Mechanisms of Glucose Lowering of Dipeptidyl Peptidase-4 Inhibitor Sitagliptin When Used Alone or With Metformin in Type 2 Diabetes: A double-tracer study

OBJECTIVE

To assess glucose-lowering mechanisms of sitagliptin (S), metformin (M), and the two combined (M+S).

RESEARCH DESIGN AND METHODS

We randomized 16 patients with type 2 diabetes mellitus (T2DM) to four 6-week treatments with placebo (P), M, S, and M+S. After each period, subjects received a 6-h meal tolerance test (MTT) with [¹⁴C]glucose to calculate glucose kinetics. Fasting plasma glucose (FPG), fasting plasma insulin, C-peptide (insulin secretory rate [ISR]), fasting plasma glucagon, and bioactive glucagon-like peptide (GLP-1) and gastrointestinal insulinotropic peptide (GIP) were measured.

RESULTS

FPG decreased from P, 160 ± 4 to M, 150 ± 4; S, 154 ± 4; and M+S, 125 ± 3 mg/dL. Mean post-MTT plasma glucose decreased from P, 207 ± 5 to M, 191 ± 4; S, 195 ± 4; and M+S, 161 ± 3 mg/dL (P < 0.01). The increase in mean post-MTT plasma insulin and in ISR was similar in P, M, and S and slightly greater in M+S. Fasting plasma glucagon was equal (∼65–75 pg/mL) with all treatments, but there was a significant drop during the initial 120 min with S 24% and M+S 34% (both P < 0.05) vs. P 17% and M 16%. Fasting and mean post-MTT plasma bioactive GLP-1 were higher (P < 0.01) after S and M+S vs. M and P. Basal endogenous glucose production (EGP) fell from P 2.0 ± 0.1 to S 1.8 ± 0.1 mg/kg ⋅ min, M 1.8 ± 0.2 mg/kg ⋅ min (both P < 0.05 vs. P), and M+S 1.5 ± 0.1 mg/kg ⋅ min (P < 0.01 vs. P). Although the EGP slope of decline was faster in M and M+S vs. S, all had comparable greater post-MTT EGP inhibition vs. P (P < 0.05).

CONCLUSIONS

M+S combined produce additive effects to 1) reduce FPG and postmeal plasma glucose, 2) augment GLP-1 secretion and β-cell function, 3) decrease plasma glucagon, and 4) inhibit fasting and postmeal EGP compared with M or S monotherapy.In diet-treated patients with type 2 diabetes mellitus (T2DM) and HbA_1c of ∼8.0%, sitagliptin (S) reduces HbA_1c by 0.6–0.7% over a 6-month period (1). A slightly greater HbA_1c decline (∼0.8–0.9%) is observed when metformin (M) therapy is added to S (2). Dipeptidyl peptidase (DPP)-4 inhibitors predominantly affect the postprandial plasma glucose excursion, but a significant, albeit modest, reduction in fasting plasma glucose (FPG) also is observed (1–3). The mechanism of action of the DPP-4 inhibitors has been well studied and includes increased plasma glucagon-like peptide (GLP)-1 and gastrointestinal insulinotropic peptide (GIP) levels, resulting in increased insulin and reduced glucagon secretion (4–6). The increase in plasma insulin and the decline in glucagon inhibit basal endogenous glucose production (EGP) and enhance the suppression of EGP without affecting splanchnic (hepatic) glucose uptake or gastric emptying (6,7). Therapy with S and M combined (M+S) exerts an additive effect to reduce HgA_1c; the mechanism of action of this combination has yet to be examined. Several studies have demonstrated that M inhibits DPP-4 activity, thus increasing plasma active GLP-1 levels (8–10). There are also reports indicating that the decline in plasma glucose with M therapy can restore the β-cells’ sensitivity to the stimulatory effect of incretins on insulin secretion (11,12). Despite these reports, we still do not fully understand the reasons why the use of M in diabetic patients is not accompanied by changes in insulin release. In the current study, we used the double-tracer technique (7) to examine the mechanism(s) via which M+S and each agent alone reduce the fasting and postmeal plasma glucose concentration in T2DM.     

Canagliflozin Lowers Postprandial Glucose and Insulin by Delaying Intestinal Glucose Absorption in Addition to Increasing Urinary Glucose Excretion: Results of a randomized,placebo-controlled study

OBJECTIVE

Canagliflozin, a sodium glucose cotransporter (SGLT) 2 inhibitor, is also a low-potency SGLT1 inhibitor. This study tested the hypothesis that intestinal canagliflozin levels postdose are sufficiently high to transiently inhibit intestinal SGLT1, thereby delaying intestinal glucose absorption.

RESEARCH DESIGN AND METHODS

This two-period, crossover study evaluated effects of canagliflozin on intestinal glucose absorption in 20 healthy subjects using a dual-tracer method. Placebo or canagliflozin 300 mg was given 20 min before a 600-kcal mixed-meal tolerance test. Plasma glucose, ³H-glucose, ¹⁴C-glucose, and insulin were measured frequently for 6 h to calculate rates of appearance of oral glucose (R_aO) in plasma, endogenous glucose production, and glucose disposal.

RESULTS

Compared with placebo, canagliflozin treatment reduced postprandial plasma glucose and insulin excursions (incremental 0- to 2-h area under the curve [AUC_0–2h] reductions of 35% and 43%, respectively; P < 0.001 for both), increased 0- to 6-h urinary glucose excretion (UGE_0–6h, 18.2 ± 5.6 vs. <0.2 g; P < 0.001), and delayed R_aO. Canagliflozin reduced AUC R_aO by 31% over 0 to 1 h (geometric means, 264 vs. 381 mg/kg; P < 0.001) and by 20% over 0 to 2 h (576 vs. 723 mg/kg; P = 0.002). Over 2 to 6 h, canagliflozin increased R_aO such that total AUC R_aO over 0 to 6 h was <6% lower versus placebo (960 vs. 1,018 mg/kg; P = 0.003). A modest (∼10%) reduction in acetaminophen absorption was observed over the first 2 h, but this difference was not sufficient to explain the reduction in R_aO. Total glucose disposal over 0 to 6 h was similar across groups.

CONCLUSIONS

Canagliflozin reduces postprandial plasma glucose and insulin by increasing UGE (via renal SGLT2 inhibition) and delaying R_aO, likely due to intestinal SGLT1 inhibition.The sodium glucose cotransporter (SGLT) 2 is the major transporter responsible for reabsorption of glucose filtered through the renal glomerulus (1). SGLT2 is a high-capacity, low-affinity transporter expressed primarily at the luminal membrane of the early segments of the proximal renal tubules (1). SGLT1 is a low-capacity, high-affinity transporter expressed in the distal segment of the proximal tubule (1), in the intestinal mucosa of the small intestine (2), and in other tissues to a lesser extent (3). Although SGLT1 plays a smaller role in renal glucose absorption than SGLT2, SGLT1 is the primary pathway involved in intestinal glucose and galactose absorption (2,4,5).Pharmacologic inhibition of SGLT2 is a novel approach to lowering plasma glucose in hyperglycemic individuals by blocking renal glucose reabsorption, lowering the renal threshold for glucose (RT_G), and thereby markedly increasing urinary glucose excretion (UGE). Canagliflozin, an SGLT2 inhibitor in development for the treatment of patients with type 2 diabetes (6–10), is also a low-potency SGLT1 inhibitor. In vitro, canagliflozin inhibited sodium-dependent ¹⁴C-α-methylglucoside uptake in cells expressing human SGLT2 or SGLT1 with half-maximal inhibitory concentrations (IC₅₀) of 4.4 ± 1.2 and 684 ± 159 nmol/L, respectively (8). Because the maximum plasma concentrations of unbound canagliflozin in subjects treated with canagliflozin 300 mg once daily are ∼100 nmol/L (maximum plasma concentrations are ∼10 μmol/L [11] and protein binding is ∼99% [unpublished data]), only minimal systemic inhibition of SGLT1 is expected in subjects treated with canagliflozin 300 mg.In clinical studies in healthy subjects and subjects with type 2 diabetes, treatment with canagliflozin provided dose-dependent increases in UGE compared with placebo (7,9). In healthy subjects treated with escalating doses of canagliflozin given 10 min before a mixed meal, doses of canagliflozin higher than 200 mg reduced postprandial plasma glucose and insulin concentrations to a greater extent than lower doses of canagliflozin, even when compared with doses that provided similar UGE during the postprandial period (7). These pronounced reductions in postprandial glucose and insulin excursions observed with canagliflozin doses higher than 200 mg were only observed for the first meal after dosing; similar reductions beyond that expected on the basis of increased UGE were not observed after later meals (lunch and dinner) given on the same day (7). On the basis of these observations, it was hypothesized that after dosing and during drug absorption, canagliflozin concentrations within the lumen of the intestinal tract could be sufficiently high to provide transient inhibition of intestinal SGLT1-mediated glucose absorption, thereby lowering postprandial plasma glucose and insulin concentrations.The current study investigated the effects of a single 300-mg oral dose of canagliflozin on intestinal glucose absorption and metabolism in healthy subjects (ClinicalTrials.gov Identifier: NCT01173549). This study used a dual-tracer method to test the hypothesis that canagliflozin 300 mg slows the rate of systemic appearance of orally administered glucose (R_aO) during a mixed-meal tolerance test (MMTT) compared with placebo.     

Needle-Free Jet Injection of Rapid-Acting Insulin Improves Early Postprandial Glucose Control in Patients With Diabetes

OBJECTIVE

Clamp studies have shown that the absorption and action of rapid-acting insulin are faster with injection by a jet injector than with administration by conventional pen. To determine whether these pharmacokinetic changes also exist in patients with diabetes and benefit postprandial glucose control, we compared the pharmacologic profiles of insulin administration by jet injection versus conventional insulin pen after a standardized meal in patients with type 1 or type 2 diabetes.

RESEARCH DESIGN AND METHODS

In a randomized, double-blind, double-dummy crossover study, 12 patients with type 1 diabetes and 12 patients with type 2 diabetes received insulin aspart either by jet injection or by conventional pen, in both cases followed by a standardized meal. Blood was sampled for 6 h for determination of glucose and insulin levels to calculate pharmacologic profiles.

RESULTS

Insulin administration by jet injection resulted in shorter time until peak plasma insulin level (51.3 ± 6.4 vs. 91.9 ± 10.2 min; P = 0.003) and reduced hyperglycemic burden during the first hour (154.3 ± 20.8 vs. 196.3 ± 18.4 mmol · min · L⁻¹; P = 0.041) compared with conventional administration. Jet injection did not, however, significantly reduce the hyperglycemic burden during the 5-h period thereafter. There was no indication that the jet injector performed differently in patients with type 1 and type 2 diabetes.

CONCLUSIONS

The considerably more rapid insulin absorption after administration by jet injector translated to a significant if modest decrease in postprandial hyperglycemia in patients with type 1 and type 2 diabetes. The improved early postprandial glucose control may specifically benefit patients who have difficulty in limiting postprandial glucose excursions.The pharmacologic profile of rapid-acting insulin analogs, although considerably faster than regular insulin, is still relatively slow compared with the profile of endogenous insulin release. As a consequence, patients with type 1 diabetes or insulin-requiring type 2 diabetes who use these analogs still face the risk of immediate postprandial hyperglycemia and late postprandial hypoglycemia. In particular, postprandial hyperglycemia has been recognized as an important contributor to suboptimal glucose control (1), which may explain why the introduction of rapid-acting analogs has had little effect on HbA_1c in people with diabetes (2). Some have therefore suggested that these analogs should be injected at least 15 min before meals (3); however, this seems impractical to implement in daily practice.Poor adherence to insulin therapy because of injection-related anxiety may be another, often neglected, reason for failure to reach glycemic targets with current rapid- and long-acting insulin analogs (4). A sizable proportion of insulin users admit to at least occasionally skipping insulin injections or restricting the number of daily injections (4). Although true needle phobia is rare, many patients with diabetes perceive insulin injections as painful or experience some form of anxiety with injections (5,6), the presence of which is strongly associated with nonadherence and poorer glycemic control (7).Jet injectors for insulin administration provide a needle-free alternative to the use of pens or syringes and were originally developed for patients with needle phobia. Administration by jet injection significantly accelerates absorption of rapid-acting insulin from the subcutaneous area into the systemic circulation (8). Jet injectors deliver insulin at a high velocity (typically >100 m/s) directly across the skin in the subcutaneous tissue and dispense the insulin over a larger area than does injection by syringe (9). With the euglycemic clamp technique, we recently showed in healthy volunteers that administration of insulin aspart by jet injection reduced both the time until peak plasma insulin levels and the time to maximal glucose-lowering effect by approximately 50% when compared with insulin administered by conventional insulin pen (10).Although the euglycemic clamp technique is a reliable method to investigate the pharmacodynamics of therapeutic insulin, it cannot be used to predict the glucose-lowering effect of insulin when injected before a meal, particularly in patients with diabetes. The aim of the current study was therefore to investigate the pharmacology of insulin injected by jet injector before a standardized meal in patients with type 1 diabetes and insulin-requiring type 2 diabetes. We also wanted to investigate whether patients would perceive insulin administration with the current jet injector device as more or less painful as insulin injection by pen.     

Cost-effectiveness of Insulin Glargine Versus Sitagliptin in Insulin-naïve Patients With Type 2 Diabetes Mellitus

PurposeIn the EASIE (Evaluation of Insulin Glargine Versus Sitagliptin in Insulin-Naïve Patients) trial, insulin glargine found a significant reduction in glycosylated hemoglobin compared with sitagliptin in patients with type 2 diabetes who are inadequately controlled with metformin. The objective of this study was to assess the cost-effectiveness of insulin glargine compared with sitagliptin in type 2 diabetes patients, from the perspective of the publicly funded Canadian health care system.MethodsThe IMS CORE Diabetes Model, a standard Markov structure and Monte Carlo simulation model, was used. The model used a lifetime horizon to capture the long-term complications associated with type 2 diabetes. The efficacy of insulin glargine and sitagliptin in terms of glycosylated hemoglobin reduction and corresponding rates of hypoglycemia were obtained from the EASIE trial. Health utility and cost data were obtained from recently published Canadian publications. Univariate and probabilistic sensitivity analyses were conducted.FindingsIn the lifetime base-case analysis, treatment with insulin glargine resulted in cost savings of $1434 CAD in 2012 and a gain of 0.08 quality-adjusted life years per patient. A probabilistic sensitivity analysis found the robustness of the base-case analysis, with 88% probability of insulin glargine being dominant (ie, cost savings and more quality-adjusted life years).ImplicationsInsulin glargine is a clinically superior and cost-effective alternative to sitagliptin in patients with type 2 diabetes who are inadequately controlled with metformin.     

Acute Pancreatitis in Type 2 Diabetes Treated With Exenatide or Sitagliptin: A retrospective observational pharmacy claims analysis

OBJECTIVE

Cases of acute pancreatitis have been reported in association with exenatide, sitagliptin, and type 2 diabetes without use of these medications. It remains unknown whether exenatide or sitagliptin increase the risk of acute pancreatitis.

RESEARCH DESIGN AND METHODS

A retrospective cohort study of a large medical and pharmacy claims database was performed. Data for 786,656 patients were analyzed. Cox proportional hazard models were built to compare the risk of acute pancreatitis between diabetic and nondiabetic subjects and between exenatide, sitagliptin, and control diabetes medication use.

RESULTS

Incidence of acute pancreatitis in the nondiabetic control group, diabetic control group, exenatide group, and sitagliptin group was 1.9, 5.6, 5.7, and 5.6 cases per 1,000 patient years, respectively. The risk of acute pancreatitis was significantly higher in the combined diabetic groups than in the nondiabetic control group (adjusted hazard ratio 2.1 [95% CI 1.7–2.5]). Risk of acute pancreatitis was similar in the exenatide versus diabetic control group (0.9 [0.6–1.5]) and sitagliptin versus diabetic control group (1.0 [0.7–1.3]).

CONCLUSIONS

Our study demonstrated increased incidence of acute pancreatitis in diabetic versus nondiabetic patients but did not find an association between the use of exenatide or sitagliptin and acute pancreatitis. The limitations of this observational claims-based analysis cannot exclude the possibility of an increased risk.The most recently approved classes of agents for treatment of type 2 diabetes are the glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 inhibitors. Postmarketing surveillance of exenatide, the first GLP-1 receptor agonist, and sitagliptin, the first dipeptidyl peptidase-4 inhibitors, has raised the possibility of acute pancreatitis in association with their use (1–4). Based on case reports, the U.S. Food and Drug Administration (FDA) has added warnings about acute pancreatitis to the labeling information of exenatide and sitagliptin (5,6). More recently, acute pancreatitis has been reported to occur more often in clinical trials of patients who took liraglutide, a GLP-1 agonist approved by the FDA in January 2010 (7). The FDA is requiring a risk evaluation and mitigation strategy to help patients and health care providers understand the potential risk of acute pancreatitis with liraglutide.As the use of incretin-based therapies increases, it is critical that potential adverse effects be fully characterized so clinicians and patients can balance potential benefits and harms of these agents. Clinical trials are unlikely to provide definitive answers about whether incretin-based therapies increase acute pancreatitis because this condition occurs at a very low frequency and because type 2 diabetes is associated with increased incidence of acute pancreatitis (8). Although epidemiological analyses have numerous limitations and cannot provide definitive conclusions, they may be helpful in exploring relationships between medication use and very low frequency adverse events. We performed an analysis of a large medical and pharmacy claims database to evaluate the relationship between exenatide, sitagliptin, and acute pancreatitis.     

Glulisine Versus Human Regular Insulin in Combination With Glargine in Noncritically Ill Hospitalized Patients With Type 2 Diabetes: A randomized double-blind study

OBJECTIVE

To compare the efficacy and safety of the rapid-acting insulin analog glulisine and regular insulin in hyperglycemic hospitalized patients.

RESEARCH DESIGN AND METHODS

A total of 180 hospitalized patients with type 2 diabetes received either glulisine (n = 88) or regular insulin (n = 92) before each meal in combination with insulin glargine at bedtime in a randomized double-blind fashion. All previous diabetes medications were discontinued if applicable. Doses of insulin were adjusted to obtain target blood glucose concentrations of <130 mg/dl before meals and at bedtime while avoiding hypoglycemia.

RESULTS

Overall mean blood glucose concentrations were ∼8 mg/dl lower in the glulisine group than in the regular insulin group (152.6 ± 66.6 vs. 160.4 ± 70.8 mg/dl; P < 0.0002). This improvement was wholly due to ∼22 mg/dl lower levels after 4 days of therapy (140 ± 55 vs. 162 ± 71 mg/dl; P < 0.0007); after day 4, this difference progressively increased such that mean blood glucose concentrations from day 7 onward were ∼31 mg/dl lower in the glulisine group. The mean daily incidence of hypoglycemia was slightly but not significantly lower in the glulisine than the regular insulin group (0.10 ± 0.02 vs. 0.14 ± 0.03 episode/day; P > 0.35).

CONCLUSIONS

In hospitalized type 2 diabetic patients, glulisine may provide better glycemic control than regular insulin, especially in those who have a prolonged length of stay.Accumulating evidence suggests that hyperglycemia is associated with an increased risk of complications and mortality in hospitalized patients. In critically ill patients, improved glycemic control reduces short- and long-term mortality, rates of multiorgan failure, systemic infections, and length of hospitalization (1–3). Likewise, in patients admitted to general medical and surgical areas hyperglycemia is associated with a prolonged hospital stay, infection, disability, and death (4–6), suggesting that poor glycemic control is associated with poor clinical outcome.Insulin is the most effective and the most preferred agent for the treatment of hyperglycemia in hospitalized patients (7). However, inpatient insulin therapy is often complicated by variable meal delivery, unpredictable food consumption, and medical conditions, including liver and kidney disease, that predispose to hypoglycemia. Rapid-acting insulin analogs, which have been shown to reduce the risk of hypoglycemia in the outpatient setting (8), may hence be a better choice than regular insulin for the treatment of hyperglycemia in noncritically ill hospitalized patients. The present study was therefore undertaken to compare the efficacy and safety of the rapid-acting insulin analog glulisine and regular insulin in hyperglycemic hospitalized patients.     

Acute Metabolic Effects of Exenatide in Patients With Type 1 Diabetes With and Without Residual Insulin to Oral and Intravenous Glucose Challenges

OBJECTIVE

Glucagon-like peptide 1 (GLP-1) is an incretin hormone that is released from the gastrointestinal tract. Treatment with GLP-1 analogs has proven to be of clinical use for patients with type 2 diabetes. Patients with type 1 diabetes, particularly those with residual β-cell function, may also respond to treatment, but the acute metabolic effects of GLP-1 analogs on these patients in reaction to both oral and intravenous glucose challenges are not well understood.

RESEARCH DESIGN AND METHODS

Seventeen patients with type 1 diabetes, half of whom had residual insulin production, underwent two mixed-meal tolerance tests (MMTTs) and two intravenous glucose tolerance tests (IVGTTs), with and without pretreatment with exenatide. No exogenous bolus insulin was administered for the studies. Glucose excursions, insulin secretion rates (ISRs), and levels of glucagon, endogenous GLP-1, and gastric inhibitory polypeptide were measured after the meal or glucose loads.

RESULTS

During the MMTT, glucose levels were suppressed with exenatide in patients with or without residual insulin production (P = 0.0003). Exenatide treatment did not change the absolute ISR, but the ISR to glucose levels were increased (P = 0.0078). Gastric emptying was delayed (P = 0.0017), and glucagon was suppressed (P = 0.0015). None of these hormonal or glucose changes were detected during the IVGTT with exenatide administration.

CONCLUSIONS

Exenatide showed a significant antidiabetogenic effect prior to an oral meal in patients with type 1 diabetes involving glucagon suppression and gastric emptying, while preserving increased insulin secretion. GLP-1 analogs may be useful as an adjunctive treatment in type 1 diabetes.     

Better Glycemic Control and Weight Loss With the Novel Long-Acting Basal Insulin LY2605541 Compared With Insulin Glargine in Type 1 Diabetes: A randomized,crossover study

OBJECTIVE

To compare effects of LY2605541 versus insulin glargine on daily mean blood glucose as part of a basal-bolus regimen for type 1 diabetes.

RESEARCH DESIGN AND METHODS

In this randomized, Phase 2, open-label, 2 × 2 crossover study, 137 patients received once-daily basal insulin (LY2605541 or glargine) plus mealtime insulin for 8 weeks, followed by crossover treatment for 8 weeks. Daily mean blood glucose was obtained from 8-point self-monitored blood glucose profiles. The noninferiority margin was 10.8 mg/dL.

RESULTS

LY2605541 met noninferiority and superiority criteria compared with insulin glargine in daily mean blood glucose (144.2 vs. 151.7 mg/dL, least squares mean difference = −9.9 mg/dL [90% CI −14.6 to −5.2], P < 0.001). Fasting blood glucose variability and A1C were reduced with LY2605541 compared with insulin glargine (both P < 0.001). Mealtime insulin dose decreased with LY2605541 and increased with insulin glargine. Mean weight decreased 1.2 kg with LY2605541 and increased 0.7 kg with insulin glargine (P < 0.001). The total hypoglycemia rate was higher for LY2605541 (P = 0.04) and the nocturnal hypoglycemia rate was lower (P = 0.01), compared with insulin glargine. Adverse events (including severe hypoglycemia) were similar, although more gastrointestinal-related events occurred with LY2605541 (15% vs. 4%, P < 0.001). Mean changes (all within normal range) were higher for alanine aminotransferase, aspartate aminotransferase, triglycerides, and LDL-cholesterol and lower for HDL-cholesterol with LY2605541 compared with insulin glargine (all P < 0.02).

CONCLUSIONS

In type 1 diabetes, compared with insulin glargine, LY2605541, a novel, long-acting basal insulin, demonstrated greater improvements in glycemic control, increased total hypoglycemia, and reduced nocturnal hypoglycemia, as well as reduced weight and lowered mealtime insulin doses.The quest to prolong the action of insulin, which led to modern basal insulins, began in the 1930s with development of protamine zinc insulin (1,2). Basal insulins, such as protamine zinc, lente, isophane (NPH insulin), and ultralente insulins, were originally developed as suspensions to prolong action by delaying absorption (3,4). More recently, insulins glargine (GL) and detemir were developed to prolong subcutaneous absorption by altering amino acid structure (GL) or adding fatty acylated side chains (detemir) (4,5). Insulin degludec, a basal insulin in development, has the goal to achieve an effect longer than 24 h by prolonging subcutaneous absorption (6). Longer-acting insulins may be expected to reduce the need for twice-daily injections, variability, and the risk of hypoglycemia, as well as to provide minimal peak activity. Despite these refinements, current basal insulins cannot restore physiologic distribution of the twofold portal to systemic insulinemia because of subcutaneous systemic absorption, which results in similar portal and systemic levels. Thus, reduced hepatic insulin action must be balanced with excess peripheral insulin action to maintain glucose homeostasis.LY2605541 is a novel, long-acting basal insulin consisting of insulin lispro covalently modified with a 20-kDa polyethylene glycol moiety. It is a solution-based basal insulin with a time-action profile that is believed to be modulated indirectly through slowed depot absorption and reduced clearance due to increased molecular size. LY2605541 has a duration of action of more than 36 h with low variability, acting considerably longer than insulin glargine (7).This exploratory Phase 2 clinical trial was designed to determine if LY2605541 was noninferior to insulin GL for reduction of daily mean blood glucose (BG) in patients with type 1 diabetes on a basal-bolus regimen and to compare safety and efficacy of LY2605541 and insulin GL.     

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.     

Treatment With the Human Once-Weekly Glucagon-Like Peptide-1 Analog Taspoglutide in Combination With Metformin Improves Glycemic Control and Lowers Body Weight in Patients With Type 2 Diabetes Inadequately Controlled With Metformin Alone: A double-blind placebo-controlled study

OBJECTIVE

To evaluate the efficacy and safety of taspoglutide (R1583/BIM51077), a human once-weekly glucagon-like peptide-1 analog, in patients with type 2 diabetes inadequately controlled with metformin.

RESEARCH DESIGN AND METHODS

Type 2 diabetic (n = 306) patients who failed to obtain glycemic control (A1C 7–9.5%) despite 1,500 mg metformin daily were randomly assigned to 8 weeks of double-blind subcutaneous treatment with placebo or taspoglutide, either 5, 10, or 20 mg once weekly or 10 or 20 mg once every 2 weeks, and followed for 4 additional weeks. All patients received their previously established dose of metformin throughout the study. Glycemic control was assessed by change in A1C (percent) from baseline.

RESULTS

Significantly greater (P < 0.0001) reductions in A1C from a mean ± SD baseline of 7.9 ± 0.7% were observed in all taspoglutide groups compared with placebo after 8 weeks of treatment: –1.0 ± 0.1% (5 mg once weekly), –1.2 ± 0.1% (10 mg once weekly), –1.2 ± 0.1% (20 mg once weekly), –0.9 ± 0.1% (10 mg Q2W), and –1.0 ± 0.1% (20 mg Q2W) vs. –0.2 ± 0.1% with placebo. After 8 weeks, body weight loss was significantly greater in the 10 mg (–2.1 ± 0.3 kg, P = 0.0035 vs. placebo) and 20 mg (–2.8 ± 0.3 kg, P < 0.0001) once-weekly groups and the 20 mg once every 2 weeks (–1.9 ± 0.3 kg, P = 0.0083) group than with placebo (–0.8 ± 0.3 kg). The most common adverse event was dose-dependent, transient, mild-to-moderate nausea; the incidence of hypoglycemia was very low.

CONCLUSIONS

Taspoglutide used in combination with metformin significantly improves fasting and postprandial glucose control and induces weight loss, with a favorable tolerability profile.Approximately 50% of patients with type 2 diabetes fail to achieve the American Diabetes Association–recommended target A1C level of 7% (1), indicating the need for additional treatment options. A new class of antidiabetic agents is the glucagon-like peptide-1 (GLP-1) receptor agonists, which act through multiple mechanisms (2), similar to the incretin hormone GLP-1 (3–6). Taspoglutide (R1583/BIM51077) is a human GLP-1 analog with a pharmacokinetic profile suitable for weekly subcutaneous administration, through two amino acid substitutions in positions 8 and 35 with aminoisobutyric acid and a sustained release formulation. Taspoglutide has 93% homology with endogenous GLP-1 and comparable in vitro potency. Taspoglutide is resistant to degradation by dipeptidyl peptidase-4 and other proteases, resulting in a 12-fold increase in stability over the native GLP-1 when incubated in rat serum (7). Taspoglutide has been shown to enhance the rate of glucose-induced insulin secretion from isolated, cultured rat islets and the perfused ZDF rat pancreas (7,8). Furthermore, in vivo studies with taspoglutide in Sprague-Dawley rats and diabetic db/db mice have shown a dose-related enhancement of glucose-dependent insulin release, which lowered blood glucose in the db/db mouse model of type 2 diabetes (9). Thus, the biological activity of taspoglutide is similar to that of native GLP-1, with the added benefit of a prolonged action profile.The sustained release formulation of taspoglutide showed a release profile up to 26 days in dogs, making it an attractive candidate for human investigation (10). Of note, in patients with type 2 diabetes not well controlled with metformin, a single 30-mg dose of the same 10% formulation of taspoglutide improved fasting and postprandial glucose for up to 14 days in nearly all subjects treated (11). The aim of the current study was to evaluate the efficacy, safety, and tolerability of a range of doses of taspoglutide, given either once weekly or once every 2 weeks, in patients with type 2 diabetes inadequately controlled with metformin alone.     

Canagliflozin Compared With Sitagliptin for Patients With Type 2 Diabetes Who Do Not Have Adequate Glycemic Control With Metformin Plus Sulfonylurea: A 52-week randomized trial

OBJECTIVE

To evaluate the efficacy and safety of canagliflozin, a sodium glucose cotransporter 2 inhibitor, compared with sitagliptin in subjects with type 2 diabetes inadequately controlled with metformin plus sulfonylurea.

RESEARCH DESIGN AND METHODS

In this 52-week, randomized, double-blind, active-controlled, phase 3 study, subjects using stable metformin plus sulfonylurea (N = 755) received canagliflozin 300 mg or sitagliptin 100 mg daily. Primary end point was change from baseline in A1C at 52 weeks. Secondary end points included change in fasting plasma glucose (FPG) and systolic blood pressure (BP), and percent change in body weight, triglycerides, and HDL cholesterol. Safety was assessed based on adverse event (AE) reports.

RESULTS

At 52 weeks, canagliflozin 300 mg demonstrated noninferiority and, in a subsequent assessment, showed superiority to sitagliptin 100 mg in reducing A1C (−1.03% [−11.3 mmol/mol] and −0.66% [−7.2 mmol/mol], respectively; least squares mean difference between groups, −0.37% [95% CI, −0.50 to −0.25] or −4.0 mmol/mol [−5.5 to −2.7]). Greater reductions in FPG, body weight, and systolic BP were observed with canagliflozin versus sitagliptin (P < 0.001). Overall AE rates were similar with canagliflozin (76.7%) and sitagliptin (77.5%); incidence of serious AEs and AE-related discontinuations was low for both groups. Higher incidences of genital mycotic infections and osmotic diuresis–related AEs were observed with canagliflozin, which led to one discontinuation. Hypoglycemia rates were similar in both groups.

CONCLUSIONS

Findings suggest that canagliflozin may be a new therapeutic tool providing better improvement in glycemic control and body weight reduction than sitagliptin, but with increased genital infections in subjects with type 2 diabetes using metformin plus sulfonylurea.Patients with type 2 diabetes often require combinations of antihyperglycemic agents (AHAs) to maintain glycemic control because of the progressive nature of the disease (1,2). Metformin is the recommended first-line pharmacologic therapy for type 2 diabetes (1,2). For patients who do not achieve or sustain sufficient glycemic control with metformin, a second AHA is often added (2). With further decline in glycemic control (3,4), the addition of a third oral agent is increasingly common. Currently available classes of AHAs, such as dipeptidyl peptidase-4 inhibitors, peroxisome proliferator–activated receptor (PPAR)γ agonists, and sulfonylureas, have distinct risk/benefit profiles (2,5). A recent position statement by the American Diabetes Association and the European Association for the Study of Diabetes recommends individualization of treatment for patients and suggests the use of pharmacologic agents with complementary mechanisms of action in triple therapy combinations if A1C targets are not attained with dual combination therapy (2).Canagliflozin is an inhibitor of the sodium glucose cotransporter 2 (SGLT2) in development for the treatment of patients with type 2 diabetes (6–10). SGLT2 is responsible for the majority of glucose reabsorption in the kidney (11). Almost all glucose is reabsorbed from the tubules until renal tubular resorptive capacity is exceeded and urinary glucose excretion (UGE) ensues; the glucose concentration at which this occurs is referred to as the renal threshold for glucose. Canagliflozin lowers the renal threshold for glucose, markedly increasing UGE and thereby reducing blood glucose concentrations in patients with hyperglycemia. The increase in UGE results in a mild osmotic diuresis and also provides a net caloric loss (with most patients with type 2 diabetes losing an average of 80–120 g/day) (12). This mechanism of action, distinct from the mechanisms of glucose-lowering of current AHA classes and independent of insulin, should provide additive glycemic control across stages of type 2 diabetes and range of classes, including add-on to the combination of metformin and a sulfonylurea agent. This 52-week Canagliflozin Treatment and Trial Analysis–dipeptidyl peptidase-4 inhibitor (CANTATA-D2; second comparator trial) study evaluated the efficacy and safety of canagliflozin 300 mg compared with sitagliptin 100 mg as add-on therapy in subjects with type 2 diabetes inadequately controlled with metformin plus a sulfonylurea agent.     

Efficacy and Safety of Weight-based Insulin Glargine Dose Titration Regimen Compared With Glucose Level- and Current Dose-based Regimens in Hospitalized Patients With Type 2 Diabetes: A Randomized,Controlled Study

Purpose

Insulin glargine is widely used as basal insulin. However, published dose titration regimens for insulin glargine are complex. This study aimed to compare the efficacy and safety profile of a user-friendly, weight-based insulin glargine dose titration regimen with 2 published regimens.

Methods

A total of 160 hospitalized patients with hyperglycemia in 3 medical centers were screened. Our inclusion criteria included age 18 to 80 years and being conscious. Exclusion criteria included pregnancy or breast-feeding and hepatic or renal dysfunction. A total of 149 patients were randomly assigned to receive weight-based, glucose level-based, or dose-based insulin glargine dose titration regimen between January 2011 and February 2013. The initial dose of insulin glargine was 0.2 U/kg. In the weight-based regimen (n = 49), the dose was titrated by increments of 0.1 U/kg daily. In the glucose level-based regimen (n = 51), the dose was titrated by 2, 4, 6, or 8 U daily when fasting blood glucose (FBG) was, respectively, between 7.0 and 7.9, 8.0 and 8.9, 9.0 and 9.9, or ≥10 mmol/L. In the current dose-based regimen (n = 49), titration was by daily increments of 20% of the current dose. The target FBG in all groups was ≤7.0 mmol/L. The incidence of hypoglycemia was recorded. One-way ANOVA and χ² test were used to compare data between the 3 groups.

Findings

All but 1 patient who required additional oral antidiabetic medication completed the study. The mean (SD) time to achieve target FBG was 3.2 (1.2) days with the weight-based regimen and 3.7 (1.5) days with the glucose level-based regimen (P = 0.266). These times were both shorter than that achieved with the current dose-based regimen (4.8 [2.8] days; P = 0.0001 and P = 0.005, respectively). The daily doses of insulin glargine at the study end point were 0.43 (0.13) U/kg with the weight-based regimen, 0.50 (0.20) U/kg with the glucose level-based regimen, and 0.47 (0.23) U/kg with the current dose-based regimen (P = 0.184). The incidence of hypoglycemia was 4.1%, 2.0%, and 6.3%, respectively (P = 0.557).

Implications

The currently proposed weight-based insulin glargine dose titration regimen is effective, tolerable, and user-friendly at achieving FBG target levels in hospitalized patients with hyperglycemia.     

甘精胰岛素联合二甲双胍治疗2型糖尿病患者的有效性和安全性

目的：了解甘精胰岛素联合二甲双胍治疗对口服降糖药血糖控制不理想的2型糖尿病患者的疗效和安全性。方法：对30例口服降糖药血糖控制不理想的2型糖尿病患者给与甘精胰岛素联合二甲双胍治疗,共12周。治疗前后测身高、体重、空腹血糖（FPG）、餐后2小时血糖（PPG）以及糖化血红蛋白（HbA1c）水平。了解治疗期间低血糖发生情况。结果：治疗后的FPG、PPG以及HbA1c水平明显下降,分别下降了3.03mmol/L、5.10mmol/L和1.98%,差异有统计学意义（P〈0.05）。治疗后53.30%的患者HbA1c水平〈7.0%。治疗前HbA1c水平≥7.0%-〈9.0%的患者,治疗后70.6%的患者HbA1c水平〈7.0%,治疗前HbA1c水平≥9.0%的患者,治疗后30.7%的患者HbA1c水平〈7.0%,两者的HbA1c达标率有明显差异（P〈0.05）。治疗前后体重及BMI无明显差异（P〉0.05）。30例患者中仅发生两次轻微低血糖。结论：甘精胰岛素联合二甲双胍治疗对口服降糖药治疗血糖控制不理想的2型糖尿病患者是安全有效的,尤其是对HbA1c水平〈9.0%的患者,血糖控制更好,达标率更高。     

Postprandial Vascular Effects of VIAject Compared With Insulin Lispro and Regular Human Insulin in Patients With Type 2 Diabetes

OBJECTIVE

Recent studies suggested an impact of prandial insulin delivery on postprandial regulation of tissue blood flow. This study compared the effect of VIAject with human regular insulin and insulin lispro on postprandial oxidative stress and endothelial function in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

Fourteen patients (seven men; aged 61.5 ± 1.8 years; duration of diabetes 6.6 ± 4.6 years; A1C 7.2 ± 0.5% [mean ± SEM]) received a prandial injection of VIAject, human regular insulin, and insulin lispro. At baseline and after a standardized liquid meal test (Ensure Plus), the postprandial increases in asymmetric dimethylarginine (ADMA) and nitrotyrosine levels were investigated. In addition, the postprandial effects on microvascular blood flow, skin oxygenation, and vascular elasticity were measured.

RESULTS

Treatment with VIAject resulted in a significant reduction in the peak postprandial generation of ADMA compared with human insulin and insulin lispro (VIAject −27.3 ± 22.6, human insulin 97.7 ± 24.4, and insulin lispro 66.9 ± 33.9 nmol/l; P < 0.05, respectively). The postprandial increases in nitrotyrosine levels were significantly less after VIAject than after human regular insulin (VIAject −0.22 ± 0.17 vs. human insulin 0.25 ± 0.15 μg/ml; P < 0.05), whereas nitrotyrosine after insulin lispro was in between (insulin lispro 0.09 ± 0.07 μg/ml; NS). In parallel, earlier and more pronounced increases in microvascular blood flow and skin oxygenation were obtained after VIAject compared with those after human insulin or insulin lispro (P < 0.05, respectively). All insulin formulations resulted in comparable improvements in central arterial elasticity.

CONCLUSIONS

Treatment with VIAject reduced postprandial oxidative stress and improved endothelial function compared with human regular insulin or insulin lispro.Type 2 diabetes is closely related to atherosclerosis and the development of cardiovascular complications such as myocardial infarction or stroke. Recent studies on cardiovascular end points in patients with type 2 diabetes call into question the value of A1C-focused treatments in reducing macrovascular complications of diabetes (1–3). Other markers such as glucose excursions, hypoglycemia, or postprandial generation of oxidative stress may add important information for the judgment of cardiovascular risk in patients with type 2 diabetes (1,2). Postprandial microvascular blood flow is under dynamic regulation and is diversely affected by changes in postprandial glucose and insulin levels (4). Increasing postprandial insulin levels stimulate microvascular blood flow by inducing the endothelial release of nitric oxide via the activation of the phosphatidylinositol 3-kinase system (5,6). In contrast, increasing blood glucose levels were shown to oppose the insulin effects on endothelial cells and to impair postprandial microvascular blood flow (7). A reduced first-phase insulin release with an augmented increase in postprandial glucose levels followed by an impairment in endothelial function and postprandial microvascular blood flow is an early feature of type 2 diabetes (4,8). These findings suggest that a physiological timing of prandial insulin release fulfills an important role not only in controlling postprandial blood glucose levels but also in maintaining normal tissue perfusion and nutrition. In addition, recent studies have shown that in insulin-treated patients with type 1 and type 2 diabetes, the pharmacokinetic profile of insulin formulations affects postprandial microvascular blood flow and that treatment with fast-acting insulin analogs reduces postprandial oxidative stress and restores endothelial function more effectively than treatment with human regular insulin (9–11).VIAject is a new, ultra–fast-acting insulin formulation shown to have more rapid insulin absorption than that for human regular insulin and insulin lispro. The aim of this study was to compare the effect of preprandial subcutaneous administration of insulin VIAject with preprandial application of human regular insulin and insulin lispro on several markers of endothelial and microvascular function after a standardized liquid meal test in patients with type 2 diabetes.     

Switching to Once-Daily Liraglutide From Twice-Daily Exenatide Further Improves Glycemic Control in Patients With Type 2 Diabetes Using Oral Agents

OBJECTIVE

To evaluate efficacy and safety of switching from twice-daily exenatide to once-daily liraglutide or of 40 weeks of continuous liraglutide therapy.

RESEARCH DESIGN AND METHODS

When added to oral antidiabetes drugs in a 26-week randomized trial (Liraglutide Effect and Action in Diabetes [LEAD]-6), liraglutide more effectively improved A1C, fasting plasma glucose, and the homeostasis model of β-cell function (HOMA-B) than exenatide, with less persistent nausea and hypoglycemia. In this 14-week extension of LEAD-6, patients switched from 10 μg twice-daily exenatide to 1.8 mg once-daily liraglutide or continued liraglutide.

RESULTS

Switching from exenatide to liraglutide further and significantly reduced A1C (0.32%), fasting plasma glucose (0.9 mmol/l), body weight (0.9 kg), and systolic blood pressure (3.8 mmHg) with minimal minor hypoglycemia (1.30 episodes/patient-year) or nausea (3.2%). Among patients continuing liraglutide, further significant decreases in body weight (0.4 kg) and systolic blood pressure (2.2 mmHg) occurred with 0.74 episodes/patient-year of minor hypoglycemia and 1.5% experiencing nausea.

CONCLUSIONS

Conversion from exenatide to liraglutide is well tolerated and provides additional glycemic control and cardiometabolic benefits.Glucagon-like peptide (GLP)-1 receptor agonists improve glycemic control and reduce weight with minimal risk of hypoglycemia (1,2). The first randomized head-to-head comparison of two GLP-1 receptor agonists added to oral antidiabetes agents (Liraglutide Effect and Action in Diabetes [LEAD]-6) showed that 1.8 mg once-daily liraglutide provided greater improvements in A1C and fasting plasma glucose (FPG) with lower hypoglycemia and less persistent nausea than 10 μg twice-daily exenatide after 26 weeks; similar decreases in weight (∼3 kg) and systolic blood pressure (SBP) (2.0–2.5 mmHg) occurred with both drugs (3). The objectives of this 14-week extension were to assess the safety and efficacy of switching from exenatide to liraglutide, or continuing liraglutide for up to 40 weeks.     

The Efficacy and Safety of Saxagliptin When Added to Metformin Therapy in Patients With Inadequately Controlled Type 2 Diabetes With Metformin Alone

OBJECTIVE

This 24-week trial assessed the efficacy and safety of saxagliptin as add-on therapy in patients with type 2 diabetes with inadequate glycemic control with metformin alone.

RESEARCH DESIGN AND METHODS

This was a randomized, double-blind, placebo-controlled study of saxagliptin (2.5, 5, or 10 mg once daily) or placebo plus a stable dose of metformin (1,500–2,500 mg) in 743 patients (A1C ≥7.0 and ≤10.0%). Efficacy analyses were performed using an ANCOVA model using last observation carried forward methodology on primary (A1C) and secondary (fasting plasma glucose [FPG] and postprandial glucose [PPG] area under the curve [AUC]) end points.

RESULTS

Saxagliptin (2.5, 5, and 10 mg) plus metformin demonstrated statistically significant adjusted mean decreases from baseline to week 24 versus placebo in A1C (−0.59, −0.69, and −0.58 vs. +0.13%; all P < 0.0001), FPG (−14.31, −22.03, and −20.50 vs. +1.24 mg/dl; all P < 0.0001), and PPG AUC (−8,891, −9,586, and −8,137 vs. −3,291 mg · min/dl; all P < 0.0001). More than twice as many patients achieved A1C <7.0% with 2.5, 5, and 10 mg saxagliptin versus placebo (37, 44, and 44 vs. 17%; all P < 0.0001). β-Cell function and postprandial C-peptide, insulin, and glucagon AUCs improved in all saxagliptin treatment groups at week 24. Incidence of hypoglycemic adverse events and weight reductions were similar to those with placebo.

CONCLUSIONS

Saxagliptin once daily added to metformin therapy was generally well tolerated and led to statistically significant improvements in glycemic indexes versus placebo added to metformin in patients with type 2 diabetes inadequately controlled with metformin alone.Saxagliptin is a potent, selective dipeptidyl peptidase-4 (DPP-4) inhibitor, specifically designed for extended inhibition of the DPP-4 enzyme (1,2). DPP-4 rapidly cleaves and inactivates the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) (1). GLP-1 and GIP regulate blood glucose homeostasis by stimulation of glucose-dependent insulin secretion (3). GLP-1 also delays gastric emptying and inhibits glucagon secretion (3,4). In rodents, GLP-1 has been shown to stimulate β-cell growth and differentiation and inhibit β-cell apoptosis (5). Such an approach is needed because the majority of patients with type 2 diabetes fail to achieve recommended glycemic targets with existing therapies, owing to safety and tolerability issues and loss of efficacy over time (6).Metformin is the most widely prescribed first-line agent for the management of type 2 diabetes and is standard first-line pharmacotherapy, along with diet and exercise (7). Mechanistically, metformin reduces hepatic glucose production and improves insulin sensitivity (8); however, metformin alone is frequently insufficient to maintain glycemic goals in the face of progressive β-cell failure and increasing insulin resistance (9). Consequently, many patients require multiple oral antihyperglycemic agents (9,10). Metformin works through pathways complementary to saxagliptin, and the combination of saxagliptin with metformin may improve glycemic control (11,12). Studies of other DPP-4 inhibitors in combination with metformin over 24 weeks have demonstrated increased efficacy versus placebo (13–15). The safety and efficacy of saxagliptin monotherapy in treatment-naive patients were established previously in a 12-week study across a dose range of 2.5 to 40 mg/day. Significant A1C reductions were demonstrated in all active treatment groups with maximal A1C efficacy observed with 5 mg saxagliptin. A test for log-linear trend across the treatment groups did not demonstrate a statistically significant dose response after 12 weeks of treatment. The overall frequency of adverse events was comparable across all treatment groups and placebo and did not appear to be dose related (16). The current trial (CV181-014) examined the efficacy and safety of saxagliptin in combination with metformin administered for up to 24 weeks in patients with type 2 diabetes inadequately controlled with metformin alone.     

Durability of Triple Combination Therapy Versus Stepwise Addition Therapy in Patients With New-Onset T2DM: 3-Year Follow-up of EDICT

OBJECTIVETo compare the long-term efficacy of initiating therapy with metformin/pioglitazone/exenatide in patients with new-onset type 2 diabetes mellitus (T2DM) versus sequential addition of metformin followed by glipizide and insulin.RESEARCH DESIGN AND METHODSDrug-naive patients (N = 318) with new-onset T2DM were randomly assigned to receive for 3 years either 1) combination therapy with metformin, pioglitazone, and exenatide (triple therapy) or 2) sequential addition of metformin followed by glipizide and insulin (conventional therapy) to maintain HbA_1c at <6.5% (48 mmol/mol). Insulin sensitivity and β-cell function were measured at baseline and 3 years. The primary outcome was the difference in HbA_1c between the groups at 3 years.RESULTSBaseline HbA_1c ± SEM values were 9.0% ± 0.2% and 8.9% ± 0.2% in the triple therapy and conventional therapy groups, respectively. The decrease in HbA_1c resulting from triple therapy was greater at 6 months than that produced by conventional therapy (0.30% [95% CI 0.21–0.39]; P = 0.001), and the HbA_1c reduction was maintained at 3 years in patients receiving triple therapy compared with conventional therapy (6.4% ± 0.1% and 6.9% ± 0.1%, respectively), despite intensification of antihyperglycemic therapy in the latter. Thus, the difference in HbA_1c between the two treatment groups at 3 years was 0.50% (95% CI 0.39–0.61; P < 0.0001). Triple therapy produced a threefold increase in insulin sensitivity and 30-fold increase in β-cell function. In conventional therapy, insulin sensitivity did not change and β-cell function increased by only 34% (both P < 0.0001 vs. triple therapy).CONCLUSIONSTriple therapy with agents that improve insulin sensitivity and β-cell function in patients with new-onset T2DM produces greater, more durable HbA_1c reduction than agents that lower glucose levels without correcting the underlying metabolic defects.