Further Improvement in Postprandial Glucose Control With Addition of Exenatide or Sitagliptin to Combination Therapy With Insulin Glargine and Metformin: A proof-of-concept study

OBJECTIVE

To assess the effect of a 4-week adjunctive therapy of exenatide (EXE) (5–10 μg b.i.d.) or sitagliptin (SITA) (100 mg once daily) in response to a standardized breakfast meal challenge in 48 men or women with type 2 diabetes receiving insulin glargine (GLAR) + metformin (MET).

RESEARCH DESIGN AND METHODS

This was a single-center, randomized, open-label, active comparator–controlled study with a three-arm parallel group design, consisting of: screening, 4- to 8-week run-in period, 4-week treatment period, and follow-up. In all three groups, the GLAR dose was titrated according to an algorithm (fasting blood glucose ≤100 mg/dl).

RESULTS

The unadjusted 6-h postprandial blood glucose excursion of both GLAR + MET + EXE and GLAR + MET + SITA was statistically significantly smaller than that of GLAR + MET (606 ± 104 vs. 612 ± 133 vs. 728 ± 132 mg/dl/h; P = 0.0036 and 0.0008). A1C significantly decreased in all three groups (P < 0.0001), with the greatest reduction of −1.9 ± 0.7 under GLAR + MET + EXE (GLAR + MET + SITA −1.5 ± 0.7; GLAR + MET −1.2 ± 0.5%-points; GLAR + MET + EXE vs. GLAR + MET P = 0.0154). The American Diabetes Association A1C target of <7.0% was reached by 80.0, 87.5, and 62.5% of subjects, respectively. GLAR + MET + EXE had the highest number (47) of adverse events, mostly gastrointestinal (56%) with one dropout. GLAR + MET or GLAR + MET + SITA only had 10 and 12 adverse events, respectively, and no dropouts. Hypoglycemia (blood glucose <50 mg/dl) rates were low and comparable among groups. Weight decreased with GLAR + MET + EXE (−0.9 ± 1.7 kg; P = 0.0396) and increased slightly with GLAR + MET (0.4 ± 1.5 kg; NS; GLAR + MET + EXE vs. GLAR + MET P = 0.0377).

CONCLUSIONS

EXE or SITA added to GLAR + MET further substantially reduced postprandial blood glucose excursions. Longer-term studies in a larger population are warranted to confirm these findings.The UK Prospective Diabetes Study (UKPDS) demonstrated that good glycemic control in type 2 diabetes is associated with a reduced risk of diabetes complications (1). After lifestyle modifications (diet and exercise) and oral hypoglycemic agents (OHAs) the addition of basal insulin to OHAs is common practice (2), because this kind of regimen requires only a single injection in most cases and can improve glycemic control. Its use, however, may not adequately control postprandial hyperglycemia or may be associated with hypoglycemia and/or weight gain (3,4). Because obesity is frequently present in subjects with type 2 diabetes (5) and represents a factor contributing to insulin resistance (5) and cardiovascular risk (5), weight gain may be particularly undesirable.A significant advance in basal insulin therapy was the introduction of insulin glargine, a long-acting insulin analog with an extended duration of action of ∼24 h without exhibiting a pronounced peak (6,7). In subjects with type 2 diabetes, insulin glargine was shown to confer glycemic control at least equivalent to that of NHP insulin with a lower incidence of hypoglycemia (3,8,9). However, insulin glargine still has the drawbacks of insulin treatment such as weight gain (3,8,9) and a lower effect on postprandial glucose excursions (8) than on fasting glucose values.Exenatide is the first-in-class glucagon-like peptide 1 (GLP-1) receptor agonist (or incretin mimetic) approved in the U.S. and Europe (10). Compared with placebo, exenatide statistically reduced A1C, whereas there was no difference in A1C improvement between exenatide and insulin glargine or biphasic insulin aspart (11–14). However, postprandial glycemia as well as weight was further reduced with exenatide compared with insulin glargine or biphasic insulin, with a similar risk of hypoglycemia (12,13).Sitagliptin is an approved once-daily, potent, and highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor (15). When added to metformin, sitagliptin, given at a dose of 100 mg once daily over 24 weeks, led to significant reductions in A1C, fasting, and 2-h postprandial plasma glucose and was weight-neutral (16).With this background, a therapy controlling both fasting blood glucose (FBG) and postprandial glucose excursions seems to be a promising approach for subjects with type 2 diabetes (17–21). Therefore, in the present study we investigated the influence of a 4-week adjunctive therapy of either a GLP-1 receptor agonist (exenatide) or a DPP-4 inhibitor (sitagliptin) to titrated basal insulin (insulin glargine) plus metformin versus the continuation with titrated insulin glargine plus metformin alone as active comparator in subjects with type 2 diabetes.     

DURATION-1: Exenatide Once Weekly Produces Sustained Glycemic Control and Weight Loss Over 52 Weeks

OBJECTIVE

In the Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once Weekly (DURATION-1) study, the safety and efficacy of 30 weeks of treatment with the glucagon-like peptide-1 receptor agonist exenatide once weekly (exenatide QW; 2 mg) was compared with exenatide BID in 295 patients with type 2 diabetes. We now report the safety and efficacy of exenatide QW in 1) patients who continued treatment for an additional 22 weeks (52 weeks total) and 2) patients who switched from exenatide BID to exenatide QW after 30 weeks.

RESEARCH DESIGN AND METHODS

In this randomized, multicenter, comparator-controlled, open-label trial, 258 patients entered the 22-week open-ended assessment phase (n = 128 QW-only; n = 130 BID→QW). A1C, fasting plasma glucose (FPG), body weight, blood pressure, fasting lipids, safety, and tolerability were assessed.

RESULTS

Patients continuing exenatide QW maintained A1C improvements through 52 weeks (least squares mean −2.0% [95% CI −2.1 to −1.8%]). Patients switching from exenatide BID to exenatide QW achieved further A1C improvements; both groups exhibited the same A1C reduction and mean A1C (6.6%) at week 52. At week 52, 71 and 54% of all patients achieved A1C <7.0% and ≤6.5%, respectively. In both treatment arms, FPG was reduced by >40 mg/dl, and body weight was reduced by >4 kg after 52 weeks. Nausea occurred less frequently in this assessment period and was predominantly mild. No major hypoglycemia was observed.

CONCLUSION

Exenatide QW elicited sustained improvements in glycemic control and body weight through 52 weeks of treatment. Patients switching to exenatide QW experienced further improvements in A1C and FPG, with sustained weight loss.Type 2 diabetes is a complex and increasingly prevalent disease associated with interrelated comorbidities, including obesity, dyslipidemia, and hypertension. The importance of treating not only hyperglycemia, but also the associated comorbidities, is recognized as necessary to reduce the risk of complications, particularly cardiovascular disease (1). Lifestyle modification can improve glycemic control as well as body weight, blood pressure, and lipid profiles; however, behavioral modifications are inherently difficult, and most patients eventually require multiple medications (2–6). Although several classes of antihyperglycemic medications are currently indicated for the treatment of type 2 diabetes, most of them do not improve the comorbidities and several are associated with weight gain.Exenatide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, improves glycemic control in patients with type 2 diabetes through multiple mechanisms of action: increased glucose-dependent insulin secretion, attenuated postprandial glucagon secretion, slowed gastric emptying, and increased satiety (7,8). The twice-daily formulation of exenatide (exenatide BID) improves both fasting and postprandial glucose control, resulting in A1C reductions of roughly 0.8–1.0% in placebo-controlled trials (9–12) and 1.0–1.4% in open-label trials (13–15). These improvements in glucose control were maintained in patients completing 3 years of treatment (−1.0%) (16). Exenatide therapy is also associated with weight loss and improvement in cardiovascular risk factors, including blood pressure and serum lipid profiles (16). Furthermore, the glucose-dependent mechanisms of action of exenatide minimize the risk of hypoglycemia. GLP-1R agonists have recently been added to the American Diabetes Association and European Association for the Study of Diabetes consensus algorithm for the treatment of type 2 diabetes as an option after the addition of metformin in patients in whom body weight and hypoglycemia risk are concerns (1).Exenatide BID is administered within the 60-min period before the morning and evening meals and primarily exerts its pharmacodynamic effects on glucose concentrations during the postprandial period. A long-acting once-weekly formulation of exenatide (exenatide QW) has been developed. Weekly administration of 2 mg exenatide QW results in therapeutic plasma exenatide concentrations within 2 weeks and steady-state plasma exenatide concentrations within the therapeutic target range 6–7 weeks after initiation of therapy (17,18).The Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once Weekly (DURATION-1) trial was designed as a two-stage protocol. We previously reported the first stage, a randomized open-label comparison of exenatide QW to exenatide BID in patients with type 2 diabetes over 30 weeks (17). Both therapies improved glycemic control, and the improvement in A1C observed with exenatide QW treatment was significantly greater than that observed with exenatide BID (−1.9 vs. −1.5%, respectively). Similar improvements in body weight, blood pressure, and fasting lipids were demonstrated with both forms of exenatide therapy. We now describe 52-week results from the second phase of the DURATION-1 trial which examined the safety and efficacy of 1) switching from exenatide BID to exenatide QW after 30 weeks of treatment and 2) continuing exenatide QW treatment for an additional 22 weeks (52 weeks total).     

The Role of Adjunctive Exenatide Therapy in Pediatric Type 1 Diabetes

OBJECTIVE

Exenatide improves postprandial glycemic excursions in type 2 diabetes. Exenatide could benefit type 1 diabetes as well. We aimed to determine an effective and safe glucose-lowering adjuvant exenatide dose in adolescents with type 1 diabetes.

RESEARCH DESIGN AND METHODS

Eight subjects completed a three-part double-blinded randomized controlled study of premeal exenatide. Two doses of exenatide (1.25 and 2.5 μg) were compared with insulin monotherapy. Prandial insulin dose was reduced by 20%. Gastric emptying and hormones were analyzed for 300 min postmeal.

RESULTS

Treatment with both doses of exenatide versus insulin monotherapy significantly reduced glucose excursions over 300 min (P < 0.0001). Exenatide administration failed to suppress glucagon but delayed gastric emptying (P < 0.004).

CONCLUSIONS

Adjunctive exenatide therapy reduces postprandial hyperglycemia in adolescents with type 1 diabetes. This reduction in glucose excursion occurs despite reduction in insulin dose. We suggest that exenatide has therapeutic potential as adjunctive therapy in type 1 diabetes.Intensive insulin therapy delays/prevents complications associated with type 1 diabetes (1,2). However, insulin monotherapy fails to achieve normoglycemia (3). Postprandial hyperglycemia and hypoglycemia (4,5) continue to create impediments to management. Even the closed-loop system fails to normalize postprandial hyperglycemia (6). Additional therapies to insulin are needed to achieve optimal glycemic control.Glucagon-like peptide (GLP)-1 is an incretin secreted in response to nutrient ingestion (7). Physiological GLP-1 enhances insulin secretion, delays gastric emptying, and suppresses glucagon. But because of its short half-life (8), it is unsuitable for clinical application.Exenatide is a long-acting GLP-1 receptor agonist and acts similarly to native GLP-1 (9). Exenatide is effective in decreasing postprandial hyperglycemia in type 2 diabetes (10). However, there are few studies using exenatide in type 1 diabetes and none in adolescents. The objective of our study was to examine the effect of adjuvant premeal exenatide and insulin on postprandial glucose in type 1 diabetes and establish an effective and safe glucose-lowering dose.     

Effect of Insulin Glargine and n-3FA on Carotid Intima-Media Thickness in People With Dysglycemia at High Risk for Cardiovascular Events: The Glucose Reduction and Atherosclerosis Continuing Evaluation Study (ORIGIN-GRACE)

OBJECTIVE

To evaluate the effects of insulin glargine and n-3 polyunsaturated fatty acid (n-3FA) supplements on carotid intima-media thickness (CIMT).

RESEARCH DESIGN AND METHODS

We enrolled 1,184 people with cardiovascular (CV) disease and/or CV risk factors plus impaired fasting glucose, impaired glucose tolerance, or early type 2 diabetes in a randomized multicenter 2 × 2 factorial design trial. Participants received open-label insulin glargine (targeting fasting glucose levels ≤5.3 mmol/L [95 mg/dL]) or standard glycemic care and double-blind therapy with a 1-g capsule of n-3FA or placebo. The primary trial outcome was the annualized rate of change in maximum CIMT for the common carotid, bifurcation, and internal carotid artery segments. Secondary outcomes were the annualized rates of change in maximum CIMT for the common carotid and the common carotid plus bifurcation, respectively. Baseline followed by annual ultrasounds were obtained during a median follow-up of 4.9 years.

RESULTS

Compared with standard care, insulin glargine reduced the primary CIMT outcome, but the difference was not statistically significant (difference = 0.0030 ± 0.0021 mm/year; P = 0.145) and significantly reduced the secondary CIMT outcomes (differences of 0.0033 ± 0.0017 mm/year [P = 0.049] and 0.0045 ± 0.0021 mm/year [P = 0.032], respectively). There were no differences in the primary and secondary outcomes between the n-3FA supplement and placebo groups.

CONCLUSIONS

In people with CV disease and/or CV risk factors and dysglycemia, insulin glargine used to target normoglycemia modestly reduced CIMT progression, whereas daily supplementation with n-3FA had no effect on CIMT progression.Atherosclerosis is the major cause of death and disability in people with type 2 diabetes and lesser degrees of dysglycemia (1,2). Large epidemiological studies show consistent independent associations between glycemia and cardiovascular (CV) risk (1–4), and the metabolic abnormalities associated with dysglycemia promote atherosclerosis (5). Exogenous insulin can provide effective glycemic control, but its effects on atherosclerosis are unknown. Moreover, some studies suggest possible proatherogenic effects (6,7).Essential long-chain n-3 polyunsaturated fatty acids (n-3FA) may have beneficial effects on atherosclerosis (8). Higher intake of fish or n-3FA supplements is associated with lower rates of coronary heart disease and death (9,10) and lower atherosclerotic burden (11,12), and some, but not all, previous trials reported reduced CV events in patients receiving n-3FA supplements (13–16). The effects of these supplements on human atherosclerosis progression were evaluated in a few small studies, which were inconclusive (17–21).Therefore, we evaluated the effects of insulin glargine and n-3FA supplements on carotid intima-media thickness (CIMT) in people with dysglycemia and additional risk factors for atherosclerosis progression in a substudy of the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial (22–24).     

Costs and Consequences Associated With Newer Medications for Glycemic Control in Type 2 Diabetes

OBJECTIVE

Newer medications offer more options for glycemic control in type 2 diabetes. However, they come at considerable costs. We undertook a health economic analysis to better understand the value of adding two newer medications (exenatide and sitagliptin) as second-line therapy to glycemic control strategies for patients with new-onset diabetes.

RESEARCH DESIGN AND METHODS

We performed a cost-effectiveness analysis for the U.S. population aged 25–64. A lifetime analytic horizon and health care system perspective were used. Costs and quality-adjusted life years (QALYs) were discounted at 3% annually, and costs are presented in 2008 U.S. dollars. We compared three glycemic control strategies: 1) glyburide as a second-line agent, 2) exenatide as a second-line agent, and 3) sitagliptin as a second-line agent. Outcome measures included QALYs gained, incremental costs, and the incremental cost-effectiveness ratio associated with each strategy.

RESULTS

Exenatide and sitagliptin conferred 0.09 and 0.12 additional QALYs, respectively, relative to glyburide as second-line therapy. In base case analysis, exenatide was dominated (cost more and provided fewer QALYs than the next most expensive option), and sitagliptin was associated with an incremental cost-effectiveness ratio of $169,572 per QALY saved. Results were sensitive to assumptions regarding medication costs, side effect duration, and side effect–associated disutilities.

CONCLUSIONS

Exenatide and sitagliptin may confer substantial costs to health care systems. Demonstrated gains in quality and/or quantity of life are necessary for these agents to provide economic value to patients and health care systems.Diabetes is increasingly endemic in the U.S. In 2007, 23.5 million Americans aged >20 years had diabetes compared with 18.0 million in 2002 (1). Diabetes was the seventh leading cause of death in 2006 (1). It remains the leading cause of blindness, end-stage renal disease, and nontraumatic amputations. A total of $116 billion in direct health care costs are attributable to diabetes annually (2).Large clinical trials from the U.S. and Europe have demonstrated that tighter glycemic control can prevent diabetes complications in individuals with recent-onset disease (3,4); in older individuals with longer disease duration, recent studies have found no cardiovascular benefit of tight control (5) and possible harm (6). In the past several years, the U.S. Food and Drug Administration (FDA) approved nine new products for glycemic control (7). Some are new forms or combinations of existing classes, whereas others belong to new therapeutic classes such as amylin analogs, glucagon-like peptide-1 receptor agonists, incretins, and dipeptidyl peptidase-IV inhibitors.Although these agents increase the management options available, they come at increased costs (8). Previous analyses of the health economics of glycemic control were published before the FDA approval of many new agents (9–11). Recent studies have examined the cost-effectiveness of exenatide or sitagliptin in European populations, reflecting costs and management appropriate for the modeled populations but not necessarily reflective of the U.S. (12–14).In this analysis, we estimate the costs associated with two of the most prescribed examples of these new medications: exenatide and sitagliptin. We project the gains in health outcomes necessary to have these newer medications pose good economic value for patients with new-onset diabetes, using the incremental cost-effectiveness ratio as our metric.     

Sex and Racial/Ethnic Differences in Cardiovascular Disease Risk Factor Treatment and Control Among Individuals With Diabetes in the Multi-Ethnic Study of Atherosclerosis (MESA)

OBJECTIVE

To examine sex and racial/ethnic differences in cardiovascular risk factor treatment and control among individuals with diabetes in the Multi-Ethnic Study of Atherosclerosis (MESA).

RESEARCH DESIGN AND METHODS

This study was an observational study examining mean levels of cardiovascular risk factors and proportion of subjects achieving treatment goals.

RESULTS

The sample included 926 individuals with diabetes. Compared with men, women were 9% less likely to achieve LDL cholesterol <130 mg/dl (adjusted prevalence ratio 0.91 [0.83–0.99]) and systolic blood pressure (SBP) <130 mmHg (adjusted prevalence ratio 0.91 [0.85–0.98]). These differences diminished over time. A lower percentage of women used aspirin (23 vs. 33%; P < 0.001). African American and Hispanic women had higher mean levels of SBP and lower prevalence of aspirin use than non-Hispanic white women.

CONCLUSIONS

Women with diabetes had unfavorable cardiovascular risk factor profiles compared with men. African American and Hispanic women had less favorable profiles than non-Hispanic white women.Population-based health survey data suggest that sex and racial/ethnic disparities are present in diabetes process of care measures and cardiovascular risk factor control (1–9). Available data also indicate that sex-specific race/ethnicity differences are present in cardiovascular risk factor control, but these data are limited to Medicare and Veterans'' Hospital patient populations (5,10–13). We therefore performed analyses of participants with diabetes in the Multi-Ethnic Study of Atherosclerosis (MESA) to examine sex and sex-specific racial/ethnic differences in cardiovascular risk factor treatment and control.     

Dose-Response Effects of Insulin Glargine in Type 2 Diabetes

OBJECTIVE

To determine the pharmacokinetic and pharmacodynamic dose-response effects of insulin glargine administered subcutaneously in individuals with type 2 diabetes.

RESEARCH DESIGN AND METHODS

Twenty obese type 2 diabetic individuals (10 male and 10 female, aged 50 ± 3 years, with BMI 36 ± 2 kg/m² and A1C 8.3 ± 0.6%) were studied in this single-center, placebo-controlled, randomized, double-blind study. Five subcutaneous doses of insulin glargine (0, 0.5, 1.0, 1.5, and 2.0 units/kg) were investigated on separate occasions using the 24-h euglycemic clamp technique.

RESULTS

Glargine duration of action to reduce glucose, nonessential fatty acid (NEFA), and β-hydroxybutyrate levels was close to or >24 h for all four doses. Increases in glucose flux revealed no discernible peak and were modest with maximal glucose infusion rates of 9.4, 6.6, 5.5, and 2.8 μmol/kg/min for the 2.0, 1.5, 1.0, and 0.5 units/kg doses, respectively. Glargine exhibited a relatively hepatospecific action with greater suppression (P < 0.05) of endogenous glucose production (EGP) compared with little or no increases in glucose disposal.

CONCLUSION

A single subcutaneous injection of glargine at a dose of ≥0.5 units/kg can acutely reduce glucose, NEFA, and ketone body levels for 24 h in obese insulin-resistant type 2 diabetic individuals. Glargine lowers blood glucose by mainly inhibiting EGP with limited effects on stimulating glucose disposal. Large doses of glargine have minimal effects on glucose flux and retain a relatively hepatospecific action in type 2 diabetes.Type 2 diabetes is a condition of relative or absolute insulin deficiency. Consequently, insulin replacement becomes a common and essential therapy in these individuals. Insulin therapy in type 2 diabetes can range from a single injection to basal-bolus replacement regimens with multiple daily injections. Insulin glargine is a soluble long-acting insulin analog that is widely used in clinical practice for basal insulin replacement.Numerous studies have investigated the clinical efficacy of insulin glargine in both type 1 and type 2 diabetes (1–3). Glargine has been found to lower A1C, provide effective basal insulin replacement, and reduce the risk of hypoglycemia (1–3). Despite the widespread use of glargine in clinical practice, there have been relatively few studies investigating the pharmacokinetic and pharmacodynamic characteristics of the insulin. Two studies have investigated subcutaneous doses of 0.3 and 0.35 U glargine in type 1 diabetic individuals (4,5). Other studies also using a 24-h glucose clamp technique have compared the pharmacokinetics and pharmacodynamics of single doses of glargine (0.5 and 0.8 units/kg) in patients with type 2 diabetes (6,7). These studies provide valuable information about single doses of glargine in patients with diabetes. Klein et al. (8) have also compared three doses of glargine (0.4, 0.8, and 1.4 units/kg) in type 2 diabetes during 24-h clamp studies using the Biostator. However, because the Biostator has been reported to limit maximal glucose infusions during a glucose clamp and also produce a wide variation of blood glucose concentrations around the target glucose value (9), we reasoned that further information regarding the dose-response characteristics of insulin glargine in patients with type 2 diabetes would also be useful. The aim of the present study was to use the 24-h euglycemic clamp technique to determine the pharmacokinetics and pharmacodynamics of differing large, single subcutaneous doses of glargine (similar to those used in clinical practice in treatment of obese insulin-resistant type 2 diabetic individuals). Isotope dilution methods were used to determine the effects of glargine on endogenous glucose production and glucose disappearance.     

Adding Once-Daily Lixisenatide for Type 2 Diabetes Inadequately Controlled With Newly Initiated and Continuously Titrated Basal Insulin Glargine: A 24-week,randomized, placebo-controlled study (GetGoal-Duo 1)

OBJECTIVE

When oral therapy for type 2 diabetes is ineffective, adding basal insulin improves glycemic control. However, when glycated hemoglobin (HbA_1c) remains elevated because of postprandial hyperglycemia, the next therapeutic step is controversial. We examined the efficacy and safety of lixisenatide in patients with HbA_1c still elevated after initiation of insulin glargine.

RESEARCH DESIGN AND METHODS

This double-blind, parallel-group trial enrolled patients with HbA_1c 7–10% despite oral therapy. Insulin glargine was added and systematically titrated during a 12-week run-in, after which candidates with fasting glucose ≤7.8 mmol/L and HbA_1c 7–9% were randomized to lixisenatide 20 µg or placebo for 24 weeks while insulin titration continued. The primary end point was HbA_1c change after randomization.

RESULTS

The randomized population (n = 446) had mean diabetes duration of 9.2 years, BMI 31.8 kg/m², and daily glargine dosage of 44 units. HbA_1c had decreased during run-in from 8.6 to 7.6%; adding lixisenatide further reduced HbA_1c by 0.71 vs. 0.40% with placebo (least squares mean difference, –0.32%; 95% CI, –0.46 to –0.17; P < 0.0001). More participants attained HbA_1c <7% with lixisenatide (56 vs. 39%; P < 0.0001). Lixisenatide reduced plasma glucose 2 h after a standardized breakfast (difference vs. placebo –3.2 mmol/L; P < 0.0001) and had a favorable effect on body weight (difference vs. placebo –0.89 kg; P = 0.0012). Nausea, vomiting, and symptomatic hypoglycemia <3.3 mmol/L were more common with lixisenatide.

CONCLUSIONS

Adding lixisenatide to insulin glargine improved overall and postprandial hyperglycemia and deserves consideration as an alternative to prandial insulin for patients not reaching HbA_1c goals with recently initiated basal insulin.When oral therapy does not maintain acceptable glycemic control in type 2 diabetes, adding and titrating basal insulin improves control and frequently restores glycated hemoglobin (HbA_1c) to <7.0% (<53 mmol/mol) (1–3). For those patients not fully successful with this regimen, the approach to treatment intensification is of current interest, especially with regard to improving control of postprandial hyperglycemia (4–8). Adding one or more injections of rapid-acting insulin with meals is effective for many patients but has drawbacks, including increased risk of hypoglycemia and weight gain (4,9). Another recently available option is addition of a glucagon-like peptide 1 receptor agonist (GLP-1RA) to previous oral and basal insulin therapy (10,11). Currently available GLP-1RAs are twice-daily exenatide (Byetta), once-daily liraglutide (Victoza), and once-weekly exenatide (Bydureon). Each has a glucose-dependent insulinotropic and glucagon-reducing effect, promotes satiety, and seldom causes hypoglycemia when used alone (12,13). However, short-acting exenatide appears more effective in controlling postprandial glucose (PPG) (14), whereas long-acting preparations, such as liraglutide and once-weekly exenatide, have greater effects on fasting hyperglycemia (13).Lixisenatide is a novel GLP-1RA that shares the main features of these agents but has a profile of action that appears intermediate between short-acting exenatide and longer-acting agents (13,15). Lixisenatide is effective administered once-daily yet retains the ability to reduce PPG, an effect associated with slowing of gastric emptying (15–18). The objective of this study was to assess the efficacy and safety of adding lixisenatide in the problematic subgroup of people with type 2 diabetes who have relatively acceptable control of fasting plasma glucose (FPG) after initiating and titrating basal insulin but have HbA_1c levels remaining persistently elevated (≥7.0%).     

Insulin Glargine Safety in Pregnancy: A transplacental transfer study

OBJECTIVE

Insulin glargine (Lantus) is an extended-action insulin analog with greater stability and duration of action than regular human insulin. The long duration of action and decreased incidence of hypoglycemia provide potential advantages for its use in pregnancy. However, the placental pharmacokinetics of insulin glargine have not been studied. Therefore, the objective of this study was to determine whether insulin glargine crosses the human placenta using the human perfused placental lobule technique.

RESEARCH DESIGN AND METHODS

Placentae were obtained with informed consent after elective cesarean section delivery of noncomplicated term pregnancies. Insulin glargine, at a therapeutic concentration of 150 pmol/l (20 μU/ml) was added to the maternal circulation. Additional experiments were carried out at insulin glargine concentrations 1,000-fold higher than therapeutic levels (150, 225, and 300 nmol/l). A subsequent perfusion for which the maternal circuit remained open and insulin glargine was continuously infused at 150 pmol/l was completed for further confirmation of findings. The appearance of insulin glargine in the fetal circulation was analyzed by a chemiluminescence immunoassay.

RESULTS

Results from perfusions carried out at therapeutic concentrations (150 pmol/l) of insulin glargine showed no detectable insulin glargine in the fetal circuit. After perfusion with very high insulin glargine concentrations of 150, 225, and 300 nmol/l, the rate of transfer remained low at 0.079 ± 0.01, 0.14, and 0.064 pmol · min⁻¹ · g tissue⁻¹, respectively.

CONCLUSIONS

Insulin glargine, when used at therapeutic concentrations, is not likely to cross the placenta.Several new long-acting insulin analogs, such as glargine and detemir, are currently available for the treatment of diabetes. These long-acting insulins have the advantage of a very long elimination half-life (24 h), avoiding a peak in insulin concentrations (1,2). The absence of a peak with the use of these insulin analogs has led to decreased incidence of symptomatic, overall, and nocturnal hypoglycemia in patients with type 1 diabetes (3). In addition, these analogs are increasingly being used in patients with type 2 diabetes, for whom they provide improved glycemic control and reduced hypoglycemia (4). With their increased use, more women with diabetes may find themselves pregnant while taking these insulins or find they are taking these insulins while planning a pregnancy. Such insulins may be particularly useful in pregnancy because tight glycemic control during gestation decreases the risk of maternal and fetal complications (5–10) and attenuates their severity (9). Studies have shown, however, that severe hypoglycemia is often a consequence of attempts to achieve tight glycemic control in pregnancy (11). Use of these insulin analogs would help patients achieve excellent glycemic control without the risk of maternal hypoglycemia.Insulin glargine (Lantus; Aventis Pharmaceuticals, Bridgewater, NJ) is a long-acting insulin analog that differs from regular human insulin by the addition of two molecules of arginine to the COOH terminus of the β-chain and the replacement of aspartic acid with glycine in position A21. These molecular changes cause the drug to precipitate upon subcutaneous injection, increasing stability and duration of action (12).It is believed that insulin does not cross the placental barrier because of its large molecular size. However, beef/pork insulin has been shown to cross the placenta via the formation of insulin-antibody complexes, leading to fetal macrosomia despite excellent glycemic control (13). Whereas insulin uptake into cellular compartments is mainly by receptor-mediated endocytosis, there are other mechanisms in place that may allow its transfer across biological membranes, such as pinocytosis and the involvement of membrane transporters (14). The possible consequences of transplacental transfer of insulin analogs, such as insulin glargine, include teratogenicity, immunogenicity, and mitogenicity. Specifically, structural modifications to insulin have been shown to cause altered affinity for the insulin and IGF-1 receptor (15). Although the evidence to date is conflicting (16), one study demonstrated that glargine has a six- to eightfold increased affinity for the IGF-1 receptor in the osteosarcoma cell line Saos/B10 (15). Concern exists that such growth-promoting properties may lead to increased fetal growth and other mitogenic effects should insulin cross the placenta. It is well known that excellent glucose control throughout pregnancy while minimizing maternal hypoglycemia is essential for the safe and effective treatment of women with diabetes in pregnancy. Consequently, there is a need to address the issues of fetal exposure and safety with the introduction of new and potentially beneficial insulin analogs, such as insulin glargine, for use in pregnancy. Although there are some case reports and case series describing patients who have gone through a pregnancy using glargine (17–20), there are no studies to date that have looked at the placental pharmacokinetics of glargine. The objective of the present study was to examine whether insulin glargine crosses the placenta into the fetal circulation using the ex vivo technique of human placental lobule perfusion.     

Baseline factors associated with glycemic control and weight loss when exenatide twice daily is added to optimized insulin glargine in patients with type 2 diabetes

OBJECTIVE

To determine variables associated with glycemic and body weight responses when adding exenatide to basal insulin–treated type 2 diabetes.

RESEARCH DESIGN AND METHODS

Exploratory subgroup analyses based on baseline A1C, disease duration, and BMI of a 30-week study comparing exenatide twice daily to placebo, added to optimized insulin glargine (intent-to-treat analysis: 137 exenatide; 122 placebo).

RESULTS

Exenatide participants had greater A1C reductions compared with optimized insulin glargine alone, irrespective of baseline A1C (P < 0.001). Exenatide participants with longer diabetes duration and those with lower BMI had greater A1C reductions (P < 0.01). Exenatide participants lost more weight, regardless of baseline A1C or BMI (P < 0.05). Exenatide participants with longer diabetes duration lost the most weight (P < 0.001).

CONCLUSIONS

Exenatide added to optimized basal insulin was associated with improved glycemic control and weight loss, irrespective of baseline A1C, diabetes duration, and BMI. Changes were evident in modestly obese patients and in those with longer diabetes duration.The combined use of glucagon-like peptide 1 (GLP-1) receptor agonists and insulin is of growing clinical interest (1–6), and the combined use of insulin glargine with exenatide is now approved in the U.S. In this recent study, exenatide twice daily added to optimized titration of glargine resulted in greater A1C improvements with weight loss and lesser increase in insulin dose than placebo plus optimized glargine (5). The current exploratory post hoc analysis assessed the relationship of baseline A1C, duration of diabetes, and BMI with glucose control, body weight changes, and insulin doses in that study.     

Long-Term Cardiovascular Risk in Type 2 Diabetic Compared With Nondiabetic First Acute Myocardial Infarction Patients: A population-based cohort study in southern Europe

OBJECTIVE

The aim of this study was to determine whether long-term cardiovascular risk differs in type 2 diabetic patients compared with first acute myocardial infarction patients in a Mediterranean region, considering therapy, diabetes duration, and glycemic control.

RESEARCH DESIGN AND METHODS

A prospective population-based cohort study with 10-year follow-up was performed in 4,410 patients aged 30–74 years: 2,260 with type 2 diabetes without coronary heart disease recruited in 53 primary health care centers and 2,150 with first acute myocardial infarction without diabetes recruited in 10 hospitals. We compared coronary heart disease incidence and cardiovascular mortality rates in myocardial infarction patients and diabetic patients, including subgroups by diabetes treatment, duration, and A1C.

RESULTS

The adjusted hazard ratios (HRs) for 10-year coronary heart disease incidence and for cardiovascular mortality were significantly lower in men and women with diabetes than in myocardial infarction patients: HR 0.54 (95% CI 0.45–0.66) and 0.28 (0.21–0.37) and 0.26 (0.19–0.36) and 0.16 (0.10–0.26), respectively. All diabetic patient subgroups had significantly fewer events than myocardial infarction patients: the HR of cardiovascular mortality ranged from 0.15 (0.09–0.26) to 0.36 (0.24–0.54) and that of coronary heart disease incidence ranged from 0.34 (0.26–0.46) to 0.56 (0.43–0.72).

CONCLUSIONS

Lower long-term cardiovascular risk was found in type 2 diabetic and all subgroups analyzed compared with myocardial infarction patients. These results do not support equivalence in coronary disease risk for diabetic and myocardial infarction patients.The prevalence of diabetes is reaching epidemic proportions in developed countries (1). For example, the U.S. has 18 million diabetic patients, Spain has >2 million diabetic patients, and management of the disease costs >$132 and >$3.3 billion per year, respectively (2).Some studies (3–5), several of them with great influence on important guidelines for cardiovascular prevention (3), suggest that the cardiovascular risk of diabetic patients is similar to that of coronary heart disease secondary prevention patients. Other reports, however, do not confirm these observations (6–10).Part of the discrepancy may stem from differences in the duration of diabetes, type of treatment, and baseline glucose control of diabetic patients included in the studies (3–5). These limit comparability, given the fact that time of evolution and treatment required to attain appropriate glycemic control are key determinants of prognosis (10–16).Among population-based cohort studies that compared the prognosis of diabetic patients with that of myocardial infarction patients without diabetes (3–10), only two analyzed the role of diabetes duration (11,12). Even these studies did not include unstable angina among the end points and risk was not stratified by type of treatment. To our knowledge, the effect of type 2 diabetes on coronary heart disease incidence has barely been studied in southern Europe, a region known for low cardiovascular mortality (17). The aim of this study was to determine whether long-term cardiovascular risk differed between type 2 diabetic patients and first acute myocardial infarction patients and to assess the influence of diabetes duration, type of treatment, and glycemic control at baseline.     

Weight Loss, Glycemic Control, and Changes in Cardiovascular Biomarkers in Patients With Type 2 Diabetes Receiving Incretin Therapies or Insulin in a Large Cohort Database

OBJECTIVE

Weight loss in patients with type 2 diabetes can improve glycemic control, lower blood pressure, and improve dyslipidemia. Glucagon-like peptide (GLP-1) receptor agonists are associated with weight loss and have potentially beneficial effects on cardiovascular risk biomarkers; however, there is limited information to indicate whether these effects remain outside of clinical trials.

RESEARCH DESIGN AND METHODS

Medical records from the General Electric Centricity research database were analyzed retrospectively to evaluate the relationship between weight loss and glycemic control and changes in blood pressure and lipids in patients with type 2 diabetes initiating therapy with exenatide, sitagliptin, or insulin. Baseline and follow-up (90–365 days after the index date) for weight, A1C, fasting blood glucose (FBG), blood pressure, triglycerides, and LDL, HDL, and total cholesterol were assessed.

RESULTS

A total of 6,280, 5,861, and 32,398 patients receiving exenatide, sitagliptin, or insulin, respectively, were included in the analysis. Exenatide-treated patients lost a mean ± SD of 3.0 ± 7.33 kg, sitagliptin-treated patients lost 1.1 ± 5.39 kg, and insulin-treated patients gained 0.6 ± 9.49 kg. There was a significant association between weight loss and a reduction in A1C and FBG with exenatide only and a reduction in blood pressure for all therapies. Weight loss was associated with some improvements in lipids, primarily in the GLP-1 receptor agonist group, with little association in the insulin group.

CONCLUSIONS

Weight reduction with GLP-1 receptor agonists was associated with a shift toward a more favorable cardiovascular risk profile. Outcome trials are needed to determine whether improvement in biomarkers translates into a reduction in cardiovascular events in patients with type 2 diabetes.The prevalence of type 2 diabetes continues to increase as does the number of obese individuals in the U.S. (1). There is a strong correlation between the two, with 80–95% of patients with type 2 diabetes being overweight or obese. In fact, studies have shown that the risk of developing diabetes increases in proportion to BMI (2). In addition, obesity exacerbates the metabolic abnormalities of type 2 diabetes, in particular, hyperglycemia, dyslipidemia, and hypertension (3). Obese individuals are at higher risk of developing cardiovascular disease, and the risk is even higher in those with type 2 diabetes who are obese (4).In overweight and obese individuals with type 2 diabetes, weight loss is associated with improvements in risk factors. In fact, small amounts of weight loss (∼5%) can improve glycemic control in type 2 diabetes (5,6). Longitudinal cohort studies indicate that changes in BMI in patients with type 2 diabetes are significant predictors of changes in A1C and blood pressure (7), and patients who lose weight are more likely to achieve goal A1C and blood pressure values than those who show stable weight or weight gain (8). Similarly, lifestyle intervention trials in patients with type 2 diabetes have shown that weight loss improves glycemic control, reduces blood pressure, and improves lipid levels (9), and even a modest weight loss can result in an improved cardiovascular risk profile (10). In patients with type 2 diabetes, intentional weight loss has been associated with a 28% reduction in cardiovascular disease and diabetes-related mortality (6). In addition, weight loss is associated with reduced diabetes-related health care costs (11).Proper diet and exercise is the first-line therapy to promote weight loss and improve glycemia in new-onset diabetes, but most patients will require oral antidiabetes drugs (OADs) for glycemic control and many will eventually require insulin therapy. Although these therapies are effective in lowering A1C, most therapies lead to weight gain. Sulfonylureas, thiazolidinediones, and insulin result in weight gain of ∼2 kg for every 1% decrease in A1C (12,13). Metformin, unlike other standard OADs, is often associated with slight weight loss.Incretin-based therapies, including glucagon-like peptide (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, have recently become treatment options for type 2 diabetes management, and unlike many other therapies, they do not induce weight gain (14). Therapy with GLP-1 receptor agonists results in weight loss in most patients. In controlled clinical trials, the average weight loss was ∼2 kg, which is generally sustained or progressive with long-term therapy (15). These agents have a physiological effect similar to that of native GLP-1, including enhancement of glucose-dependent insulin secretion and suppression of inappropriately high glucagon secretion. At high concentrations they also slow gastric emptying and reduce food intake (16).By blocking DPP-4, an enzyme that breaks down GLP-1, DPP-4 inhibitors have actions similar to that of GLP-1 receptor agonists; they also enhance glucose-dependent insulin secretion and suppress glucagon, but they do not delay gastric emptying or reduce food intake. In controlled clinical trials the effect of sitagliptin on weight was neutral (17,18).Data from clinical trials with exenatide, a GLP-1 receptor agonist, suggest that it has potentially beneficial effects on biomarkers of cardiovascular risk in patients with type 2 diabetes, including lowering blood pressure and improving dyslipidemia (19). However, there is limited information as to whether these effects remain outside of the setting of controlled clinical trials. In addition, it is not clear whether the effects on blood pressure and lipids are due to the weight loss that occurs with GLP-1 receptor agonists. Therefore, we evaluated patients with type 2 diabetes who initiated an incretin-based (GLP-1 receptor agonist or DPP-4 inhibitor) or insulin-based regimen to analyze the relationship between weight change and glycemic control and improvement in cardiovascular risk biomarkers in a real-world setting.     

Effects of Exenatide and Lifestyle Modification on Body Weight and Glucose Tolerance in Obese Subjects With and Without Pre-Diabetes

OBJECTIVE

To assess the effects of exenatide on body weight and glucose tolerance in nondiabetic obese subjects with normal or impaired glucose tolerance (IGT) or impaired fasting glucose (IFG).

RESEARCH DESIGN AND METHODS

Obese subjects (n = 152; age 46 ± 12 years, female 82%, weight 108.6 ± 23.0 kg, BMI 39.6 ± 7.0 kg/m², IGT or IFG 25%) were randomized to receive exenatide (n = 73) or placebo (n = 79), along with lifestyle intervention, for 24 weeks.

RESULTS

Exenatide-treated subjects lost 5.1 ± 0.5 kg from baseline versus 1.6 ± 0.5 kg with placebo (exenatide − placebo, P < 0.001). Placebo-subtracted difference in percent weight reduction was −3.3 ± 0.5% (P < 0.001). Both groups reduced their daily calorie intake (exenatide, −449 cal; placebo, −387 cal). IGT or IFG normalized at end point in 77 and 56% of exenatide and placebo subjects, respectively.

CONCLUSIONS

Exenatide plus lifestyle modification decreased caloric intake and resulted in weight loss in nondiabetic obesity with improved glucose tolerance in subjects with IGT and IFG.Several well-designed trials have demonstrated that weight reduction can reduce diabetes risk (1–4). However, with only lifestyle modification, even modest weight loss is difficult to achieve over time (5,6); therefore, optimal pharmacologic strategies for treating obesity are being developed. This study explored exenatide in combination with lifestyle modification as treatment for weight loss in nondiabetic obese subjects with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), or impaired fasting glucose (IFG).     

Efficacy and Safety of Lixisenatide Once Daily Versus Exenatide Twice Daily in Type 2 Diabetes Inadequately Controlled on Metformin: A 24-week,randomized, open-label,active-controlled study (GetGoal-X)

OBJECTIVE

To compare efficacy and safety of lixisenatide once daily versus exenatide twice daily in type 2 diabetes inadequately controlled with metformin.

RESEARCH DESIGN AND METHODS

Adults with diabetes inadequately controlled (HbA_1c 7–10%) with metformin were randomized to lixisenatide 20 μg once daily (n = 318) or exenatide 10 μg twice daily (n = 316) in a 24-week (main period), open-label, parallel-group, multicenter study. The primary objective was a noninferiority assessment of lixisenatide versus exenatide in HbA_1c change from baseline to week 24.

RESULTS

Lixisenatide once daily demonstrated noninferiority in HbA_1c reduction versus exenatide twice daily. The least squares mean change was −0.79% (mean decrease 7.97 to 7.17%) for lixisenatide versus −0.96% (mean decrease 7.96 to 7.01%) for exenatide, and treatment difference was 0.17% (95% CI, 0.033–0.297), meeting a predefined noninferiority upper CI margin of 0.4%. Responder rate (HbA_1c <7.0%) and improvements in fasting plasma glucose were comparable. Both agents induced weight loss (from 94.5 to 91.7 kg and from 96.7 to 92.9 kg with lixisenatide and exenatide, respectively). Incidence of adverse events (AEs) was similar for lixisenatide and exenatide, as was incidence of serious AEs (2.8 and 2.2%, respectively). Discontinuations attributable to AEs occurred in 33 lixisenatide (10.4%) and 41 exenatide (13.0%) patients. In the lixisenatide group, fewer participants experienced symptomatic hypoglycemia (2.5 vs. 7.9%; P < 0.05), with fewer gastrointestinal events (especially nausea; 24.5 vs. 35.1%; P < 0.05).

CONCLUSIONS

Add-on lixisenatide once daily in type 2 diabetes inadequately controlled with metformin demonstrated noninferior improvements in HbA_1c, with slightly lower mean weight loss, lower incidence of hypoglycemia, and better gastrointestinal tolerability compared with exenatide twice daily.The glucagon-like peptide-1 (GLP-1) receptor system has become an attractive target for type 2 diabetes therapies (1–5). GLP-1 receptor agonists increasingly have become established as effective therapeutic options in type 2 diabetes management (6,7).Glucose-lowering effects of GLP-1 receptor agonists are mediated by glucose-dependent stimulation of insulin release and inhibition of glucagon secretion, which decreases prandial blood glucose excursion and hepatic glucose production (1–5). Notably, GLP-1 receptor agonists achieve physiological blood glucose–insulin response with a low risk of hypoglycemia (as a result of their glucose-dependent action) (8), delay gastric emptying, and are associated with beneficial effects on weight and appetite reduction (9).Currently available GLP-1 receptor agonists include twice-daily and once-weekly formulations of exenatide, a once-daily formulation of liraglutide, and a once-daily formulation of lixisenatide. Both exenatide and liraglutide have been shown to improve glycemic control associated with beneficial effects on weight and a low risk of hypoglycemia (10,11). However, although exenatide and liraglutide share the same basic mechanisms, each has a distinct pharmacokinetic profile and molecular structure, with potential clinical implications in terms of efficacy against fasting plasma glucose (FPG) and postprandial plasma glucose, and in terms of regimen burden and safety. This has been demonstrated in a 26-week, randomized, parallel-group, open-label trial in adults with inadequately controlled type 2 diabetes who were assigned to receive additional liraglutide 1.8 mg once daily or additional exenatide 10 µg twice daily (11). Liraglutide reduced mean FPG more than did exenatide (−29.0 mg/dL vs. −10.8 mg/dL; P < 0.0001), whereas exenatide reduced postprandial plasma glucose increment after breakfast and dinner more than did liraglutide (breakfast: estimated treatment difference, 23.9 mg/dL; P < 0.0001; dinner: estimated treatment difference, 18.2 mg/dL; P = 0.0005) (11). These findings suggest that liraglutide and exenatide should not be used interchangeably, but instead should be prescribed on an individual basis according to the glycemic requirements of each patient.Lixisenatide is a once-daily prandial GLP-1 receptor agonist for the treatment of type 2 diabetes that was approved by the European Medicines Agency in February 2013 (12,13). It is a 44–amino-acid peptide that is amidated at the COOH terminal amino acid and shares some structural elements with the GLP-1 receptor agonist exenatide; the primary difference is the addition of six lysine residues at the C terminus (13). A 13-week, randomized, double-blind, placebo-controlled, dose-ranging study that evaluated the dose-dependent effects of lixisenatide (5, 10, 20, or 30 µg once daily or twice daily) found that lixisenatide 20 µg administered once daily provided the best efficacy-to-tolerability ratio, with no additional benefits with any of the twice-daily doses (14). Lixisenatide 20 μg once daily subsequently has been shown to significantly improve glycemic control, with low rates of hypoglycemia and beneficial weight effects, when administered as monotherapy (15), as add-on therapy to oral agents (14,16–18), and in combination with basal insulin with or without oral antidiabetic therapy (19–21).In the current study, we report the results from a head-to-head study (GetGoal-X) that compared the benefit/risk profile of lixisenatide once daily versus exenatide twice daily in patients with type 2 diabetes inadequately controlled with metformin monotherapy.     

Comparison of a Multiple Daily Insulin Injection Regimen (Basal Once-Daily Glargine Plus Mealtime Lispro) and Continuous Subcutaneous Insulin Infusion (Lispro) in Type 1 Diabetes: A randomized open parallel multicenter study

OBJECTIVE

Insulin pump therapy (continuous subcutaneous insulin infusion [CSII]) and multiple daily injections (MDIs) with insulin glargine as basal insulin and mealtime insulin lispro have not been prospectively compared in people naïve to either regimen in a multicenter study. We aimed to help close that deficiency.

RESEARCH DESIGN AND METHODS

People with type 1 diabetes on NPH-based insulin therapy were randomized to CSII or glargine-based MDI (both otherwise using lispro) and followed for 24 weeks in an equivalence design. Fifty people were correctly randomized, and 43 completed the study.

RESULTS

Total insulin requirement (mean ± SD) at end point was 36.2 ± 11.5 units/day on CSII and 42.6 ± 15.5 units/day on MDI. Mean A1C fell similarly in the two groups (CSII −0.7 ± 0.7%; MDI −0.6 ± 0.8%) with a baseline-adjusted difference of −0.1% (95% CI −0.5 to 0.3). Similarly, fasting blood glucose and other preprandial, postprandial, and nighttime self-monitored plasma glucose levels did not differ between the regimens, nor did measures of plasma glucose variability. On CSII, 1,152 hypoglycemia events were recorded by 23 of 28 participants (82%) and 1,022 in the MDI group by 27 of 29 patients (93%) (all hypoglycemia differences were nonsignificant). Treatment satisfaction score increased more with CSII; however, the change in score was similar for the groups. Costs were ∼3.9 times higher for CSII.

CONCLUSIONS

In unselected people with type 1 diabetes naïve to CSII or insulin glargine, glycemic control is no better with the more expensive CSII therapy compared with glargine-based MDI therapy.Insulin substitution in type 1 diabetes is based on mealtime rapid-acting and basal insulin, using multiple daily injections (MDIs) or continuous subcutaneous insulin infusion (CSII) (1,2). In meta-analyses of studies, two small trials (3,4) with the long-acting insulin analog insulin glargine suggested superiority of CSII over MDI in terms of A1C lowering. Lower A1C levels and less hypoglycemia with CSII were also recently reported by Hoogma et al. (5) in a large type 1 diabetes population (272 people) comparing CSII with MDI using NPH insulin. A more recent meta-analysis (6) proposed that CSII is beneficial to “selected” people (people with recurrent and frequent severe hypoglycemia on MDI using NPH insulin) with type 1 diabetes.Since 2000, the long-acting insulin analogs, insulin glargine and insulin detemir, have become available (2). These are progressively replacing NPH insulin as basal insulin in type 1 diabetes due to favorable pharmacokinetics and pharmacodynamics, namely, a less pronounced peak concentration and longer duration of action (7,8) resulting in lower A1C levels and less hypoglycemia (9,10). Additionally, the long-acting analogs may give more reproducible effects compared with NPH insulin (11,12).This better glycemic control with the new analogs has reopened the question of comparisons between CSII and MDI based on long-acting analogs, rather than NPH insulin. A number of studies have attempted to compare CSII with MDI using insulin glargine, but not insulin detemir, as basal insulin (13–17). However, these studies are small, nonrandomized, or of short duration.The aim of the present prospective, randomized, multicenter, international study was to assess the difference in glycemic control when people with type 1 diabetes using NPH insulin-based MDIs are randomized either to an MDI regimen with insulin glargine as basal insulin and mealtime insulin lispro or to continuous subcutaneous infusion of insulin lispro and managed on either regimen for 6 months.     

Insulin Degludec Versus Insulin Glargine in Insulin-Naive Patients With Type 2 Diabetes: A 1-year,randomized, treat-to-target trial (BEGIN Once Long)

OBJECTIVE

To compare ultra-long-acting insulin degludec with glargine for efficacy and safety in insulin-naive patients with type 2 diabetes inadequately controlled with oral antidiabetic drugs (OADs).

RESEARCH DESIGN AND METHODS

In this 1-year, parallel-group, randomized, open-label, treat-to-target trial, adults with type 2 diabetes with A1C of 7−10% taking OADs were randomized 3:1 to receive once daily degludec or glargine, both with metformin. Insulin was titrated to achieve prebreakfast plasma glucose (PG) of 3.9−4.9 mmol/L. The primary end point was confirmation of noninferiority of degludec to glargine in A1C reduction after 52 weeks in an intent-to-treat analysis.

RESULTS

In all, 1,030 participants (mean age 59 years; baseline A1C 8.2%) were randomized (degludec 773, glargine 257). Reduction in A1C with degludec was similar (noninferior) to that with glargine (1.06 vs. 1.19%), with an estimated treatment difference of degludec to glargine of 0.09% (95% CI −0.04 to 0.22). Overall rates of confirmed hypoglycemia (PG <3.1 mmol/L or severe episodes requiring assistance) were similar, with degludec and glargine at 1.52 versus 1.85 episodes/patient-year of exposure (PYE). There were few episodes of nocturnal confirmed hypoglycemia in the overall population, and these occurred at a lower rate with degludec versus glargine (0.25 vs. 0.39 episodes/PYE; P = 0.038). Similar percentages of patients in both groups achieved A1C levels <7% without hypoglycemia. End-of-trial mean daily insulin doses were 0.59 and 0.60 units/kg for degludec and glargine, respectively. Adverse event rates were similar.

CONCLUSIONS

Insulins degludec and glargine administered once daily in combination with OADs provided similar long-term glycemic control in insulin-naive patients with type 2 diabetes, with lower rates of nocturnal hypoglycemia with degludec.The increasing prevalence of type 2 diabetes and its associated complications pose a significant global health care and economic burden (1). The landmark U.K. Prospective Diabetes Study demonstrated the benefits of improved glucose control and highlighted the progressive nature of type 2 diabetes as a result of β-cell failure. Approximately 50% of patients with type 2 diabetes may require insulin therapy in addition to oral antidiabetic drugs (OADs) within 6 years of diabetes diagnosis (2,3). Clinical guidelines by the American Diabetes Association and European Association for the Study of Diabetes currently recommend initiating basal insulin in patients with type 2 diabetes either directly after metformin or after maximizing a combination of OADs with or without glucagonlike peptide-1 receptor agonists and then titrating insulin to meet a glycosylated hemoglobin (A1C) target of 7% without significant hypoglycemia (4,5).Several barriers to introducing insulin have been identified that may result in delayed achievement of glycemic control and progression of diabetes complications (6,7). These barriers include patients’ fear of injections and misconceptions about insulin therapy, clinicians’ fear of perceived complexity of insulin regimens, and both parties’ fear that introducing insulin will negatively affect patient lifestyle and weight gain (8). Additionally, the risk, consequences, and fear of hypoglycemia remain a significant limiting factor in intensifying insulin therapy and optimizing glycemic control (9).Long-acting insulin analogs have been developed to produce a more physiological basal insulin action than seen with such human insulin preparations as neutral protamine Hagedorn (NPH) insulin, and they are associated with lower hypoglycemia rates (particularly nocturnal) while achieving similar glycemic control (10–12). These analogs have lowered the barrier for insulin introduction in patients with type 2 diabetes and are recommended when OADs alone cannot maintain glucose control (10,12,13). There is still a need, however, for the development of basal insulins with improved pharmacokinetics and pharmacodynamics, with the goal of achieving glycemic targets in more patients with even less hypoglycemic risk (14). Insulin degludec is a novel, ultra-long-acting basal insulin. On subcutaneous injection, degludec forms a depot of soluble multihexamers that dissociates slowly and consistently, resulting in a flat, stable profile and a duration of action longer than 42 h (15,16). A previous phase 2 clinical trial comparing once daily degludec with glargine in insulin-naive patients with type 2 diabetes (17) and two phase 3 studies comparing once daily degludec with glargine in basal-bolus therapy in patients with type 1 (18) and type 2 diabetes (19) demonstrated that degludec provides similar glycemic control with less hypoglycemia than glargine.BEGIN Once Long is the largest phase 3 study in the clinical development program of insulin degludec and was designed as a 52-week, treat-to-target trial to compare the efficacy and safety of insulin degludec with those of insulin glargine, both administered in a basal regimen in combination with metformin, in insulin-naive participants with type 2 diabetes inadequately controlled with OADs.