are becoming prevalent globally. A further challenge is implementation of guidelines, by integration into local care processes.

Improvements in quality of life associated with insulin analogue therapies in people with type 2 diabetes: results from the A1chieve observational study.

AIMS: To determine the effects on quality of life after starting insulin with, or switching to, insulin analogue therapies in the 24-week, prospective, non-interventional, observational A(1)chieve study conducted across four continents in people with type 2 diabetes. METHODS: Health-related quality of life (HRQoL) was assessed at baseline and at 24 weeks by the validated EQ-5D questionnaire (visual analogue score [VAS] and five dimensions) in 66,726 people who had started using basal insulin detemir, mealtime insulin aspart (with or without a basal insulin) or biphasic insulin aspart 30. RESULTS: For the overall cohort, reported HRQoL increased significantly by 13.8 points from 63.4 points at baseline to 77.2 points at 24 weeks (p<0.001) (scale 1-100, 100=best health imaginable). Beginning or changing insulin was associated with a significant increase in HRQoL score (+15.0 points and +11.1 points, respectively), resulting in a similar score at 24 weeks in the two populations (77.8 and 75.9 points). Reported HRQoL also increased statistically significantly in people administering any insulin analogue regimen and across all regions, although there were some marked regional differences in reported HRQoL at baseline. CONCLUSION: Compared with baseline scores, beginning insulin with, or switching to, insulin analogue therapies are associated with increased HRQoL.

Observational studies: going beyond the boundaries of randomized controlled trials.

The term observational study describes a wide range of study designs including prospective and retrospective cohort studies, case-control studies, and cross-sectional studies, a defining feature of which is that any intervention studied is determined by clinical practice and not the protocol. Data from large, prospective observational studies provide information about the safety and efficacy of medicines in daily clinical use. Such observational studies are generally carried out once a medicine has received approval from regulatory agencies. Observational trials have inherent limitations in terms of their susceptibility to bias and confounding, restricting their ability to define causality. However, their strengths include that they reflect daily clinical practice more closely than randomized controlled trials (RCTs), both in terms of the heterogeneous patient populations that are included, and the medical interventions that they receive. Therefore, observational trials can provide clinically relevant information that is not necessarily provided by RCTs. Given the limitations of an observational study approach, it is important to optimize their study design to maximize their validity, and thus, in particular, known causes of bias and confounding should be measured. Medical investigators, health authorities, and the pharmaceutical industry all have important roles to play in designing, approving, and performing observational studies.