Goals for Medical Treatment in Obesity and Prediabetes: Improving Outcomes Leigh Perreault, MD Associate Professor of Medicine Endocrinology, Metabolism and Diabetes University of Colorado Anschutz Medical Campus Associate Professor of Epidemiology Colorado School of Public Health
Disclosures Personal fees for consulting or speaking received from: Novo Nordisk, Merck/Pfizer, Boehringer-Ingelheim/Lilly, Sanofi, Astra Zeneca, Janssen, Medscape, WebMD
Trends in age-standardized rates of diabetes-related complications among U.S. adults with diabetes, 1990-2010 Cases/10,000 persons 140 120 100 80 60 40 20 0 Acute MI Stroke Amputation ESRD Death from Acute Hypoglycemia 1990 1995 2000 2005 2010-52.9% -67.8% -51.4% -28.3% -64.4% Gregg et al. N Engl J Med 370: 1514 1523, 2014
Intervention Trials to Reduce Progression of IGT to Type 2 Diabetes Glucose lowering medications DPP met IDPP met STOP NIDDM acarbose NAVI- GATOR nateg ORIGIN glargine CANOE met/rosi DPP trog DREAM rosi ACT NOW pio 31% 26% 25% -2.1% 20% 27% 1.Knowler, NEJM, 2002 2.Ratner, 2005, Diabetes Care 3. Chiasson, Lancet, 2002 4. NAVIGATOR Study Group NEJM 2010 5. ORIGIN 2012 NEJM 6. Zinnman Lancet 2010 7. Knowler, Diabetes, 2005 8. DREAM Trial Investigators, Lancet 2006 9. DeFronzo NEJM 2011 75% 60% 72%
Intervention Trials to Reduce Progression of IGT to Type 2 Diabetes Weight loss medications XENDOS orlistat BLOSSOM BLOOM lorcaserin SEQUEL top/phent SCALE liraglutide 45% 36% 89% 79%
Slide 6 CW2 MS37 MS51 Dear Leigh - we would like to suggest to change the title of this slide since the objective of trials was not (consistently) to reduce progression of T2. Carolyn Whiting, 10/14/2015 Dr. Perreault: Slide 9: how about the title as Reduction in the Progression to Diabetes: Post-hoc Analyses. Mike Small, 10/20/2015 Dear Dr. Perreault - I've changed the title Mike Small, 10/22/2015 CW19 Dear Leigh, based on some research, we believe there is another top/phent study that did look at progression to T2. http://www.ncbi.nlm.nih.gov/pubmed/24103901 - so we may want to replace the SEQUEL value Carolyn Whiting, 10/18/2015 MS38 MS52 CW20 CW21 MS39 MS40 MS53 Dr. Perreault: Totally fine to replace the SEQUEL # if you found another reference. Mike Small, 10/20/2015 Dear Dr. Perreault - I've updated this number Mike Small, 10/22/2015 Dear Leigh - can you please point me in the right direction of the reference for Lorcaserin? Carolyn Whiting, 10/18/2015 Please note, we changed the valude for liraglutide to 80% - can you please tell us where 88% was from? Carolyn Whiting, 10/18/2015 Dr. Perreault: Reference for the locaserin trial was mentioned here: Endocrine Practice June 2015, Vol. 21, No. 6, pp. 634-644 Mike Small, 10/20/2015 Dr. Perreault: ANTI-OBESITY PHARMACOTHERAPY AND THE POTENTIAL FOR PREVENTING PROGRESSION FROM PREDIABETES TO TYPE 2 DIABETES Alan J. Garber (doi: 10.4158/EP14460.RA) Mike Small, 10/20/2015 Dear Dr. Perreault - I've added in this reference Mike Small, 10/22/2015
Intervention Trials to Reduce Progression of IGT to Type 2 Diabetes MS57 Intensive lifestyle intervention CHINA SWEDEN FINLAND INDIA JAPAN USA 51% 63% 58% 29% 67% 58%
Slide 7 MS57 Dear Dr. Perreault - I've updated this slide based on the table below and any new references mentioned in the notes section. The references have been added in as well. Mike Small, 10/22/2015
Historical Trends in Coronary Heart Disease: Diabetes vs. Prediabetes Perreault, Curr Diab Rep 2017
Glucose Lowering Decreases CVD in Pre-diabetes Probability of Any Cardiovascular Event 0.06 0.05 0.04 0.03 0.02 0.01 P = 0.04 (Log-Rank test) P = 0.03 (Cox Proportional Model) Placebo Acarbose 49% 0.00 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 Days After Randomisation Chiasson, JAMA 2003
IRIS N=3876 Recent TIA or stroke HOMA-IR>3 Pio vs. placebo 4.8 year f/u Mean A1c=5.8% Kernan, NEJM 2016
Intervention Trials to Reduce Progression of IGT to Type 2 Diabetes Intensive lifestyle intervention FINLAND: 3.2 years 7 years 10 years 13 years Weight Diabetes CVD 3kg 58% 43% 0% 39% Tuomilehto, NEJM 2001; Lindstrom, Lancet 2006; Uusitupa, Plos One 2009; Lindsrtrom, Diabetologia 2013
Intervention Trials to Reduce Progression of IGT to Type 2 Diabetes Intensive lifestyle intervention and metformin USA: Weight 6 kg 3.2 years Diabetes 31% 58% MET ILS Knowler, NEJM 2002; Knowler, Lancet 2009; Knowler, Lancet 2015
Intervention Trials to Reduce Progression of IGT to Type 2 Diabetes Intensive lifestyle intervention and metformin USA: Weight 3.2 years Diabetes 10 years 6 kg 31% 18% 58% 34% MET ILS Knowler, NEJM 2002; Knowler, Lancet 2009; Knowler, Lancet 2015
Intervention Trials to Reduce Progression of IGT to Type 2 Diabetes Intensive lifestyle intervention and metformin USA: Weight 3.2 years Diabetes 10 years 15 years MVD CAC 6 kg 31% 18% 18% 58% MET 34% 27% 21%* Women in ILS 11%* Men in MET ILS Knowler, NEJM 2002; Knowler, Lancet 2009; Knowler, Lancet 2015
Intervention Trials to Reduce Progression of IGT to Type 2 Diabetes Intensive lifestyle intervention CHINA: 6 years 20 years 23 years Weight Diabetes Retinopathy CV death 1.8 kg 51% 43% 47% 45% 41% Pan, Diab Care 1997; Li, Lancet 2008; Li, Lancet 2014
Weight loss in patients with prediabetes reduces longterm incidence of cardiovascular mortality CVD mortality in proportion of participants (%) 25 20 15 10 5 0 HR 0.59, 95% CI (0.36 0.96) Control Intervention 0 2 4 6 8 10 12 14 16 18 20 22 23 Years Cumulative death incidence (%; 95% CI) Intervention (n=430) Control (n=138) Hazard ratio (95% CI) p value All-cause mortality 28.1% (23.9 32.4) 38.4% (30.0 46.5) 0.71 (0.51 0.99) 0.049 Cardiovascular disease mortality 11.9% (8.8 15.0) 19.6% (12.9 26.3) 0.59 (0.36 0.96) 0.033 Diabetes incidence 72.6% (68.4 76.8) 89.9% (84.9 94.9) 0.55 (0.40 0.76) 0.001 Data are n(%) unless stated otherwise. HR, hazard ratios adjusted by clinic. Li et al. Lancet Diabetes Endocrinol 2014;2:474 80
Intervention studies for primary prevention of CVD in pre-diabetes Least studies CVD, cardiovascular disease Source: http://clinicaltrials.gov Most studies
Can we improve outcomes by changing the shape of the curve?
XENDOS Torgerson, Diab Care 2004
Intervention Trials to Reduce Progression of IGT to Type 2 Diabetes Weight loss medications XENDOS: orlistat 4 years Diabetes SBP LDL cholesterol 2.7 kg 45% 5 mmhg 13 mg/dl Torgerson, Diab Care 2004
Slide 21 CW2 MS37 MS51 Dear Leigh - we would like to suggest to change the title of this slide since the objective of trials was not (consistently) to reduce progression of T2. Carolyn Whiting, 10/14/2015 Dr. Perreault: Slide 9: how about the title as Reduction in the Progression to Diabetes: Post-hoc Analyses. Mike Small, 10/20/2015 Dear Dr. Perreault - I've changed the title Mike Small, 10/22/2015 CW19 Dear Leigh, based on some research, we believe there is another top/phent study that did look at progression to T2. http://www.ncbi.nlm.nih.gov/pubmed/24103901 - so we may want to replace the SEQUEL value Carolyn Whiting, 10/18/2015 MS38 MS52 CW20 CW21 MS39 MS40 MS53 Dr. Perreault: Totally fine to replace the SEQUEL # if you found another reference. Mike Small, 10/20/2015 Dear Dr. Perreault - I've updated this number Mike Small, 10/22/2015 Dear Leigh - can you please point me in the right direction of the reference for Lorcaserin? Carolyn Whiting, 10/18/2015 Please note, we changed the valude for liraglutide to 80% - can you please tell us where 88% was from? Carolyn Whiting, 10/18/2015 Dr. Perreault: Reference for the locaserin trial was mentioned here: Endocrine Practice June 2015, Vol. 21, No. 6, pp. 634-644 Mike Small, 10/20/2015 Dr. Perreault: ANTI-OBESITY PHARMACOTHERAPY AND THE POTENTIAL FOR PREVENTING PROGRESSION FROM PREDIABETES TO TYPE 2 DIABETES Alan J. Garber (doi: 10.4158/EP14460.RA) Mike Small, 10/20/2015 Dear Dr. Perreault - I've added in this reference Mike Small, 10/22/2015
BLOOM Smith, NEJM 2010
Intervention Trials to Reduce Progression of IGT to Type 2 Diabetes Weight loss medications BLOSSOM BLOOM: lorcaserin 1 year Diabetes PreT2D SBP LDL cholesterol 2 kg 36% 36% 2 mmhg 2 mg/dl Smith, NEJM 2010, Nesto, Postgrad Med 2016
Slide 23 CW2 MS37 MS51 Dear Leigh - we would like to suggest to change the title of this slide since the objective of trials was not (consistently) to reduce progression of T2. Carolyn Whiting, 10/14/2015 Dr. Perreault: Slide 9: how about the title as Reduction in the Progression to Diabetes: Post-hoc Analyses. Mike Small, 10/20/2015 Dear Dr. Perreault - I've changed the title Mike Small, 10/22/2015 CW19 Dear Leigh, based on some research, we believe there is another top/phent study that did look at progression to T2. http://www.ncbi.nlm.nih.gov/pubmed/24103901 - so we may want to replace the SEQUEL value Carolyn Whiting, 10/18/2015 MS38 MS52 CW20 CW21 MS39 MS40 MS53 Dr. Perreault: Totally fine to replace the SEQUEL # if you found another reference. Mike Small, 10/20/2015 Dear Dr. Perreault - I've updated this number Mike Small, 10/22/2015 Dear Leigh - can you please point me in the right direction of the reference for Lorcaserin? Carolyn Whiting, 10/18/2015 Please note, we changed the valude for liraglutide to 80% - can you please tell us where 88% was from? Carolyn Whiting, 10/18/2015 Dr. Perreault: Reference for the locaserin trial was mentioned here: Endocrine Practice June 2015, Vol. 21, No. 6, pp. 634-644 Mike Small, 10/20/2015 Dr. Perreault: ANTI-OBESITY PHARMACOTHERAPY AND THE POTENTIAL FOR PREVENTING PROGRESSION FROM PREDIABETES TO TYPE 2 DIABETES Alan J. Garber (doi: 10.4158/EP14460.RA) Mike Small, 10/20/2015 Dear Dr. Perreault - I've added in this reference Mike Small, 10/22/2015
SEQUEL Garvey, Diab Care 2014
Intervention Trials to Reduce Progression of IGT to Type 2 Diabetes Weight loss medications SEQUEL top/phent 2 years Diabetes MetS SBP LDL cholesterol 12 kg 89% 19% 5 mmhg 0 mg/dl Garvey, Diab Care 2014
Slide 25 CW2 MS37 MS51 Dear Leigh - we would like to suggest to change the title of this slide since the objective of trials was not (consistently) to reduce progression of T2. Carolyn Whiting, 10/14/2015 Dr. Perreault: Slide 9: how about the title as Reduction in the Progression to Diabetes: Post-hoc Analyses. Mike Small, 10/20/2015 Dear Dr. Perreault - I've changed the title Mike Small, 10/22/2015 CW19 Dear Leigh, based on some research, we believe there is another top/phent study that did look at progression to T2. http://www.ncbi.nlm.nih.gov/pubmed/24103901 - so we may want to replace the SEQUEL value Carolyn Whiting, 10/18/2015 MS38 MS52 CW20 CW21 MS39 MS40 MS53 Dr. Perreault: Totally fine to replace the SEQUEL # if you found another reference. Mike Small, 10/20/2015 Dear Dr. Perreault - I've updated this number Mike Small, 10/22/2015 Dear Leigh - can you please point me in the right direction of the reference for Lorcaserin? Carolyn Whiting, 10/18/2015 Please note, we changed the valude for liraglutide to 80% - can you please tell us where 88% was from? Carolyn Whiting, 10/18/2015 Dr. Perreault: Reference for the locaserin trial was mentioned here: Endocrine Practice June 2015, Vol. 21, No. 6, pp. 634-644 Mike Small, 10/20/2015 Dr. Perreault: ANTI-OBESITY PHARMACOTHERAPY AND THE POTENTIAL FOR PREVENTING PROGRESSION FROM PREDIABETES TO TYPE 2 DIABETES Alan J. Garber (doi: 10.4158/EP14460.RA) Mike Small, 10/20/2015 Dear Dr. Perreault - I've added in this reference Mike Small, 10/22/2015
SCALE Le Roux, Lancet 2017
Intervention Trials to Reduce Progression of IGT to Type 2 Diabetes Weight loss medications SCALE liraglutide 3 years Diabetes PreT2D SBP LDL cholesterol 7kg 3 mmhg 0 mg/dl 79% 66% Le Roux, Lancet 2017
Slide 27 CW2 MS37 MS51 Dear Leigh - we would like to suggest to change the title of this slide since the objective of trials was not (consistently) to reduce progression of T2. Carolyn Whiting, 10/14/2015 Dr. Perreault: Slide 9: how about the title as Reduction in the Progression to Diabetes: Post-hoc Analyses. Mike Small, 10/20/2015 Dear Dr. Perreault - I've changed the title Mike Small, 10/22/2015 CW19 Dear Leigh, based on some research, we believe there is another top/phent study that did look at progression to T2. http://www.ncbi.nlm.nih.gov/pubmed/24103901 - so we may want to replace the SEQUEL value Carolyn Whiting, 10/18/2015 MS38 MS52 CW20 CW21 MS39 MS40 MS53 Dr. Perreault: Totally fine to replace the SEQUEL # if you found another reference. Mike Small, 10/20/2015 Dear Dr. Perreault - I've updated this number Mike Small, 10/22/2015 Dear Leigh - can you please point me in the right direction of the reference for Lorcaserin? Carolyn Whiting, 10/18/2015 Please note, we changed the valude for liraglutide to 80% - can you please tell us where 88% was from? Carolyn Whiting, 10/18/2015 Dr. Perreault: Reference for the locaserin trial was mentioned here: Endocrine Practice June 2015, Vol. 21, No. 6, pp. 634-644 Mike Small, 10/20/2015 Dr. Perreault: ANTI-OBESITY PHARMACOTHERAPY AND THE POTENTIAL FOR PREVENTING PROGRESSION FROM PREDIABETES TO TYPE 2 DIABETES Alan J. Garber (doi: 10.4158/EP14460.RA) Mike Small, 10/20/2015 Dear Dr. Perreault - I've added in this reference Mike Small, 10/22/2015
Long-term weight loss in prediabetes doesn t just prevent diabetes
Drug: 52 wk exposure Phentermine Pharmacologic Weight Loss Placebo subtracted weight loss 5 kg* Orlistat Phentermine/topiramate Lorcaserin QD-BID Naltrexone/buproprion Liraglutide 3.0 mg 3 kg 8.7 kg 3.6 kg 4.8 kg 5.6 kg Munro, BMJ 1968; LeBlanc, Ann Int Med 2011; Gadde, Lancet 2011; Smith, NEJM 2010; Greenway, Lancet 2010; Pi-Sunyer, NEJM 2015
Pharmacologic Weight Loss Drug: 52 wk exposure Placebo subtracted Actual weight loss weight loss Phentermine 9 kg* 12.7 kg* *36-weeks Orlistat 3 kg 5.8 kg Phentermine/topiramate 8.7 kg 10 kg Lorcaserin QD-BID 3.6 kg 5.8 kg Naltrexone/buproprion 4.8 kg 6.1 kg Liraglutide 3.0 mg 5.6 kg 8 kg Munro, BMJ 1968; LeBlanc, Ann Int Med 2011; Gadde, Lancet 2011; Smith, NEJM 2010; Greenway, Lancet 2010; Pi-Sunyer, NEJM 2015
Minimal weight loss in placebo arm: LOOK AHEAD Wing, Arch Int Med 2010; Pi-Sunyer, Diab Care 2007; Bray, Diab Vasc Dis Res 2006
Minimal weight loss in placebo arm: The Diabetes Prevention Program and Outcomes Study Knowler,Lancet 2009
BLOOM Smith, NEJM 2010
Classic Placebo Concept cohort placebo randomization active drug measured outcome some response greater response
The Placebo Effect Expectation Desire Conditioning* *common but not essential Vase, Psych Mod Pain 2004
Expectation post-op pain medication administered by person vs. machine Amanzio, Pain 2001
Desire 29% placebo response 45% active drug response Both increasing over time Walsh, JAMA 2002
Pecina, JAMA 2015
Desire Placebo Effect: Neuroscience Dopamine response to placebo in Parkinson s disease Before After } +20% Before After } 16% improved Dopamine release (PET) Motor function (blinded clinical exam) De la Fuente-Fernandez, Science 2001; Goetz, Neurol 2000
Conditioning Cyclosporine on IFN- in multiple sclerosis Goebel, Faseb 2002
Conditioning Cyclosporine on IFN- in multiple sclerosis Change from baseline (%) Cyclosporine before Conditioned effect re-exposure effect Goebel, Faseb 2002
Weight loss medications appetite suppressants Phentermine Topiramate Locaserin Buproprion / naltrexone Farooqi, Cell Metab 2006
The Placebo Effect Expectation Desire Conditioning* *common but not essential Vase, Psych Mod Pain 2004
Conclusions Modest - and often transient - weight loss achieved by lifestyle modification can delay diabetes. It also lowers complications of diabetes, but it takes 15-25 years to see the benefits. Weight loss achieved through pharmacotherapy has also been shown to prevent or delay diabetes. Might these medications also prevent diseases and more robustly - associated with obesity and diabetes?