Drugs. 2008;68(15):2131-62. doi: 10.2165/00003495-200868150-00005.
New drugs for type 2 diabetes mellitus: what is their place in therapy?.
Drugs
Andrew J Krentz, Mayank B Patel, Clifford J Bailey
Affiliations
Affiliations
- Department of Diabetes and Endocrinology, Southampton University Hospitals and University of Southampton, Southampton, UK. [email protected]
PMID: 18840004
DOI: 10.2165/00003495-200868150-00005
Abstract
Oral therapy for type 2 diabetes mellitus, when used appropriately, can safely assist patients to achieve glycaemic targets in the short to medium term. However, the progressive nature of type 2 diabetes usually requires a combination of two or more oral agents in the longer term, often as a prelude to insulin therapy. Issues of safety and tolerability, notably weight gain, often limit the optimal application of anti-diabetic drugs such as sulfonylureas and thiazolidinediones. Moreover, the impact of different drugs, even within a single class, on the risk of long-term vascular complications has come under scrutiny. For example, recent publication of evidence suggesting potential detrimental effects of rosiglitazone on myocardial events generated a heated debate and led to a reduction in use of this drug. In contrast, current evidence supports the view that pioglitazone has vasculoprotective properties. Both drugs are contraindicated in patients who are at risk of heart failure. An additional recently identified safety concern is an increased risk of fractures, especially in postmenopausal women.Several new drugs with glucose-lowering efficacy that may offer certain advantages have recently become available. These include (i) injectable glucagon-like peptide-1 (GLP-1) receptor agonists and oral dipeptidyl peptidase-4 (DPP-4) inhibitors; (ii) the amylin analogue pramlintide; and (iii) selective cannabinoid receptor-1 (CB1) antagonists. GLP-1 receptor agonists, such as exenatide, stimulate nutrient-induced insulin secretion and reduce inappropriate glucagon secretion while delaying gastric emptying and reducing appetite. These agents offer a low risk of hypoglycaemia combined with sustained weight loss. The DPP-4 inhibitors sitagliptin and vildagliptin are generally weight neutral, with less marked gastrointestinal adverse effects than the GLP-1 receptor agonists. Potential benefits of GLP-1 receptor stimulation on beta cell neogenesis are under investigation. Pancreatitis has been reported in exenatide-treated patients. Pramlintide, an injected peptide used in combination with insulin, can reduce insulin dose and bodyweight. The CB1 receptor antagonist rimonabant promotes weight loss and has favourable effects on aspects of the metabolic syndrome, including the hyperglycaemia of type 2 diabetes. However, in 2007 the US FDA declined approval of rimonabant, requiring more data on adverse effects, notably depression. The future of dual peroxisome proliferator-activated receptor-alpha/gamma agonists, or glitazars, is presently uncertain following concerns about their safety.In conclusion, several new classes of drugs have recently become available in some countries that offer new options for treating type 2 diabetes. Beneficial or neutral effects on bodyweight are an attractive feature of the new drugs. However, the higher cost of these agents, coupled with an absence of long-term safety and clinical outcome data, need to be taken into consideration by clinicians and healthcare organizations.
References
- Diabet Med. 1999 Mar;16(3):179-92 - PubMed
- Annu Rev Med. 2006;57:265-81 - PubMed
- Diabetes. 2007 May;56(5):1475-80 - PubMed
- Lancet. 2008 Mar 29;371(9618):1073-84 - PubMed
- Lancet. 2007 Nov 17;370(9600):1687-97 - PubMed
- Diabetologia. 2005 Sep;48(9):1700-13 - PubMed
- Lancet. 2005 Apr 16-22;365(9468):1389-97 - PubMed
- Lancet. 2005 Apr 16-22;365(9468):1415-28 - PubMed
- Nat Clin Pract Endocrinol Metab. 2007 Mar;3(3):270-8 - PubMed
- Diabetes Care. 2002 Dec;25(12):2244-8 - PubMed
- Diabetologia. 2002 Jul;45(7):S13-7 - PubMed
- Diabetologia. 2006 Sep;49(9):2049-57 - PubMed
- Lancet. 2007 May 26;369(9575):1823-31 - PubMed
- J Clin Endocrinol Metab. 2000 Nov;85(11):4053-9 - PubMed
- Lancet. 2006 Nov 11;368(9548):1660-72 - PubMed
- J Clin Invest. 2000 Aug;106(4):453-8 - PubMed
- Diabetes Care. 2005 Jan;28(1):154-63 - PubMed
- Horm Metab Res. 2004 Nov-Dec;36(11-12):842-5 - PubMed
- Diabetes Obes Metab. 2007 Nov;9(6):781-91 - PubMed
- Adv Pharmacol. 2005;52:99-121 - PubMed
- Curr Med Res Opin. 2004 Apr;20(4):565-72 - PubMed
- N Engl J Med. 2005 Jan 13;352(2):174-83 - PubMed
- Trends Pharmacol Sci. 2004 Feb;25(2):86-91 - PubMed
- JAMA. 2006 Feb 15;295(7):826-8 - PubMed
- Diabet Med. 2008 Aug;25 Suppl 2:2-8 - PubMed
- N Engl J Med. 2005 Jul 21;353(3):300-2 - PubMed
- Diabetologia. 2004 Mar;47(3):575-580 - PubMed
- J Clin Endocrinol Metab. 2001 Jul;86(7):3257-65 - PubMed
- Diabetes Care. 2006 Dec;29(12):2638-43 - PubMed
- Diabetes Care. 2007 Jun;30(6):1487-93 - PubMed
- Diabet Med. 2007 Mar;24(3):223-32 - PubMed
- Drugs Aging. 2000 Nov;17(5):411-25 - PubMed
- Curr Diab Rep. 2003 Oct;3(5):365-72 - PubMed
- Cochrane Database Syst Rev. 2006 Oct 18;(4):CD006060 - PubMed
- Diabetologia. 2001 Sep;44(9):1118-20 - PubMed
- Clin Ther. 2006 Oct;28(10):1556-68 - PubMed
- Drug Saf. 2007;30(12):1127-42 - PubMed
- Drugs. 2005;65(3):385-411 - PubMed
- J Biol Chem. 1992 Apr 15;267(11):7402-5 - PubMed
- Ann Intern Med. 1999 Mar 2;130(5):389-96 - PubMed
- Diabetes. 2005 Jan;54(1):146-51 - PubMed
- Diabetes Care. 2005 May;28(5):1092-100 - PubMed
- J Clin Endocrinol Metab. 2002 Mar;87(3):1239-46 - PubMed
- N Engl J Med. 1993 Jun 10;328(23):1676-85 - PubMed
- Drugs. 2002;62(10 ):1463-80 - PubMed
- Diabetes Care. 2006 Mar;29(3):510-4 - PubMed
- Curr Med Res Opin. 2008 Jan;24(1):275-86 - PubMed
- Lancet. 2002 Jun 15;359(9323):2072-7 - PubMed
- J Clin Endocrinol Metab. 2008 Jan;93(1):103-9 - PubMed
- Lancet. 2007 Nov 17;370(9600):1671-2 - PubMed
- Diabetes Care. 2007 Jun;30(6):1608-10 - PubMed
- Diabetes Obes Metab. 1999 Jan;1(1):13-22 - PubMed
- N Engl J Med. 2008 Feb 7;358(6):580-91 - PubMed
- JAMA. 2008 Apr 2;299(13):1561-73 - PubMed
- Lancet. 2007 Nov 17;370(9600):1706-13 - PubMed
- Curr Diab Rep. 2006 Jun;6(3):194-201 - PubMed
- N Engl J Med. 2003 Jan 30;348(5):383-93 - PubMed
- Diabetes Care. 2005 Aug;28(8):1936-40 - PubMed
- J Clin Endocrinol Metab. 2007 Nov;92(11):4165-71 - PubMed
- Diabetes Metab. 2003 Sep;29(4 Pt 2):6S44-52 - PubMed
- Diabetologia. 2004 Feb;47(2):157-69 - PubMed
- Treat Endocrinol. 2005;4(6):361-70 - PubMed
- Best Pract Res Clin Endocrinol Metab. 2007 Dec;21(4):587-605 - PubMed
- Lancet. 1998 Sep 12;352(9131):854-65 - PubMed
- Ann Intern Med. 2005 Oct 18;143(8):559-69 - PubMed
- Lancet. 1998 Sep 12;352(9131):837-53 - PubMed
- Clin Ther. 2006 May;28(5):652-65 - PubMed
- Lancet. 2001 Jun 9;357(9271):1870-5 - PubMed
- N Engl J Med. 2004 Sep 9;351(11):1106-18 - PubMed
- Diabetes Care. 2007 Nov;30(11):2767-72 - PubMed
- N Engl J Med. 2008 Sep 11;359(11):1092-5 - PubMed
- Br J Clin Pharmacol. 2008 Mar;65(3):338-46 - PubMed
- Diabetologia. 2006 Feb;49(2):253-60 - PubMed
- Expert Opin Investig Drugs. 2008 Jan;17(1):105-13 - PubMed
- Nature. 2001 Dec 13;414(6865):821-7 - PubMed
- N Engl J Med. 2008 Jun 12;358(24):2545-59 - PubMed
- Clin Ther. 2007 Nov;29(11):2333-48 - PubMed
- Clin Ther. 2005 Oct;27(10):1500-12 - PubMed
- Diabetes Obes Metab. 2008 Nov;10(11):1114-24 - PubMed
- N Engl J Med. 2005 Nov 17;353(20):2121-34 - PubMed
- Expert Opin Investig Drugs. 2007 Feb;16(2):231-7 - PubMed
- Expert Opin Pharmacother. 2006 Jun;7(8):1055-64 - PubMed
- Ann Pharmacother. 2007 Dec;41(12):2014-8 - PubMed
- Expert Opin Emerg Drugs. 2006 Sep;11(3):525-39 - PubMed
- N Engl J Med. 2007 Jul 5;357(1):67-9 - PubMed
- Diabetes Obes Metab. 2008 Dec;10(12):1221-38 - PubMed
- Horm Metab Res. 2006 Jun;38(6):423-8 - PubMed
- Diabetes Care. 2004 May;27(5):1047-53 - PubMed
- Diabetes Care. 2007 Apr;30(4):890-5 - PubMed
- Nat Rev Drug Discov. 2006 Apr;5(4):295-309 - PubMed
- Best Pract Res Clin Endocrinol Metab. 2007 Dec;21(4):657-85 - PubMed
- Horm Metab Res. 2002 Sep;34(9):504-8 - PubMed
- Expert Opin Pharmacother. 2007 Oct;8(15):2593-608 - PubMed
- BMJ. 2000 Jul 29;321(7256):252-3 - PubMed
- Diabet Med. 2005 Aug;22(8):963-72 - PubMed
- Ann Intern Med. 2007 Apr 3;146(7):477-85 - PubMed
- Diabetologia. 2006 Nov;49(11):2564-71 - PubMed
- JAMA. 2001 May 16;285(19):2486-97 - PubMed
- JAMA. 2007 Jul 11;298(2):194-206 - PubMed
- J Clin Invest. 2006 Mar;116(3):581-9 - PubMed
- Lancet. 2007 Sep 29;370(9593):1129-36 - PubMed
- Diabetologia. 2006 May;49(5):930-6 - PubMed
- N Engl J Med. 1996 Feb 29;334(9):574-9 - PubMed
- Diabetes Obes Metab. 2007 Sep;9(5):640-7 - PubMed
- Lancet. 2008 Oct 4;372(9645):1240-50 - PubMed
- Endocr Pract. 2006 Jan-Feb;12 Suppl 1:142-7 - PubMed
- N Engl J Med. 2007 Jul 5;357(1):28-38 - PubMed
- Diabetes Metab. 2007 Feb;33(1):3-12 - PubMed
- Diabetologia. 2007 Feb;50(2):259-67 - PubMed
- Diabetes Care. 2004 Jun;27(6):1335-42 - PubMed
- Diabetologia. 2004 Sep;47(9):1519-27 - PubMed
- Curr Atheroscler Rep. 2006 Sep;8(5):397-404 - PubMed
- Curr Opin Endocrinol Diabetes Obes. 2007 Aug;14(4):269-76 - PubMed
- Diabetologia. 2006 Mar;49(3):442-51 - PubMed
- N Engl J Med. 2008 Jun 12;358(24):2560-72 - PubMed
- Endocrinol Metab Clin North Am. 2005 Mar;34(1):155-97 - PubMed
- Diabetes Technol Ther. 2006 Jun;8(3):385-96 - PubMed
- Diabetes. 2005 Apr;54(4):1150-6 - PubMed
- Nat Rev Drug Discov. 2004 Sep;3(9):771-84 - PubMed
- Circulation. 2004 Mar 2;109(8):962-5 - PubMed
- Trends Endocrinol Metab. 2004 May-Jun;15(4):158-65 - PubMed
- Curr Cardiol Rep. 2007 May;9(3):167-9 - PubMed
- Arterioscler Thromb Vasc Biol. 2001 Mar;21(3):295-6 - PubMed
- Diabetologia. 2006 Mar;49(3):434-41 - PubMed
- N Engl J Med. 2007 Aug 30;357(9):844-6 - PubMed
- N Engl J Med. 2007 Oct 25;357(17):1716-30 - PubMed
- Diabetes Care. 2008 Jan;31(1):30-5 - PubMed
- N Engl J Med. 2008 Jan 17;358(3):293-7 - PubMed
- Lancet. 2001 Nov 17;358(9294):1709-16 - PubMed
- Diabetes. 1999 Jan;48(1):86-93 - PubMed
- Diabetes Obes Metab. 2007 Sep;9(5):733-45 - PubMed
- JAMA. 2006 Feb 15;295(7):761-75 - PubMed
- J Clin Pharmacol. 2008 May;48(5):592-8 - PubMed
- Drug Saf. 1994 Oct;11(4):223-41 - PubMed
- Diabet Med. 2005 Aug;22(8):1016-23 - PubMed
- Lancet. 2005 Oct 8;366(9493):1241-2 - PubMed
- Cardiovasc Drugs Ther. 2005 Jan;19(1):9-11 - PubMed
- Obes Rev. 2007 Sep;8(5):381-4 - PubMed
- Lancet. 2006 Nov 11;368(9548):1696-705 - PubMed
- N Engl J Med. 2008 Jun 12;358(24):2630-3 - PubMed
- Endocrinol Metab Clin North Am. 2001 Dec;30(4):1011-30 - PubMed
- J Med Chem. 2004 Aug 12;47(17):4135-41 - PubMed
- Curr Med Res Opin. 2008 Jan;24(1):79-85 - PubMed
- Horm Metab Res. 2007 Nov;39(11):826-9 - PubMed
- Diabetes Care. 2008 Jan;31(1):173-5 - PubMed
- Endocrinology. 2004 Jun;145(6):2653-9 - PubMed
- Diabetes Metab Res Rev. 2000 Mar-Apr;16(2):125-32 - PubMed
- Nat Med. 2004 Apr;10(4):355-61 - PubMed
- Curr Med Res Opin. 2008 Feb;24(2):401-17 - PubMed
- Diabetologia. 2007 Jun;50(6):1148-55 - PubMed
- Diabetes Metab. 1998 Sep;24(4):311-20 - PubMed
- Lancet. 2006 Sep 23;368(9541):1096-105 - PubMed
- N Engl J Med. 2008 Oct 9;359(15):1577-89 - PubMed
- Nephron Clin Pract. 2005;100(4):c120-5 - PubMed
- J Clin Endocrinol Metab. 2004 Aug;89(8):3629-43 - PubMed
- Am J Med. 2005 May;118 Suppl 5A:14S-20S - PubMed
- Exp Clin Endocrinol Diabetes. 2006 Feb;114(2):75-81 - PubMed
- Am J Physiol Endocrinol Metab. 2006 Jul;291(1):E175-81 - PubMed
- Curr Opin Cardiol. 2006 Jan;21(1):1-6 - PubMed
- Am J Cardiol. 2007 Jun 18;99(12A):34i-43i - PubMed
- J Clin Endocrinol Metab. 2001 Mar;86(3):1306-12 - PubMed
- Diabetes Obes Metab. 2007 Mar;9(2):194-205 - PubMed
- Expert Opin Investig Drugs. 2006 Mar;15(3):205-10 - PubMed
- Diabet Med. 2006 Mar;23(3):240-5 - PubMed
- J Clin Endocrinol Metab. 2008 Feb;93(2):459-64 - PubMed
- Ann Intern Med. 2006 Jul 18;145(2):125-34 - PubMed
- Drugs Today (Barc). 2006 Mar;42(3):139-46 - PubMed
- Diabetologia. 2005 Dec;48(12):2454-9 - PubMed
- Am J Med. 2003 Dec 8;115 Suppl 8A:20S-23S - PubMed
- Diabetes Care. 1999 Jun;22(6):960-4 - PubMed
- Drug Saf. 1999 Jul;21(1):7-22 - PubMed
- Eur J Clin Invest. 2004 Aug;34(8):535-42 - PubMed
- J Clin Endocrinol Metab. 2003 Jun;88(6):2422-9 - PubMed
- JAMA. 2008 Jan 23;299(3):316-23 - PubMed
- Diabetes Care. 2004 Dec;27(12):2874-80 - PubMed
- Pharmacotherapy. 2005 Jun;25(6):803-9 - PubMed
- Int J Clin Pract. 2006 Nov;60(11):1454-70 - PubMed
- Diabetes Obes Metab. 2008 May;10(5):376-86 - PubMed
- Diabetes Obes Metab. 2008 Nov;10(11):1047-56 - PubMed
- N Engl J Med. 2007 Jun 14;356(24):2457-71 - PubMed
- Diabetes Care. 2003 Mar;26(3):886-91 - PubMed
- Diabetologia. 2005 May;48(5):838-48 - PubMed
- JAMA. 2008 Apr 2;299(13):1547-60 - PubMed
- BMJ. 2008 Mar 1;336(7642):458-9 - PubMed
- JAMA. 1999 Jun 2;281(21):2005-12 - PubMed
- Lancet. 2006 Jul 1;368(9529):29-36 - PubMed
- N Engl J Med. 2007 Aug 23;357(8):753-61 - PubMed
- Treat Endocrinol. 2006;5(4):201-10 - PubMed
- Am J Med Sci. 2006 May;331(5):257-63 - PubMed
- J Clin Endocrinol Metab. 2004 Jun;89(6):2728-35 - PubMed
- J Cardiovasc Risk. 2003 Apr;10(2):121-8 - PubMed
- Curr Diab Rep. 2007 Apr;7(2):114-22 - PubMed
- Endocrinology. 2001 Feb;142(2):521-7 - PubMed
- Diabetes Metab. 2006 Apr;32(2):113-20 - PubMed
- Atheroscler Suppl. 2006 Apr;7(1):43-9 - PubMed
- Diabetes Care. 2006 Aug;29(8):1963-72 - PubMed
- Circulation. 2006 Jun 27;113(25):2914-8 - PubMed
- Lancet. 2005 Apr 9-15;365(9467):1333-46 - PubMed
- JAMA. 2005 Nov 23;294(20):2581-6 - PubMed
- N Engl J Med. 2006 Dec 7;355(23):2427-43 - PubMed
- Cell Metab. 2008 Jan;7(1):68-78 - PubMed
- Am J Manag Care. 2006 Aug;12(8):435-40 - PubMed
Substances
MeSH terms
Publication Types