Achieving glycemic goal with initial versus sequential combination therapy using metformin and pioglitazone in type 2 diabetes mellitus

Abstract

Objective:

To compare glycemic goal achievement (HbA_1c?<?7%) in type 2 diabetes patients receiving initial metformin plus pioglitazone combination therapy and initial metformin monotherapy augmented with pioglitazone in a cohort follow-up study.     

Glycemic control and treatment failure with pioglitazone versus glibenclamide in type 2 diabetes mellitus: a 42-month,open-label,observational, primary care study

ABSTRACT

Background: Insulin resistance and declining β-cell function are the core defects in type2 diabetes mellitus. It has been suggestedthat deteriorating glycemic control is relatedto baseline hemoglobin A_1c (HbA_1c) values andremaining β-cell function.

Patients and methods: We report glycemic data from a 3.5‐year, open-label, observational, primary care study comparing 30?mg/day pioglitazone with 3.5?mg/day glibenclamide add-on to stable metformin monotherapy in 500 patients with type 2 diabetes. Insulin commencement was considered for patients with HbA_1c ≥ 8.0% or when vascular complications occurred. The change in HbA_1c compared with baseline and the difference in time to failure to maintain glycemic control were calculated.

Results: At endpoint, HbA_1c had decreased by 1.0% in the pioglitazone group (?p < 0.005) and by 0.6% in the glibenclamide group (?p < 0.05). Annual progression rates to insulin treatment were 6.6% (pioglitazone) and 16.4% (glibenclamide; p < 0.001 between-group difference). Mean weight increases of 3.5 ± 0.42?kg in the pioglitazone group and 3.3 ± 0.38?kg in the glibenclamide group were noted. Overall, both treatments were well tolerated.

Conclusions: Pioglitazone add-on to metformin revealed significant benefits in long-term glycemic control compared with glibenclamide. This difference may be explained by a large between-group difference in HOMA-S, which was shown to correlate significantly to the change in HbA_1c. This suggests that a strategy to reduce insulin resistance to lower the burden of the β‐cell is superior to treatment with glibenclamide.     

Effects of early use of pioglitazone in combination with metformin in patients with newly diagnosed type 2 diabetes

ABSTRACT

Background: Type 2 diabetes is characterised by a progressive decline in HbA_1c control over time. Early combination therapy, rather than sequential introduction of individual oral glucose-lowering agents, has been proposed to prevent this gradual rise in HbA_1c. This observational study assessed the effect of early dual combination oral glucose-lowering therapies within 6 months of diagnosis in newly diagnosed, drug-naïve patients with type 2 diabetes.

Patients and methods: This was an observational, open-label, non-randomised study in newly diagnosed patients with type 2 diabetes, aged 35–70 years, with HbA_1c levels >?8.0% at diagnosis or >?7.0% at the 3–6-month follow-up. Patients were allocated to dietary management alone if the HbA_1c level was 7.0–8.0% at diagnosis. Metformin combined with gliclazide, repaglinide, or pioglitazone was given at diagnosis if the HbA_1c was >?8.0%. Similar treatments were introduced at 3–6 months if the HbA_1c was >?7.0%. Over a 3-year period, HbA_1c was measured at 3-monthly intervals. All patients underwent regular dietetic review. Target HbA_1c was ≤?7.0%.

Results: 416 patients were considered eligible for inclusion, with a mean (±?SD) age of 54.1 ± 9.2 years, BMI of 33.5 ± 6.1?kg/m², and baseline HbA_1c of 8.6 ± 1.7%. A mixed model analysis of variance on the 178 patients who started with combination therapy, either immediately or after a 3–6 month period on diet, showed that metformin plus gliclazide, repaglinide, or pioglitazone was associated with a gradual increase in HbA_1c values. Amongst those patients treated with the metformin/pio­glitazone combination there was an estimated 0.1% increase in HbA_1c/year. This was much less pronounced than the rises seen in HbA_1c/year of 0.5% with the met­formin/gliclazide and metformin/repaglinide combinations.

Conclusions: This preliminary analysis of an obervational, non-randomised, open-label ongoing study has shown that early use of combination therapy at time of diagnosis or within the first 3–6 months following diagnosis with metformin plus pioglitazone in newly diagnosed type 2 diabetes results in a slower deterioration in glycaemic control than that with metformin combined with either gliclazide or repaglinide. This may be due to the β?cell protective properties of pioglitazone. These results need to be confirmed by further studies with a more robust design and methodology.     

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin added to pioglitazone in patients with type 2 diabetes: a randomized,double-blind,placebo-controlled study

ABSTRACT

Objectives: To evaluate the efficacy and safety of alogliptin in patients with type 2 diabetes inadequately controlled by therapy with a thiazolidinedione (TZD).

Research design and methods: In a multicenter, double-blind, placebo-controlled clinical study, 493 patients 18–80 years old with inadequate glycemic control after stabilization (i.e., glycosylated hemoglobin [HbA_1c] 7.0–10.0%) despite ongoing treatment with a TZD were randomly assigned (2:2:1) to treatment with pioglitazone plus alogliptin 12.5?mg, alogliptin 25?mg or placebo once daily. Concomitant therapy with metformin or sulfonylurea at prestudy doses was permitted.

Main outcome measures: The primary efficacy endpoint was change in HbA_1c from baseline to Week 26. Secondary endpoints included changes in fasting plasma glucose (FPG) and body weight, and incidences of marked hyperglycemia (FPG?≥?200?mg/dL [11.10?mmol/L]) and rescue for hyperglycemia.

Results: Least squares (LS) mean change in HbA_1c was significantly (p?<?0.001) greater for alogliptin 12.5?mg (?0.66%) or 25?mg (?0.80%) than for placebo (?0.19%). A significantly (p?≤?0.016) larger proportion of patients achieved HbA_1c?≤?7% with alogliptin 12.5?mg (44.2%) or 25?mg (49.2%) than with placebo (34.0%). LS mean decreases in FPG were significantly (p?=?0.003) greater with alogliptin 12.5?mg (?19.7?mg/dL [?1.09?mmol/L]) or 25?mg (?19.9?mg/dL [?1.10?mmol/L]) than with placebo (?5.7?mg/dL [?0.32?mmol/L]). The percentage of patients with marked hyperglycemia was significantly (p?<?0.001) lower for alogliptin (≤25.0%) than placebo (44.3%). The incidences of overall adverse events and hypoglycemia were similar across treatment groups, but cardiac events occurred more often with active treatment than placebo.

Conclusions: Addition of alogliptin to pioglitazone therapy significantly improved glycemic control in patients with type 2 diabetes and was generally well tolerated. The study did not evaluate the effect of combination therapy on long-term clinical outcomes and safety.

Clinical trial registration: NCT00286494, clinicaltrials.gov.     

Efficacy and safety of sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes

ABSTRACT

Objective: The purpose of this study was to evaluate the efficacy and safety of sitagliptin as an add-on to metformin therapy in patients with moderately severe (hemoglobin A_1c ≥?8.0% and ≤?11.0%) type 2 diabetes mellitus (T2DM).

Research design and methods: This was a multi­national, randomized, placebo-controlled, parallel-group, double-blind study conducted in 190 patients with T2DM. After ≥?6?weeks of stable metformin monotherapy (≥?1500?mg/day), patients were randomized to either the addition of sitagliptin 100?mg once daily or placebo to ongoing metformin for 30?weeks.

Main outcome measures: The primary efficacy endpoint was reduction in hemoglobin A_1c (HbA_1c) measured after 18?weeks of sitagliptin treatment. Key secondary end­points included reduction in fasting plasma glucose (FPG) and 2-hour (2-h) postprandial plasma glucose (PPG) at 18 weeks, and HbA_1c at 30 weeks. The proportion of patients meeting the goal of HbA_1c <?7.0% was also analyzed.

Results: Sitagliptin significantly reduced HbA_1c, FPG, and 2-h PPG, compared with placebo (all p < 0.001). The net improvement in HbA_1c was –1.0% at both 18 and 30 weeks, and a significantly greater proportion of patients treated with sitagliptin achieved HbA_1c <?7.0% by the end of the study (22.1% vs. 3.3%, p < 0.001). Sitagliptin was well-tolerated. Compared with placebo, sitagliptin had a neutral effect on body weight and did not signif­icantly increase the risk of hypoglycemia or gastro­intestinal adverse events.

Conclusions: Addition of sitagliptin 100?mg once daily to ongoing metformin therapy was well-tolerated and resulted in significant glycemic improvement in patients with moderately severe T2DM who were treated for 30 weeks.

Trial registration: ClinicalTrials.gov identifier: NCT00337610.     

Effect of saxagliptin monotherapy in treatment-naïve patients with type 2 diabetes

ABSTRACT

Objective: To evaluate the efficacy and safety of once-daily saxagliptin monotherapy in treatment-naïve patients with type 2 diabetes (T2D) and inadequate glycemic control.

Research design and methods: This study included a main treatment cohort (MTC) with 401 patients (HbA_1c?≥?7% and ≤10%) randomized and treated with oral saxagliptin 2.5, 5, or 10?mg once daily or placebo for 24 weeks and a separate open-label cohort (OLC) with 66 patients (HbA_1c?>?10% and ≤12%) who received saxagliptin 10?mg once daily for 24 weeks. Primary endpoint was HbA_1c change from baseline to week 24. Secondary endpoints included change from baseline to week 24?in fasting plasma glucose (FPG), proportion of patients achieving HbA_1c?<?7%, and changes in postprandial glucose area-under-the-curve (PPG-AUC). Efficacy analyses for continuous variables were performed using an ANCOVA model with last-observation-carried-forward methodology.

Results: In the MTC, saxagliptin demonstrated statistically significant decreases in adjusted mean HbA_1c changes from baseline (mean, 7.9%) to week 24 (?0.43%, ?0.46%, ?0.54%) for saxagliptin 2.5, 5, and 10?mg, respectively, vs. +0.19% for placebo (all p?<?0.0001). Adjusted mean FPG was significantly reduced from baseline (?15, ?9, ?17?mg/dL) for saxagliptin 2.5, 5, and 10?mg, respectively, vs. +6?mg/dL for placebo (p?=?0.0002, p?=?0.0074, p?<?0.0001, respectively). More saxagliptin-treated patients achieved HbA_1c?<?7% at week 24 (35% [p?=?NS], 38% [p?=?0.0443], 41% [p?=?0.0133]) for saxagliptin 2.5, 5, and 10?mg, respectively, than placebo (24%). PPG-AUC was reduced for saxagliptin 2.5, 5, and 10?mg (?6868, ?6896, ?8084?mg·min/dL, respectively) vs. placebo (?647?mg·min/dL) with statistical significance demonstrated for saxagliptin 5?mg (p?=?0.0002) and 10?mg (p?<?0.0001). HbA_1c, FPG, and PPG-AUC reductions were also observed in the OLC at 24 weeks. In the MTC, adverse event frequency was similar across all study arms. No cases of confirmed hypoglycemia (symptoms, with fingerstick glucose ≤50?mg/dL) were observed in either cohort. Saxagliptin was not associated with weight gain. Study limitations included the lack of a control group for the OLC and the use of prespecified rescue criteria, which limited the exposure time during which patients could remain on their originally randomized medication without the introduction of additional antihyperglycemic rescue treatment.

Conclusions: Once-daily saxagliptin monotherapy for 24 weeks was generally well tolerated and demonstrated clinically meaningful reductions in key parameters of glycemic control vs. placebo.

Trial Registration: Clinical Trials NCT00121641     

Effect of pioglitazone on metabolic syndrome risk factors: results of double-blind,multicenter, randomized clinical trials

ABSTRACT

Objective: To evaluate the effect of pioglitazone, metformin, and/or sulfonylurea on metabolic syndrome and its component parameters after a year of treatment.

Methods: Adult patients with poorly controlled type 2 diabetes were enrolled in 4 multicenter, double-blind studies and received pioglitazone, sulfonylurea, metformin, or a combination of any 2 agents. Post hoc analyses were performed on data from patients with evaluations at baseline and week 52, and treatment groups were compared to determine change from baseline in metabolic syndrome status and its component variables by using the McNemar test and analysis of covariance, respectively.

Results: Most patients (72.1%) had metabolic syndrome at baseline. Change in the proportion of patients with metabolic syndrome status was significant in each monotherapy and the pioglitazone plus metformin combination groups. Pioglitazone alone or in combination with metformin resulted in a significantly greater percent decrease from baseline in triglycerides (pioglitazone vs. metformin, 10.3%; pioglitazone vs. sulfonylurea, 6.5%; pioglitazone plus metformin vs. sulfonylurea plus metformin, 13.4%; P < 0.05) and a greater percent increase from baseline in high-density lipoprotein (HDL) cholesterol (pioglitazone vs. metformin, 9.1%; pioglitazone vs. sulfonylurea, 12.6%; pioglitazone plus metformin vs. sulfonylurea plus metformin, 17.8%; P < 0.001) at week 52 than did the respective comparison groups. A significant decrease from baseline in the ratio of urinary albumin to creatinine was found only with pioglitazone monotherapy (–1.764?mg/mmol; P < 0.001), which was significantly greater than the change in the metformin monotherapy group (2.1%; P < 0.05). Significant decrease in blood pressure was observed in the pioglitazone monotherapy and pioglitazone plus sulfonylurea groups, with no significant treatment group differences.

Conclusions: Treatment with pioglitazone as monotherapy or combination therapy led to sustained, positive effects on important components of metabolic syndrome in patients with type 2 diabetes, independent of effects on blood glucose control and, as such, could be translated to potential for reducing the risk of cardiovascular disease.     

Efficacy and tolerability of initial combination therapy with nateglinide and metformin in treatment-naïve patients with type 2 diabetes

SUMMARY

Objective: To assess the efficacy and tolerability of the combination of nateglinide (120?mg, ac) and metformin (500?mg, tid) as initial treatment in drug-naïve patients with type 2 diabetes mellitus (T2DM).

Research design and methods: This study reports data from the treatment-naïve (TN) subgroup of patients in a previously published, randomized, multicenter, placebo-controlled, 24-week trial that compared nateglinide, metformin, and the combination therapy (CT) in 701 patients with T2DM with baseline HbA_1c between 6.8% and 11.0%. Of the 401 TN patients, 104, 104, 89, and 104 patients received nateglinide (120?mg, ac), metformin (500?mg, tid), CT, and placebo, respectively. The baseline characteristics of each group were similar, with mean age, BMI, duration of diabetes, HbA_1c, and fasting plasma glucose (FPG) levels of approximately 58 years, 30?kg/m², 4 years, 8.2%, and 10.2?mmol/L, respectively.

Results: In patients receiving initial CT, HbA_1c decreased substantially (? = –1.6 ± 0.1%, p < 0.0001 vs. baseline or placebo) from a mean baseline of 8.2 ± 0.1%, an effect significantly greater than the 0.8% reduction observed with both monotherapies (?p < 0.001); whereas, in placebo-treated patients, HbA_1c increased modestly (? = +0.3 ± 0.1%, p < 0.05) from an identical baseline value. Seventy percent of CT-treated patients achieved a target HbA_1c of < 7.0%. Both fasting plasma glucose (FPG) and the 2-hour postprandial glucose excursion (PPGE) after a liquid meal challenge decreased by 2.3?mmol/L in patients receiving CT, while the changes from baseline values in FPG and PPGE were +0.2 ± 0.3?mmol/L and –0.5 ± 0.2?mmol/L, respectively, in placebo-treated patients. The incremental 30-minute post-load insulin levels increased by 88 ± 32?pmol/L (?p = 0.006) in patients receiving CT and did not change significantly in placebo-treated patients. Gastrointestinal side effects occurred in 27% of patients receiving CT (vs. 27.9% in the metformin monotherapy, and 14.4% in the placebo groups). Confirmed hypoglycemia (glucose ≤ 2.8?mmol/L) occurred in 3.4% of patients receiving CT.

Conclusions: Initial CT with the rapid-acting insulinotropic agent, nateglinide, and metformin, an agent with insulin-sensitizing effects in the liver and periphery, is a safe and effective means of achieving glycemic targets in TN patients with T2DM.     

Metabolic effect of repaglinide or acarbose when added to a double oral antidiabetic treatment with sulphonylureas and metformin: a double-blind,cross-over,clinical trial

ABSTRACT

Objective: To compare the metabolic effects of acarbose and repaglinide in type 2 diabetic patients who are being treated with a sulphonylurea–metformin combination therapy. The primary endpoint of the study was to evaluate which add-on treatment between acarbose and repaglinide is more efficacious in reducing PPG. The second endpoint was to evaluate which of these two treatment is more efficacious in the global management of glucose homeostasis in the enrolled patients.

Research design and methods: After a 4-week run-in period with a suplonylurea–metformin combination, 103 patients were randomised to receive in addition either repaglinide, up to 6?mg/day (2?mg three times a day) or acarbose, up to 300?mg/day (100?mg three times a day) with forced titration (independently of their glycaemic control, unless side-effects developed due to the drug dosage) for 15 weeks. The treatment was then crossed-over for further 12 weeks until the 27th week. We assessed body mass index (BMI), glycosylated haemoglobin (HbA_1c), fasting plasma glucoe (FPG), postprandial plasma glucose (PPG), fasting plasma insulin (FPI), postprandial plasma insulin (PPI), homeostatic model assesssment (HOMA) index, systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (Tg), at baseline and at 1, 2, 15 and 27 weeks of treatment.

Results: Seven patients did not complete the study, comprising one patient who was lost to follow-up and a further six through side-effects (two in week 1, one in week 15 and three after cross-over) Side-effects were classified as nausea (one in acarbose group), gastrointestinal events (four in acarbose group), and hypoglycaemia (one in repaglinide group). After 15 weeks of therapy, the repaglinide-treated patients experienced a significant decrease in HbA_1c (?1.1%, p?<?0.05), FPG (?9.5%, p?<?0.05), and PPG (?14.9%, p?<?0.05), when compared to the baseline values. However, the same treatment was associated with a significant increase in body weight (+2.3%, p?<?0.05), BMI (+3.3%, p?<?0.05) and FPI (+22.5%, p?<?0.05); The increase was reversed during the cross-over phase. After 15 weeks of therapy, the acarbose-treated patients experienced a significant decrease in body weight (?1.9%, p?<?0.05), BMI (?4.1%, p?<?0.05), HbA_1c (?1.4%, p?<?0.05), FPG (?10.7%, p?<?0.05), PPG (?16.2%, p?<?0.05), FPI (?16.1%, p?<?0.05), PPI (?26.9%, p?<?0.05), HOMA index (?30.1%, p?<?0.05), when compared to the baseline values. All these changes were reversed during the cross-over study phase, except those relating to HbA_1c, FPG and PPG. The only changes that significantly differed when directly comparing acarbose- and repaglinide-treated patients were those relating to FPI (?16.1% vs. +22.5%, respectively, p?<?0.05) and HOMA index (?30.1% vs. +2.7%, p?<?0.05).

Conclusion: In addition from having a similar effect to repaglinide on PPG, acarbose appeared to have a more comprehensive positive effect on glucose metabolism compared to repaglinide in this relatively small sample of type 2 diabetic patients when used as add-on therapy to sulphonylureas and metformin.     

Efficacy and safety of initial combination therapy with sitagliptin and metformin in patients with type 2 diabetes: a 54-week study

ABSTRACT

Objective: To assess the 54-week efficacy and safety of initial combination therapy with sitagliptin and metformin in patients with type 2 diabetes and inadequate glycemic control (HbA_1c 7.5–11%) on diet and exercise.

Methods and materials: This was multinational study conducted at 140 clinical sites in 18 countries. Following an initial 24-week, double-blind, placebo-controlled period, patients entered a double-blind continuation period for an additional 30 weeks. Following the week 24 evaluation, patients remained on their previously assigned active, oral treatments: sitagliptin 50?mg b.i.d.?+?metformin 1000?mg b.i.d. (S100?+?M2000), sitagliptin 50?mg b.i.d.?+?metformin 500?mg b.i.d. (S100?+?M1000), metformin 1000?mg b.i.d. (M2000), metformin 500?mg b.i.d. (M1000), and sitagliptin 100?mg q.d. (S100). Patients initially randomized to placebo were switched to M2000 (designated PBO/M2000) at week 24. This report summarizes the overall safety and tolerability data for the 54-week study and presents efficacy results for patients randomized to continuous treatments who entered the 30-week continuation period.

Results: Of the 1091 randomized patients, 906 completed the 24-week placebo-controlled phase and 885 patients continued into the 30-week continuation period (S100?+?M2000 n?=?161, S100+M1000 n?=?160, M2000 n?=?153, M1000 n?=?147, S100 n?=?141, PBO/M2000 n?=?123). At baseline, patients included in the efficacy analysis had mean age of 54 years, mean BMI of 32?kg/m², mean HbA_1c of 8.7% (8.5–8.8% across groups), and mean duration of type 2 diabetes of 4 years. At week 54, in the all-patients-treated analysis of continuing patients, least-squares (LS) mean changes in HbA_1c from baseline were ?1.8% (S100?+?M2000), ?1.4% (S100?+?M1000), ?1.3% (M2000), ?1.0% (M1000), and ?0.8% (S100). The proportions of continuing patients with an HbA_1c?<?7% at week 54 were 67% (S100?+?M2000), 48% (S100?+?M1000), 44% (M2000), 25% (M1000), and 23% (S100). For the patients completing treatment through week 54, LS mean changes in HbA_1c from baseline were ?1.9% (S100?+?M2000), ?1.7% (S100?+?M1000), ?1.6% (M2000), ?1.2% (M1000), and ?1.4% (S100). Glycemic response was generally durable over time across treatments. All treatments improved measures of β-cell function (e.g., HOMA-β, proinsulin/insulin ratio). Mean body weight decreased from baseline in the combination and metformin monotherapy groups and was unchanged from baseline in the sitagliptin monotherapy group. The incidence of hypoglycemia was low (1–3%) across treatment groups. The incidence of gastrointestinal adverse experiences with the co-administration of sitagliptin and metformin was similar to that observed with metformin alone.

Limitations: The patient population evaluated in the 54-week efficacy analysis was a population of patients who entered the continuation period without receiving glycemic rescue therapy in the 24-week placebo-controlled period. Because the baseline HbA_1c inclusion criteria ranged from 7.5 to 11% and the glycemic rescue criterion was an HbA_1c?>?8% after week 24, there was a greater likelihood of glycemic rescue in the monotherapy groups; this led to more missing data in the continuation all-patients-treated population(CAPT) analysis and fewer patients contributing to the completers analysis in the monotherapy groups.

Conclusions: In this study, initial treatment with sitagliptin, metformin, or the combination therapy of sitagliptin and metformin provided substantial and durable glycemic control, improved markers of β-cell function, and was generally well-tolerated over 54 weeks in patients with type 2 diabetes.     

A cost-effectiveness analysis of pioglitazone plus metformin compared with rosiglitazone plus metformin from a third-party payer perspective in the US*

ABSTRACT

Objective: The long-term cost-effectiveness of using pioglitazone plus metformin (Actoplusmet^?) compared with rosiglitazone plus metformin (Avandamet^?) in treating type 2 diabetes (T2DM) was assessed from a US third-party payer perspective.

Research design and methods: Clinical efficacy (change in HbA_1c and lipids) and baseline cohort parameters were extracted from a 12-month, randomized clinical trial (Derosa et al., 2006) evaluating the efficacy and tolerability of pioglitazone versus rosiglitazone, both in addition to metformin, in adult T2DM patients with insufficient glucose control (n?=?96). A Markov-based model was used to project clinical and economic outcomes over 35 years, discounted at 3% per annum. Costs for complications were taken from published sources. Base-case assumptions were assessed through several sensitivity analyses.

Main outcome measures: Outcomes included incremental life-years, quality-adjusted life-years (QALYs), total direct medical costs, cumulative incidence of complications and associated costs, and incremental cost–effectiveness ratios (ICERs).

Results: Compared to rosiglitazone plus metformin, pioglitazone plus metformin was projected to result in a modest improvement in 0.187 quality-adjusted life-years. Over patients’ lifetimes, total direct medical costs were projected to be marginally lower with pioglitazone plus metformin (difference –$526.), largely due to reduced CVD complication costs. While costs were higher among renal, ulcer/amputation/neuropathy, and eye complications in the pioglitazone plus metformin group, the cost savings for CVD complications outweighed their economic impact. Pioglitazone plus metformin was found to be a dominant long-term treatment strategy in the US compared to rosiglitazone plus metformin. Sensitivity analyses showed findings to be robust under almost all scenarios, including short-term time horizons, 6% discounting, removal of individual lipid parameters, and modifications of patient cohort to more closely represent a US T2DM population. Pioglitazone plus metformin was no longer dominant with 0% discounting, with 25% reduction in its HbA_1c effects, or with a 15% increase in its acquisition price.

Conclusions: Under a range of assumptions and study limitations around cohorts, clinical effects, and treatment patterns, this long-term analysis showed that pioglitazone plus metformin, when compared to rosiglitazone plus metformin, was a dominant treatment strategy within the US payer setting. Results were driven by the combination of modest differences in QALYs and modest savings in total complication costs over 35 years.     

Pioglitazone as monotherapy or in combination with sulfonylurea or metformin enhances insulin sensitivity (HOMA-S or QUICKI) in patients with type 2 diabetes

Background: Miyazaki etal, demonstrated using the hyperinsulinemic, euglycemic clamp that pioglitazone (PIO) enhanced insulin sensitivity in patients (n?=?23) with type 2 diabetes (T2D). Although considered the reference method for measuring insulin sensitivity, the clamp is seldom used in large clinical trials because of its complexity. The Homeostasis Model Assessment-Insulin Sensitivity (HOMA-S) and Quantitative Insulin Sensitivity Check Index (QUICKI) are two alternative insulin sensitivity surrogates that correlate with the clamp method and are suitable for use with large study populations.

Study aim: To evaluate the effect of PIO monotherapy and in combination therapy with sulfonylurea (SU) or metformin (MET) on insulin sensitivity as assessed by HOMA-S and QUICKI in a large group of patients (～1000).

Research design and methods: Patient data from three randomized, double blind, multicenter, parallel group, placebo-controlled registration trials (Studies-001 PIO monotherapy and 010 and 027 combination therapy with SU or MET, respectively) were analyzed for this study. We

evaluated insulin sensitivity for all three studies using HOMA-S and QUICKI.

Results: PIO 15, 30 and 45?mg enhanced HOMA-S compared with baseline (56.9-63.6%, p?=?0.0298); (53.7-64.7%, p?=?0.0008); (59.0-75.9%, p?<?0.0001), respectively. Only the 45?mg dose showed a difference from placebo (p?=?0.0025). Similarly, PIO enhanced QUICKI versus baseline (0.290-0.296, p?=?0.0026); (0.287-0.299, p?=?0.0001); (0.290-0.306, p?=?0.0001), respectively. Both the 30 and 45mg doses were different from placebo for QUICKI (p?=?0.0005, p?<?0.0001). PIO 15 and 30mg plus SU enhanced HOMA-S compared with baseline (58.4–.7%, p?=?0.0007; 53.2–68.4%, p?<?0.0001) and placebo plus SU (p?=?0.0129, p?<?0.0001, respectively). Likewise, PIO 15 and 30?mg plus SU enhanced QUICKI versus baseline (0.289-0.300, p?=?0.0001; 0.287-0.305, p?=?0.0001, respectively). Both doses had different effects from placebo plus SU (p?=?0.0001) for QUICKI. PIO 30mg combined with MET enhanced HOMA-S versus baseline (66.2–82.2%, p?<?0.0001) and placebo plus MET (p?=?0.0002).     

Once-daily sitagliptin,a dipeptidyl peptidase-4 inhibitor,for the treatment of patients with type 2 diabetes

ABSTRACT

Objective: Sitagliptin, an oral, potent, and selective dipeptidyl peptidase-4 (DPP?4) inhibitor was evaluated as once-daily monotherapy in a 12-week randomized, double-blind, placebo-controlled, parallel group, dose-ranging study. Additionally, the glycemic response to sitagliptin 100?mg daily was evaluated as a once-daily (100?mg once-daily) or twice-daily (50?mg twice-daily) dosing regimen.

Research design and methods: In a multinational, double-blind, randomized, placebo-controlled, parallel-group, dose-range finding study, 555 patients, 23–74 years of age, with HbA_1c of 6.5–10.0% were randomized to one of five treatment groups: placebo, sitagliptin 25, 50 or 100?mg once-daily, or sitagliptin 50?mg twice-daily for 12 weeks. The efficacy analysis was based on the all-patients-treated population using an ANCOVA model.

Results: Mean baseline HbA_1c ranged from 7.6 to 7.8% across treatment groups, with 29% of all patients with values ≤?7%. After 12 weeks, treatment with all doses of sitagliptin significantly (?p < 0.05) reduced HbA_1c by –0.39 to –0.56% and fasting plasma glucose by –11.0 to –17.2?mg/dLrelative to placebo, with the greatest reduction observed in the 100-mg once-daily group. Mean daily glucose was significantly (?p < 0.05) reduced by –14.0 to –22.6?mg/dL with all doses of sitagliptin relative to placebo. HOMA?β was significantly (?p < 0.05) increased by 11.3–15.2 with all sitagliptin doses relative to placebo. QUICKI and HOMA?IR were not significantly changed with sitagliptin treatment. There were no significant differences observed between the sitagliptin 100?mg once-daily and 50?mg twice-daily groups for any parameter. For sitagliptin, the incidence of adverse events of hypoglycemia was low, with one event in each of the 25- and 50-mg once-daily and 50-mg twice-daily treatment groups and two events in the 100?mg once-daily treatment group. There was no mean change in body weight with sitagliptin relative to placebo. Study duration may be a limitation because the extent of the glycemic response and the safety and tolerability may not have been fully elucidated in this 12-week study.

Conclusion: Sitagliptin monotherapy improved indices of glycemic control compared to placebo and was generally well-tolerated in patients with type 2 diabetes. The glycemic response to treatment with sitagliptin 100?mg/day was similar between the sitagliptin 100-mg once-daily and 50-mg twice-daily dose regimens.     

Glimepiride versus pioglitazone combination therapy in subjects with type 2 diabetes inadequately controlled on metformin monotherapy: results of a randomized clinical trial

ABSTRACT

Objective: To compare the effect of add-on glimepiride or pioglitazone in subjects with type 2 diabetes inadequately controlled on metformin monotherapy.

Research design and methods: Multicenter, randomized, parallel-group, open-label, forced-titration study involving 203 adults with poorly controlled type 2 diabetes (A1C 7.5–10%) on metformin monotherapy. Subjects were randomized to receive glimepiride or pioglitazone, titrated to the maximum dose for 26 weeks. Subjects were evaluated for A1C changes, fasting plasma glucose (FPG), insulin, C‐peptide, and lipid levels. Safety outcomes and diabetes-related healthcare resource utilization were also evaluated.

Results: Both treatment groups achieved similar and significant mean decreases from baseline to endpoint (week 26) in A1C (?p = 0.0001) and FPG (?p < 0.05). Glimepiride therapy, however, resulted in a more rapid decline in A1C levels at weeks 6, 12, and 20 vs. pioglitazone (?p < 0.05). A mean A1C ≤ 7% was reached faster in the glimepiride group (median, 80–90 days vs. 140–150 days [p = 0.024]). Total and LDL cholesterol were significantly higher with pioglitazone treatment than with glimepiride at endpoint (?p < 0.05). Glimepiride treatment was associated with an increased risk of hypoglycemia and pioglitazone with higher rate of peripheral edema. Healthcare resource utilization was similar between groups, but total healthcare costs were significantly lower for glimepiride versus pioglitazone over the course of the study, driven largely by drug costs. The use of fasting C‐peptide concentration ≥ 0.27?nmol/L in the inclusion criteria was a potential limitation as it may have included those patients with an improved probability for glimepiride or pioglitazone response. In addition, a larger patient population would have provided a greater degree of data applicability.

Conclusions: In patients with type 2 diabetes inadequately controlled on metformin monotherapy, add-on glimepiride or pioglitazone results in similar overall improvements in glycemic control. Compared with pioglitazone, glimepiride is associated with faster glycemic control, lower total and LDL cholesterol levels and reduced short-term healthcare costs.     

Thiazolidinediones: comparison of long-term effects on glycemic control and cardiovascular risk factors

SUMMARY

Objective: To compare the long-term effects on HbA_1c, lipid parameters, body weight, and hepatotoxicity after switching type 2 diabetes patients from troglitazone to either pioglitazone or rosiglitazone.

Methods: Of 125 study candidates from a previous prospective study, 100 patients (51 pioglitazone, 49 rosiglitazone) met criteria for comparing HbA_1c, lipids, body weight, and incidence of hepatotoxicity over 2 successive observation periods (3.1 and 12.6?months).

Results: Mean absolute HbA_1c decreased significantly, 0.53 and 0.27% in the pioglitazone and rosiglitazone groups, respectively, at the 12.6-month observation. Mean triglyceride (TG) decreased in the pioglitazone group at each interval with a cumulative decrease of 26.4% from baseline. In contrast, TG increased in the rosiglitazone patients by 43.3% at 3.1?months and then decreased (but remained above baseline) at 12.6?months. Mean high density lipoprotein (HDL) increased 22.1% with pioglitazone and 13.3% with rosiglitazone. In patients who had a baseline HDL < 35?mg/dL (0.91?mmol/L), pioglitazone-treated patients experienced a significant increase at each interval resulting in a 52.6% increase in HDL compared to a 26.9% increase for rosiglitazone patients. Patients in both treatment groups had similar weight increases at each interval and no hepatotoxicity was noted.

Conclusion: With pioglitazone or rosiglitazone, changes in glycemic control, lipid effects, and body weight appear to continue over time. Pioglitazone treatment resulted in decreased triglyceride levels, while rosiglitazone was associated with an increase in triglyceride levels. HDL increased in both treatment groups, but in patients with a baseline HDL < 35?mg/dL (0.91?mmol/L), pioglitazone improved the HDL to a greater extent than rosiglitazone.     

Once-daily insulin detemir in a cohort of insulin-naïve patients with type 2 diabetes: a sub-analysis from the PREDICTIVE study

ABSTRACT

Objective: PREDICTIVE^* is a large, observational study of the empirical use of insulin detemir in patients with type 1 or type 2 diabetes (T1DM/T2DM). This post hoc analysis evaluates insulin-naïve patients with T2DM uncontrolled on oral antidiabetic drugs (OADs) who were initiated and remained on once-daily insulin detemir for 12 weeks.

Research design and methods: This observational, multinational, multi-center, open-label prospective study evaluated the efficacy and safety of insulin detemir in 1653 insulin-naïve patients with T2DM (mean age 60.8?±?10.9 years, BMI 29.8?±?4.8?kg/m², and HbA_1C 8.82?±?1.50%). Statistical comparisons were made between baseline and 12-week follow up data. Our study was subject to the usual limitations of observational studies.

Main outcome measures: Endpoints were: incidence of serious adverse drug reactions, including number of hypoglycemic events (total, major, and nocturnal), glycemic parameters, and weight change.

Results: Following insulin initiation, no significant change occurred in the number of nocturnal hypoglycemic events or total hypoglycemic events (p?=?0.4513), and no serious adverse drug reactions were observed during the 12 weeks of treatment. HbA_1C decreased by a mean 1.25% (SD?±?1.25%; p?<?0.0001), with 30% of patients (n?=?383) achieving HbA_1C <7% at 12 weeks. Mean changes in fasting blood glucose and fasting blood glucose variability were –3.62?mmol/L (SD?±?2.93; p?<?0.0001) and ?0.48?mmol/L (SD?±?1.03; p?<?0.0001), respectively. Body weight decreased by a mean 0.5?kg (SD?±?3.3; p?<?0.0001), with weight loss or no weight change occurring in a substantial percentage of patients in each BMI category (<25, 25–30, 30–35, and >35?kg/m²). Patients with higher baseline BMI lost the most weight, with the greatest weight loss (–1.20?kg) reported in those with BMI >35?kg/m².

Conclusions: Empirical use of insulin detemir as an insulin initiation strategy can improve glycemic control with good tolerability, including a low risk of hypoglycemia and a weight benefit, in a majority of insulin-naïve patients uncontrolled on OADs.     

Long-term efficacy of insulin glargine therapy with an educational programme in type 1 diabetes patients in clinical practice

ABSTRACT

Objective: To investigate the effect of initiating insulin glargine (glargine: LANTUS*), a once-daily basal insulin analogue, plus an educational programme, on glycaemic control and body weight in patients with type 1 diabetes in clinical practice.

Research design and methods: A retrospective analysis of the medical records of 65 patients (mean age: 40.7 ± 13.3 years) with type 1 diabetes was performed. Patients had previously been treated with NPH insulin (NPH; n = 54) or NPH insulin + lente insulin (NPH + lente; n = 11) and then received glargine once daily (bedtime), plus short-acting prandial insulin, for 30 months. Before initiation of glargine, patients participated in a diabetes educational programme and then received physician consultations throughout the study. Metabolic control, body weight and severe hypoglycaemia data were analysed at 9 and 30 months.

Results: Following initiation of glargine, patients showed a decrease in HbA_1c from 7.29 ± 1.1% to 7.06 ± 1.0%; p < 0.01 at 30 months. When the results were analysed by pre-treatment, both NPH-pre-treated and NPH+lente-pre-treated patients showed a significant reduction in HbA_1c of 0.14% and 0.82%, respectively, at 30 months (7.27 ± 1.2% to 7.13 ± 1.1% and 7.42 ± 1.2 to 6.60 ± 0.3%, respectively; p < 0.01). No change in body weight was observed in the overall group. No episodes of severe hypoglycaemia (blood glucose <?40?mg/dL [<?2.2?mmol/L] occurred.

Conclusions: In this retrospective study of medical records, patients with type 1 diabetes treated with insulin glargine over 30 months in combination with educational support and close clinical supervision decreased their HbA_1c levels without weight gain versus previous treatment with NPH insulin or insulin lente. Further studies in a larger cohort of patients would help to confirm these results.     

Exenatide effects on diabetes,obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years

ABSTRACT

Background: Exenatide, an incretin mimetic for adjunctive treatment of type 2 diabetes (T2DM), reduced hemoglobin A_1c (A1C) and weight in clinical trials. The objective of this study was to evaluate the effects of?≥?3 years exenatide therapy on glycemic control, body weight, cardiometabolic markers, and safety.

Methods: Patients from three placebo-controlled trials and their open-label extensions were enrolled into one open-ended, open-label clinical trial. Patients were randomized to twice daily (BID) placebo, 5?µg exenatide, or 10?µg exenatide for 30 weeks, followed by 5?µg exenatide BID for 4 weeks, then 10?µg exenatide BID for ≥3 years of exenatide exposure. Patients continued metformin and/or sulfonylureas.

Results: 217 patients (64% male, age 58?±?10 years, weight 99?±?18?kg, BMI 34?±?5?kg/m², A1C 8.2?±?1.0% [mean?±?SD]) completed 3 years of exenatide exposure. Reductions in A1C from baseline to week 12 (?1.1?±?0.1% [mean?±?SEM]) were sustained to 3 years (?1.0?±?0.1%; p?<?0.0001), with 46% achieving A1C?≤?7%. Exenatide progressively reduced body weight from baseline (?5.3?±?0.4?kg at 3 years; p?<?0.0001). Patients with elevated serum alanine aminotransferase (ALT) at baseline (n?=?116) had reduced ALT (?10.4?±?1.5?IU/L; p?<?0.0001) and 41% achieved normal ALT. Patients with elevated ALT at baseline tended to lose more weight than patients with normal ALT at baseline (?6.1?±?0.6?kg vs. ?4.4?±?0.5?kg; p?=?0.03), however weight change was minimally correlated with baseline ALT (r?=??0.01) or ALT change (r?=?0.31). Homeostasis Model Assessment B (HOMA-B), blood pressure, and aspartate aminotransferase (AST) all improved. A subset achieved 3.5 years of exenatide exposure and had serum lipids available for analysis (n?=?151). Triglycerides decreased 12% (p?=?0.0003), total cholesterol decreased 5% (p?=?0.0007), LDL-C decreased 6% (p?<?0.0001), and HDL-C increased 24% (p <?0.0001). Exenatide was generally well tolerated. The most frequent adverse event was mild-to-moderate nausea. The main limitation of this study is the open-label, uncontrolled nature of the study design which does not provide a placebo group for comparison.

Conclusion: Adjunctive exenatide treatment for ≥3 years in T2DM patients resulted in sustained improvements in glycemic control, cardiovascular risk factors, and hepatic biomarkers, coupled with progressive weight reduction.     

Effect of non-persistent use of oral glucose-lowering drugs on HbA1c goal attainment

ABSTRACT

Objectives: The aim of this study was to quantify the effect of non-persistence with oral glucose-lowering drugs (OGLD) on HbA_1c goal attainment (<?7%) in daily practice.

Methods: From the PHARMO Record Linkage System comprising among others linked drug dispensing and clinical laboratory data from approximately 2.5 million individuals in the Netherlands, new users of OGLD in the period 1999–2004 were identified. Patients with a baseline HbA_1c ≥?7% and at least one HbA_1c measurement in the period of 6–12?months after treatment onset were included in the study cohort. Persistence with OGLD in the first year of treatment was determined using the method of Catalan. In case the first treatment episode overlapped the first HbA_1c measurement within 6–12?months after treatment onset, a patient was considered persistent at that measurement. Patients with a HbA_1c <?7% were defined as having attained goal.

Results: The study cohort included 2023 patients with a mean baseline HbA_1c of 8.9?±?1.8%. Three-quarters (1512 patients) were persistent with any OGLD at the first HbA_1c measurement within 6–12?months after treatment onset; of these, 861 (57%) were at goal. Of the 511 non-persistent patients, 239 (47%) were at goal. Non-persistent patients were about 20% less likely to attain goal (RRadj 0.82; 95%CI 0.74–0.91), compared to persistent OGLD users.

Conclusion: Non-persistent use of OGLD leads to a 20% decreased probability of HbA_1c goal attainment in daily practice. This effect of non-persistence seems modest, but represents around 12?000 new and 10?000 prevalent OGLD users a year in the Netherlands in whom OGLD use could be better controlled.     

Effect of tesaglitazar,a dual PPARα/γ agonist,on glucose and lipid abnormalities in patients with type 2 diabetes: a 12‐week dose-ranging trial

ABSTRACT

Objective: The Glucose and Lipid Assessment in Diabetes (GLAD) trial examined the dose-response relationship of the dual peroxisome proliferatoractivated receptor (PPAR) α/γ agonist tesaglitazar in type 2 diabetic patients.

Study design: GLAD was a 12‐week, multicenter, international, randomized, parallel-group trial. Five-hundred men and women aged 30–80 years with type 2 diabetes (fasting plasma glucose [FPG] ≥ 126?mg/dL [≥ 7.0?mmol/L]) received once-daily, double-blind placebo or tesaglitazar (0.1?mg, 0.5?mg, 1.0?mg, 2.0?mg, or 3.0?mg) or open-label pioglitazone (45?mg), included as a therapeutic benchmark.

Main outcome measures: Placebo-corrected changes from baseline in FPG (primary end point), plasma lipids, and insulin-resistance measures.

Results: At baseline, the mean patient age was 56.1 years, 57.5 years, and 58.9 years for placebo, across tesaglitazar groups, and for pioglitazone, respectively. For the corresponding groups, mean body mass index was 30.6?kg/m², 30.9?kg/m², and 29.7?kg/m², and mean HbA_1c was 7.0%, 7.2%, and 7.0%, respectively. At 12 weeks, tesaglitazar 0.5?mg, 1.0?mg, 2.0?mg, and 3.0?mg produced statistically significant reductions in FPG (–30.3?mg/dL, –41.1?mg/dL, –55.0?mg/dL, –60.9?mg/dL; p < 0.0001), triglycerides (–17.2%, –32.9%, –41.0%, –40.9%; p < 0.01), and apolipoprotein B (–15.0%, –15.7%, –21.0%, –22.3%, respectively; p < 0.0001). Tesaglitazar at doses ≥ 1.0?mg significantly increased high-density lipoprotein-cholesterol (HDL‐C) (15.0%, 13.0%, 12.9%; p < 0.001), and reduced non-HDL‐C (–13.2%, –22.2%, –25.0%; p < 0.0001), very-low-density lipoprotein-cholesterol (VLDL‐C) (–36.9%, –49.8%, –52.5%; p < 0.0001), and total cholesterol (–6.8%, –14.1%, –15.5%, respectively; p < 0.01). Tesaglitazar ≥ 0.5?mg improved insulin-resistance measures. Although no formal statistical analyses were performed between active treatments, improvements in efficacy measures with tesaglitazar 1.0?mg were numerically similar to or greater than those with pioglitazone. Similar numbers of adverse events occurred in the tesaglitazar ≤ 1.0?mg, placebo, and pioglitazone arms, but there was an increasing frequency of discontinuations due to pre-specified hematologic and clinical-chemistry criteria with tesaglitazar doses ≥ 1.0?mg.

Conclusions: In type 2 diabetic patients, tesaglitazar dose-dependently reduced FPG levels at doses ≥ 0.5?mg. Other markers of glycemic control, atherogenic dyslipidemia, and measures associated with insulin resistance were improved at doses ≥ 0.5?mg or ≥ 1.0?mg. Study limitations included that the majority of patients were white, patients had good glycemic control at baseline, and the increased number of early withdrawals in the tesaglitazar 2.0?mg and 3.0?mg doses limits conclusions about the efficacy of these doses. The 0.5?mg and 1.0?mg tesaglitazar doses were identified for further investigation.