Effect of once-daily insulin detemir on oral antidiabetic drug (OAD) use in patients with type 2 diabetes.

WHAT IS KNOWN AND OBJECTIVE: There are acknowledged benefits to continuing metformin when initiating insulin, but there appears to be growing concern over the role of sulphonylureas and thiazolidinediones when used in combination with insulin. This analysis investigates the effects of continuing or discontinuing oral antidiabetic drugs (OADs) following the initiation of once-daily insulin detemir. METHODS: SOLVE is a 24-week, multinational observational study of insulin detemir initiation in patients with type 2 diabetes mellitus treated with one or more OADs. RESULTS: In the total cohort (n = 17 374), there were significant improvements in HbA1c (-1·3%, 95% CI -1·34; -1·27%) and weight (-0·6 kg, 95% CI -0·65; -0·47 kg), with an increase in the incidence rate of minor hypoglycaemia (+0·256 events ppy, P < 0·001), but not severe hypoglycaemia (-0·038 events ppy, P < 0·001). Study participants had information on OAD use either prior to (n = 17 086) or during insulin initiation (n = 16 346). HbA1c reductions were significantly greater in patients continuing treatment with metformin (-1·3% vs. -1·1%, P < 0·01), thiazolidinediones (-1·3% vs. -1·0%, P < 0·01) and DPP-IV inhibitors (-1·3% vs. -0·9%, P < 0·001). Final insulin doses were significantly greater in patients discontinuing treatment with sulphonylureas (0·29 vs. 0·26 IU/kg, P < 0·001), glinides (0·28 vs. 0·26 IU/kg, P < 0·01), thiazolidinediones (0·31 vs. 0·26 IU/kg, P < 0·001) and DPP-IV inhibitors (0·35 vs. 0·29 IU/kg, P < 0·001) compared with patients continuing these respective agents. All patient subgroups had a mean weight loss irrespective of OAD continuation, apart from those continuing thiazolidinediones (+0·2 kg). The largest improvements in weight were seen following the withdrawal of sulphonylureas and thiazolidinediones (-1·1 and -1·1 kg, respectively). WHAT IS NEW AND CONCLUSION: Discontinuation (or switching) of OADs at the time of insulin initiation appears to be governed principally by concerns about hypoglycaemia and weight. HbA1c improvements were smaller in patients discontinuing OADs at the time of insulin initiation and may be associated with insufficient insulin titration.

Incretin-based therapy in combination with basal insulin: a promising tactic for the treatment of type 2 diabetes.

Incretin therapies such as dipeptidyl peptidase-4 inhibitors (DPP-4Is) and GLP-1 receptor agonists (GLP-1RAs) have become well-established treatments for type 2 diabetes. Both drug classes reduce blood glucose through physiological pathways mediated by the GLP-1 receptor, resulting in glucose-dependent enhancement of residual insulin secretion and inhibition of glucagon secretion. In addition, the GLP-1RAs reduce gastrointestinal motility and appear to have appetite-suppressing actions and, so, are often able to produce clinically useful weight loss. The glucose-dependency of their glucagon-inhibiting and insulin-enhancing effects, together with their weight-sparing properties, make the incretin therapies a logical proposition for use in combination with exogenous basal insulin therapy. This combination offers the prospect of an additive or synergistic glucose-lowering effect without a greatly elevated risk of hypoglycaemia compared with insulin monotherapy, and any insulin-associated weight gain might also be mitigated. Furthermore, the incretin therapies can be combined with metformin, which is usually continued when basal insulin is introduced in type 2 diabetes. Although the combination of incretin and insulin therapy is currently not addressed in internationally recognized treatment guidelines, several clinical studies have assessed its use. The data, summarized in this review, are encouraging and show that glycaemic control is improved and weight gain is limited or reversed (especially with the combined use of GLP-1RAs and basal insulin), and that the use of an incretin therapy can also greatly reduce insulin dose requirements. The addition of basal insulin to established incretin therapy is straightforward, but insulin dose adjustment (though not discontinuation) is usually necessary if the sequence is reversed.

The safety and efficacy of adding once-daily insulin detemir to oral hypoglycaemic agents in patients with type 2 diabetes in a clinical practice setting in 10 countries.

AIMS: Evaluate the safety and efficacy of once-daily insulin detemir initiated in routine clinical practice in patients with type 2 diabetes mellitus inadequately controlled with oral hypoglycaemic agents (OHAs). METHODS: This large observational study was conducted in 10 countries. Adverse event data (including hypoglycaemia) and glycaemic control were recorded before and 24 weeks following insulin initiation while patients continued routine clinical management. RESULTS: In this study, 17 374 patients (53% male) were included. Mean pre-insulin values (±s.d.) were: age 62 ± 12 years; body mass index (BMI) 29.3 ± 5.4 kg/m(2); diabetes duration 10 ± 7 years; haemoglobin A1c (HbA1c) 8.9 ± 1.6%. During the study, 27 patients experienced serious adverse drug reaction, severe hypoglycaemic events or both; and there were 31 episodes of severe hypoglycaemia in 21 patients. After 24 weeks, HbA1c was 7.5 ± 1.2% (change of -1.3%; p < 0.001) and mean weight change was -0.6 kg (confidence interval -0.7, -0.5 kg, p < 0.001). Daily insulin dose increased from 13 ± 6 U (0.16 ± 0.09 U/kg) to 22 ± 16 U (0.27 ± 0.17U/kg) by 24 weeks. Multivariate regression analysis identified several independent demographic and treatment predictors of end of study HbA1c. CONCLUSIONS: Addition of once-daily insulin detemir to patients with type 2 diabetes mellitus on OHA therapy resulted in few adverse events, significant improvements in glycaemic control, small reductions in weight and low rates of hypoglycaemia. On the basis of this study, concerns about hypoglycaemia or weight gain should not preclude initiation of basal insulin analogues in patients with poor glycaemic control on OHAs.

Study of Once Daily Levemir (SOLVE™): insights into the timing of insulin initiation in people with poorly controlled type 2 diabetes in routine clinical practice.

AIMS: The aim of this analysis is to determine the timing of insulin initiation in routine clinical practice, especially in relation to glycaemic control and use of oral antidiabetic drugs (OADs). METHODS: Study of Once Daily Levemir was a 24-week international observational study involving 10 countries which evaluated the safety and effectiveness of initiating once-daily insulin detemir in people with type 2 diabetes mellitus (T2DM) being treated with one or more OADs (clinical trial number NCT00825643 and NCT00740519). RESULTS: A total of 17 374 participants were enrolled in the study: aged 62 ± 12 years, 53% male, T2DM duration 10 ± 7 years, body mass index 29.3 ± 5.4 kg/m(2) . Pre-insulin HbA1c was 8.9 ± 1.6%. The proportion of patients with HbA1c ≥9.0% ranged from 64% (UK) to 23% (Poland). Pre-insulin OAD treatment included metformin (81%), sulphonylureas (59%), glinides (16%), thiazolidinediones (TZD) (12%), α-glucosidase inhibitors (12%) and dipeptidyl peptidase (DPP)-IV inhibitors (7%). The mean starting dose of insulin detemir for the total cohort was 0.16 ± 0.09 U/kg. Differences in OAD use and insulin doses at initiation were evident among participating countries. The largest proportional changes in OAD prescribing at insulin initiation were seen with glinides (+15%), sulphonylureas (-19%), TZD (-31%) and DPP-IV inhibitors (-28%). CONCLUSIONS: Despite well-documented benefits of timely glycaemic control and consensus guidelines encouraging earlier use of insulin, considerable clinical inertia exists with respect to initiating appropriate insulin therapy in people with T2DM. Considerable regional differences exist in the timing of insulin initiation and in the use of OADs.

Weight beneficial treatments for type 2 diabetes.

CONTEXT: The close link between type 2 diabetes and excess body weight highlights the need to consider the weight effects of different treatment regimens. We examine the impact of "weight-friendly" type 2 diabetes pharmacotherapies and suggest treatment strategies that mitigate weight gain. EVIDENCE ACQUISITION: Evidence was identified via PubMed search by class and agent and in bibliographies of review articles, with final articles for inclusion selected by author consensus. EVIDENCE SYNTHESIS: Substantial evidence confirms the weight benefits of metformin and shows that, of the newer available agents, glucagon-like peptide-1 (GLP-1) agonists and amylin analogs promote weight loss. Dipeptidyl peptidase-4 (DPP-4) inhibitors and bile acid sequestrants are weight-neutral. Liraglutide and exenatide appear to have similar effects on weight; however, recent research suggests a potentially greater effect of liraglutide on glycemic control compared to exenatide, when used as a second-line therapy. Mounting evidence suggests that insulin detemir may provide the most favorable weight benefits of available insulins. CONCLUSIONS: Weight-beneficial agents should be considered in patients, particularly obese patients, who fail to reach glycemic targets on metformin therapy. We propose the following treatment choices based on potential weight benefit and blood glucose increment: long-acting GLP-1 agonists (liraglutide), DPP-4 inhibitors, bile acid sequestrants, amylin analogs, and basal insulin for patients with elevated fasting plasma glucose; and short-acting (exenatide) or long-acting GLP-1 agonists, amylin analogs, DPP-4 inhibitors, acarbose, and bile acid sequestrants for patients with elevated postprandial glucose. The weight-sparing effects of insulin detemir, notably in patients with high body mass index, should also be considered when initiating insulin therapy.

Practical guidance on intensification of insulin therapy with BIAsp 30: a consensus statement.

BACKGROUND: Basal insulin and premix insulin are commonly prescribed first-line insulin therapies for patients failing to maintain glycaemic control on oral therapy. When control on these insulins starts to drift, premix analogues, such as biphasic insulin aspart 30/70 (BIAsp 30), are a simple and effective tool for intensification as they can be injected up to three-times daily (TID). However, at present, international recommendations for intensification of insulin therapy using premix analogues are limited and specific guidance on dosing is not available for many scenarios. METHODS: In October 2008, an international expert panel met to review the current guidelines for insulin intensification with BIAsp 30 in patients with type 2 diabetes, with the aim of developing practical guidance for general and specialist practitioners. RESULTS: Simple treatment algorithms have been developed for (i) patients on basal insulin (human or analogue) once daily or twice daily (BID) who need intensification to BIAsp 30 BID, and (ii) patients on BIAsp 30 once daily or BID who can be intensified to BIAsp 30 BID or TID. As well as these algorithms, specific guidance has been provided on dose transfer (from basal insulin to BIAsp 30), dose split (when intensifying from once daily to BID), and combination oral therapies. In addition, a guide to dose titration is included. CONCLUSIONS: The guidelines presented here should enable general or specialist practitioners to use BIAsp 30 to intensify the insulin therapy of patients failing on basal insulin or BIAsp 30 once or twice daily.

Sub-optimal drug treatment of diabetes and cardiovascular risk in diabetic patients in Turkey. A countrywide survey.

OBJECTIVES: The present study is a snapshot of how diabetic patients are treated for diabetes and coexisting cardiovascular risk factors in Turkey. We also addressed the question of what percentage of these patients are treated appropriately according to the current guidelines. Next step will be to determine which pharmacological treatment strategies affect mortality and morbidity in these patients and whether there are regional differences in these outcomes. METHODS: To get a representative picture, Turkey was splitted into four parts with different ethnic and socioeconomic features then centers were randomized within each of these parts. Number of the centers in a region were calculated according to the population of that region. 305 physicians in 11 cities participated in data collection during a period of 3 months. Consecutive 2226 diabetic patients patients who were above 55 years of age were included. Detailed information was obtained about the demographic features and the cardiovascular risk factor and diabetes status of the patients together with relevant drug treatment. Laboratory analyses were done locally and recorded if performed during the last 3 months. RESULTS: Most patients were treated with oral antidiabetic monotherapy regardless of diabetes duration, metabolic control and complication and cardiovascular risk factor status. There was a trend among physicians except for endocrinologists to underprescribe insulin. Monotherapy also was the main mode of treatment for hypertension. Angiotensin converting enzyme inhibitors were generally not used as first line treatment contrary to the recommendations and angiotensin converting enzyme inhibitors and angiotensin receptor blockers are not prescribed for renoprotection in microalbuminuric patients. Statins, fibrates, metformin and aspirin were largely underused. CONCLUSION: The present study indicates that diabetic patients are undertreated in Turkey. Therefore every effort should be spent to implement current guidelines in diabetic patients in order to prevent macro and microvascular complications of diabetes.

Increased intestinal permeability as a cause of fluctuating postprandial blood glucose levels in Type 1 diabetic patients.

BACKGROUND: In diabetic patients, postprandial glucose levels, which have a major impact on metabolic control, are determined by the rate of nutrient delivery into the intestine, absorption of nutrients from the small intestine, and the metabolism of the absorbed nutrients by the liver. The present study addresses whether Type 1 diabetic patients have increased intestinal permeability and intestinal permeability predicts postprandial glucose variability. MATERIAL AND METHODS: Thirty Type 1 diabetic patients together with 15 sex- and age-matched healthy controls were enrolled in the study. After an overnight fasting all patients and controls received 100 micro Ci 51Cr of EDTA as a radioactive tracer and the percentage of the isotope excreted in a 24-h urinary specimen was the permeability measure. Instant blood glucose was measured just before the test, and the patients performed and recorded self-monitoring of fasting and 2nd-hour postprandial blood glucose levels during the following week. RESULTS: We found that intestinal permeability is increased in Type 1 diabetic patients compared with age- and sex-matched healthy controls. Increased intestinal permeability is related at least in part to the instant blood glucose level and the presence of diabetic autonomic neuropathy. CONCLUSION: Increased intestinal permeability leads to higher variation in postprandial blood glucose levels, thereby worsening metabolic control.

Higher blood pressure in normoalbuminuric type 1 diabetic patients with a familial history of type 2 diabetes.

BACKGROUND: To address whether type 1 diabetic patients with type 2 diabetic first degree relatives are different from others in terms of cardiovascular risk factors, insulin resistance and daily insulin dosage. METHODS: We studied 18 type 1 diabetic patients with type 2 diabetic first degree relatives and 36 type 1 diabetic patients without such relatives. Patients with diabetic complications (including microalbuminuria) were excluded. The groups were similar in terms of baseline characteristics. We measured systolic and diastolic blood pressures, body mass index, waist circumference, total cholesterol, triglycerides, LDL, VLDL, HDL, daily insulin dosage and insulin sensitivity. Insulin sensitivity was tested using insulin tolerance test. RESULTS: Type 1 diabetic patients having first degree relatives with type 2 diabetes had significantly higher systolic and diastolic blood pressures (although within the normal range) than others (p < 0.001). They were more insulin resistant according to insulin tolerance test and were using higher daily insulin dosages. In this group, waist circumference, triglyceride and VLDL levels also tended to be higher, but differences were not significant statistically. Total cholesterol, LDL and HDL levels were similar in both groups. CONCLUSION: Family history of type 2 diabetes increases blood pressure and decreases insulin sensitivity in type 1 diabetic patients. Thus such patients should be treated more aggressively in terms of both cardiovascular risk factors and glucose control.

The role of coping with disease in adherence to treatment regimen and disease control in type 1 and insulin treated type 2 diabetes mellitus.

BACKGROUND: Coping is defined as the behavioral and cognitive efforts used in an attempt to deal with stressful events. The objective of this study was to explore the relationship between coping with diabetes and the following outcome variables in type 1 and insulin treated type 2 diabetes mellitus: glycemic control, microangiopathic complications, adherence to self monitoring of blood glucose, adherence to insulin injections, and adherence to diet. METHODS: Subjects were 196 insulin treated adult diabetes patients visiting an outpatient clinic at a government university hospital in Istanbul, Turkey. Coping with disease was measured with the Turkish version of the Diabetes Coping Measure and adherence to treatment regimen was measured with a questionnaire adapted from the subscales of the Summary of Diabetes Self-Care Activities Questionnaire. Data on patients' HbA(1c) levels and severity of microangiopathic complications were obtained from their medical records. RESULTS: Partial correlations controlling for background variables suggested that coping was a good predictor of outcome for both type 1 and insulin treated type 2 diabetes mellitus. These associations were more pronounced for type 1 patients when compared to type 2 patients. Regressing the outcome variables on the two second-order coping factors (obtained by a factor analysis) also supported the hypothesis that coping is an important construct in explaining the outcome variables. Finally, the effect of coping on HbA(1c) was only partially mediated by adherence. CONCLUSION: Coping with diabetes-related issues is an important factor in both types of diabetes, with type 1 patients showing slightly stronger associations. Therefore, training and education programs for diabetic adults might benefit from including a component that is aimed at improving coping with issues specific to diabetes.

Does instantaneous blood glucose affect vibration perception threshold measurement using biothesiometer?

Diabetic neuropathy is a common and troublesome complication of diabetes mellitus. Vibration sensation is a measure of large fiber nerve conduction, which is very commonly affected in diabetes. The present study addresses the question of whether vibration perception threshold (VPT) measurement using a biothesiometer is reproducible under different levels of blood glucose at different hours of the day. Seventy-five diabetic patients, 31 insulin-dependent diabetes mellitus and 44 non-insulin-dependent diabetes mellitus, with mean age 50.33+/-14.22 years (21-70 years) and diabetes duration of 14.3+/-10.6 years (1-60 years) were included in the study. Forty-one patients were male and 34 were female. In conclusion, VPT was found to be reproducible under different blood glucose levels at different hours of the day, which is affected only by the height of the patient.

Lipid metabolism alterations in patients with gestational diabetes mellitus associated fetal macrosomia.

Fetal macrosomia is commonly associated with gestational diabetes mellitus (GDM) which may lead to various complications. It has been suggested that some other metabolites apart from maternal hyperglycemia are responsible for the genesis of macrosomia. Lipid metabolism changes in GDM patients having macrosomic fetuses were studied. A lipid tolerance test (10% Lipovenous solution) was performed in 14 GDM. Pre- and post-infusion plasma lipid levels and their elimination rates were measured and compared to the ones of 8 non diabetic control pregnant women. HbA1c, basal glucose and triglyceride levels were found to be higher in GDM group and significantly higher levels of triglycerides persisted throughout the infusion. FFA, glycerol and phospholipid levels increased following infusion in both groups without significant differences. Glucose, C-peptide and insulin levels remained unchanged after the infusion. Increased basal triglycerides with slowed triglyceride metabolism may be responsible for the fetal macrosomia in mild GDM patients whose fasting blood glucose are below 105 mg/dl. A better metabolic control that provides plasma lipid regulation as well as glucose control may forestall the occurrence of fetal macrosomia.

Safety and efficacy of [Lys(B28), Pro(B29)]-human insulin in patients with diabetes mellitus.

The primary objectives of this study were to assess the efficacy and safety of Lys(B28), Pro(B29) in the treatment of patients with diabetes mellitus and to compare Lys(B28), Pro(B29) to currently available regular insulin with respect to quality of life. This study was designed as an open-label, non-comparative one. The number of patients enrolled in the trial was 39. At Visit 1 (week 0), blood samples for fasting, 1- and 2-hour postprandial blood glucose, and HbA1c were taken. At Visit 2 (week 6) and Visit 3 (week 12), fasting, 1- and 2-hour postprandial blood glucose, and HbA1c levels were measured again. There was no significant change in HbA1c, fasting blood glucose and 1- and 2-hour postprandial blood glucose levels. The 1- and 2-hour postprandial blood glucose excursions decreased significantly from Visit 1 to Visit 3. There were no serious adverse events during the study. Half of the patients had less hypoglycemia with LysPro insulin, while 25% had an increase in episodes. Thirty percent of patients were more satisfied with LysPro insulin than with the short-acting insulin that they had previously used. In conclusion, LysPro therapy can be regarded as safe, since there were no unexpected adverse events and no changes in the usual physical parameters.