Diabetes mellitus: new drugs for a new epidemic
2011; Elsevier BV; Volume: 107; Issue: 1 Linguagem: Inglês
10.1093/bja/aer120
ISSN1471-6771
Autores Tópico(s)Pancreatic function and diabetes
ResumoThe prevalence of diabetes mellitus (DM) is increasing rapidly in the 21st century as a result of obesity, an ageing population, lack of exercise, and increased migration of susceptible patients. This costly and chronic disease has been likened recently to the 'Black Death' of the 14th century. Type 2 DM is the more common form and the primary aim of management is to delay the micro- and macrovascular complications by achieving good glycaemic control. This involves changes in lifestyle, such as weight loss and exercise, and drug therapy. Increased knowledge of the pathophysiology of diabetes has contributed to the development of novel treatments: glucagon-like peptide-1 (GLP-1) mimetics, dipeptidyl peptidase-4 (DPP-4) inhibitors, thiazolidinediones (TZDs), and insulin analogues. GLP-1 agonists mimic the effect of this incretin, whereas DPP-4 inhibitors prevent the inactivation of the endogenously released hormone. Both agents offer an effective alternative to the currently available hypoglycaemic drugs but further evaluation is needed to confirm their safety and clinical role. The past decade has seen the rise and fall in the use of the TZDs (glitazones), such that the only glitazone recommended is pioglitazone as a third-line treatment. The association between the use of rosiglitazone and adverse cardiac outcomes is still disputed by some authorities. The advent of new insulin analogues, fast-acting, and basal release formulations, has enabled the adoption of a basal-bolus regimen for the management of blood glucose. This regimen aims to provide a continuous, low basal insulin release between meals with bolus fast-acting insulin to limit hyperglycaemia after meals. Insulin therapy is increasingly used in type 2 DM to enhance glycaemic control. Recently, it has been suggested that the use of the basal-release insulins, particularly insulin glargine may be associated with an increased risk of cancer. Although attention is focused increasingly on newer agents in the treatment of diabetes, metformin and the sulphonylureas are still used in many patients. Metformin, in particular, remains of great value and may have novel anti-cancer properties. The prevalence of diabetes mellitus (DM) is increasing rapidly in the 21st century as a result of obesity, an ageing population, lack of exercise, and increased migration of susceptible patients. This costly and chronic disease has been likened recently to the 'Black Death' of the 14th century. Type 2 DM is the more common form and the primary aim of management is to delay the micro- and macrovascular complications by achieving good glycaemic control. This involves changes in lifestyle, such as weight loss and exercise, and drug therapy. Increased knowledge of the pathophysiology of diabetes has contributed to the development of novel treatments: glucagon-like peptide-1 (GLP-1) mimetics, dipeptidyl peptidase-4 (DPP-4) inhibitors, thiazolidinediones (TZDs), and insulin analogues. GLP-1 agonists mimic the effect of this incretin, whereas DPP-4 inhibitors prevent the inactivation of the endogenously released hormone. Both agents offer an effective alternative to the currently available hypoglycaemic drugs but further evaluation is needed to confirm their safety and clinical role. The past decade has seen the rise and fall in the use of the TZDs (glitazones), such that the only glitazone recommended is pioglitazone as a third-line treatment. The association between the use of rosiglitazone and adverse cardiac outcomes is still disputed by some authorities. The advent of new insulin analogues, fast-acting, and basal release formulations, has enabled the adoption of a basal-bolus regimen for the management of blood glucose. This regimen aims to provide a continuous, low basal insulin release between meals with bolus fast-acting insulin to limit hyperglycaemia after meals. Insulin therapy is increasingly used in type 2 DM to enhance glycaemic control. Recently, it has been suggested that the use of the basal-release insulins, particularly insulin glargine may be associated with an increased risk of cancer. Although attention is focused increasingly on newer agents in the treatment of diabetes, metformin and the sulphonylureas are still used in many patients. Metformin, in particular, remains of great value and may have novel anti-cancer properties. Editor's key points•Prevalence of diabetes mellitus is increasing rapidly in the 21st century.•Several new drugs have been introduced, some with novel modes of action.•Incretin mimetics show promise in managing type 2 diabetes.•New insulin analogues permit the adoption of the basal-bolus regimen to glucose control.•Thiazolidinediones (pioglitazone) are now only a third-line treatment. •Prevalence of diabetes mellitus is increasing rapidly in the 21st century.•Several new drugs have been introduced, some with novel modes of action.•Incretin mimetics show promise in managing type 2 diabetes.•New insulin analogues permit the adoption of the basal-bolus regimen to glucose control.•Thiazolidinediones (pioglitazone) are now only a third-line treatment. The International Diabetes Federation estimated in 2008 that 246 million adults worldwide had diabetes mellitus (DM) and the prevalence was expected to reach 380 million by 2025.1Editorial. The global challenge of diabetes.Lancet. 2008; 371: 1723Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar The World Health Organization (WHO) has revised its estimates for the prevalence of DM in the USA in 2025 from 21.9 million to 30.3 (prevalence of 11.2%).2Wild SH Farouhi NG What is the scale of the future diabetes epidemic and how certain are we about it?.Diabetologica. 2007; 50: 903-905Crossref PubMed Scopus (21) Google Scholar 3Wild S Roglic G Green A et al.Global prevalence of diabetes. Estimates for the year 2000 and projections for 2030.Diabetes Care. 2004; 27: 1047-1053Crossref PubMed Scopus (11924) Google Scholar This increase in DM results from a rise in new patients of type 2 DM, which is a consequence of obesity, an ageing population, lack of exercise, and increased migration of susceptible patients. Indeed, the global pandemic of obesity and type 2 DM has been compared with the 'Black Death' of the 14th century.4Matthews DR Matthews PC Type 2 diabetes as an 'infectious' disease: is this the Black Death of the 21st century?.Diabet Med. 2011; 28: 2-9Crossref PubMed Scopus (37) Google Scholar DM is a costly chronic disease and patients develop micro- and macrovascular complications that often need surgery. Patients with type 2 DM can expect a 10 yr reduction in life expectancy and, globally, 5% of all deaths could be attributed to DM (both types 1 and 2) in 2000 and this increased to 6.8% in 2010.5Roglic G Unwin N Bennett PH et al.The burden of mortality attributable to diabetes. Realistic estimates for the year 2000.Diabetes Care. 2005; 28: 2130-2135Crossref PubMed Scopus (663) Google Scholar 6Roglic G Unwin N Mortality attributable to diabetes: estimates for the year 2010.Diabetes Res Clin Pract. 2009; 87: 15-19Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar Improved glycaemic control has been shown to delay the onset of microvascular complications (nephropathy, retinopathy, and neuropathy), whereas the beneficial effects on macrovascular complications are less clear. However, the 10 yr follow-up of United Kingdom Prospective Diabetes Study (UKPDS), again emphasized the benefits of long-term glycaemic control on all-cause death, micro- and macrovascular complications in type 2 DM.7Holman RR Paul SK Bethel MA Matthews DR Neil HA 10-year follow-up of intensive glucose control in type 2 diabetes.N Engl J Med. 2008; 359: 1577-1589Crossref PubMed Scopus (5241) Google Scholar Increased knowledge of pathophysiology of type 2 DM, particularly insulin signalling and insulin resistance, has contributed to the development of novel treatments. The primary aim of managing type 2 DM is to delay, or even prevent, the complications of the disease by achieving good glycaemic control. In addition to drug therapy, this often involves changes in lifestyle such as diet and exercise. Patients with DM presenting for surgery are challenging for a number of reasons. They may have vascular, renal, or neurological disease as a consequence of their underlying DM and are more prone to wound infections. Maintaining normal blood glucose concentrations has been shown to reduce perioperative morbidity and mortality, although the evidence for this derives mainly from studies in patients undergoing cardiac surgery. However, a recent retrospective survey found that perioperative hyperglycaemia was associated with increased length of hospital stay, morbidity, and mortality after non-cardiac general surgery in diabetic and non-diabetic patients.8Frisch A Chandra P Smiley D et al.Prevalence and clinical outcome of hyperglycaemia in the perioperative period in noncardiac surgery.Diabetes Care. 2010; 33: 1783-1788Crossref PubMed Scopus (412) Google Scholar It was notable that the risk of death increased proportionally with the increase in glucose values in non-diabetic patients but not in those with DM. A number of studies have identified substantial gaps in inpatient diabetic care in the UK9Sampson MJ Brennan C Dhatariya K et al.A national survey of in-patient diabetic services in the United Kingdom.Diabet Med. 2007; 24: 643-649Crossref PubMed Scopus (31) Google Scholar with prolonged inpatient length of stay being a significant problem in those patients with cardiac or surgical conditions.10Sampson MJ Dozio N Ferguson B Dhatariya K Total and excess bed occupancy by age, speciality and insulin use for nearly one million diabetes patients discharged from all English Acute Hospitals.Diabetes Res Clin Pract. 2007; 77: 92-99Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar The aim of this review is to explore novel agents used in diabetic management in the 21st century. The difficulty in diagnosing DM is the lack of a unique qualitative, biological marker that separates all people with diabetes from non-diabetics.11The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus Follow-up report on the diagnosis of Diabetes Mellitus.Diabetes Care. 2003; 26: 3160-3167Crossref PubMed Scopus (3100) Google Scholar Diabetic retinopathy is one such characteristic but has the obvious disadvantage that it usually becomes evident many years after the onset of DM. Because of the lack of a suitable marker, metabolic abnormalities such as hyperglycaemia provide the most useful diagnostic tests. Different parameters such as fasting plasma glucose (FPG), impaired fasting glucose (IFG), and impaired glucose tolerance (IGT) have all been used. In 1997, an International Expert Committee re-examined the classification and diagnostic criteria from the 1979 National Diabetes Data Group and the 1985 WHO study group and proposed some changes to the diagnostic criteria for DM and impaired glucose regulation.12The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus Report of the Expert Committee on the diagnosis and classification of diabetes mellitus.Diabetes Care. 1997; 20: 1183-1197Crossref PubMed Scopus (7542) Google Scholar The 1997 guidelines included recommending the use of FPG as part of the diagnostic tests but the cut-off point was reduced from 7.8 to 7.0 mmol l−1. Normal FPG was defined as 11.1 mmol l−1. However, because of the inconvenience, increased costs, and difficulties in reproducibility, the use of this test for diagnostic purposes was discouraged but the diagnostic category of IGT was retained. This refers to individuals with a normal FPG but a 2 h PG of 7.8–11 mmol l−1 after a 75 g oral glucose challenge. IFG was defined as FPG between 6.1 and 6.9 mmol l−1. Since 1997, many studies relating to the diagnosis of diabetes have been published and a number of questions have been raised including the use of FPG vs the 2 h PG after OGTT. It has been noted that the category of IGT is associated with cardiovascular disease risk factors and events, whereas IFG is much less strongly associated with cardiovascular events or mortality.13Hanefield M Temelkova-Kurktschiev T Schaper F et al.Impaired fasting glucose is not a risk factor for atherosclerosis.Diabet Med. 1999; 16: 212-218Crossref PubMed Scopus (89) Google Scholar, 14The DECODE Study Group, the European Diabetes Epidemiology Group Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-hour diagnostic criteria.Arch Intern Med. 2001; 161: 397-404Crossref PubMed Scopus (1338) Google Scholar, 15The DECODE Study Group, on behalf of the European Diabetes Epidemiology Group Is the current definition for diabetes relevant to mortality risk from all causes and cardiovascular and noncardiovascular diseases?.Diabetes Care. 2003; 26: 688-696Crossref PubMed Scopus (498) Google Scholar It was shown that lifestyle changes such as diet and exercise and the use of metformin or acarbose may delay or prevent the progression from IGT to overt DM. In 2003, a reconstituted International Expert Committee met to evaluate these issues and make appropriate revisions to the previous criteria.11The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus Follow-up report on the diagnosis of Diabetes Mellitus.Diabetes Care. 2003; 26: 3160-3167Crossref PubMed Scopus (3100) Google Scholar The principal recommendations were that the cut-off points of FPG and 2 h PG should remain as in the 1997 report: ≥7.0 and ≥11.1 mmol l−1, respectively, but that lowering the IFG cut-off point from 6.1 to 5.6 mmol l−1 would optimize its sensitivity and specificity. The committee noted that measurement of HbA1c has numerous advantages including an indication of glucose concentrations over a number of weeks and is a useful monitor of both diagnosis and response to treatment. However, in 2003, it was considered premature to add HbA1c to the list of tests used for the definitive diagnosis of DM. Both the FPG and the 2 h PG have advantages and disadvantages; the 2 h PG is a more sensitive assay but the FPG is more reproducible, less costly, and likely to be more convenient. More recently, since the introduction of a new standardized HbA1c assay, the use of HbA1c both as a diagnostic tool and as a predictor of perioperative outcomes has been re-examined. Two studies used HbA1c values >6.5% (48 mmol mol−1) as a single diagnostic marker for DM compared with standard glucose-based methods and concluded that it lacked sensitivity.16Cavagnolli G Comerlatot J Comerlatot C et al.HbA1c measurement for the diagnosis of diabetes: is it enough?.Diabet Med. 2011; 28: 31-35Crossref PubMed Scopus (42) Google Scholar 17Pajunen P Peltonen M Eriksson JG et al.HbA1c in diagnosing and predicting type 2 diabetes in impaired glucose tolerance: the Finnish Diabetes Prevention study.Diabet Med. 2011; 28: 36-42Crossref PubMed Scopus (36) Google Scholar However, HbA1c may have a greater role in predicting perioperative outcomes in patients with or without DM undergoing a variety of surgical procedures.18Halkos ME Lattouf OM Puskas JD et al.Elevated preoperative hemoglobin A1c level is associated with reduced long-term survival after coronary artery bypass surgery.Ann Thorac Surg. 2008; 86: 1431-1437Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar, 19Marchant MH Viens NA Cook C et al.The impact of glycemic control and diabetes mellitus on perioperative outcomes after total joint arthroplasty.J Bone Joint Surg Am. 2009; 91: 1621-1629Crossref PubMed Scopus (389) Google Scholar, 20Gustafsson UO Thorall A Soop M et al.Haemoglobin A1c as a predictor of postoperative hyperglycaemia and complications after major colorectal surgery.Br J Surg. 2009; 96: 1358-1364Crossref PubMed Scopus (130) Google Scholar DM is defined by an absolute (type 1) or relative (type 2) deficiency of insulin. Type 2 DM is characterized by insulin resistance, abnormal hepatic glucose production, and progressive worsening of pancreatic β-cell function over time.21Cefalu WT Pharmacotherapy for the treatment of patients with type 2 diabetes mellitus: rationale and specific agents.Clin Pharmacol Ther. 2007; 81: 636-649Crossref PubMed Scopus (38) Google Scholar Prevention and treatment of DM is a major public health challenge. In the Diabetes Prevention Programme (DPP) 10 yr follow-up study, lifestyle management including diet and exercise led to a 31–58% reduction in the incidence of diabetes.22Misra A Prevention of type-2 diabetes: the long and winding road.Lancet. 2009; 374: 1655-1656Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar 23Diabetes Prevention Program research Group 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study.Lancet. 2009; 374: 1677-1686Abstract Full Text Full Text PDF PubMed Scopus (2058) Google Scholar Greater understanding of the pathophysiology of DM has contributed to the development of new pharmacological approaches. The currently available classes of anti-diabetic agents are glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-IV (DPP-4) inhibitors, thiazolidinediones (TZDs; glitazones), insulin analogues, biguanides, sulphonylureas, meglitinides, α-glucosidase inhibitors, and synthetic amylin analogues (Table 1). In addition, endocannabinoid antagonists acting at the CB1 receptor show promise for affecting food intake and improving glucose homeostasis. Insulin treatment, particularly with new basal formulations, is used increasingly in type 2 diabetics.Table 1Current drugs available for the treatment of diabetes mellitus. Sodium glucose co-transporter inhibitor—insufficient data at presentNew agents—primary treatment GLP-1 receptor agonists DPP-4 inhibitors Thiazolidinediones Insulin analogues, basal, and short-actingCurrent proved agents—primary treatment Biguanides SulphonylureasNew agents—secondary treatment Meglitimides α-Glucosidase inhibitors Synthetic amylin analogues Open table in a new tab At present, there is little published information on the perioperative management of patients taking the newer agents but guidelines have been agreed by the Joint British Diabetic Societies (Management of adults with diabetes undergoing surgery and elective procedures: improving standards) and can be accessed at www.diabetes.nhs.uk. Incretins are gut-derived peptides secreted in response to meals; the incretin effect refers to the augmented release of insulin from oral ingestion of glucose compared with an i.v. glucose challenge. The two major incretins are GLP-1, which is produced by the neuroendocrine L cells of the ileum and colon, and glucose-dependent insulinotropic peptide, which is produced by the K cells of the duodenum and jejunum. Both are released rapidly after a meal and they limit postprandial glucose excursions.24Inzucchi SE McGuire DK New drugs for the treatment of diabetes mellitus. Part II. Incretin-based therapy and beyond.Circulation. 2008; 117: 574-584Crossref PubMed Scopus (145) Google Scholar Incretins stimulate insulin production from pancreatic β cells and GLP-1 also decreases glucagon secretion, slows gastric emptying, and suppresses appetite. GLP-1 may also reduce β-cell apoptosis and promote β-cell proliferation.25Drucker DJ The biology of incretin hormones.Cell Metab. 2006; 3: 153-165Abstract Full Text Full Text PDF PubMed Scopus (1689) Google Scholar 26Wong VS Brubaker PL From cradle to grave: pancreatic beta-cell mass and glucagon-like peptide-1.Minerva Endocrinol. 2006; 31: 107-124PubMed Google Scholar Patients with diabetes demonstrate a blunted rise in GLP-1 concentrations after food intake.27Nathan DM Schreiber E Fogel H et al.Insulinotropic action of glucagon-like peptide-1-(7-37) in diabetic and nondiabetic subjects.Diabetes Care. 1992; 15: 270-276Crossref PubMed Scopus (287) Google Scholar I.V. GLP-1 infusion will increase insulin release and reduce fasting blood glucose concentrations, even in patients with longstanding type 2 DM.21Cefalu WT Pharmacotherapy for the treatment of patients with type 2 diabetes mellitus: rationale and specific agents.Clin Pharmacol Ther. 2007; 81: 636-649Crossref PubMed Scopus (38) Google Scholar One of the major clinical concerns about the use of GLP-1 is its rapid enzymatic degradation by DPP-4. To counteract this, agents that are resistant to DPP-4 degradation such as exenatide and liraglutide have been developed. Another approach is the development of specific DPP-4 inhibitors. There are two commercially available GLP-1 agonists in the UK—exenatide and liraglutide. Exenatide is derived from the naturally occurring peptide, exendin-4, which was isolated from the salivary secretions of the lizard Heloderma suspectum (Gila monster). This lizard eats once a month and the function of exendin-4 is to rapidly increase the production of insulin in response to nutrients entering the gut. Exenatide is a complete agonist at the GLP-1 receptor, is resistant to DPP-4 degradation, and is cleared by the kidneys. It is usually administered twice daily as injections and provides adequate daily replacement of GLP-1. Exenatide is approved for the treatment of type 2 DM in patients receiving concurrent metformin or sulphonylurea treatment, although the dose of sulphonylurea may need to be reduced to avoid hypoglycaemia. Clinical trials have demonstrated a reduction in both fasting and postprandial glucose concentrations, a 1–2% reduction in HbA1c concentrations, and a moderate weight loss of 2–5 kg.28Buse JB Henry RR Han J et al.Effects of exenatide (exendin-1) on glycaemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes.Diabetes Care. 2004; 27: 2628-2635Crossref PubMed Scopus (1151) Google Scholar, 29Defronzo RA Ratner RE Han J et al.Effects of exenatide (exendin-4) on glycaemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes.Diabetes Care. 2005; 28: 1092-1100Crossref PubMed Scopus (1333) Google Scholar, 30Kendall DM Riddle MC Rosenstock J et al.Effects of exenatide (exendin-4) on glycaemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea.Diabetes Care. 2005; 28: 1083-1091Crossref PubMed Scopus (1090) Google Scholar Side-effects of exenatide include nausea and less commonly, vomiting or diarrhoea, particularly when starting therapy. It is recommended that treatment is initiated with a dose of 5 µg twice daily which may be increased to 10 µg twice daily approximately 1 month later. A recent study of once-weekly dosing using a sustained release formulation of exenatide showed improvements in glycaemic control, no increased risk of hypoglycaemia, and similar reductions in body weight.31Drucker DJ Buse JB Taylor K for the DURATION-1 Study group et al.Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study.Lancet. 2008; 372: 1240-1250Abstract Full Text Full Text PDF PubMed Scopus (889) Google Scholar Liraglutide, another incretin mimetic, is administered once daily, is not excreted by the kidneys, is not subjected to DPP-4 degradation, and may be a promising alternative.32Vilsboll T Liraglutide: a once daily GLP-1 analogue for the treatment of type 2 diabetes mellitus.Expert Opin Investig Drugs. 2007; 16: 231-237Crossref PubMed Scopus (95) Google Scholar It provides greater improvements in glycaemic control, induces weight loss, improves obesity-related risk factors, and reduces pre-diabetes. It is also associated with reductions in HbA1c and blood pressure.33Garber A Henry R Ratner R et al.Liraglutide versus glimepiride monotherapy for type-2 diabetes (LEAD-3 Mono): a randomised 52-week, phase III, double-blind, parallel-treatment trial.Lancet. 2009; 373: 473-481Abstract Full Text Full Text PDF PubMed Scopus (917) Google Scholar, 34Buse JB Rosenstock J Sesti G et al.Liraglutide once a day versus exenatide twice a day for type-2 diabetes: a 26-week randomised, parallel-group, multi-national, open-label trial (LEAD-6).Lancet. 2009; 374: 39-47Abstract Full Text Full Text PDF PubMed Scopus (1263) Google Scholar, 35Astrup A Rössner S Van Gaal L et al.Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study.Lancet. 2009; 374: 1606-1616Abstract Full Text Full Text PDF PubMed Scopus (800) Google Scholar Animal studies have shown an increased occurrence of thyroid medullary cancer with high doses of liraglutide but the clinical relevance of this work is unclear. Early clinical trials of liraglutide suggested an increased incidence of pancreatitis. In summary, incretin therapy appears to offer an effective alternative to the currently available hypoglycaemic agents. Continued evaluation and further long-term studies will confirm its safety and clinical role.36Amori RE Lau J Pittas AG Efficacy and safety of incretin therapy in type 2 diabetes.JAMA. 2007; 298: 194-206Crossref PubMed Scopus (962) Google Scholar The effects of endogenous incretins are short-lived because of rapid degradation and inactivation by the enzyme DPP-4. This enzyme is widely expressed throughout the body and circulates in a soluble form. Its acts by cleavage of the two NH2-terminal amino acids of bioactive peptides, provided the second amino acid is alanine or proline. Cleavage is rapid and endogenous GLP-1 has a short half-life (<2 min). Inhibitors of DPP-4 have been developed to prevent the inactivation of GLP-1 and prolong the activity of the endogenously released hormone.37Ahrén B Dipeptidyl peptidase-4 inhibitors.Diabetes Care. 2007; 30: 1344-1350Crossref PubMed Scopus (169) Google Scholar In contrast to GLP-1 receptor agonists, these drugs are available orally and have a longer duration of action, requiring only once daily dosing. The drugs currently available in the UK are sitagliptin, saxagliptin, and vildagliptin as sole agents and also combined with metformin. They are effective at controlling hyperglycaemia, reducing HbA1c concentrations by around 1%, improving pancreatic β-cell function, and can be used as monotherapy or in combination with other agents. They are safe and well-tolerated with a low risk of hypoglycaemia, but do not reduce appetite or cause weight loss such as GLP-1 agonists.38Pratley RE Salsali A Inhibition of DPP-4: a new therapeutic approach for the treatment of type 2 diabetes.Curr Med Res Opin. 2007; 23: 919-931Crossref PubMed Scopus (164) Google Scholar One potential concern, however, is the ability of DPP-4 to cleave other bioactive peptides, including neuropeptide Y, gastrin-releasing peptide, substance P, and various chemokines.37Ahrén B Dipeptidyl peptidase-4 inhibitors.Diabetes Care. 2007; 30: 1344-1350Crossref PubMed Scopus (169) Google Scholar Inhibition of DPP-4 activity may cause adverse events such as increased blood pressure, neurogenic inflammation, and immunological reactions. No severe effects have been reported to date, but further long-term trials are needed. The 21st century has seen the increase and decrease of TZDs. TZDs, like metformin, belong to the class of drugs known as insulin sensitizers. Metformin acts mainly on the muscle and the hepatocyte, while TZDs act predominantly on the adipocyte and the muscle. TZDs enhance insulin sensitivity by increasing the efficiency of glucose transporters, lowering HbA1C by 1–2%, and reducing both fasting and postprandial glucose concentrations.39Fonseca VA Kulkarni KD Management of type 2 diabetes: oral agents, insulin and injectables.J Am Diet Assoc. 2008; 108: S29-S33Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar They do not cause hypoglycaemia when used as a single agent but can do so when used in combination with other agents. Troglitazone was the first TZD approved to treat type 2 DM in 1997, but was withdrawn from clinical practice in 2000 because of rare idiosyncratic hepatotoxicity, a side-effect not observed with rosiglitazone and pioglitazone. TZDs activate peroxisome proliferator-activated gamma nuclear receptors throughout the body, exerting their main insulin-sensitization in fat and muscles. This in turn results in altered gene transcription in adipocytes, a modulation of fatty acid metabolism and a reduction in circulating free fatty acids by 20–40%.40Fonseca V Rosenstock J Patwardhan R Salzman A Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: a randomized controlled trial.JAMA. 2000; 283: 1695-1702Crossref PubMed Scopus (523) Google Scholar 41Phillips LS Grunberger G Miller E Patwardhan R Rappaport EB Salzman A the Rosiglitazone Clinical Trials Study Group Once- and twice-daily dosing with rosiglitazone improves glycemic control in patients with type 2 diabetes.Diabetes Care. 2001; 24: 308-315Crossref PubMed Scopus (275) Google Scholar A decrease in circulating free fatty acids is postulated to enhance insulin-receptor signalling in skeletal muscle, resulting in increased insulin sensitivity throughout the whole body. A further benefit may be favourable effects on pancreatic β-cell function by reducing exposure of β-cells to lipotoxicity, which may contribute to β-cell death.40Fonseca V Rosenstock J Patwardhan R Salzman A Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: a randomized controlled trial.JAMA. 2000; 283: 1695-1702Crossref PubMed Scopus (523) Google Scholar 42Bell DS Ovalle F Tissue tr
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