- Email: [email protected]
PPAR-α and PPAR-γ agonists for type 2 diabetes
Comment
nutrition also do not specifically include severe acute malnutrition. If there was ever a face of poverty and policy failure that we might focus on, it is the proportion of severely malnourished children and fundamentals of equitable access to food and health care.
5
Zulfiqar A Bhutta
8
Division of Women & Child Health, Aga Khan University, Karachi 74800, Pakistan zulfi[email protected]
6
7
9
I declare that I have no conflicts of interest. 1
2 3
4
Black RE, Allen LH, Bhutta ZA, et al, for the Maternal and Child Undernutrition Study Group. Maternal and child undernutrition: global and regional exposures and health consequences. Lancet 2008; 371: 243–60. Collins S, Dent N, Binns P, Bahwere P, Sadler K, Hallam A. Management of severe acute malnutrition in children. Lancet 2006; 368: 1992–2000. Fergusson P, Tomkins A. HIV prevalence and mortality among children undergoing treatment for severe acute malnutrition in sub-Saharan Africa: a systematic review and meta-analysis. Trans R Soc Trop Med Hyg 2009; 103: 541–48. Ashraf H, Ahmed T, Hossain MI, et al. Day-care management of children with severe malnutrition in an urban health clinic in Dhaka, Bangladesh. J Trop Pediatr 2007; 53: 171–78.
10
11
12
13
Bejon P, Mohammed S, Mwangi I, et al. Fraction of all hospital admissions and deaths attributable to malnutrition among children in rural Kenya. Am J Clin Nutr 2008; 88: 1626–31. Bhutta ZA, Ahmed T, Black RE, et al, for the Maternal and Child Undernutrition Study Group. What works? Interventions for maternal and child undernutrition and survival. Lancet 2008; 371: 417–40. Collins S, Sadler K, Dent N, et al. Key issues in the success of community-based management of severe malnutrition. Food Nutr Bull 2006; 27 (suppl 3): S49–82. Adu-Afarwuah S, Lartey A, Brown KH, Zlotkin S, Briend A, Dewey KG. Randomized comparison of 3 types of micronutrient supplements for home fortification of complementary foods in Ghana: effects on growth and motor development. Am J Clin Nutr 2007; 86: 412–20. Defourny I, Minetti A, Harczi G, et al. A large-scale distribution of milk-based fortified spreads: evidence for a new approach in regions with high burden of acute malnutrition. PLoS One 2009; 4: e5455. Kerac M, Bunn J, Seal A, et al. Probiotics and prebiotics for severe acute malnutrition (PRONUT study): a double-blind efficacy randomised controlled trial in Malawi. Lancet 2009; 374: 136–44. Heikens GT, Bunn J, Amadi B, et al, for the Blantyre Working Group. Case management of HIV-infected severely malnourished children: challenges in the area of highest prevalence. Lancet 2008; 371: 1305–07. Nielsen CC, Islam MA, Thilsted SH, Ishrat F. Why do some families become defaulters in a hospital based nutrition rehabilitation follow-up programme? Trop Geogr Med 1992; 44: 346–51. Bhutta ZA, Soofi S. Community-based newborn care: are we there yet? Lancet 2008; 372: 1124–26.
PPAR-α and PPAR-γ agonists for type 2 diabetes Published Online June 8, 2009 DOI:10.1016/S01406736(09)61040-0 See Articles page 126
96
In The Lancet today, Robert Henry and colleagues1 report on SYNCHRONY, a phase II dose-ranging trial of aleglitazar (a dual peroxisome proliferator-activated receptor [PPAR]-α/γ agonist) in patients with type 2 diabetes. This trial suggests a favourable efficacy and safety profile for the 150 μg daily dose, and should motivate phase III studies to establish the clinical interest of this promising agent. Type 2 diabetes is a major risk factor for microvascular and cardiovascular disease. The benefit of improved glucose control on microvascular disease has been clearly shown,2 but the effect of glucose lowering on macrovascular disease is open to debate,3 since the five major controlled outcome trials individually did not show a benefit. One reason for these results could be that type 2 diabetes is a complex disease that combines hyperglycaemia, dyslipidaemia, high blood pressure, and insulin resistance; it thus requires treatments aimed at multiple targets, as shown by the Steno 2 Study.4 The PPARs, as regulators of lipid and glucose metabolism,5 are therefore of great interest; the fibrate class of hypolipidaemic drugs acts through PPAR-α and the thiazolidinedione class of antidiabetic agents through PPAR-γ. PPAR-α/γ dual agonists are a promising com-
bination strategy for type 2 diabetes to achieve a range of metabolic effects and reduce morbidity and mortality by improvement of insulin resistance, hyperglycaemia, and atherogenic dyslipidaemia. PPAR-α agonists stimulate lipid oxidation, decrease circulating triglycerides, increase HDL cholesterol, and have antiatherosclerotic activity.6 Clinical studies with gemfibrosil have been encouraging; in the FIELD trial, fenofibrate did not show a significant cardiovascular benefit,7 although post-hoc analyses suggest a beneficial effect on microvascular outcomes, retinopathy,8 and minor amputations.9 PPAR-γ agonists stimulate adipocyte differentiation, improve insulin sensitivity, reduce hyperglycaemia, and have shown experimental pleiotropic prevention of atherosclerosis.5 The only available clinical outcome study is the PROactive study10 that showed an encouraging 16% reduction in the secondary combined endpoint of death, nonfatal myocardial infarction, and non-fatal stroke with pioglitazone, a PPAR-γ agonist, compared with placebo, although the primary composite endpoint, including leg amputation, did not reach statistical significance. These findings are of interest for the prospects for single agent PPAR-α/γ agonists.11 www.thelancet.com Vol 374 July 11, 2009
Comment
More than 50 investigational new drug applications have been filed for PPARs since the approval of thiazolidinediones, although none have yet reached the market, because of safety concerns. Among various dual PPARα/γ agonists, muraglitazar and tesaglitazar have been assessed in phase III clinical trials before discontinuation of development.12 As expected, these agents had higher efficacy compared with specific PPAR-γ agonists, simultaneously improving glucose and lipid homoeostasis; nevertheless, both were discontinued owing to safety concerns, including increase in serum creatinine and decrease in glomerular filtration rate (tesaglitazar) or increased risk of cardiovascular events (muraglitazar).13 Development of other dual PPAR agonists has been stopped owing to carcinogenicity in rodents (a 2-year rodent carcinogenicity study is required by regulatory agencies before clinical trials). Different PPARs regulate distinct metabolic pathways (figure), and the ultimate goal of the combination agonist strategy is to activate each receptor subtype to provide maximum efficacy on appropriate target genes while keeping adverse side-effects to a minimum. That these adverse effects have diverse origins (eg, cancer, renal dysfunction, cardiovascular risk) suggests that many of these problems are compound specific rather than a result of the dual activation of PPARs, which lends support to the development of new agents of this class. From this point of view, aleglitazar seems to be promising. It is a balanced dual PPAR-α/γ agonist designed to optimise glycaemic and lipid benefits, and minimise weight gain and oedema. Preclinical studies14 have shown favourable effects of aleglitazar on glycaemic control, insulin sensitivity, and dyslipidaemia, compared with rosiglitazone. The overall toxicity profile from non-clinical safety studies is claimed to be reassuring. SYNCHRONY is a well designed, short-term, doseranging phase II study with a placebo and a pioglitazone group. The results confirm the hopes of preclinical development, at least for efficacy: dose-dependent reductions in haemoglobin A1c (HbA1c), triglycerides, and LDL cholesterol were recorded, along with a dose-dependent increase in HDL cholesterol. The blood-glucose lowering effect of 150 μg daily of aleglitazar (0·85% HbA1c decrease vs placebo) might be similar to that of pioglitazone 45 mg, with a better lipid profile; however, the study was not powered for a firm conclusion. The LDL cholesterol www.thelancet.com Vol 374 July 11, 2009
↓Steatosis, ↓hyperglycaemia, ↓dyslipidaemia, ↑endothelial function, ↓atherosclerosis
Liver
Muscle ↑Apo AI, AII ↓Apo CIII
↓FA uptake and storage
↑HDL ↑FFA oxidation ↓Triglyceride synthesis
↑Glucose utilisation ↑Insulin sensitivity
↓Triglycerides ↓Circulating FA PPAR-α
Balanced dual agonist
PPAR-γ
Adipocyte ↓FA release
Heart and vessels
↑FA uptake and storage
↑Cholesterol efflux from macrophages ↓Proinflammatory and adhesion molecules ↓Cardiac lipid abnormalities • Various pleiotropic effects
Figure: Synergistic beneficial actions of balanced PPAR-α/γ agonists Apo AI=apolipoprotein A1. Apo AII=apolipoprotein A2. Apo CIII=apolipoprotein C3. FA=fatty acids. FFA=free fatty acids. Figure adapted from Balakumar and colleagues5 and Fievet and colleagues11
decrease, a measure that slightly increases with pioglitazone, is of particular interest. From the safety point of view, PPAR-α (creatinine increase) and PPAR-γ related effects (oedema, haemodilution, and weight gain) were seen in a dose-dependent manner. Considering the adverse renal events of tesaglitazar, a dedicated renal function study is currently ongoing. In SYNCHRONY, the PPAR-γ related side-effects were less frequent with aleglitazar than with pioglitazone at a glycaemicequivalent reducing dose. Henry and colleagues’ study, therefore, suggests that the 150 μg daily dose might offer the best risk–benefit profile for designing further long-term studies. 97
Comment
The balance of safety and efficacy in today’s study is encouraging, but it is impossible to draw definitive clinical conclusions from such a phase II study. Experience with muraglitazar has shown that a good lipid and blood glucose profile is not sufficient to predict clinical outcomes. It is a strength that cardiovascular events, including heart failure, were adjudicated in SYNCHRONY (two cases of heart failure, no myocardial infarctions), but the sample size and short duration of the study do not allow firm conclusions. Diabetes is a complex disease and agents of the PPAR class could be promising owing to the multiple effects of these drugs and the development of selective PPAR modulators,15 but long-term safety is a major concern. Research in this difficult area must be encouraged, and the coming years will tell whether hopes raised by the SYNCHRONY study for aleglitazar are confirmed by appropriate long-term clinical trials.
2 3
4
5 6 7
8
9
10
11
Bernard Charbonnel Diabetes and Endocrinology Department, Institut du Thorax, University of Nantes, 44000 Nantes, France [email protected]
12
13
DC has received fees for consultancy, honoraria, speaking, travel, or accommodation from Takeda, GlaxoSmithKline, Merck Sharpe & Dohme, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Novo Nordisk, Roche, Sanofi-Aventis, and Novartis.
14
1
15
Henry RR, Lincoff AM, Mudaliar S, Rabbia M, Chognot C, Herz M. Effect of the dual peroxisome proliferator-activated receptor-α/γ agonist aleglitazar on risk of cardiovascular disease in patients with type 2 diabetes (SYNCHRONY): a phase II, randomised, dose-ranging study. Lancet 2009; published online June 8. DOI:10.1016/S0140-6736(09)60870-9.
Kahn SE. Glucose control in type 2 diabetes. Still worthwhile and worth pursuing. JAMA 2009; 301: 1590–92. Ray KK, Seshasai SR, Wijesuriya S, et al. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. Lancet 2009; 373: 1765–72. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008; 358: 580–91. Balakumar P, Rose M, Ganti S, Krishan P, Singh M. PPAR dual agonists: are they opening Pandora’s box? Pharmacol Res 2007; 56: 90–98. Staels B, Fruchart JC. Therapeutic roles of peroxisome proliferator-activated receptor agonists. Diabetes 2005; 54: 2460–70. The FIELD study investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005; 366: 1849–61. Keech AC, Mitchell P, Summanen PA, et al. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet 2007; 370: 1687–97. Rajamani K, Colman PG, Li LP, et al, on behalf of the FIELD study investigators. Effect of a fenofibrate on amputation events in people with type 2 diabetes mellitus (FIELD study): a prespecified analysis of a randomised controlled trial. Lancet 2009; 373: 1780–88. Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005; 366: 1279–89. Fievet C, Fruchard JC, Staels B. PPARα and PPARγ dual agonists for the treatment of type 2 diabetes and the metabolic syndrome. Curr Opin Pharmacol 2006; 6: 606–14. Rubenstrunk A, Hanf R, Hum D, Fruchart JC, Staels B. Safety issues and prospects for future generations of PPAR modulators. Biochim Biophys Acta 2007; 1771: 1065–81. Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes. JAMA 2005; 294: 2581–86. Bénardeau A, Benz J, Binggeli A, et al. Aleglitazar, a new, potent, and balanced dual PPARα/γ agonist for the treatment of type II diabetes. Bioorg Med Chem Lett 2009; 19: 2468–73. Gelman L, Neige J, Desvergne B. Molecular basis of selective PPAR modulation for the treatment of type 2 diabetes. Biochim Biophys Acta 2007; 1771: 1094–107.
Reporting genetic association studies: the STREGA statement The completion of sequencing of the human genome created high hopes for the translational potential of knowledge from genetic association studies. The combination of advances in genomic and related technologies and methods of conventional epidemiology has produced one of the most dynamic fields of medical research. Genome-wide association studies have led to an unparalleled growth and improved accuracy in genetic information.1 At the same time, the complexity of the available data has increased substantially. However, advances in the application of this knowledge, such as determination of an individual’s risk of disease or development of personalised therapies, might not become available 98
as quickly as expected.2 The devil is in the detail. For instance, for the suggested relation between several genetic polymorphisms and occurrence of sepsis in human beings, systematic review in 2006 of the study reports showed that the information needed to assess the risk of bias was lacking.3 Results of medical research need to be reported with sufficient accuracy and transparency to enable critical appraisal. Reporting guidelines aim to improve the research literature by the use of checklists with items deemed essential by multidisciplinary working groups.4 The STrengthening the Reporting of OBservational Studies in Epidemiology (STROBE) statement was developed to help authors to improve the reporting www.thelancet.com Vol 374 July 11, 2009
nutrition also do not specifically include severe acute malnutrition. If there was ever a face of poverty and policy failure that we might focus on, it is the proportion of severely malnourished children and fundamentals of equitable access to food and health care.
5
Zulfiqar A Bhutta
8
Division of Women & Child Health, Aga Khan University, Karachi 74800, Pakistan zulfi[email protected]
6
7
9
I declare that I have no conflicts of interest. 1
2 3
4
Black RE, Allen LH, Bhutta ZA, et al, for the Maternal and Child Undernutrition Study Group. Maternal and child undernutrition: global and regional exposures and health consequences. Lancet 2008; 371: 243–60. Collins S, Dent N, Binns P, Bahwere P, Sadler K, Hallam A. Management of severe acute malnutrition in children. Lancet 2006; 368: 1992–2000. Fergusson P, Tomkins A. HIV prevalence and mortality among children undergoing treatment for severe acute malnutrition in sub-Saharan Africa: a systematic review and meta-analysis. Trans R Soc Trop Med Hyg 2009; 103: 541–48. Ashraf H, Ahmed T, Hossain MI, et al. Day-care management of children with severe malnutrition in an urban health clinic in Dhaka, Bangladesh. J Trop Pediatr 2007; 53: 171–78.
10
11
12
13
Bejon P, Mohammed S, Mwangi I, et al. Fraction of all hospital admissions and deaths attributable to malnutrition among children in rural Kenya. Am J Clin Nutr 2008; 88: 1626–31. Bhutta ZA, Ahmed T, Black RE, et al, for the Maternal and Child Undernutrition Study Group. What works? Interventions for maternal and child undernutrition and survival. Lancet 2008; 371: 417–40. Collins S, Sadler K, Dent N, et al. Key issues in the success of community-based management of severe malnutrition. Food Nutr Bull 2006; 27 (suppl 3): S49–82. Adu-Afarwuah S, Lartey A, Brown KH, Zlotkin S, Briend A, Dewey KG. Randomized comparison of 3 types of micronutrient supplements for home fortification of complementary foods in Ghana: effects on growth and motor development. Am J Clin Nutr 2007; 86: 412–20. Defourny I, Minetti A, Harczi G, et al. A large-scale distribution of milk-based fortified spreads: evidence for a new approach in regions with high burden of acute malnutrition. PLoS One 2009; 4: e5455. Kerac M, Bunn J, Seal A, et al. Probiotics and prebiotics for severe acute malnutrition (PRONUT study): a double-blind efficacy randomised controlled trial in Malawi. Lancet 2009; 374: 136–44. Heikens GT, Bunn J, Amadi B, et al, for the Blantyre Working Group. Case management of HIV-infected severely malnourished children: challenges in the area of highest prevalence. Lancet 2008; 371: 1305–07. Nielsen CC, Islam MA, Thilsted SH, Ishrat F. Why do some families become defaulters in a hospital based nutrition rehabilitation follow-up programme? Trop Geogr Med 1992; 44: 346–51. Bhutta ZA, Soofi S. Community-based newborn care: are we there yet? Lancet 2008; 372: 1124–26.
PPAR-α and PPAR-γ agonists for type 2 diabetes Published Online June 8, 2009 DOI:10.1016/S01406736(09)61040-0 See Articles page 126
96
In The Lancet today, Robert Henry and colleagues1 report on SYNCHRONY, a phase II dose-ranging trial of aleglitazar (a dual peroxisome proliferator-activated receptor [PPAR]-α/γ agonist) in patients with type 2 diabetes. This trial suggests a favourable efficacy and safety profile for the 150 μg daily dose, and should motivate phase III studies to establish the clinical interest of this promising agent. Type 2 diabetes is a major risk factor for microvascular and cardiovascular disease. The benefit of improved glucose control on microvascular disease has been clearly shown,2 but the effect of glucose lowering on macrovascular disease is open to debate,3 since the five major controlled outcome trials individually did not show a benefit. One reason for these results could be that type 2 diabetes is a complex disease that combines hyperglycaemia, dyslipidaemia, high blood pressure, and insulin resistance; it thus requires treatments aimed at multiple targets, as shown by the Steno 2 Study.4 The PPARs, as regulators of lipid and glucose metabolism,5 are therefore of great interest; the fibrate class of hypolipidaemic drugs acts through PPAR-α and the thiazolidinedione class of antidiabetic agents through PPAR-γ. PPAR-α/γ dual agonists are a promising com-
bination strategy for type 2 diabetes to achieve a range of metabolic effects and reduce morbidity and mortality by improvement of insulin resistance, hyperglycaemia, and atherogenic dyslipidaemia. PPAR-α agonists stimulate lipid oxidation, decrease circulating triglycerides, increase HDL cholesterol, and have antiatherosclerotic activity.6 Clinical studies with gemfibrosil have been encouraging; in the FIELD trial, fenofibrate did not show a significant cardiovascular benefit,7 although post-hoc analyses suggest a beneficial effect on microvascular outcomes, retinopathy,8 and minor amputations.9 PPAR-γ agonists stimulate adipocyte differentiation, improve insulin sensitivity, reduce hyperglycaemia, and have shown experimental pleiotropic prevention of atherosclerosis.5 The only available clinical outcome study is the PROactive study10 that showed an encouraging 16% reduction in the secondary combined endpoint of death, nonfatal myocardial infarction, and non-fatal stroke with pioglitazone, a PPAR-γ agonist, compared with placebo, although the primary composite endpoint, including leg amputation, did not reach statistical significance. These findings are of interest for the prospects for single agent PPAR-α/γ agonists.11 www.thelancet.com Vol 374 July 11, 2009
Comment
More than 50 investigational new drug applications have been filed for PPARs since the approval of thiazolidinediones, although none have yet reached the market, because of safety concerns. Among various dual PPARα/γ agonists, muraglitazar and tesaglitazar have been assessed in phase III clinical trials before discontinuation of development.12 As expected, these agents had higher efficacy compared with specific PPAR-γ agonists, simultaneously improving glucose and lipid homoeostasis; nevertheless, both were discontinued owing to safety concerns, including increase in serum creatinine and decrease in glomerular filtration rate (tesaglitazar) or increased risk of cardiovascular events (muraglitazar).13 Development of other dual PPAR agonists has been stopped owing to carcinogenicity in rodents (a 2-year rodent carcinogenicity study is required by regulatory agencies before clinical trials). Different PPARs regulate distinct metabolic pathways (figure), and the ultimate goal of the combination agonist strategy is to activate each receptor subtype to provide maximum efficacy on appropriate target genes while keeping adverse side-effects to a minimum. That these adverse effects have diverse origins (eg, cancer, renal dysfunction, cardiovascular risk) suggests that many of these problems are compound specific rather than a result of the dual activation of PPARs, which lends support to the development of new agents of this class. From this point of view, aleglitazar seems to be promising. It is a balanced dual PPAR-α/γ agonist designed to optimise glycaemic and lipid benefits, and minimise weight gain and oedema. Preclinical studies14 have shown favourable effects of aleglitazar on glycaemic control, insulin sensitivity, and dyslipidaemia, compared with rosiglitazone. The overall toxicity profile from non-clinical safety studies is claimed to be reassuring. SYNCHRONY is a well designed, short-term, doseranging phase II study with a placebo and a pioglitazone group. The results confirm the hopes of preclinical development, at least for efficacy: dose-dependent reductions in haemoglobin A1c (HbA1c), triglycerides, and LDL cholesterol were recorded, along with a dose-dependent increase in HDL cholesterol. The blood-glucose lowering effect of 150 μg daily of aleglitazar (0·85% HbA1c decrease vs placebo) might be similar to that of pioglitazone 45 mg, with a better lipid profile; however, the study was not powered for a firm conclusion. The LDL cholesterol www.thelancet.com Vol 374 July 11, 2009
↓Steatosis, ↓hyperglycaemia, ↓dyslipidaemia, ↑endothelial function, ↓atherosclerosis
Liver
Muscle ↑Apo AI, AII ↓Apo CIII
↓FA uptake and storage
↑HDL ↑FFA oxidation ↓Triglyceride synthesis
↑Glucose utilisation ↑Insulin sensitivity
↓Triglycerides ↓Circulating FA PPAR-α
Balanced dual agonist
PPAR-γ
Adipocyte ↓FA release
Heart and vessels
↑FA uptake and storage
↑Cholesterol efflux from macrophages ↓Proinflammatory and adhesion molecules ↓Cardiac lipid abnormalities • Various pleiotropic effects
Figure: Synergistic beneficial actions of balanced PPAR-α/γ agonists Apo AI=apolipoprotein A1. Apo AII=apolipoprotein A2. Apo CIII=apolipoprotein C3. FA=fatty acids. FFA=free fatty acids. Figure adapted from Balakumar and colleagues5 and Fievet and colleagues11
decrease, a measure that slightly increases with pioglitazone, is of particular interest. From the safety point of view, PPAR-α (creatinine increase) and PPAR-γ related effects (oedema, haemodilution, and weight gain) were seen in a dose-dependent manner. Considering the adverse renal events of tesaglitazar, a dedicated renal function study is currently ongoing. In SYNCHRONY, the PPAR-γ related side-effects were less frequent with aleglitazar than with pioglitazone at a glycaemicequivalent reducing dose. Henry and colleagues’ study, therefore, suggests that the 150 μg daily dose might offer the best risk–benefit profile for designing further long-term studies. 97
Comment
The balance of safety and efficacy in today’s study is encouraging, but it is impossible to draw definitive clinical conclusions from such a phase II study. Experience with muraglitazar has shown that a good lipid and blood glucose profile is not sufficient to predict clinical outcomes. It is a strength that cardiovascular events, including heart failure, were adjudicated in SYNCHRONY (two cases of heart failure, no myocardial infarctions), but the sample size and short duration of the study do not allow firm conclusions. Diabetes is a complex disease and agents of the PPAR class could be promising owing to the multiple effects of these drugs and the development of selective PPAR modulators,15 but long-term safety is a major concern. Research in this difficult area must be encouraged, and the coming years will tell whether hopes raised by the SYNCHRONY study for aleglitazar are confirmed by appropriate long-term clinical trials.
2 3
4
5 6 7
8
9
10
11
Bernard Charbonnel Diabetes and Endocrinology Department, Institut du Thorax, University of Nantes, 44000 Nantes, France [email protected]
12
13
DC has received fees for consultancy, honoraria, speaking, travel, or accommodation from Takeda, GlaxoSmithKline, Merck Sharpe & Dohme, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Novo Nordisk, Roche, Sanofi-Aventis, and Novartis.
14
1
15
Henry RR, Lincoff AM, Mudaliar S, Rabbia M, Chognot C, Herz M. Effect of the dual peroxisome proliferator-activated receptor-α/γ agonist aleglitazar on risk of cardiovascular disease in patients with type 2 diabetes (SYNCHRONY): a phase II, randomised, dose-ranging study. Lancet 2009; published online June 8. DOI:10.1016/S0140-6736(09)60870-9.
Kahn SE. Glucose control in type 2 diabetes. Still worthwhile and worth pursuing. JAMA 2009; 301: 1590–92. Ray KK, Seshasai SR, Wijesuriya S, et al. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. Lancet 2009; 373: 1765–72. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008; 358: 580–91. Balakumar P, Rose M, Ganti S, Krishan P, Singh M. PPAR dual agonists: are they opening Pandora’s box? Pharmacol Res 2007; 56: 90–98. Staels B, Fruchart JC. Therapeutic roles of peroxisome proliferator-activated receptor agonists. Diabetes 2005; 54: 2460–70. The FIELD study investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005; 366: 1849–61. Keech AC, Mitchell P, Summanen PA, et al. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet 2007; 370: 1687–97. Rajamani K, Colman PG, Li LP, et al, on behalf of the FIELD study investigators. Effect of a fenofibrate on amputation events in people with type 2 diabetes mellitus (FIELD study): a prespecified analysis of a randomised controlled trial. Lancet 2009; 373: 1780–88. Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005; 366: 1279–89. Fievet C, Fruchard JC, Staels B. PPARα and PPARγ dual agonists for the treatment of type 2 diabetes and the metabolic syndrome. Curr Opin Pharmacol 2006; 6: 606–14. Rubenstrunk A, Hanf R, Hum D, Fruchart JC, Staels B. Safety issues and prospects for future generations of PPAR modulators. Biochim Biophys Acta 2007; 1771: 1065–81. Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes. JAMA 2005; 294: 2581–86. Bénardeau A, Benz J, Binggeli A, et al. Aleglitazar, a new, potent, and balanced dual PPARα/γ agonist for the treatment of type II diabetes. Bioorg Med Chem Lett 2009; 19: 2468–73. Gelman L, Neige J, Desvergne B. Molecular basis of selective PPAR modulation for the treatment of type 2 diabetes. Biochim Biophys Acta 2007; 1771: 1094–107.
Reporting genetic association studies: the STREGA statement The completion of sequencing of the human genome created high hopes for the translational potential of knowledge from genetic association studies. The combination of advances in genomic and related technologies and methods of conventional epidemiology has produced one of the most dynamic fields of medical research. Genome-wide association studies have led to an unparalleled growth and improved accuracy in genetic information.1 At the same time, the complexity of the available data has increased substantially. However, advances in the application of this knowledge, such as determination of an individual’s risk of disease or development of personalised therapies, might not become available 98
as quickly as expected.2 The devil is in the detail. For instance, for the suggested relation between several genetic polymorphisms and occurrence of sepsis in human beings, systematic review in 2006 of the study reports showed that the information needed to assess the risk of bias was lacking.3 Results of medical research need to be reported with sufficient accuracy and transparency to enable critical appraisal. Reporting guidelines aim to improve the research literature by the use of checklists with items deemed essential by multidisciplinary working groups.4 The STrengthening the Reporting of OBservational Studies in Epidemiology (STROBE) statement was developed to help authors to improve the reporting www.thelancet.com Vol 374 July 11, 2009