Diabetes duration and the efficacy and safety of insulin glargine versus comparator treatment in patients with type 2 diabetes mellitus.

OBJECTIVE: To evaluate the effect of diabetes duration on efficacy and safety in patients with type 2 diabetes mellitus (T2DM) using insulin glargine versus comparator (oral antidiabetic drugs [OADs], dietary changes, or other insulins). METHODS: Data were pooled from randomized controlled clinical trials conducted in adults with T2DM with at least 24-week treatment with insulin glargine or a comparator, where predefined insulin titration algorithms were utilized to achieve fasting plasma glucose (FPG) concentrations of ≤100 mg/dL. Glycated hemoglobin A1C (A1C), FPG, and insulin dose and safety (hypoglycemia) outcomes were analyzed. RESULTS: Nine studies were included in the analysis of 2,930 patients. Patients with shorter duration of diabetes were more likely to have greater reductions in A1C compared with those who had longer-duration disease (P<.0001). Disease duration did not affect change in FPG concentrations (P = .9017), but lower weight-adjusted insulin dose was correlated with longer-duration disease (P<.0001). Patients with longer-duration diabetes had increased risks of symptomatic hypoglycemia, confirmed hypoglycemia (self-monitored blood glucose <50 mg/dL and <70 mg/dL), and nocturnal hypoglycemia (all P<.001). No significant relationship was found between severe hypoglycemia and duration of diabetes. However, treatment with insulin glargine lowered A1C values more effectively than comparator treatments with fewer hypoglycemic episodes. CONCLUSION: Patients with shorter-duration T2DM better achieved target A1C levels and had less hypoglycemia than those with longer disease duration. Insulin glargine was associated with reduced A1C and fewer hypoglycemic events than comparators, regardless of disease duration.

Effectiveness of sensor-augmented insulin-pump therapy in type 1 diabetes.

BACKGROUND: Recently developed technologies for the treatment of type 1 diabetes mellitus include a variety of pumps and pumps with glucose sensors. METHODS: In this 1-year, multicenter, randomized, controlled trial, we compared the efficacy of sensor-augmented pump therapy (pump therapy) with that of a regimen of multiple daily insulin injections (injection therapy) in 485 patients (329 adults and 156 children) with inadequately controlled type 1 diabetes. Patients received recombinant insulin analogues and were supervised by expert clinical teams. The primary end point was the change from the baseline glycated hemoglobin level. RESULTS: At 1 year, the baseline mean glycated hemoglobin level (8.3% in the two study groups) had decreased to 7.5% in the pump-therapy group, as compared with 8.1% in the injection-therapy group (P<0.001). The proportion of patients who reached the glycated hemoglobin target (<7%) was greater in the pump-therapy group than in the injection-therapy group. The rate of severe hypoglycemia in the pump-therapy group (13.31 cases per 100 person-years) did not differ significantly from that in the injection-therapy group (13.48 per 100 person-years, P=0.58). There was no significant weight gain in either group. CONCLUSIONS: In both adults and children with inadequately controlled type 1 diabetes, sensor-augmented pump therapy resulted in significant improvement in glycated hemoglobin levels, as compared with injection therapy. A significantly greater proportion of both adults and children in the pump-therapy group than in the injection-therapy group reached the target glycated hemoglobin level. (Funded by Medtronic and others; ClinicalTrials.gov number, NCT00417989.)

Primary Care Physicians' Knowledge of the Cardiovascular Effects of Diabetes Medications: Findings from an Online Survey.

INTRODUCTION: Cardiovascular (CV) outcomes trial (CVOT) results have led to changes in indications for some glucose-lowering agents, with recommendations based on the presence of comorbidities. OBJECTIVE: This study aimed to understand internal medicine (IM) and family medicine (FM) physicians' knowledge of CVOTs and beliefs about type 2 diabetes mellitus (T2DM) medications, excluding insulin, for CV disease risk reduction. METHODS: WebMD, LLC, fielded a 23-item online survey from September 18 to 20, 2018, to 47,534 Medscape members (US IM and FM physicians) who were invited to participate via e-mail (quota = 500). RESULTS: Of the 702 physicians who responded, 503 were eligible and completed the survey. Overall, 39% of respondents were not familiar with the 2018 American Diabetes Association treatment recommendations for those with T2DM and atherosclerotic CV disease. Respondents reported they were most familiar with TECOS (42%), LEADER (39%), EMPA-REG OUTCOME (33%), and CANVAS (30%). Many respondents did not know which CVOT showed superiority for major adverse CV events (26%) or CV mortality (31%). When provided with a list of seven treatment priorities, 33% of respondents ranked using T2DM medications with CV benefits as least important. CONCLUSIONS: Findings from this 2018 survey suggest that there are knowledge gaps among IM and FM physicians regarding the results from CVOTs, with implications for the treatment of patients with T2DM and CV disease.

Post hoc efficacy and safety analysis of insulin glargine/lixisenatide fixed- ratio combination in North American patients compared with the rest of world.

Objective: To assess the efficacy and safety of iGlarLixi (titratable fixed-ratio combination of insulin glargine (iGlar) and lixisenatide) in patients with type 2 diabetes (T2D) living in North America (NA; USA and Canada) compared with the rest of the world (RoW). Research design and methods: Post hoc analysis included patient-level data from 509 sites/centers across two phase III trials: LixiLan-O (NCT02058147; insulin-naive patients; NA, n=371; RoW, n=796) and LixiLan-L (NCT02058160; inadequately controlled patients on basal insulin; NA, n=196; RoW, n=535). Efficacy outcomes were: change from baseline to Week 30 in glycated hemoglobin (HbA1c), postprandial glucose (PPG), PPG excursions, fasting plasma glucose (FPG) and body weight; proportion of patients achieving HbA1c <42 mmol/mol (<7.0%); proportion of patients achieving composite endpoint: HbA1c <42 mmol/mol (<7.0%), no weight gain or symptomatic hypoglycemia (blood glucose ≤3.9 mmol/L (≤70 mg/dL)). Safety endpoints included incidence of documented symptomatic hypoglycemia and gastrointestinal (GI) adverse events. Results: Significantly larger reductions (p≤0.003) in HbA1c from baseline to Week 30 were achieved with iGlarLixi, compared with iGlar or lixisenatide, in NA and RoW patients in LixiLan-O (iGlarLixi vs iGlar: -0.31 and -0.29, respectively; iGlarLixi vs lixisenatide: -0.84 and -0.69, respectively) and in LixiLan-L (iGlarLixi vs iGlar: -0.5 and -0.51, respectively). Documented symptomatic hypoglycemia was similar between NA and RoW patients. iGlarLixi resulted in significant weight benefits versus iGlar (change from baseline -1.58 and -1.29 kg for NA and RoW patients, respectively; p<0.001). GI adverse events were similar for iGlarLixi and iGlar, but significantly higher for lixisenatide. Conclusions: iGlarLixi improved glycemic parameters versus iGlar or lixisenatide alone in both NA and RoW patients, with beneficial weight effects versus iGlar. iGlarLixi treatment responses, hypoglycemia risk and GI adverse events in NA patients were comparable with patients in the RoW. Trial registry: Clinicaltrials.gov NCT02058147 and NCT02058160.

Efficacy and safety of lixisenatide as add-on therapy to basal insulin in older adults with type 2 diabetes in the GetGoal-O Study.

BACKGROUND: This study compared the efficacy and safety of lixisenatide with placebo as add-on therapy to basal insulin (BI) in adults aged ≥70 years with type 2 diabetes (T2D), with or without moderate renal insufficiency. METHODS: This post hoc analysis evaluated data from non-frail patients with T2D inadequately controlled on BI with or without oral antidiabetic drugs (n = 108), randomized to once-daily lixisenatide 20 µg or placebo for 24 weeks (GetGoal-O Study). The primary endpoint was the change in HbA1c from baseline to Week 24. Secondary endpoints included changes from baseline in fasting plasma glucose, 2-hour postprandial plasma glucose (PPG), average seven-point self-monitored plasma glucose (SMPG), area under the curve for SMPG, daily BI dose, body weight, proportion of patients achieving HbA1c > 0.5%, and composite endpoints. Safety outcomes included the incidence of documented symptomatic hypoglycemia (plasma glucose <60 mg/dL) and gastrointestinal treatment-emergent adverse events (TEAEs). Outcomes were also analyzed by the occurrence of moderate renal insufficiency. RESULTS: Compared with placebo, lixisenatide-treated patients had significantly greater reductions in HbA1c, 2-hour PPG, average seven-point SMPG, and body weight. Documented symptomatic hypoglycemia was approximately two-fold higher in patients treated with placebo than lixisenatide (12.7% vs 5.7%). GI TEAEs occurred more frequently in the lixisenatide- than placebo-treated group (34% vs 9.1%). Moderate renal insufficiency (estimated glomerular filtration rate between ≥30 and <60 mL/min/1.73 m2 ) did not negatively affect lixisenatide efficacy or safety. A greater proportion of patients treated with lixisenatide than placebo achieved composite endpoints. CONCLUSIONS: Add-on therapy with lixisenatide in non-frail patients aged ≥70 years with T2D uncontrolled with BI is effective, safe, and well tolerated and should be considered in this population.

Once-Weekly Efpeglenatide Dose-Range Effects on Glycemic Control and Body Weight in Patients With Type 2 Diabetes on Metformin or Drug Naive, Referenced to Liraglutide.

OBJECTIVE: To explore the efficacy, safety, and tolerability of once-weekly efpeglenatide, a long-acting glucagon-like peptide 1 receptor agonist (GLP-1 RA), in early type 2 diabetes (T2D) (drug naive or on metformin monotherapy). RESEARCH DESIGN AND METHODS: EXCEED 203 was a 12-week, randomized, placebo-controlled, double-blind, parallel-group, dose-ranging study of efpeglenatide once weekly referenced to open-label liraglutide 1.8 mg (exploratory analysis). Participants, ∼90% on metformin monotherapy, were randomized to one of five efpeglenatide doses (0.3, 1, 2, 3, or 4 mg q.w.; n = 181), placebo (n = 37), or liraglutide (≤1.8 mg daily; n = 36). The primary efficacy end point was change in HbA1c from baseline to week 13. RESULTS: From a baseline HbA1c of 7.7-8.0% (61.0-63.9 mmol/mol), all efpeglenatide doses ≥1 mg significantly reduced HbA1c versus placebo (placebo-adjusted least squares [LS] mean changes 0.6-1.2%, P < 0.05 for all) to a final HbA1c of 6.3-6.8% (45.4-50.6 mmol/mol); masked efpeglenatide 4 mg was noninferior to open-label liraglutide. Greater proportions treated with efpeglenatide ≥1 mg than placebo achieved HbA1c <7% (61-72% vs. 24%, P < 0.05 for all), and greater reductions in body weight were observed with efpeglenatide 3 and 4 mg versus placebo (placebo-adjusted LS mean differences -1.4 and -2.0 kg, respectively, P < 0.05 for both). Rates of nausea and vomiting were consistent with other GLP-1 RAs and rapidly subsided after the initial 2 weeks. No neutralizing antibodies were detected with efpeglenatide. CONCLUSIONS: Efpeglenatide once weekly led to significant reductions in HbA1c and weight, with a safety profile consistent with the GLP-1 RA class in patients with early T2D mostly on metformin monotherapy.

Improved glycaemic control and lower hypoglycaemia risk with reduced prior oral antidiabetes drug therapy in patients with type 2 diabetes treated with insulin glargine 300 U/mL.

AIMS: Data from the EDITION 3 randomized study and the Clinformatics claims database were analysed to determine whether insulin glargine 300 U/mL (Gla-300) could provide insulin-naive patients with type 2 diabetes (T2D) on oral antidiabetes drugs (OADs) with reductions in prior OAD therapy without compromising glycaemic control, and while preserving its known low incidence of hypoglycaemia compared with insulin glargine 100 U/mL (Gla-100). METHODS: Patient-level data from EDITION 3 and de-identified data from the Clinformatics real-world claims database were analysed. RESULTS: At baseline, 70% of patients in EDITION 3 were on a background of ≥2 OADs. Among the 435 and 437 patients who initiated basal insulin with Gla-300 and Gla-100, respectively, at Month 6, 336 (77%) and 338 (77%) were using ≤1 OAD. Adding Gla-300 or Gla-100 similarly allowed for a reduction in background OAD medication in the Clinformatics dataset (N = 6430), such that, at 6 months postbasal insulin initiation, 14% of patients were no longer taking any OADs. In the analysis of the EDITION 3 study, reduction in OAD burden did not compromise glycaemic benefit, and the low incidence of hypoglycaemia associated with Gla-300 compared with Gla-100 was also preserved. Documented symptomatic hypoglycaemia (blood glucose ≤70 mg/dL) occurred in 30.5% vs 41.0% of patients treated with Gla-300 and Gla-100, respectively (P = 0.0442). CONCLUSION: Patients with T2D who initiate basal insulin with Gla-300 could potentially reduce their prior OAD use without compromising glycaemic control and with less hypoglycaemia than with Gla-100.

Assessing glycemic control with self-monitoring of blood glucose and hemoglobin A(1c) measurements.

Hemoglobin A(1c) (HbA(1c)) is the gold standard for monitoring glycemic control and serves as a surrogate for diabetes-related complications. Although HbA(1c) measures mean glycemic exposure during the preceding 2 to 3 months, it does not provide iInformation about day-to-day changes in glucose levels. Self-monitoring of blood glucose represents an important adjunct to HbA(1c) because it can distinguish among fasting, preprandial, and postprandial hyperglycemia; detect glycemic excursions; identify hypoglycemia; and provide immediate feedback to patients about the effect of food choices, activity, and medication on glycemic control.

Developing a pulmonary insulin delivery system for patients with diabetes.

BACKGROUND: Many patients with type 1 or type 2 diabetes mellitus (DM) do not achieve recommended glycemic goals. Insulin therapy is often delayed, despite its effectiveness in maintaining glycemic control, for reasons such as fear of needles or dislike of the complexity of injections. Inhaled dry powder insulin (IDPI) is approved for preprandial use in both the United States and Europe. METHODS: Relevant English-language publications were identified through a search of the PubMed database (1980-2007). Search terms included diabetes, in combination with subcutaneous and/or inhaled insulin. A similar search of abstracts from the 2006 American Diabetes Association 66th Annual Scientific Sessions was also performed. RESULTS: Eight clinical studies to date have reported that IDPI consistently improved glycemic control, whether used in combination with longer-acting SC insulin regimens in patients with type 1 or type 2 DM or to supplement or replace oral agent therapy in patients with type 2 DM. Evidence to date suggests that IDPI is associated with an acceptable tolerability profile, with a risk of hypoglycemia similar to that of SC insulin (risk ratios in 2 studies were 0.94 and 0.96, in favor of IDPI). Moreover, no clinically significant changes in pulmonary function have been noted. Patients treated with IDPI in clinical studies reported significantly greater improvements in overall satisfaction with treatment compared with SC insulin (P < 0.01) or oral agent therapy (P = 0.02). CONCLUSION: IDPI is effective and well tolerated for the treatment of diabetes and may be an option for patients to achieve glycemic control.

Triple therapy in type 2 diabetes: insulin glargine or rosiglitazone added to combination therapy of sulfonylurea plus metformin in insulin-naive patients.

OBJECTIVE: To evaluate the efficacy and safety of add-on insulin glargine versus rosiglitazone in insulin-naïve patients with type 2 diabetes inadequately controlled on dual oral therapy with sulfonylurea plus metformin. RESEARCH DESIGN AND METHODS: In this 24-week multicenter, randomized, open-label, parallel trial, 217 patients (HbA(1c) [A1C] 7.5-11%, BMI >25 kg/m(2)) on > or =50% of maximal-dose sulfonylurea and metformin received add-on insulin glargine 10 units/day or rosiglitazone 4 mg/day. Insulin glargine was forced-titrated to target fasting plasma glucose (FPG) < or =5.5-6.7 mmol/l (< or =100-120 mg/dl), and rosiglitazone was increased to 8 mg/day any time after 6 weeks if FPG was >5.5 mmol/l. RESULTS: A1C improvements from baseline were similar in both groups (-1.7 vs. -1.5% for insulin glargine vs. rosiglitazone, respectively); however, when baseline A1C was >9.5%, the reduction of A1C with insulin glargine was greater than with rosiglitazone (P < 0.05). Insulin glargine yielded better FPG values than rosiglitazone (-3.6 +/- 0.23 vs. -2.6 +/- 0.22 mmol/l; P = 0.001). Insulin glargine final dose per day was 38 +/- 26 IU vs. 7.1 +/- 2 mg for rosiglitazone. Confirmed hypoglycemic events at plasma glucose <3.9 mmol/l (<70 mg/dl) were slightly greater for the insulin glargine group (n = 57) than for the rosiglitazone group (n = 47) (P = 0.0528). The calculated average rate per patient-year of a confirmed hypoglycemic event (<70 mg/dl), after adjusting for BMI, was 7.7 (95% CI 5.4-10.8) and 3.4 (2.3-5.0) for the insulin glargine and rosiglitazone groups, respectively (P = 0.0073). More patients in the insulin glargine group had confirmed nocturnal hypoglycemia of <3.9 mmol/l (P = 0.02) and <2.8 mmol/l (P < 0.05) than in the rosiglitazone group. Effects on total cholesterol, LDL cholesterol, and triglyceride levels from baseline to end point with insulin glargine (-4.4, -1.4, and -19.0%, respectively) contrasted with those of rosiglitazone (+10.1, +13.1, and +4.6%, respectively; P < 0.002). HDL cholesterol was unchanged with insulin glargine but increased with rosiglitazone by 4.4% (P < 0.05). Insulin glargine had less weight gain than rosiglitazone (1.6 +/- 0.4 vs. 3.0 +/- 0.4 kg; P = 0.02), fewer adverse events (7 vs. 29%; P = 0.0001), and no peripheral edema (0 vs. 12.5%). Insulin glargine saved $235/patient over 24 weeks compared with rosiglitazone. CONCLUSIONS: Low-dose insulin glargine combined with a sulfonylurea and metformin resulted in similar A1C improvements except for greater reductions in A1C when baseline was > or =9.5% compared with add-on maximum-dose rosiglitazone. Further, insulin glargine was associated with more hypoglycemia but less weight gain, no edema, and salutary lipid changes at a lower cost of therapy.

Lixisenatide Therapy in Older Patients With Type 2 Diabetes Inadequately Controlled on Their Current Antidiabetic Treatment: The GetGoal-O Randomized Trial.

OBJECTIVE: To evaluate the efficacy and safety of lixisenatide versus placebo on glycemic control in older patients with type 2 diabetes uncontrolled on their current antidiabetic treatment. RESEARCH DESIGN AND METHODS: In this phase III, double-blind, randomized, placebo-controlled, two-arm, parallel-group, multicenter trial, patients aged ≥70 years were randomized to receive once-daily lixisenatide 20 µg or placebo before breakfast concomitantly with their existing antidiabetic therapy (including insulin) for 24 weeks. Patients at risk for malnutrition or with moderate to severe cognitive impairment were excluded. The primary end point was absolute change in HbA1c from baseline to week 24. Secondary end points included change from baseline to week 24 in 2-h postprandial plasma glucose (PPG) and body weight. RESULTS: A total of 350 patients were randomized. HbA1c decreased substantially with lixisenatide (-0.57% [6.2 mmol/mol]) compared with placebo (+0.06% [0.7 mmol/mol]) from baseline to week 24 (P < 0.0001). Mean reduction in 2-h PPG was significantly greater with lixisenatide (-5.12 mmol/L) than with placebo (-0.07 mmol/L; P < 0.0001). A greater decrease in body weight was observed with lixisenatide (-1.47 kg) versus placebo (-0.16 kg; P < 0.0001). The safety profile of lixisenatide in this older population, including rates of nausea and vomiting, was consistent with that observed in other lixisenatide studies. Hypoglycemia was reported in 17.6% of patients with lixisenatide versus 10.3% with placebo. CONCLUSIONS: In nonfrail older patients uncontrolled on their current antidiabetic treatment, lixisenatide was superior to placebo in HbA1c reduction and in targeting postprandial hyperglycemia, with no unexpected safety findings.

The metabolic syndrome: a call to action.

Metabolic syndrome, a cluster of risk factors that enhances the risk for atherosclerotic cardiovascular disease, has received increasing attention in recent years, especially as the worldwide prevalence of obesity has become better defined. Recent controversy has questioned the scientific basis for metabolic syndrome, but does not negate its value as a description of a common phenotype of patients encountered in clinical practice. Revised and refined diagnostic criteria may be useful for physicians. While more research is needed to understand the pathology of the metabolic syndrome, there is no ambiguity that physicians should treat cardiovascular risk factors in individuals with metabolic syndrome.

Reduced hypoglycemia risk with insulin glargine: a meta-analysis comparing insulin glargine with human NPH insulin in type 2 diabetes.

OBJECTIVE: Insulin glargine (LANTUS) is a once-daily basal insulin analog with a smooth 24-h time-action profile that provides effective glycemic control with reduced hypoglycemia risk (particularly nocturnal) compared with NPH insulin in patients with type 2 diabetes. A recent "treat-to-target" study has shown that more patients on insulin glargine reached HbA(1c) levels < or =7.0% without confirmed nocturnal hypoglycemia compared with NPH insulin. We further assessed the risk for hypoglycemia in a meta-analysis of controlled trials of a similar design for insulin glargine versus once- or twice-daily NPH insulin in adults with type 2 diabetes. RESEARCH DESIGN AND METHODS: All studies were 24-28 weeks long, except one 52-week study, for which interim 20-week data were used. RESULTS: Patient demographics were similar between the insulin glargine (n = 1,142) and NPH insulin (n = 1,162) groups. The proportion of patients achieving target HbA(1c) (< or =7.0%) was similar between insulin glargine-and NPH insulin-treated patients (30.8 and 32.1%, respectively). There was a consistent significant reduction of hypoglycemia risk associated with insulin glargine, compared with NPH insulin, in terms of overall symptomatic (11%; P = 0.0006) and nocturnal (26%; P < 0.0001) hypoglycemia. Most notably, the risk of severe hypoglycemia and severe nocturnal hypoglycemia were reduced with insulin glargine by 46% (P = 0.0442) and 59% (P = 0.0231), respectively. CONCLUSIONS: These results confirmed that insulin glargine given once daily reduces the risk of hypoglycemia compared with NPH insulin, which can facilitate more aggressive insulin treatment to a HbA(1c) target of < or =7.0% in patients with type 2 diabetes.

A novel option for prandial insulin therapy: inhaled insulin.

Many adults with type 2 diabetes (T2D) do not achieve or maintain glycemic targets on oral antidiabetes drugs (OADs) alone and require insulin therapy. Although initiating basal insulin is common when treatment needs to be intensified, individualization of therapy (in line with current guidelines) may lead more health care professionals (HCPs) to add rapid-acting insulin (RAI) to OAD regimens for treatment of postprandial hyperglycemia to achieve glycated hemoglobin (A1C) targets. HCPs and patients are concerned about the burden associated with injections. Inhaled Technosphere® insulin (inhaled TI) - as an alternative to injectable bolus doses of prandial insulin - may increase patient and HCP willingness to intensify therapy and improve compliance with more complex regimens. Clinical studies have shown that inhaled TI is effective and well tolerated as a prandial insulin, and has the potential to improve treatment satisfaction and quality of life in adults with T2D. The favorable pharmacokinetic profile of inhaled TI (i.e., a very rapid onset of action and a short duration of anti-hyperglycemic effect) may reduce the risk of insulin stacking (overlapping effects of RAI injections taken < 4 hours apart) and postprandial hypoglycemia. In this review, we present inhaled TI as an alternative to OADs or injected insulin as adjunctive therapy, for consideration by HCPs striving to achieve glycemic targets for their patients.

Insulin glulisine provides improved glycemic control in patients with type 2 diabetes.

OBJECTIVE: Insulin glulisine is a novel analog of human insulin designed for use as a rapid-acting insulin. This study compared the safety and efficacy of glulisine with regular human insulin (RHI) in combination with NPH insulin. RESEARCH DESIGN AND METHODS: In total, 876 relatively well-controlled patients with type 2 diabetes (mean HbA1c 7.55%) were randomized and treated with glulisine/NPH (n = 435) or RHI/NPH (n = 441) for up to 26 weeks in this randomized, multicenter, multinational, open-label, parallel-group study. Subjects were allowed to continue the same dose of prestudy regimens of oral antidiabetic agent (OAD) therapy (unless hypoglycemia necessitated a dose change). RESULTS: A slightly greater reduction from baseline to end point of HbA1c was seen in the glulisine group versus RHI (-0.46 vs. -0.30% with RHI; P = 0.0029). Also, at end point, lower postbreakfast (156 vs. 162 mg/dl [8.66 vs. 9.02 mmol/l]; P < 0.05) and postdinner (154 vs. 163 mg/dl [8.54 vs. 9.05 mmol/l]; P < 0.05) blood glucose levels were noted. Symptomatic hypoglycemia (overall, nocturnal, and severe) and weight gain were comparable between the two treatment groups. There were no between-group differences in baseline-to-end point changes in insulin dose. CONCLUSIONS: Twice-daily glulisine associated with NPH can provide small improvements in glycemic control compared with RHI in patients with type 2 diabetes who are already relatively well controlled on insulin alone or insulin plus OADs. The clinical relevance of such a difference remains to be established.

Empagliflozin for the treatment of type 2 diabetes mellitus: An overview of safety and efficacy based on Phase 3 trials.

In the treatment of type 2 diabetes mellitus (T2DM), a relatively new class of oral agents inhibits sodium-glucose cotransporter 2 (SGLT2), reducing reabsorption of filtered glucose and increasing urinary glucose excretion. Numerous SGLT2 inhibitors have been approved for the treatment of T2DM in adults, most recently empagliflozin, which was approved in Europe and the US in 2014. The Phase 3 program has enrolled >14,000 patients and has assessed the efficacy and safety of empagliflozin as monotherapy and in combination. These studies have demonstrated improvements in glycemic control, and modest reductions in body weight and blood pressure. Empagliflozin was generally well tolerated, with no increased risk of hypoglycemia versus placebo as monotherapy or as add-on therapy, except when given with sulfonylurea. The studies showed an increased risk of urinary tract and genital infections with empagliflozin, although most infections were mild to moderate in intensity. Furthermore, small (but clinically insignificant) increases in hematocrit and lipid levels have been observed for empagliflozin. Due to the mode of action of empagliflozin, care should be exercised when treating patients at risk of volume depletion. The risks and benefits must be weighed for each patient, but the data reviewed herein show promise for empagliflozin as a treatment for patients with T2DM.

Recognizing and minimizing hypoglycemia: The need for individualized care.

Hypoglycemia is a condition known to disrupt many everyday activities and is associated with increased risks of hospitalization, falls, motor vehicle accidents and mortality. Many patients with diabetes have an increased risk of hypoglycemia due to interventions targeting glycemic control. In these patients, hypoglycemia and fear of hypoglycemia may further reduce adherence to glucose-lowering regimens, contributing to the further aggravation of diabetes-related complications. Avoiding hypoglycemia should be one of the principal goals of any treatment strategies employing agents that can induce hypoglycemia in order to prevent the occurrence of associated symptoms and consequences. The education of patients and their families is an important feature of individualized management strategies in order to prevent, mitigate and treat hypoglycemic episodes. Patients with diabetes need to be made aware of how to recognize the signs of hypoglycemia and of the simple, highly effective steps that they can take to self-manage hypoglycemic episodes. Clinicians should be familiar with the risk factors for hypoglycemia, especially the profiles of the different classes of glucose-lowering medications such as the sulfonylureas and insulin. This article aims to review the risk factors for hypoglycemia and its implications for patients and healthcare systems, and provide practical advice for minimizing the risk of hypoglycemia and its consequences.

Glycemic control with glyburide/metformin tablets in combination with rosiglitazone in patients with type 2 diabetes: a randomized, double-blind trial.

PURPOSE: To assess the efficacy and safety of adding rosiglitazone to an established regimen of glyburide/metformin in patients with type 2 diabetes who had not achieved adequate glycemic control (glycosylated hemoglobin [HbA1C] levels >7.0% and < or =10.0%). METHODS: Following an open-label, lead-in phase to optimize the dosing of glyburide/metformin tablets, 365 patients randomly received additive therapy comprising rosiglitazone (4 mg once daily) or placebo for 24 weeks. Based on glycemic response, rosiglitazone dose was maintained or increased to 4 mg twice daily. Glyburide/metformin dose was maintained or reduced by 2.5/500 mg for symptomatic hypoglycemia. The primary endpoint was the change in HbA1C level from baseline to week 24. The proportions of patients achieving HbA1C levels <7% and a fasting plasma glucose level <126 mg/dL were also assessed. RESULTS: After 24 weeks, therapy with glyburide/metformin plus rosiglitazone resulted in a greater reduction in HbA1C levels (-1.0%, P<0.001) compared with combination therapy that included placebo, and in a larger proportion of patients (42% vs. 14%) who attained levels <7%. The difference in fasting plasma glucose levels between groups was -48 mg/dL (P<0.001), favoring glyburide/metformin plus rosiglitazone. The adverse event profile in the rosiglitazone-treated group included mild-to-moderate edema (8%), hypoglycemia (22%), and weight gain of 3 kg. No patient experienced hypoglycemia requiring third-party assistance. CONCLUSION: In patients with inadequate glycemic control despite established glyburide/metformin therapy, the addition of rosiglitazone improves glycemic control, allowing more patients to achieve an HbA1C level <7% and perhaps delaying the need for insulin treatment.

New strategies for basal insulin treatment in type 2 diabetes mellitus.

BACKGROUND: The clinical progression of type 2 diabetes mellitus (DM) is well understood. Glycemic control gradually deteriorates, and progression of DM eventually leads to an increased risk for microvascular and macrovascular complications. Reassessment of current insulin treatment strategies leading to restoration of glycemic control is essential to prevent or stop the progression of type 2 DM and its complications. OBJECTIVE: The purpose of this article was to review the importance of instituting a strategy of basal insulin therapy in patients with type 2 DM. METHODS: Relevant articles were obtained through an online search of PubMed and MEDLINE for literature published from 1990 to 2003. The search terms used were insulin therapy, combination oral therapy, treatment failure, glycemic control, insulin analogues, insulin glargine, basal insulin, and microvascular complications. RESULTS: Large-scale intervention trials, such as the United Kingdom Prospective Diabetes Study (UKPDS), have reported that patients with type 2 DM treated with oral combination therapy are unable to maintain glycemic control. These observations have led to a reassessment of the role of insulin therapy in type 2 DM. The importance of tight glycemic control through the aggressive use of insulin early in the course of the disease is apparent from the UKPDS, Diabetes Control and Complications Trial, and other, smaller studies. Considerable evidence indicates that initiating a basal insulin-replacement strategy with an existing oral regimen can result in regaining glycemic control. Evidence emerging from recent studies indicates that use of intensive insulin therapy early in the course of the disease may have a positive clinical impact on outcome and slow the progression of complications. The availability of basal insulin analogues has expanded treatment options and improved the efficacy of therapeutic regimens for type 2 DM. CONCLUSIONS: The available data suggest using an earlier transition from monotherapy to combination therapy to minimize disease-associated morbidity. The availability of new insulin analogues has expanded therapeutic options and offers the potential to enhance the efficacy of therapeutic regimens for type 2 DM as well as improve the ease and safety of treatment when glycosylated hemoglobin cannot be maintained <7% on > or =1 oral antidiabetic agent.

Lipid effects of glyburide/metformin tablets in patients with type 2 diabetes mellitus with poor glycemic control and dyslipidemia in an open-label extension study.

BACKGROUND: Because both type 2 diabetes and elevated plasma lipid levels are important independent risk factors for cardiovascular disease and coronary heart disease, the choice of an antihyperglycemic agent for patients with type 2 diabetes--in whom abnormal plasma lipid levels are often seen-should take into account effects on lipids as well as on markers of glycemic control. OBJECTIVE: This study assessed the effects on lipid levels of glyburide/metformin tablets in the treatment of type 2 diabetes, particularly in a group of patients who had poor glycemic control and dyslipidemia at baseline. METHODS: This 52-week, open-label study was an extension of a 32-week, double-blind, placebo-controlled study. The patient population was drawn from 3 groups: those who completed the double-blind study, those who were discontinued from the double-blind study, and those who were ineligible for the double-blind study based on predefined measures of glycemic control (screening fasting plasma glucose > 240 mg/dL and glycosylated hemoglobin [HbA1c] < or = 12%, or HbA1c 11%-12%) and were directly enrolled in the open-label extension study. Patients with an HbA1c of < 9% received glyburide/ metformin tablets 1.25 mg/250 mg BID; those with an HbA1c > or = 9% received glyburide/ metformin tablets 2.5 mg/500 mg BID. Changes in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels were assessed for 52 weeks. RESULTS: The study population included 828 patients: 515 who completed the double-blind study, 138 who were discontinued from the double-blind study, and 175 who were enrolled directly. Direct enrollees had poor glycemic control and dyslipidemia at baseline. Improvements in plasma lipid levels were seen as early as week 13. At week 52, the mean change in TC from baseline was -8.0 mg/dL for the total population (95% CI, -10.9 to -5.2; P < 0.05) and -23.2 mg/dL for direct enrollees (95% CI, -30.1 to -16.4; P < 0.05). The mean decrease in LDL-C from baseline for the total population was 2.86 mg/dL (95% CI, -5.3 to -0.4; P < 0.05), compared with a reduction of 13.3 mg/dL for direct enrollees (95% CI, -18.5 to -8.1; P < 0.05). Mean HDL-C levels were minimally affected. Mean TG levels decreased by 27.8 mg/dL for the entire population (95% CI, -42.9 to -12.8; P < 0.05) and by 99.7 mg/dL for direct enrollees (95% CI, -152.5 to -46.8; P < 0.05). CONCLUSION: In this open-label extension study, treatment with glyburide/ metformin tablets for type 2 diabetes had a durable, favorable effect on lipid levels, particularly in those with poor glycemic control and dyslipidemia at baseline.