dis Drug Evaluation
Exenatide
A Review of Its Use in Patients with Type 2 Diabetes Mellitus (as an Adjunct to Metformin and/or a Sulfonylurea) Risto S. Cvetković &
Greg L. Plosker
Drugs volume 67, pages 935–954 (2007)Cite this article
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Summary
Abstract
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
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lisinopril, lovastatin, warfarin).
Therapeutic Efficacy
In several large, randomised, multicentre, phase III trials in patients with type 2 diabetes who had inadequate glycaemic control despite therapy with metformin and/or a sulfonylurea, the addition of subcutaneous exenatide 5–10μg twice daily resulted in significantly improved glycaemic control and reduced bodyweight.
In three 30-week, triple-blind, phase III trials, the mean change from baseline in HbA1c (primary efficacy endpoint) was significantly better with either exenatide 5μg or 10μg twice daily than with placebo. In each study, HbA1c values in the exenatide treatment arms declined linearly during the first 12 weeks and remained stable thereafter. A statistically significant difference between exenatide and placebo recipients in HbA1c values was seen as early as week 2 or 4 of treatment and was maintained for ≥2 years in the nonblind extension of placebo-controlled, phase III trials. Among patients with baseline HbA1c >7% in each trial, significantly more patients receiving exenatide 5μg or 10μg twice daily than those receiving placebo achieved a target HbA1c of ≤7% at week 30. Likewise, mean changes from baseline in fasting plasma glucose levels at week 30 were significantly better with exenatide 5μg or 10μg twice daily than with placebo in patients also receiving metformin, alone or in combination with a sulfonylurea. In patients receiving concurrent therapy with sulfonylurea alone, a statistically significant improvement in fasting plasma glucose levels was seen only in recipients of exenatide 10μg twice daily. Exenatide also produced a significantly greater reduction from baseline in postprandial plasma glucose levels compared with placebo in subgroups of patients from two trials who underwent a standardised meal tolerance test. The effect was evident as early as week 4 and maintained through week 30 in both trials.
In two nonblind, phase III trials of 26 and 52 weeks’ duration, the efficacy of adjunctive therapy with exenatide 10μg twice daily was similar to that of once-daily insulin glargine or twice-daily biphasic insulin aspart (insulin doses target-titrated) in improving glycaemic control in patients with type 2 diabetes who were inadequately controlled with metformin plus a sulfonylurea. In both trials, exenatide was noninferior to the insulin comparator in achieving the mean reduction from baseline in HbA1c levels (primary efficacy endpoint). Likewise, there were no statistically significant differences between exenatide and either insulin comparator in the proportion of patients achieving a target HbA1c of ≤7% at study endpoints, and between exenatide and biphasic insulin aspart in reducing fasting plasma glucose levels. Insulin glargine was more effective than exenatide in reducing baseline fasting plasma glucose levels at week 26, although both drugs produced clinically relevant effects. As adjunctive therapy in both trials, exenatide provided better postprandial glycaemic control (e.g. lower blood glucose levels after both morning and evening meals) then either insulin glargine or biphasic insulin aspart.
Adjunctive therapy with twice-daily exenatide was associated with significant (compared with placebo) and progressive reduction from baseline in bodyweight that manifested as early as week 2 of treatment, affected the majority of overweight patients in all phase III trials and was sustained for up to 2 years in a nonblind extension of placebo-controlled trials. The weight loss was dose dependent, did not correlate with the occurrence of nausea and appeared directly proportional to patients’ baseline body mass index. By comparison, patients receiving insulin glargine or biphasic insulin aspart progressively gained weight over 26 and 52 weeks in phase III trials.
Exenatide exhibited similar efficacy to insulin glargine in significantly improving the treatment satisfaction and HR-QOL in patients with type 2 diabetes who were receiving metformin plus a sulfonylurea in a 26-week phase III trial. Importantly, exenatide was cost effective compared with pioglitazone, gliben-clamide, insulin glargine (all in combination with metformin and/or a sulfonylurea) and metformin alone, in two pharmacoeconomic analyses from the US and the UK.
Tolerability
Subcutaneous exenatide 5μg or 10μg twice daily administered in combination with oral metformin and/or sulfonylurea was generally well tolerated in patients with type 2 diabetes in randomised, phase III trials. The majority of treatment-emergent adverse events were mild or moderate in severity, rarely caused treatment discontinuation and, with the exception of hypoglycaemia, were predominantly gastrointestinal in nature. In all trials, nausea was the most common adverse event and occurred more frequently with exenatide (in up to 57% of patients) than with placebo, insulin glargine or biphasic insulin aspart. Hypoglycaemia, which occurred more frequently with exenatide than with placebo only in patients receiving concomitant therapy with a sulfonylurea (with or without metformin), was rarely of clinical significance. The overall rates of hypoglycaemia were low and similar in patients receiving twice-daily exenatide and those receiving once-daily insulin glargine or twice-daily biphasic insulin aspart, all of whom also received metformin plus a sulfonylurea. Exenatide was associated with a significantly lower incidence of nocturnal hypoglycaemia than both insulin comparators, and a significantly higher incidence of daytime hypoglycaemia compared with insulin glargine. The presence of anti-exenatide antibodies (in up to half of all exenatide recipients) had no predictive effect on glycaemic control or adverse events.
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Authors and Affiliations
Wolters Kluwer Health / Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore, Auckland, 0754, New Zealand
Risto S. Cvetković & Greg L. Plosker
Wolters Kluwer Health, Conshohocken, Pennsylvania, USA
Risto S. Cvetković & Greg L. Plosker
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Correspondence to Risto S. Cvetković.
Additional information
Various sections of the manuscript reviewed by: S. Bloom, Department of Metabolic Medicine, Division of Investigative Science, Imperial College London, Hammersmith Hospital, London, UK; R.K. Campbell, Washington State University, Pullman, Washington, USA; D. Elahi, Department of Surgery, Surgical Endocrinology & Metabolism Laboratory, The John Hopkins University, John Hopkins Bayview Medical Center, Baltimore, Maryland, USA; B. Gallwitz, Department of Medicine IV, Eberhard-Karls-University, Tübingen, Germany; D. Hinnen, Mid America Diabetes Associates, Wichita, Kansas, USA; U. Kabadi, Department of Internal Medicine, Division of Endocrinology, University of Iowa College of Medicine, Iowa City, Iowa, USA; B. Tuch, Diabetes Transplant Unit, University of New South Wales and Prince of Wales Hospital, Sydney, New South Wales, Australia.
Data Selection
Sources: Medical literature published in any language since 1980 on ‘exenatide’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Wolters Kluwer Health | Adis). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: MEDLINE, EMBASE and AdisBase search terms were ‘exenatide’. Searches were last updated on 19 March 2007.
Selection: Studies in patients with type 2 diabetes mellitus who received exenatide in addition to metformin and/or a sulfonylurea. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.
Index terms: Exenatide, incretin mimetic, type 2 diabetes mellitus, pharmacoeconomics, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability, treatment satisfaction, health-related quality of life.
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Cvetković, R.S., Plosker, G.L. Exenatide. Drugs 67, 935–954 (2007). https://doi.org/10.2165/00003495-200767060-00008
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Published18 September 2012
Issue DateApril 2007
DOIhttps://doi.org/10.2165/00003495-200767060-00008
KeywordsMetformin
Glycaemic Control
Sulfonylurea
Insulin Glargine
Exenatide
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Exenatide
A Review of Its Use in Patients with Type 2 Diabetes Mellitus (as an Adjunct to Metformin and/or a Sulfonylurea) Risto S. Cvetković &
Greg L. Plosker
Drugs volume 67, pages 935–954 (2007)Cite this article
598 Accesses
68 Citations
3 Altmetric
Metrics details
Summary
Abstract
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
تقييم المخدرات{ إكسيناتيد
مراجعة لاستخدامه في مرضى السكري من النوع 2 (كعامل مساعد للميتفورمين و / أو السلفونيل يوريا) Risto S.
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حجم الأدوية 67 ، الصفحات 935-954 (2007) استشهد بهذا المقال
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خلاصة
Exenatide (Byetta ™) هو ببتيد جديد ، اصطناعي ، مقلد للإنكريتين ، منظم جلوكوري معتمد في الولايات المتحدة وأوروبا لعلاج مرضى السكري من النوع 2 الذين يعانون من نقص في التحكم في نسبة السكر في الدم على الرغم من تلقيهم العلاج بأقصى جرعات يمكن تحملها من الميتفورمين و / أو سلفونيل يوريا. في التجارب العشوائية والمضبوطة والمرحلة الثالثة والتحليلات التكميلية اللاحقة في هذه المجموعة السكانية من المرضى ، أدت إضافة exenatide تحت الجلد مرتين يوميًا إلى تحسين التحكم في نسبة السكر في الدم بشكل ملحوظ وارتبط بالتخفيض التدريجي والكبير في وزن الجسم من خط الأساس لمدة تصل إلى سنتين. كانت الكثافة الإجمالية للتحكم في نسبة السكر في الدم باستخدام exenatide مماثلة لتلك التي تم تحقيقها مع الأنسولين جلارجين مرة واحدة يوميًا أو الأنسولين ثنائي الطور الأسبارت مرتين يوميًا. كان Exenatide جيد التحمل بشكل عام. كانت معظم الأحداث الضائرة خفيفة إلى معتدلة في شدتها وذات طبيعة معدية معوية. كان المعدل الإجمالي لنقص سكر الدم مشابهًا للمعدلات التي لوحظت مع الدواء الوهمي (عند تناوله مع الميتفورمين) ومقارنات الأنسولين (عند تناوله مع الميتفورمين والسلفونيل يوريا). أدت إضافة exenatide إلى العلاج بالميتفورمين والسلفونيل يوريا إلى تحسينات كبيرة في الرضا عن العلاج ونوعية الحياة المتعلقة بصحة المرضى (HR-QOL). كان الدواء أيضًا فعالًا من حيث التكلفة مقارنةً بـ pioglitazone و glibenclamide (glyburide) و insulin glargine (كل ذلك مع الميتفورمين و / أو السلفونيل يوريا) والميتفورمين وحده. بشكل عام ، يعد العلاج المساعد باستخدام exenatide خيارًا علاجيًا قيمًا للمرضى المصابين بداء السكري من النوع 2 الذين يحتاجون إلى تحسينات معتدلة في التحكم في نسبة السكر في الدم على الرغم من العلاج بالميتفورمين و / أو
Pharmacological Properties
Exenatide is a synthetic peptide drug with structural and functional
similarity to human incretin hormone glucagon-like peptide-1 (GLP-1).
Exenatide shares most of the glucoregulatory actions of GLP-1, but
unlike GLP-1, is resistant to in vivo proteolytic degradation by
dipeptidyl peptidase-IV and has a significantly longer elimination
half-life. The insulinotropic activity of exenatide is mediated through
stimulation of pancreatic GLP-1 receptors. The glucoregulatory
mechanisms of exenatide are (i) acute: enhancement of glucose-dependent
insulin secretion, suppression of inappropriately elevated glucagon
secretion and slowing of gastric emptying; and (ii) chronic: reduction
of food intake and bodyweight and enhanced insulin sensitivity. In
patients with type 2 diabetes, twice-daily administration of
subcutaneous exenatide causes rapid and significant reduction in fasting
and postprandial plasma glucose levels and significant and
dose-dependent reduction in glycosylated haemoglobin (HbA1c).
Following subcutaneous administration of exenatide in patients with type
2 diabetes, total drug exposure increases in a dose-proportional
manner, whereas increases in peak plasma drug concentrations (Cmax) are
less then proportional. Bioavailability of exenatide is similar whether
injected into the upper arm, abdomen or thigh. Median Cmax is reached in
≈2 hours. Exenatide has a high apparent volume of distribution. Kidneys
are the primary route of elimination and metabolic inactivation of
exenatide. Exenatide does not appear to have clinically significant
pharmacokinetic interactions with metformin, sulfonylureas or other
orally administered drugs commonly used in patients with type 2 diabetes
(e.g. paracetamol [acetaminophen], digoxin
الترجمة
الخصائص الدوائية
Exenatide هو عقار ببتيد اصطناعي له تشابه بنيوي ووظيفي مع هرمون إنكريتين بشري يشبه الجلوكاجون الببتيد -1 (GLP-1). يشترك Exenatide في معظم إجراءات تنظيم الجلوكوز في GLP-1 ، ولكن على عكس GLP-1 ، فهو مقاوم للتدهور التحلل البروتيني في الجسم الحي عن طريق dipeptidyl peptidase-IV ولديه عمر نصف للتخلص أطول بشكل ملحوظ. يتم التوسط في نشاط الأنسولين الموجه للإكسيناتيد من خلال تحفيز مستقبلات البنكرياس GLP-1. آليات تنظيم الجلوكوز في exenatide هي (1) حادة: تعزيز إفراز الأنسولين المعتمد على الجلوكوز ، وقمع إفراز الجلوكاجون المرتفع بشكل غير مناسب وإبطاء إفراغ المعدة ؛ و (2) المزمنة: الحد من تناول الطعام ووزن الجسم وتعزيز حساسية الأنسولين. في المرضى الذين يعانون من مرض السكري من النوع 2 ، يؤدي تناول exenatide تحت الجلد مرتين يوميًا إلى انخفاض سريع وكبير في مستويات الجلوكوز في البلازما بعد الأكل والصيام وانخفاض كبير يعتمد على الجرعة في الهيموغلوبين الغليكوزيلاتي (HbA1c).
بعد إعطاء exenatide تحت الجلد في مرضى السكري من النوع 2 ، يزيد التعرض الكلي للأدوية بطريقة تتناسب مع الجرعة ، في حين أن الزيادات في تراكيز الدواء في البلازما (Cmax) تكون أقل من التناسب. التوافر البيولوجي لإكسيناتيد مشابه سواء تم حقنه في الجزء العلوي من الذراع أو البطن أو الفخذ. يتم الوصول إلى Median Cmax في 2 ساعة. يحتوي Exenatide على حجم توزيع واضح. الكلى هي الطريق الأساسي للتخلص من exenatide وتعطيل التمثيل الغذائي. لا يبدو أن Exenatide يحتوي على تفاعلات حركية دوائية مهمة سريريًا مع الميتفورمين أو السلفونيل يوريا أو الأدوية الأخرى التي يتم تناولها عن طريق الفم والمستخدمة بشكل شائع في مرضى السكري من النوع 2 (مثل الباراسيتامول [أسيتامينوفين] ، الديجوكسين ،,
lisinopril, lovastatin, warfarin).
Therapeutic Efficacy
In several large, randomised, multicentre, phase III trials in patients with type 2 diabetes who had inadequate glycaemic control despite therapy with metformin and/or a sulfonylurea, the addition of subcutaneous exenatide 5–10μg twice daily resulted in significantly improved glycaemic control and reduced bodyweight.
In three 30-week, triple-blind, phase III trials, the mean change from baseline in HbA1c (primary efficacy endpoint) was significantly better with either exenatide 5μg or 10μg twice daily than with placebo. In each study, HbA1c values in the exenatide treatment arms declined linearly during the first 12 weeks and remained stable thereafter. A statistically significant difference between exenatide and placebo recipients in HbA1c values was seen as early as week 2 or 4 of treatment and was maintained for ≥2 years in the nonblind extension of placebo-controlled, phase III trials. Among patients with baseline HbA1c >7% in each trial, significantly more patients receiving exenatide 5μg or 10μg twice daily than those receiving placebo achieved a target HbA1c of ≤7% at week 30. Likewise, mean changes from baseline in fasting plasma glucose levels at week 30 were significantly better with exenatide 5μg or 10μg twice daily than with placebo in patients also receiving metformin, alone or in combination with a sulfonylurea. In patients receiving concurrent therapy with sulfonylurea alone, a statistically significant improvement in fasting plasma glucose levels was seen only in recipients of exenatide 10μg twice daily. Exenatide also produced a significantly greater reduction from baseline in postprandial plasma glucose levels compared with placebo in subgroups of patients from two trials who underwent a standardised meal tolerance test. The effect was evident as early as week 4 and maintained through week 30 in both trials.
In two nonblind, phase III trials of 26 and 52 weeks’ duration, the efficacy of adjunctive therapy with exenatide 10μg twice daily was similar to that of once-daily insulin glargine or twice-daily biphasic insulin aspart (insulin doses target-titrated) in improving glycaemic control in patients with type 2 diabetes who were inadequately controlled with metformin plus a sulfonylurea. In both trials, exenatide was noninferior to the insulin comparator in achieving the mean reduction from baseline in HbA1c levels (primary efficacy endpoint). Likewise, there were no statistically significant differences between exenatide and either insulin comparator in the proportion of patients achieving a target HbA1c of ≤7% at study endpoints, and between exenatide and biphasic insulin aspart in reducing fasting plasma glucose levels. Insulin glargine was more effective than exenatide in reducing baseline fasting plasma glucose levels at week 26, although both drugs produced clinically relevant effects. As adjunctive therapy in both trials, exenatide provided better postprandial glycaemic control (e.g. lower blood glucose levels after both morning and evening meals) then either insulin glargine or biphasic insulin aspart.
Adjunctive therapy with twice-daily exenatide was associated with significant (compared with placebo) and progressive reduction from baseline in bodyweight that manifested as early as week 2 of treatment, affected the majority of overweight patients in all phase III trials and was sustained for up to 2 years in a nonblind extension of placebo-controlled trials. The weight loss was dose dependent, did not correlate with the occurrence of nausea and appeared directly proportional to patients’ baseline body mass index. By comparison, patients receiving insulin glargine or biphasic insulin aspart progressively gained weight over 26 and 52 weeks in phase III trials.
Exenatide exhibited similar efficacy to insulin glargine in significantly improving the treatment satisfaction and HR-QOL in patients with type 2 diabetes who were receiving metformin plus a sulfonylurea in a 26-week phase III trial. Importantly, exenatide was cost effective compared with pioglitazone, gliben-clamide, insulin glargine (all in combination with metformin and/or a sulfonylurea) and metformin alone, in two pharmacoeconomic analyses from the US and the UK.
Tolerability
Subcutaneous exenatide 5μg or 10μg twice daily administered in combination with oral metformin and/or sulfonylurea was generally well tolerated in patients with type 2 diabetes in randomised, phase III trials. The majority of treatment-emergent adverse events were mild or moderate in severity, rarely caused treatment discontinuation and, with the exception of hypoglycaemia, were predominantly gastrointestinal in nature. In all trials, nausea was the most common adverse event and occurred more frequently with exenatide (in up to 57% of patients) than with placebo, insulin glargine or biphasic insulin aspart. Hypoglycaemia, which occurred more frequently with exenatide than with placebo only in patients receiving concomitant therapy with a sulfonylurea (with or without metformin), was rarely of clinical significance. The overall rates of hypoglycaemia were low and similar in patients receiving twice-daily exenatide and those receiving once-daily insulin glargine or twice-daily biphasic insulin aspart, all of whom also received metformin plus a sulfonylurea. Exenatide was associated with a significantly lower incidence of nocturnal hypoglycaemia than both insulin comparators, and a significantly higher incidence of daytime hypoglycaemia compared with insulin glargine. The presence of anti-exenatide antibodies (in up to half of all exenatide recipients) had no predictive effect on glycaemic control or adverse events.
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Authors and Affiliations
Wolters Kluwer Health / Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore, Auckland, 0754, New Zealand
Risto S. Cvetković & Greg L. Plosker
Wolters Kluwer Health, Conshohocken, Pennsylvania, USA
Risto S. Cvetković & Greg L. Plosker
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Correspondence to Risto S. Cvetković.
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Various sections of the manuscript reviewed by: S. Bloom, Department of Metabolic Medicine, Division of Investigative Science, Imperial College London, Hammersmith Hospital, London, UK; R.K. Campbell, Washington State University, Pullman, Washington, USA; D. Elahi, Department of Surgery, Surgical Endocrinology & Metabolism Laboratory, The John Hopkins University, John Hopkins Bayview Medical Center, Baltimore, Maryland, USA; B. Gallwitz, Department of Medicine IV, Eberhard-Karls-University, Tübingen, Germany; D. Hinnen, Mid America Diabetes Associates, Wichita, Kansas, USA; U. Kabadi, Department of Internal Medicine, Division of Endocrinology, University of Iowa College of Medicine, Iowa City, Iowa, USA; B. Tuch, Diabetes Transplant Unit, University of New South Wales and Prince of Wales Hospital, Sydney, New South Wales, Australia.
Data Selection
Sources: Medical literature published in any language since 1980 on ‘exenatide’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Wolters Kluwer Health | Adis). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: MEDLINE, EMBASE and AdisBase search terms were ‘exenatide’. Searches were last updated on 19 March 2007.
Selection: Studies in patients with type 2 diabetes mellitus who received exenatide in addition to metformin and/or a sulfonylurea. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.
Index terms: Exenatide, incretin mimetic, type 2 diabetes mellitus, pharmacoeconomics, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability, treatment satisfaction, health-related quality of life.
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Cvetković, R.S., Plosker, G.L. Exenatide. Drugs 67, 935–954 (2007). https://doi.org/10.2165/00003495-200767060-00008
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Published18 September 2012
Issue DateApril 2007
DOIhttps://doi.org/10.2165/00003495-200767060-00008
KeywordsMetformin
Glycaemic Control
Sulfonylurea
Insulin Glargine
Exenatide
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