Exenatide: a review of its use in patients with type 2 diabetes mellitus (as an adjunct to metformin and/or a sulfonylurea)

Exenatide (Byetta) is a novel, synthetic, incretin mimetic, glucoregulatory peptide approved in the US and Europe for the treatment of patients with type 2 diabetes mellitus who have inadequate glycaemic control despite receiving treatment with maximum tolerated doses of metformin and/or a sulfonylurea. In randomised, controlled, phase III trials and post hoc completer analyses in this patient population, the addition of subcutaneous exenatide twice daily significantly improved glycaemic control and was associated with progressive and significant bodyweight reduction from baseline for up to 2 years. The overall intensity of glycaemic control with exenatide was similar to that achieved with once-daily insulin glargine or twice-daily biphasic insulin aspart. Exenatide was generally well tolerated. Most adverse events were mild to moderate in severity and gastrointestinal in nature. The overall rate of hypoglycaemia was similar to rates observed with placebo (when administered with metformin) and insulin comparators (when administered with metformin and a sulfonylurea). The addition of exenatide to therapy with metformin and a sulfonylurea provided significant improvements in treatment satisfaction and patients' health-related quality of life (HR-QOL). The drug was also cost effective compared with pioglitazone, glibenclamide (glyburide), insulin glargine (all in combination with metformin and/or a sulfonylurea) and metformin alone. Overall, adjunctive therapy with exenatide is a valuable therapeutic option in patients with type 2 diabetes requiring moderate improvements in glycaemic control despite treatment with metformin and/or a sulfonylurea.     

Exenatide.

PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, and dosage and administration of exenatide are discussed. SUMMARY: Exenatide, derived from a compound found in the saliva of the Gila monster, is an incretin mimetic agent that enhances glucose-dependent insulin secretion and has several other antihyperglycemic actions. The drug is indicated as adjunctive therapy to improve glycemic control in patients with type 2 diabetes mellitus who are taking metformin, a sulfonylurea, or both but who have not achieved adequate glycemic control. Peak plasma concentration following subcutaneous administration of exenatide is attained in 2.1 hours. The mean apparent volume of distribution after administration of a single subcutaneous dose is 28.3 L. The terminal half-life of the drug is 2.4 hours. Based on animal studies, the bioavailability of exenatide after subcutaneous injection has been estimated to be between 65% and 75%. The drug is predominantly eliminated by glomerular filtration followed by proteolytic degradation. Clinical trials have shown that exenatide given subcutaneously twice daily significantly reduced glycosylated hemoglobin values when maximum doses of a sulfonylurea, metformin, or both were ineffective. The most common adverse effects are nausea, vomiting, diarrhea, jitteriness, dizziness, headache, and dyspepsia. Drug-drug interactions with digoxin, lovastatin, lisinopril, and acetaminophen have been documented. The recommended starting dosage is 5 microg subcutaneously twice daily within one hour before the morning and evening meals. CONCLUSION: Exenatide offers a novel treatment option for patients with type 2 diabetes mellitus who are refractory to metformin or sulfonylurea therapy or both.     

Exenatide: from the Gila monster to the pharmacy.

OBJECTIVE: To explain the incretin concept and review the pharmacology and clinical utility of exenatide (Byetta-Amylin; Lilly), a new agent for the treatment of patients with type 2 diabetes mellitus, and provide pharmacists with information necessary for counseling patients in the use of exenatide. DATA SOURCES: Review articles, clinical trials, and data on file with the manufacturers. STUDY SELECTION: By the authors. DATA EXTRACTION: By the authors. DATA SYNTHESIS: Exenatide is a synthetic form of a protein found in the saliva of the Gila monster that mimics the action of glucagon-like peptide-1, an incretin important in glucose homeostasis and deficient in patients with diabetes mellitus. Three pivotal clinical trials of exenatide as an add-on therapy in patients with type 2 diabetes mellitus who were unable to achieve glycemic control with maximum doses of metformin, sulfonylurea, or these drugs in combination demonstrated significant reductions in glycosylated hemoglobin (A1C) levels following twice-daily self-injection of exenatide compared with placebo. Weight loss was observed in patients in conjunction with A1C improvement, which occurred without additional patient instruction, intentional caloric deficit, or exercise. Mild-to-moderate nausea was the most common adverse event with exenatide treatment, occurring at the beginning of therapy, lessening over time, and reduced by titration of the dose. CONCLUSION: Exenatide offers a wide range of beneficial glucoregulatory effects, including enhancement of glucose-dependent insulin secretion, restoration of first-phase insulin response, suppression of inappropriately elevated glucagon secretion, slowing of gastric emptying, and reduction of food intake. These positive effects depend on the patient's understanding of the proper administration technique and timing, the need for continued adherence, and what to do if adverse effects occur, all elements that can be conveyed by pharmacists in their counseling and education of patients with type 2 diabetes mellitus.     

Exenatide

Exenatide is an incretin mimetic. It improves glycaemic control via various glucoregulatory mechanisms, including glucose-dependent insulinotropism, suppression of inappropriately high glucagon levels, delayed gastric emptying and reduction of food intake. In three large, well designed, phase III trials in adults with type 2 diabetes mellitus and suboptimal glycaemic control despite treatment with metformin and/or a sulfonylurea, mean changes from baseline in glycosylated haemoglobin (HbA(1c)) significantly favoured subcutaneous exenatide 5 or 10microg twice daily over placebo after 30 weeks' treatment (primary endpoint). Relative to placebo, reductions from baseline in bodyweight were significantly greater with twice-daily exenatide 5microg (in two studies) or 10microg (in all three studies). Post hoc completer analyses revealed that the beneficial effects of exenatide on HbA(1c) and bodyweight were maintained for up to 82 weeks. Adjunctive therapy with subcutaneous exenatide 10microg twice daily improved glycaemic control to a similar extent as insulin glargine in patients with type 2 diabetes suboptimally controlled with metformin plus a sulfonylurea in a large, well designed, 26-week, phase III trial. Subcutaneous exenatide was generally well tolerated in patients with type 2 diabetes. The incidence of hypoglycaemia in patients receiving exenatide plus metformin was similar to that seen in placebo plus metformin recipients; however, in patients receiving a sulfonylurea (with or without metformin), the incidence of hypoglycaemia was numerically higher with exenatide than with placebo.     

Recent evidence of sustained benefit with exenatide in Type 2 diabetes

Exenatide has been shown to improve glycaemic control (over 30 weeks) in subjects with Type 2 diabetes. A recent extension study has shown that, in metformin-treated subjects with Type 2 diabetes, exenatide remained beneficial at 82 weeks. For those subjects who completed the study, in addition to the 1% fall in glycosylated haemoglobin (HbA1c) at 30 weeks, there was another 0.2% fall in HbA1c by 82 weeks. The weight loss achieved was a mean of 3 kg after 30 weeks, and this increased to 5.3 kg after 82 weeks in the completer cohort. In another extension study, continued benefit with exenatide was shown in subjects treated with metformin and/or sulfonylureas. For those subjects who completed the study, in addition to the 0.9% fall in HbA(1c) at 30 weeks, there was another 0.2% fall in HbA(1c) by 82 weeks. The weight loss achieved was a mean of 1.6 kg after 30 weeks, and this increased to 2.1 kg after 82 weeks in the completer cohort. The subjects taking exenatide with metformin had a greater weight loss (5.3 kg), compared with those treated with a sulfonylurea (3.9 kg) and those taking metformin and a sulfonylurea (4.1 kg). In conclusion, extension studies have confirmed that exenatide is an exciting new and useful medicine for Type 2 diabetes.     

Managed care perspective on three new agents for type 2 diabetes

BACKGROUND: Despite effective monotherapy for diabetes, approximately 50% of patients require additional medications after 3 years to achieve target glycosylated hemoglobin (A1C) < 7%. Three new agents, each the first in its therapeutic class with a unique mechanism of action, have been approved for the treatment of type 2 diabetes by the U.S. Food and Drug Administration: pramlintide in March 2005, exenatide in April 2005, and sitagliptin in October 2006. OBJECTIVE: To review the efficacy and safety of 3 new agents for type 2 diabetes (exenatide and pramlintide by subcutaneous injection and sitagliptin by oral administration) and to define their place in therapy given their relatively high cost and unknown long-term safety and efficacy. METHODS: A MEDLINE search (1950 to June 2007) for English-language articles of studies in human subjects was conducted using these search terms: type 2 diabetes, exenatide, pramlintide, and sitagliptin. This database was supplemented by systematic reviews and meta-analyses through December 2007 and reference citations from the articles identified in the MEDLINE search. RESULTS: Exenatide, pramlintide, and sitagliptin have all been shown to have a modest effect on reducing A1C. In several relatively short-term trials (generally 15-30 weeks in duration), exenatide injection has been shown to be safe and effective for patients with type 2 diabetes who are either at the maximum doses of or cannot tolerate metformin, sulfonylurea, and/or thiazolidinedione therapy and need to further decrease A1C by at least 0.5% to 1%. While weight loss of 1.5 kg to 2.5 kg associated with exenatide is modest, this effect is of obvious value in many patients with type 2 diabetes. Nausea is the most notable side effect with exenatide, occurring in up to 50% of patients within the first 8 weeks of therapy but decreasing to 5% to 10% by week 24. In addition, the risk for hypoglycemia increases 4- to 5-fold when used in combination with sulfonylureas. Like exenatide, pramlintide injection reduces A1C by approximately 0.5% to 1%, carries the advantage of modest weight loss (1.5 kg over 1 year), and has a high incidence of nausea. Pramlintide can also result in severe hypoglycemia because of its ability to enhance the effects of insulin, a concern given that it is only indicated for use in combination with insulin. Sitagliptin is an oral agent that can be used alone or in combination with other oral hypoglycemic agents and has been shown to reduce A1C by 0.5% to 0.7%. It has only been studied in short-term studies, to date, so the long-term safety and efficacy are unknown. There is potential for severe allergic and dermatologic reactions with sitagliptin. CONCLUSIONS: The 3 new agents for the management of type 2 diabetes have been shown to reduce A1C by no more than 1.0%, modest by comparison with insulin and the older oral agents. The 3 newer agents have either modest positive effects on body weight or are weight neutral. The longterm safety and efficacy of the 3 newer agents are unknown, and their cost is considerably higher than the first-line agents, metformin and sufonylureas, which are available by generic name. The newer agents offer treatment options in select patients, although their use should be reserved for patients who are not adequately managed by agents with known longterm efficacy and safety, which are often available at a lower cost.     

Exenatide

Exenatide is the first in a new class of compounds, which possess similar activity to the naturally-occurring hormone glucagon-like peptide-1 (GLP-1). It mirrors many of the effects of GLP-1, improving glycaemic control through a combination of mechanisms, which include glucose-dependent stimulation of insulin secretion, suppression of glucagon secretion, slowing of gastric emptying and reduced appetite. Phase III clinical trials showed exenatide therapy for 30 weeks significantly reduced glycated haemoglobin, and fasting and postprandial plasma glucose compared with baseline when added to metformin and sulfonylureas or a combination of the two, with an average weight loss of approximately 2 kg. Exenatide can also be used in combination with thiazolidinediones and may be an alternative to insulin in patients requiring additional therapy. In patients with established Type 2 diabetes, control of both glycaemia and body weight are important to minimise the risk of future diabetes complications. Open-label extensions from these pivotal trials demonstrate that patients treated with exenatide for < or = 3 years sustained the reductions in glycaemic control achieved at 30 weeks and had a progressive reduction in body weight. Exenatide is generally well tolerated; nausea is the most commonly reported side effect, but can be significantly reduced when a target dose of exenatide is achieved in patients with gradual dose titration. Hypoglycaemia has been encountered in clinical trials of exenatide, especially on initiation of therapy with sulfonylureas (not with metformin). Exenatide may enable patients with Type 2 diabetes to improve glycaemic control and reduce or eliminate the risk of hypoglycaemia and weight gain.     

Application of economic analyses in U.S. managed care formulary decisions: a private payer's experience

BACKGROUND: Promoting use of pharmaco-economic models by formulary reviewers is a goal of the Academy of Managed Care Pharmacy (AMCP) Format for Formulary Submissions, but relatively few decision makers use such models, and many doubt that they provide meaningful input. OBJECTIVE: To demonstrate how sophisticated disease-based pharmaco-economic models can aid formulary decision makers when long-term outcomes data are lacking. METHODS: The Center for Outcomes Research (CORE) Diabetes Model (CDM), a published, validated Markov pharmaco-economic model that projects clinical and economic endpoints, was used to model the cost-effectiveness of exenatide, a new injectable antidiabetic agent that enhances glucose-dependent insulin secretion, in a standard cohort of type 2 diabetes patients (mean body mass index [BMI] = 27.5 3 kg/m2), compared with a modified obese cohort (mean BMI = 35 3 kg/m2) that was otherwise demographically identical at baseline to the standard cohort. The standard cohort was assumed to maintain baseline weight during treatment, and the modified obese cohort was assumed to experience weight loss of approximately 9% (mean = 3 kg/m2), with corresponding improvements in blood pressure, low density lipoprotein cholesterol, and triglycerides. We selected a 30-year time horizon because it was the time interval during which the CDM predicted most of the subjects would have died, and the costs obtained thus reasonably projected lifetime total direct medical costs for these cohorts. While treatment options certainly will change over a 30-year period, our goal was to estimate the incremental effect of exenatide over other available therapies. RESULTS: The model predicted reduced long-term treatment costs in obese patients, driven by an 11% decrease in cardiovascular disease burden and derived from the presumed weight loss. The incremental cost-effectiveness ratio (ICER) for adding exenatide over 3 years was 35,000 dollars/quality-adjusted life-year (QALY). Using a 30-year horizon, ICER values were 13,000 dollars/QALY versus insulin, 32,000 dollars versus generic glyburide, and 16,000 dollars versus no additional treatment. Exenatide dominated pioglitazone. By comparison, the 30-year ICER for exenatide versus insulin in the nonobese cohort was 33,000 dollars. These results were presented to the pharmacy and therapeutics (P&T) committee and influenced its decision to add exenatide to the drug formulary. While our modeling assumed certain patient characteristics (e.g., obesity, need of further A1c reduction at baseline, motivation to lose weight), the P&T committee imposed only a step-therapy requirement to try either metformin or a sulfonylurea before trying exenatide and did adopt a nonspecific requirement for physician reauthorization of refills before the fourth pharmacy claim for exenatide. CONCLUSIONS: Disease-based pharmaco-economic models may help third party payers project costs and be particularly useful when only data from short-term clinical trials are available. In the present case, the pharmacy staff of a health plan used a pharmaco-economic model for drug treatment of type 2 diabetes provided by the manufacturer as part of the AMCP Format dossier process to project cost outcomes for exenatide, adjunct injectable therapy for patients taking metformin and/or sulfonylurea. The P&T committee approved the drug for inclusion in the drug formulary based in part on the results of the pharmaco-economic model produced from the cost inputs entered into the model by the health plan pharmacists.     

Exenatide: A New Promising Antidiabetic Agent

Exenatide is a unique agent which can effectively control blood glucose levels in type 2 diabetes mellitus without producing dangerous adverse effects. In addition, it can lower body weight which is very essential for the treatment of obese type 2 diabetes mellitus patients. Since it can delay the destruction of islet beta-cells, type 2 diabetes mellitus patients are not rapidly converted to type 1 diabetes mellitus and ultimately appearance of complications of the disease is halted or delayed. Its long-acting-release formula, which would be used once per week, simultaneously retaining all the properties of twice-daily subcutaneous administration, is undergoing clinical trial. This drug is considered as an adjunct to metformin/sulfonylureas/insulin.     

Exenatide once weekly for the treatment of type 2 diabetes

Exenatide is the first glucagon-like peptide-1 (GLP-1) receptor agonist approved for the treatment of type 2 diabetes mellitus (T2DM). Exenatide lowers blood glucose through multiple mechanisms, including enhancement of glucose-dependent insulin secretion, suppression of excess glucagon secretion, reduction of food intake and slowing of gastric emptying. The current formulation of exenatide requires twice-daily dosing (exenatide BID), and an extended-release formulation of exenatide is now in development for use as a once-weekly injection (exenatide QW). The purpose of this report is to review the most current clinical data on the development of exenatide QW for the treatment of T2DM. In clinical trials, exenatide QW significantly improved glycemic control, resulted in patient weight loss, and was well tolerated in patients with T2DM. In a head-to-head clinical trial, exenatide QW caused greater improvements in glycemic control and was better tolerated than exenatide BID. Given the rapidly increasing prevalence of diabetes and obesity worldwide, exenatide QW is a promising development candidate for the treatment of T2DM.     

Targeting the pathophysiology of type 2 diabetes: rationale for combination therapy with pioglitazone and exenatide

ABSTRACT

Objective: The objectives of this article are to review the pathophysiology of type 2 diabetes mellitus (T2DM), present the rationale for a pathophysiologically based treatment approach for patients with T2DM and discuss the role of the therapeutic combination of pioglitazone and exenatide in the management of T2DM.

Methods: References were identified from searches of the PubMed database that were conducted in May 2007, October 2007 and March 2008 and updates to product labeling that occurred between May 2007 and December 2007. Information was selected for inclusion on the basis of its relevance to the pathophysiology of T2DM or the clinical use of thiazolidinediones or exenatide. Discussion of other anti-diabetic treatment strategies is not included.

Results: T2DM results from a combination of insulin resistance and beta-cell dysfunction. The combination of a thiazolidinedione and an incretin mimetic offers a combination of characteristics (e.g., glycemic control, reduced insulin resistance, decreased weight, potential cardiovascular benefits, beta-cell preservation) that addresses many of the pathophysiologic underpinnings of T2DM. A recent small placebo-controlled study assessed the effects of exenatide used with a thiazolidinedione (TZD; pioglitazone or rosiglitazone) with or without metformin. Exenatide demonstrated a greater incidence of glycosylated hemoglobin (HbA_1c) <?7%; greater reductions in fasting blood glucose, postprandial plasma glucose and body weight; and improved beta-cell function versus the TZD/placebo group. However, exenatide was associated with a high dropout rate, and the 16-week duration of treatment in this study precluded evaluation of the long-term effects of the exenatide/pioglitazone combination. Furthermore, exenatide/pioglitazone has not been compared with any other anti-diabetic combination in a head-to-head clinical study.

Conclusions: Dual effects on insulin sensitivity (TZD) and insulin secretion (exenatide) make the TZD/exenatide combination a rational treatment option for patients who do not attain glycemic control with a single agent. Studies undertaken to evaluate the effects on cardiovascular outcomes and the potential for prevention of T2DM with impaired glucose tolerance may reveal additional advantages of this combination approach.     

Exenatide: new drug. Type 2 diabetes for some overweight patients

(1) When type 2 diabetes is inadequately controlled with oral antidiabetic therapy, one option is to add subcutaneous insulin injections (or to accept less stringent glycaemic control). However, since the effects of adding insulin have only been evaluated in the short-term, effects on long-term clinical outcomes remain unknown. (2) Exenatide, a drug belonging to a new pharmacological class (incretin analogues), is marketed as a subcutaneously administered adjunct to inadequately effective oral antidiabetic therapy in adults with type 2 diabetes. (3) Three placebo-controlled trials lasting 7 months showed that adding exenatide to metformin and/or a glucose-lowering sulphonylurea yielded an HbA1c level of 7% or less in about 40% of patients treated with exenatide 10 micrograms twice a day, versus about 10% of patients on placebo. The potential impact of exenatide on morbidity and mortality is not known. (4) In two trials versus insulin glargine and in one trial versus insulin aspart (+ isophane insulin), exenatide was as effective as the various insulins in controlling HbA1c levels. (5) During clinical trials, patients receiving exenatide lost an average of about 2 kg after 6 months, while insulin was associated with a weight gain of about 2 kg. (6) There was a similar incidence of hypoglycaemia with exenatide and insulin. In patients treated with exenatide, concomitant use of glucose-lowering sulphonylurea increases the risk of hypoglycaemia. (7) More than half of patients on exenatide experienced nausea, versus fewer than 10% of patients on insulin glargine. (8) The long-term consequences of the presence of antiexenatide antibodies on the effectiveness of treatment are not known. (9) Exenatide is administered in two subcutaneous injections a day, at fixed doses. Insulin is administered in one or several injections a day, at doses adjusted to self-monitored blood glucose levels. (10) Adding insulin rather than exenatide is a better option in general when oral antidiabetic therapy fails in patients with type 2 diabetes, as we have more experience with insulin and there is no evidence of important advantages with exenatide. The latter should be reserved for situations in which weight gain is a major problem.     

Patient characteristics,drug adherence patterns,and hypoglycemia costs for patients with type 2 diabetes mellitus newly initiated on exenatide or insulin glargine

ABSTRACT

Objective: Examine real-world effectiveness and hypoglycemia cost burden in patients with type?2 diabetes newly initiated on exenatide or insulin glargine.

Design and methods: Retrospective cohort study describing patient characteristics, drug adherence patterns, and 1-year hypoglycemia rates with associated costs using an administrative claims database. Adult subjects with type?2 diabetes had an initial claim for exenatide or insulin glargine between May?1, 2005 and June?30, 2007, and had continuous eligibility for ≥?6 months pre- and ≥?12 months post-initiation.

Results: The exenatide cohort (n?=?3262) was 53?±?10?years (±SD); 54% female. The insulin glargine cohort (n?=?3038) was 56?±?12?years; 41% female. The mean Deyo-Charlson comorbidity index score was 1.45 for exenatide versus 1.82 for insulin glargine (p?<?0.001). Baseline OAD use rates for exenatide and insulin glargine, respectively, were 77% versus 69% metformin; 47% versus 65% sulfonylurea; 50% versus 49% thiazolidinedione; 56% versus 60% multiple OAD. For patients with two or more pharmacy claims for exenatide or insulin glargine, the 12-month medication possession ratio (MPR) was 68?±?29% for exenatide and 58?±?28% for insulin glargine (p?<?0.001). MPR ≥?80% was higher for exenatide (p?<?0.001) and fewer patients discontinued therapy (p?<?0.001). The probability of a hypoglycemic event was significantly lower for exenatide (p?<?0.005), resulting in lower associated annual costs.

Conclusions: This study provides the first real-world observational comparison of type?2 diabetes patients newly initiated on exenatide or insulin glargine. Exenatide patients had a lower comorbidity burden, better drug adherence, and a lower rate of hypoglycemic events with associated costs. Retrospective database analyses examine medical care utilization in large populations using a relatively inexpensive and expedient approach. However, data are only representative of a commercial health-care plan with limited information on multiple variables usually collected during clinical trials.     

Is exenatide advancing the treatment of type 2 diabetes?

Glucagon-like peptide 1 is an intestinal peptide hormone that is secreted in response to food to regulate the postprandial blood glucose concentration. Exendin-4 is a 39-amino acid peptide that acts as an agonist at the glucagon-like peptide 1 receptor. Synthetic exendin-4 (exenatide) has recently been trialled in patients with Type 2 diabetes taking either metformin alone or a combination of metformin and a sulfonylurea. In both trials, exenatide 5 and 10 microg s.c. was shown to improve glycaemic control, with few adverse events. Exenatide represents a new and useful addition to the medicines used to treat Type 2 diabetes.     

Saxagliptin: a review of its use as combination therapy in the management of type 2 diabetes mellitus in the EU

Saxagliptin (Onglyza?) is a dipeptidyl peptidase 4 inhibitor widely approved for the treatment of type 2 diabetes mellitus. In the EU, saxagliptin is indicated as combination therapy with metformin, a sulfonylurea, a thiazolidinedione, or insulin (with or without metformin) for the treatment of adult patients with type 2 diabetes, including those with mild to severe renal impairment. This article reviews the clinical efficacy and tolerability of add-on saxagliptin therapy in patients with type 2 diabetes, in line with its approved indications in the EU, and summarizes the drug's pharmacological properties. The clinical efficacy of saxagliptin 5?mg/day in combination with metformin, glibenclamide (glyburide), a thiazolidinedione, or insulin (with or without metformin) has been demonstrated in several randomized, double-blind, placebo-controlled, multicentre, phase III trials (18-104 weeks in duration) in patients with type 2 diabetes. In these trials, glycosylated haemoglobin (HbA(1c)) was changed from baseline (primary endpoint) by a greater extent with add-on saxagliptin 5?mg/day (-1.09% to +0.03%) than with comparator regimens (-0.44% to +0.69%). Two other randomized, double-blind trials showed that saxagliptin 5?mg/day as add-on therapy to metformin was noninferior to uptitrated glipizide in terms of lowering HbA(1c) (-0.74% vs -0.80%) at 52 weeks, or sitagliptin (-0.52% vs -0.62%) at 18 weeks. Saxagliptin 2.5?mg/day as add-on to existing anti-diabetic therapy was also effective for up to 52 weeks in a randomized, double-blind, placebo-controlled, multicentre trial in patients with type 2 diabetes and renal impairment (HbA(1c) was reduced by 1.08% vs 0.36%; p?≤?0.007). Saxagliptin as add-on therapy for up to 4 years was generally well tolerated in clinical trials. Treatment with saxagliptin did not increase the risk of hypoglycaemia or cardiovascular outcomes relative to placebo or active comparators, and was generally weight neutral. In conclusion, saxagliptin is a useful option as add-on therapy to metformin, a sulfonylurea, a thiazolidinedione, or insulin (with or without metformin) in patients with type 2 diabetes who require combination therapy.     

Exenatide

Exenatide is the first in a new class of compounds that exhibit activity similar to the naturally occurring hormone glucagon-like peptide-1 (GLP-1). Released from cells in the gut in response to food, GLP-1 binds to pancreatic beta-cell receptors to stimulate the release of insulin. Exenatide mirrors many of the effects of GLP-1, improving glycemic control through a combination of mechanisms, which include glucose-dependent stimulation of insulin secretion, suppression of glucagon secretion, slowing of gastric emptying, reduced appetite and enhanced beta-cell function. As stimulation of insulin secretion occurs only in the presence of elevated blood glucose concentrations, the risk of hypoglycemia should be greatly reduced with exenatide. In addition to positive therapeutic effects on fasting and postprandial glucose levels, exenatide treatment is associated with significant, dose-dependent reductions in glycated hemoglobin (HbA1c) from baseline and progressive reductions in body weight. Exenatide is generally well tolerated; nausea is the most commonly reported side effect, but it can be significantly reduced when a target dose of exenatide is achieved in patients with gradual dose titration. Exenatide may enable patients with type 2 diabetes to achieve glycemic control while reducing or eliminating the risk of hypoglycemia and weight gain. These would represent significant therapeutic gains.     

Incretin mimetics and dipeptidyl peptidase 4 inhibitors in clinical trials for the treatment of type 2 diabetes

Background: Exenatide is an incretin mimetic, while sitagliptin and vildagliptin are incretin enhancers used as adjunctive therapy in patients with type 2 diabetes failing oral agents. Sitagliptin and vildagliptin can also be used as monotherapy in patients with type 2 diabetes uncontrolled by diet. Objective: To provide a critical review of clinical trials of exenatide, sitagliptin and vildagliptin. Method: Review of Phase III clinical trials based on Medline search published up to April 2008. Results: The use of exenatide is associated with reduction in average hemoglobin A1c (HbA1c) levels of approximately 0.8% compared with baseline. The corresponding reduction with either sitagliptin or vildagliptin is 0.7%. The actions of incretin-based drugs predominantly target postprandial hyperglycemia. Treatment-related hypoglycemia is generally mild, and mainly occurs when used with sulfonylureas (SUs). Exenatide treatment leads to a mild weight loss of around 2 kg after 30 weeks, whereas sitagliptin and vildagliptin have generally neutral effect on weight. Sitagliptin and vildagliptin are well tolerated in trials lasting up to 52 weeks. Meanwhile, 5 – 10% of patients cannot tolerate exenatide due to adverse effects, mainly nausea and vomiting. The three drugs are limited by the lack of long-term safety and efficacy data, as well as by their high cost. Conclusion: Exenatide, sitagliptin and vildagliptin are useful add-on therapy for type 2 diabetes that is suboptimally controlled on oral agents, particularly when there is concern about weight gain and hypoglycemia, or when postprandial hyperglycemia is the major cause of inadequate glycemic control. Sitagliptin and vildagliptin may be used as monotherapy in patients who cannot tolerate metformin or SU, and sitagliptin may be used as alternative to metformin in renal insufficiency.     

Evaluation of adverse events of oral antihyperglycemic monotherapy experienced by a geriatric population in a real-world setting: a retrospective cohort analysis

BACKGROUND AND OBJECTIVE: To evaluate and compare the risk of adverse events (AEs) associated with the use of metformin, sulfonylureas and thiazolidinediones among geriatric patients in a usual care setting. METHODS: An electronic medical record database was utilized to identify geriatric patients with type 2 diabetes mellitus aged > or =65 years from 1996 to 2005. Patients naive to oral antihyperglycemic drug (OAD) therapy were followed for 395 days post initiation of metformin, sulfonylurea or thiazolidinedione treatment. AEs related to study drugs were evaluated during the follow-up period, and the risks of developing an AE were evaluated and adjusted for differences in baseline characteristics by OAD treatment. RESULTS: A total of 5438 patients (mean age 73.2 [SD 5.08] years, 56.1% female) were identified. During the follow-up period, 12.5% of patients experienced an AE (8.3% of metformin, 13.9% of sulfonylurea and 19.8% of thiazolidinedione recipients). Sulfonylurea (odds ratio [OR] 1.74; 95% CI 1.41, 2.13) and thiazolidinedione (OR 2.86; 95% CI 2.23, 3.65) recipients were more likely to experience an AE than metformin recipients, after adjustment for baseline demographic and co-morbidity differences. The average time to onset of a metformin AE (175 days) was less than that for sulfonylurea or thiazolidinedione treatment (192 and 201 days, respectively). The most common AEs were abdominal pain with metformin (42.3%) and weight gain >4.5 kg for sulfonylureas (63.2%) and thiazolidinediones (68.2%). Hypoglycaemia occurred in 2.6% and 2.2% of sulfonylurea and thiazolidinedione recipients, respectively. DISCUSSION AND CONCLUSIONS: Geriatric patients in a real-world setting experienced AEs with metformin, sulfonylurea and thiazolidinedione therapy, although rates differed from those seen in clinical trials, particularly for weight gain and hypoglycaemia. Lactic acidosis occurred at a higher rate with metformin therapy than has been reported in clinical trials, but our results were in the same range for abdominal pain and lower for diarrhoea, nausea/vomiting and dyspepsia. AEs related to sulfonylurea therapy were in the same range as in clinical trials for weight gain but lower for hypoglycaemia, dizziness and headaches. AEs related to thiazolidinedione therapy were more common in our study than in clinical trials, and within the same range for weight gain and elevated liver enzymes but lower for hypoglycaemia and oedema. While AE reporting is likely to be different in a real-world setting than in clinical trials, the observed variances may also be due to the aetiology of diabetes and the physiological response to hypoglycaemia in an older population.     

Current management strategies for coexisting diabetes mellitus and obesity

Besides genetic predisposition, obesity is the most important risk factor for the development of diabetes mellitus. Weight reduction has been shown to markedly improve blood glucose control and vascular risk factors associated with insulin resistance in obese individuals with type 2 diabetes. Therapeutic strategies for the obese diabetic patient include: (i) promoting weight loss, through lifestyle modifications (low-calorie diet and exercise) and antiobesity drugs (orlistat, sibutramine, etc.); (ii) improving blood glucose control, through agents decreasing insulin resistance (metformin or thiazolidinediones, e.g. pioglitazone and rosiglitazone) or insulin needs (alpha-glucosidase inhibitors, e.g. acarbose) in preference to agents stimulating defective insulin secretion (sulphonylureas, meglitinide analogues); and (iii) treating common associated risk factors, such as arterial hypertension and dyslipidaemias, to improve cardiovascular prognosis. Whenever insulin is required by the obese diabetic patient after failure to respond to oral drugs, it should be preferably prescribed in combination with an oral agent, more particularly metformin or acarbose, or possibly a thiazolidinedione. When morbid obesity is present, both restoring a good glycaemic control and correcting associated risk factors can only be obtained through a marked and sustained weight loss. This objective justifies more aggressive weight reduction programmes, including very-low-calorie diets and bariatric surgery, but only within a multidisciplinary approach and long-term strategy.     

艾塞那肽治疗初诊2型糖尿病的疗效观察

目的 观察艾塞那肽治疗初诊2型糖尿病的疗效.方法 将初诊肥胖2型糖尿病患者86例完全随机分为艾塞那肽组(42例)和二甲双胍组(44例).艾塞那肽组给予艾塞那肽治疗(5 ～0 μg,2次/d),二甲双胍组使用二甲双胍治疗(500 mg/次,3次/d).比较治疗前和治疗16周后2组患者空腹血糖(FBG)、餐后2h血糖(2 h PG)、糖化血红蛋白(HbA1c)、BMI、空腹C肽(FPC-P)、餐后2hC肽(2 h PPC-P),以及低血糖发生次数及不良反应.结果 治疗16周后,2组的FBG、2 hPG、HbA1c、BMI、TC、TG均下降[艾塞那肽组:(6.6 ±1.3)mmol/L比(7.6±2.1)mmol/L,(9.1±1.9) mmol/L比(16.6±1.4) mmol/L,(6.2±0.9)％比(8.2±1.7)％,(24.4±1.4) kg/m2比(28.0±2.3)kg/m2,(5.2±1.4) mmol/L比(6.6 ±2.1)mmol/L,(1.4±1.2) mmol/L比(2.6±1.6) mmol/L;二甲双胍组:(6.8±1.3)mmol/L比(7.6±2.1)mmol/L,(9.0±2.1) mmol/L比(16.9±1.6)mmol/L,(6.6±1.8)％比(8.4±1.9)％,(25.4±1.8) kg/m2比(27.9±2.5)kg/m2,(6.0±1.6) mmol/L比(6.7±2.4) mmol/L,(2.2±1.5) mmol/L比(2.8±1.6) mmol/L],差异均有统计学意义(P＜0.05或P＜0.01).与二甲双胍组比较,艾塞那肽组的BMI、TG、TC下降更明显,差异有统计学意义(P＜0.05).2组均无低血糖及严重不良反应发生.结论 艾塞那肽可有效控制初诊2型糖尿病患者血糖,并且能明显降低BMI、TC、TG等代谢指标,改善胰腺功能.