Glycaemic control and hypoglycaemia risk with insulin glargine 300 U/mL versus glargine 100 U/mL: A patient-level meta-analysis examining older and younger adults with type 2 diabetes.

AIM: Older people with type 2 diabetes (T2DM) are at an increased risk of hypoglycaemia and its consequences. However, efficacy and safety data for basal insulin therapy are limited in these individuals. This patient-level meta-analysis assessed the treatment effects of insulin glargine 300 U/mL (Gla-300) versus glargine 100 U/mL (Gla-100) in people with T2DM ≥ 65 years old. METHODS: Data were pooled for patients randomised to receive Gla-300 or Gla-100 in the Phase 3a, treat-to-target EDITION 1, 2 and 3 trials. Glycaemic efficacy, hypoglycaemia, changes in body weight and insulin dosage and adverse events were examined over 6 months' treatment with Gla-300 versus Gla-100 for participants aged ≥ 65 and < 65 years. RESULTS: Of 2496 participants randomised, 662 were ≥ 65 years (Gla-300, n = 329; Gla-100, n = 333). Glycaemic control was comparable for Gla-300 and Gla-100 in participants ≥ 65 years (LS mean [95% CI] difference in HbA1c change from baseline to month 6: 0.00 [-0.14 to 0.15] %; 0.00 [-1.53 to 1.64] mmol/mol) and < 65 years (0.00 [-0.09 to 0.08] %; 0.00 [-0.98 to 0.87] mmol/mol). Fewer participants receiving Gla-300 versus Gla-100 experienced nocturnal confirmed (≤ 3.9 mmol/L [≤ 70 mg/dL]) or severe hypoglycaemia (relative risk: ≥ 65 years: 0.70 [0.57 to 0.85]; < 65 years: 0.77 [0.68 to 0.87]). Annualised rates of nocturnal confirmed or severe hypoglycaemia were lower with Gla-300 than Gla-100 for both age groups. CONCLUSION: Gla-300 was associated with a reduced risk of nocturnal hypoglycaemia versus Gla-100, accompanied by comparable glycaemic improvement, for people aged ≥ 65 and < 65 years with T2DM.

Efficacy and adherence of glucagon-like peptide-1 receptor agonist treatment in patients with type 2 diabetes mellitus in real-life settings.

Despite the availability of a large number of therapeutic options throughout the world, rates of optimal glycaemic control in adult patients with type 2 diabetes mellitus remain low. Delays in treatment intensification to insulin and low adherence to insulin regimes, which are well-documented contributors to poor glycaemic control, are in many cases driven by fear of hypoglycaemic events, weight gain and injections. Over the last 10 years, injectable glucagon-like peptide-1 receptor agonists (GLP1-RAs) have emerged as alternatives to basal insulin for treatment intensification in patients inadequately controlled with oral antidiabetic drugs. As a class, GLP1-RAs are associated with weight loss and fewer hypoglycaemic events than insulin. In addition, some of them are available in once-a-week formulations and therefore require fewer injections. However, as randomized controlled trials are not representative of everyday practice, physicians should consider the results of real-life studies to guide their treatment decisions. In this review, while significant variations in efficacy, tolerability and adherence data were noted from one study to another, rates of glycaemic control overall were low. Indeed, our present analysis has suggested that regular re-evaluations of treatment, including response, tolerability, adherence, cost and quality of life, are necessary.

After the LEADER trial and SUSTAIN-6, how do we explain the cardiovascular benefits of some GLP-1 receptor agonists?

Recent cardiovascular outcome trials - the LEADER with liragutide and SUSTAIN-6 with semaglutide - have shown significant reductions of major cardiovascular (CV) events with these glucagon-like peptide (GLP)-1 receptor agonists. Progressive separation of the treatment and placebo curves, starting clearly between 12 and 18 months of the trial period, and significant reductions in the risk of myocardial infarction and stroke, indicate that the beneficial CV effects observed with GLP-1 receptor agonists could be due to an antiatherogenic effect. So far, the reasons for such an effect of GLP-1 receptor agonists have not been entirely clear, although several hypotheses may be proposed. As the reductions in glycated haemoglobin and systolic blood pressure (SBP) in these trials were modest, and both trials lasted only a short period of time, reductions in hyperglycaemia and SBP are unlikely to be involved in the beneficial CV effects of GLP-1 receptor agonists. On the other hand, their effect on lipids and, in particular, the dramatic decrease in postprandial hypertriglyceridaemia may explain their beneficial CV actions. Reduction of body weight, including a significant decrease in visceral fat in patients using GLP-1 receptor agonists, may also have beneficial CV effects by reducing chronic proatherogenic inflammation. In addition, there are in-vitro data showing a direct anti-inflammatory effect with these agents that could also be involved in their beneficial CV effects. Moreover, studies in humans have shown significant beneficial effects on ischaemic myocardium after a very short treatment period, suggesting a direct effect of GLP-1 receptor agonists on myocardium, although the precise mechanism remains unclear. Finally, as a reduction in insulin resistance has been associated with a decrease in CV risk, it cannot be ruled out that the lowering of insulin resistance induced by GLP-1 receptor agonists might also be involved in their beneficial CV actions.

Which oral antidiabetic drug to combine with metformin to minimize the risk of hypoglycemia when initiating basal insulin?: A randomized controlled trial of a DPP4 inhibitor versus insulin secretagogues.

We conducted a pilot study to evaluate two therapeutic strategies at the time of insulin initiation in type 2 diabetic patients insufficiently controlled with metformin+insulin-secretagogues (IS, sulfonylureas or glinides). Patients were randomized to remain under the same dual therapy or to receive metformin+DPP4 inhibitors while starting insulin. Similar glycemic control was achieved in both groups. However less hypoglycemia was observed with DPP4 inhibitors despite higher doses of insulin.

Comparison of insulin glargine and liraglutide added to oral agents in patients with poorly controlled type 2 diabetes.

AIM: To compare safety and efficacy of insulin glargine and liraglutide in patients with type 2 diabetes (T2DM). METHODS: This randomized, multinational, open-label trial included subjects treated for T2DM with metformin ± sulphonylurea, who had glycated haemoglobin (HbA1c) levels of 7.5-12%. Subjects were assigned to 24 weeks of insulin glargine, titrated to target fasting plasma glucose of 4.0-5.5 mmol/L or liraglutide, escalated to the highest approved clinical dose of 1.8 mg daily. The trial was powered to detect superiority of glargine over liraglutide in percentage of people reaching HbA1c <7%. RESULTS: The mean [standard deviation (s.d.)] age of the participants was 57 (9) years, the duration of diabetes was 9 (6) years, body mass index was 31.9 (4.2) kg/m(2) and HbA1c level was 9.0 (1.1)%. Equal numbers (n = 489) were allocated to glargine and liraglutide. Similar numbers of subjects in both groups attained an HbA1c level of <7% (48.4 vs. 45.9%); therefore, superiority of glargine over liraglutide was not observed (p = 0.44). Subjects treated with glargine had greater reductions of HbA1c [-1.94% (0.05) and -1.79% (0.05); p = 0.019] and fasting plasma glucose [6.2 (1.6) and 7.9 (2.2) mmol/L; p < 0.001] than those receiving liraglutide. The liraglutide group reported a greater number of gastrointestinal treatment-emergent adverse events (p < 0.001). The mean (s.d.) weight change was +2.0 (4.0) kg for glargine and -3.0 (3.6) kg for liraglutide (p < 0.001). Symptomatic hypoglycaemia was more common with glargine (p < 0.001). A greater number of subjects in the liraglutide arm withdrew as a result of adverse events (p < 0.001). CONCLUSION: Adding either insulin glargine or liraglutide to subjects with poorly controlled T2DM reduces HbA1c substantially, with nearly half of subjects reaching target levels of 7%.

Frequency and predictors of confirmed hypoglycaemia in type 1 and insulin-treated type 2 diabetes mellitus patients in a real-life setting: results from the DIALOG study.

AIM: DIALOG assessed the prevalence and predictors of hypoglycaemia in patients with type 1 (T1DM) or insulin-treated type 2 diabetes mellitus (T2DM) in a real-life setting. METHODS: In this observational study, insulin-treated patients (n=3048) completed prospective daily questionnaires reporting the frequency and consequences of severe/confirmed non-severe hypoglycaemia over 30 days. Patients (n=3743) also retrospectively reported severe hypoglycaemia over the preceding year. RESULTS: In this prospective survey, 85.3% and 43.6% of patients with T1DM and T2DM, respectively, reported experiencing at least one confirmed hypoglycaemic event over 30 days, while 13.4% and 6.4%, respectively, reported at least one severe event. Hypoglycaemia frequency increased with longer duration of diabetes and insulin therapy. Strongly predictive factors for hypoglycaemia were previous hypoglycaemia, >2 injections/day, BMI<30kg/m(2) and duration of insulin therapy>10 years. HbA1c level was not predictive of hypoglycaemia in either T1DM or T2DM. The confirmed hypoglycaemia rate was increased in the lowest compared with the highest tertile of HbA1c in T1DM, but not T2DM. At the time of enrolment, physicians reported severe hypoglycaemia in 23.6% and 11.9% of T1DM and T2DM patients, respectively, during the preceding year; the retrospective survey yielded frequencies of 31.5% and 21.7%, respectively. Also, severe hypoglycaemia led to medical complications in 10.7% and 7.8% of events in T1DM and T2DM patients, respectively, over 30 days. CONCLUSION: Using a unique combined prospective and retrospective approach, the DIALOG study found a relatively high frequency of hypoglycaemia among insulin-treated patients. These findings emphasize the importance of a patient-centred approach for managing diabetes in which hypoglycaemia risk evaluation is critical. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01628341.

Effects of glucose-lowering agents on vascular outcomes in type 2 diabetes: a critical reappraisal.

Type 2 diabetes mellitus (T2DM) is strongly associated with cardiovascular complications, especially coronary artery disease. Numerous epidemiological studies have shown a close relationship between major cardiovascular events and glycaemia, and several pathophysiological mechanisms have been described that explain how hyperglycaemia induces vascular damage. However, randomized controlled trials investigating either an intensive glucose-lowering strategy vs standard care or the addition of a new glucose-lowering agent vs a placebo have largely failed to demonstrate any clinical benefits in terms of cardiovascular morbidity or mortality. This lack of evidence has led some people to contest the clinical efficacy of lowering blood glucose in patients with T2DM, despite its positive effects on microvascular complications. This article analyzes the various reasons that might explain such discrepancies. There are still strong arguments in favour of targeting hyperglycaemia while avoiding other counterproductive effects, such as hypoglycaemia and weight gain, and of integrating the glucose-lowering approach within a global multi-risk strategy to reduce the burden of cardiovascular disease in T2DM.

A direct comparison of long- and short-acting GLP-1 receptor agonists (taspoglutide once weekly and exenatide twice daily) on postprandial metabolism after 24 weeks of treatment.

AIMS: T-emerge 2 was a randomized, open-label, 24-week trial comparing subcutaneous taspoglutide 10 mg weekly (Taspo10), taspoglutide 20 mg weekly (Taspo20; titrated after 4 weeks of Taspo10), with exenatide 10 mcg BID (Exe; after 4 weeks of Exe 5 mcg) in patients inadequately controlled on metformin, a thiazolidinedione, or both. T-emerge 2 showed that once-weekly Taspo provided better glycaemic control than Exe. This report focuses on a subset of T-emerge 2 participants undergoing a standardized liquid meal comparing Taspo to Exe, which has been previously shown to lower postprandial glucose. METHODS: Meal tolerance tests (MTT) were performed at baseline and at week 24 in a subset of Taspo10, Taspo20 and Exe patients (n = 42, 39 and 67, respectively). Blood samples for glucose, insulin, glucagon and C-peptide were obtained before and after (30, 60, 90, 120 and 180 min) ingestion of a standardized liquid meal. RESULTS: The 2-h postprandial, mean 0-3 h and iAUC0-3 h glucose during the MTT was reduced to a similar extent in all groups and the time profile of the postprandial glucose showed a similar pattern. Taspo10 and Taspo20, but not Exe, significantly increased insulin from baseline (both mean and iAUC0-3 h). Although changes from baseline in C-peptide were not significant within any treatment group, the mean change from baseline (both mean 0-3 h and iAUC0-3 h) was significantly increased in Taspo10 vs. Exe. Mean glucagon showed significant decreases in all groups. CONCLUSION: Taspoglutide and Exe improved postprandial glucose tolerance to a similar extent but possibly with different intimate mechanisms.

Efficacy and safety over 26 weeks of an oral treatment strategy including sitagliptin compared with an injectable treatment strategy with liraglutide in patients with type 2 diabetes mellitus inadequately controlled on metformin: a randomised clinical trial.

AIMS/HYPOTHESIS: The aim of this work was to compare treatment intensification strategies based on orally administered vs injectable incretin-based antihyperglycaemic agents in patients with type 2 diabetes mellitus on metformin monotherapy. METHODS: In a 26 week, open-label study, 653 patients (baseline HbA1c = 8.2% [66 mmol/mol]) were randomised at 111 sites in 21 countries in a 1:1 ratio to a strategy using oral agents (starting with sitagliptin 100 mg/day) or a strategy using the injectable drug liraglutide starting at a dose of 0.6 mg/day, up-titrated to 1.2 mg/day after 1 week. The following patients with type 2 diabetes mellitus were recruited for the study: those aged 18-79 years, on a stable dose of metformin monotherapy ≥1,500 mg/day for ≥12 weeks, with an HbA1c ≥7.0% (53 mmol/mol) and ≤11.0% (97 mmol/mol) and a fasting fingerstick glucose (FFG) <15 mmol/l (<270 mg/dl) at the randomisation visit, deemed capable by the investigator of using a Victoza pen injection device (containing 6 mg/ml liraglutide; Novo Nordisk, Bagsværd, Denmark). Women taking part in the study agreed to remain abstinent or use an acceptable method of birth control during the study. Randomisation was performed via a computer-generated allocation schedule using an interactive voice response system. After 12 weeks, patients on sitagliptin with HbA1c ≥ 7.0% (53 mmol/mol) and fasting glucose >6.1 mmol/l had their treatment intensified with glimepiride; patients on liraglutide with HbA1c ≥ 7.0% (53 mmol/mol) had the dose up-titrated to 1.8 mg/day. The primary analysis assessed whether the strategy using oral drugs was non-inferior to that using an injectable drug regarding HbA1c change from baseline at week 26 using a per-protocol (PP) population and a non-inferiority margin of 0.4%. RESULTS: In the PP population (522 patients included: oral strategy, n = 269; injectable strategy, n = 253) antihyperglycaemic therapy was intensified at week 12 in 50.2% and 28.5%, respectively. HbA1c decreased over 26 weeks in both treatment strategy groups, with a larger initial reduction at week 12 in the injectable strategy group. The LS mean change in HbA1c at week 26 was -1.3% (95% CI -1.4, -1.2) in the oral strategy group and -1.4% (95% CI -1.5, -1.3) in the injectable strategy group; the study met the non-inferiority criterion. Both treatment regimens were generally well tolerated; hypoglycaemia was reported more often with the oral strategy, while nausea, vomiting, diarrhoea and abdominal pain were reported more often with the injectable strategy. CONCLUSIONS/INTERPRETATION: An oral, incretin-based treatment strategy with sitagliptin and, if needed, glimepiride may be a good approach in many patients with type 2 diabetes mellitus for managing inadequate glycaemic control on metformin monotherapy, as compared with an injectable treatment strategy with liraglutide. The oral and injectable strategies had similar effects on HbA1c and had good overall tolerability. Trial registration ClinicalTrials.gov NCT01296412 Funding The study was sponsored by Merck Sharp & Dohme Corp., a subsidiary of Merck and Co., Inc., Whitehouse Station, NJ, USA.

Insulin therapy for diabetes mellitus: treatment regimens and associated costs.

AIMS: To describe insulin therapy in patients with diabetes, to determine treatment costs and to compare costs among treatment regimens. METHODS: This observational study was performed by 734 French pharmacists. Adult patients filling an insulin prescription were invited to participate. Participants provided information on their diabetes history and management. Levels of intensification of insulin therapy were determined by the number of injections in type 1 diabetes mellitus (T1DM) patients, and by the different schemes used in type 2 (T2DM) patients, such as basal/intermediate-acting insulin only, and regimens using both basal and rapid-acting insulin. Costs were evaluated according to official medication costs, nurse visits and glucose monitoring kits. RESULTS: A total of 361 patients with T1DM and 1902 with T2DM were enrolled in the survey. Patients with T1DM more frequently took 1-2 injections per day (46.3% of patients) and used single-dose basal insulin together with ≥1 dose of rapid insulin (43.8%). Patients with T2DM used multiple treatment regimens, with 58 different combinations documented. Most took basal/intermediate insulin only (42.5%) or combinations of basal/intermediate and rapid insulins (52.7%). Mean cost of insulin therapy was €27.4/week for T1DM and €45.4/week for T2DM. In T1DM, insulin was the biggest cost component and increased with the number of injections/day. In T2DM, nurse visits were the most important cost contributors irrespective of treatment regimen. Overall, the cost of insulin therapy increased with the complexity of the insulin schemes. CONCLUSION: Considerable heterogeneity is found in insulin treatment regimens used in everyday diabetes care. Payers should consider the full costs associated with the use of insulin rather than the cost of insulin alone. Treatment algorithms to harmonize insulin therapy should help to improve care, while encouraging patients to self-inject insulin should help to reduce costs.

High-density lipoprotein-cholesterol and not HbA1c was directly related to cardiovascular outcome in PROactive.

AIM: In PROactive, pioglitazone reduced the incidence of death, myocardial infarction and stroke, and significantly improved HbA1c, systolic blood pressure (SBP), triglycerides and high-density lipoprotein (HDL)-cholesterol relative to placebo. As these glycaemic and lipid parameters are major cardiovascular (CV) risk factors, we assessed their separate contribution to the reduced incidence of CV outcomes. METHODS: Patients (n = 5238) with type 2 diabetes and macrovascular disease were randomized to 45 mg pioglitazone or placebo. Relationships among treatment, outcome (time to first event of all-cause mortality, myocardial infarction and stroke) and 10 laboratory measurements and vital signs were investigated using log-linear models. Continuous variable measurements (percent changes from baseline to average of all postbaseline values prior to censoring) were made discrete by categorizing into tertiles. Log-linear models were fitted to multiway tables of discrete data and analysis of deviance used to summarize sources of variation in the data. RESULTS: Although pioglitazone treatment was associated with a decrease in HbA1c and an increase in HDL-cholesterol (HDL-C), only the change from baseline HDL-C predicted the outcome (χ(2) = 28.89, p < 0.0001). No other variables, including HbA1c, triglycerides and systolic blood pressure, showed significant direct associations with outcome. When the analysis was extended to include baseline statin use, this was associated with an improved outcome independently of HDL-C changes. CONCLUSIONS: This post hoc analysis suggests that HDL-C, but probably not HbA1c, is a driver of pioglitazone's favourable influence on CV outcome.

Comparative pharmacodynamic and pharmacokinetic characteristics of subcutaneous insulin glulisine and insulin aspart prior to a standard meal in obese subjects with type 2 diabetes.

AIMS: A multinational, randomized, double-blind, two-way crossover trial to compare the pharmacokinetic and pharmacodynamic properties of bolus, subcutaneously administered insulin glulisine (glulisine) and insulin aspart (aspart) in insulin-naÏve, obese subjects with type 2 diabetes. METHODS: Thirty subjects [9/21 females/males; mean ± SD age: 60.7 ± 7.7 years; body mass index (BMI): 33.5 ± 3.3 kg/m(2) ; duration of diabetes: 6.8 ± 4.6 years; HbA1c: 7.1 ± 0.8%] were included in the analysis. They fasted overnight and then received a 0.2 U/kg subcutaneous dose of glulisine or aspart 2 min before starting a standardized test meal, 7 days apart, according to a randomization schedule. Blood samples were taken every 15 min, starting 20 min before the meal and ending 6 h postprandially. RESULTS: The area under the absolute glucose concentration-time curve between 0 and 1 h after insulin injection and maximal glucose concentration was significantly lower with glulisine than with aspart (p = 0.0455 and 0.0337, respectively). However, for the total study period, plasma glucose concentration was similar for glulisine and aspart. Peak insulin concentration was significantly higher for glulisine than for insulin aspart (p < 0.0001). Hypoglycaemic events (≤ 70 mg/dl with or without symptoms) occurred in 13 and 16 subjects treated with glulisine and aspart, respectively, but there were no cases of severe hypoglycaemia requiring intervention. CONCLUSIONS: Glulisine was associated with lower glucose levels during the first hour after a standard meal; the remaining glucose profiles were otherwise equivalent, with higher insulin levels observed throughout the study period.

Pharmacological management of type 2 diabetes: the potential of incretin-based therapies.

Management guidelines recommend metformin as the first-line therapy for most patients with type 2 diabetes uncontrolled by diet and exercise. Efficacy with metformin therapy is usually of limited duration, which necessitates the early introduction of one or two additional oral agents or the initiation of injections, glucagon-like peptide-1 (GLP-1) agonists or insulin. Although safe and effective, metformin monotherapy has been associated with gastrointestinal side effects (≈20% of treated patients in randomized studies) and is contraindicated in patients with renal insufficiency or severe liver disease. Patients treated with a sulphonylurea are at increased risk for hypoglycaemia and moderate weight gain, whereas those receiving a thiazolidinedione are subject to an increased risk of weight gain, oedema, heart failure or fracture. Weight gain and hypoglycaemia are associated with insulin use. Thus, there is an unmet need for a safe and efficacious add-on agent after initial-therapy failure. Evidence suggests that incretin-based agents, such as GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors, can successfully achieve glycaemic targets and potentially provide cardiovascular and ß-cell-function benefits. This review will examine current approaches for treating type 2 diabetes and discuss the place of incretin therapies, mainly GLP-1 agonists, in the type 2 diabetes treatment spectrum.

Is the ADA/EASD algorithm for the management of type 2 diabetes (January 2009) based on evidence or opinion? A critical analysis.

The ADA and the EASD recently published a consensus statement for the medical management of hyperglycaemia in patients with type 2 diabetes. The authors advocate initial treatment with metformin monotherapy and lifestyle modification, followed by addition of basal insulin or a sulfonylurea if glycaemic goals are not met (tier 1 recommendations). All other glucose-lowering therapies are relegated to a secondary (tier 2) status and only recommended for selected clinical settings. In our view, this algorithm does not offer physicians and patients the appropriate selection of options to individualise and optimise care with a view to sustained control of blood glucose and reduction both of diabetes complications and cardiovascular risk. This paper critically assesses the basis of the ADA/EASD algorithm and the resulting tiers of treatment options.

Clinical and metabolic characteristics of patients with latent autoimmune diabetes in adults (LADA): absence of rapid beta-cell loss in patients with tight metabolic control.

AIM AND METHODS: The present study compared the clinical and metabolic characteristics of latent autoimmune diabetes in adults (LADA) with type 2 diabetes, as well as the residual beta-cell function and progression to insulin treatment, over a 2-year follow-up period, of antibody (Ab)-positive and Ab-negative patients who achieved tight glycaemic control (HbA(1c) 7.0+/-0.8% and 6.5+/-0.9%, respectively, at the time of entry into the study). RESULTS: Glutamic acid decarboxylase antibodies (GADA) and/or islet cell antibodies (ICA) were detected in 10% of patients presenting with non-insulin-dependent diabetes. Around half of Ab-positive patients required insulin treatment during the follow-up. Ab-positive patients displayed lower stimulated C-peptide levels both at entry and during the follow-up compared with Ab-negative patients, although no significant decline in C-peptide levels was observed in either subgroup over two years. Nevertheless, Ab-positive patients progressed more frequently to insulin treatment, and stimulated C-peptide tended to decrease in LADA patients who subsequently required insulin, whereas it remained stable in those who were non-insulin-dependent. In those who progressed, the trend towards C-peptide decline persisted even after starting insulin treatment. CONCLUSION: LADA patients demonstrate lower residual beta-cell function than do type 2 diabetes patients. However, those who achieve tight metabolic control do not present with a rapid decline in beta-cell function. Further studies are needed to determine the optimal treatment strategy in such patients.

Long-term glycaemic effects of pioglitazone compared with placebo as add-on treatment to metformin or sulphonylurea monotherapy in PROactive (PROactive 18).

AIMS: To assess the long-term glycaemic effects, concomitant changes in medications and initiation of permanent insulin use (defined as daily insulin use for a period of > or = 90 days or ongoing use at death/final visit) with pioglitazone vs. placebo in diabetic patients receiving metformin or sulphonylurea monotherapy at baseline in the PROspective pioglitAzone Clinical Trial in macroVascular Events (PROactive). METHODS: In PROactive, patients with Type 2 diabetes and macrovascular disease were randomized to pioglitazone (force titrated to 45 mg/day) or placebo, in addition to other existing glucose-lowering therapies. In a post-hoc analysis, we categorized patients not receiving insulin at baseline and treated by oral monotherapy into two main cohorts: add-on to metformin alone (n = 514) and sulphonylurea alone (n = 1001). The follow-up averaged 34.5 months. RESULTS: There were significantly greater reductions in glycated haemoglobin (HbA(1c)) with pioglitazone than with placebo and more pioglitazone-treated patients achieved HbA(1c) targets, irrespective of the baseline oral glucose-lowering regimen and despite a decrease in the use of other glucose-lowering agents. Approximately twice as many in the placebo groups progressed to permanent insulin use than in the pioglitazone groups across the two cohorts: 3.4% for pioglitazone and 6.5% for placebo when added to metformin monotherapy and 6.3% and 14.8%, respectively, when added to sulphonylurea monotherapy. The overall safety of both dual therapies was good. CONCLUSIONS: Intensifying an existing oral monotherapy regimen to a dual oral regimen by adding pioglitazone resulted in sustained improvements in glycaemic control and reduced progression to insulin therapy. The efficacy and safety of adding pioglitazone to either metformin monotherapy or sulphonylurea monotherapy were good.

Long-term glycaemic control with metformin-sulphonylurea-pioglitazone triple therapy in PROactive (PROactive 17).

AIMS: We assessed the long-term glycaemic effects and the safety profile of triple therapy with the addition of pioglitazone vs. placebo in patients with Type 2 diabetes treated with combined metformin-sulphonylurea therapy in the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive). METHODS: In a post-hoc analysis, we identified patients treated with metformin plus sulphonylurea combination therapy and not receiving insulin at baseline (n = 1314). In those patients, we compared the effects of pioglitazone (force-titrated to 45 mg/day, n = 654) vs. placebo (n = 660) on glycated haemoglobin (HbA(1c)) reduction, concomitant changes in medications and initiation of permanent insulin use (defined as daily insulin use for a period of > or = 90 days or ongoing use at death/final visit). RESULTS: Significantly greater reductions in HbA(1c) and greater proportions of patients with HbA(1c) at target were noted with pioglitazone vs, placebo, despite a decrease in the use of other oral glucose-lowering agents. There was an approximate twofold increase in progression to permanent insulin use in the placebo group vs. the pioglitazone group: 31.1 vs. 16.1%, respectively, when added to combination therapy. The overall safety of the metformin-sulphonylurea-pioglitazone triple therapy was good. CONCLUSIONS: Intensifying an existing dual oral therapy regimen to a triple oral regimen by adding pioglitazone to the classical metformin-sulphonylurea combination resulted in sustained improvements in glycaemic control and reduced progression to insulin therapy. The advantages and disadvantages of adding pioglitazone instead of adding basal insulin should be assessed further.