National and global trends indiabetes prevalence 1980-2008         2008,     N= 347 millions               1980, N= 153   ...
National and global trends indiabetes prevalence 1980-2008      Effective preventive interventions are needed, andhealth s...
National and global trends indiabetes prevalence 1980-2008      Effective preventive interventions are needed, andhealth s...
National and global trends indiabetes prevalence 1980-2008      Effective preventive interventions are needed, andhealth s...
Macrovascular and microvascular               complications occur frequently in people with                               ...
Hazard ratios for major causes of death,              according to baseline levels of fasting                             ...
ACCORD, ADVANCE & VADT – Effect ofintesive treatment on glycemic control                             ACCORD        VADT   ...
Effect of intensive glucose control in                T2DM patients               Primary Outcome                         ...
Failure to observe reduction in     macrovascular events in ACCORD,           ADVANCE, and VADT•   Wrong sample size    …m...
VADT in the context of the “natural                 history” of Type 2 diabetes                                  Generate ...
Long-Term Effects of Intensive Glucose        in Newly Diagnosed Type 2 Diabetic Patients                   Intensive (SU/...
The lesson of the intervention trials• Aim at near-normal glycemic• Aim at near-normal glycemic  control  control• Adopt a...
Management of Hyperglycemia in Type 2 Diabetes: A Patient-                  Centered Approach                             ...
Glycaemic targets in diabetes.            The ADA/AHA position statement                A1c <7.0%                        A...
Beyond the ADA/EASD algorithm
The A1C and ABCD of glycaemia management       in T2DM: a physician’s personalized approach                Age            ...
Effect of noninsulin antidiabetic drugs          added to metformin on glycemic                       control             ...
The A1C and ABCD of glycaemia managementin T2DM: a physician’s personalized approachAGEBODY WEIGHTCOMPLICATIONDURATION
The A1C and ABCD of glycaemia managementin T2DM: a physician’s personalized approachAGEBODY WEIGHTCOMPLICATIONDURATION
Glycaemic control and all-cause           mortality – A U shaped curve?                                       100         ...
Glycaemic control and all-cause           mortality – A U shaped curve?                                       100         ...
Glycaemic control and all-cause           mortality – A U shaped curve?Currie JE et al Lancet 2010; 375:481
High prevalence of T2DM in the elderly              population                     20                                     ...
The management of T2DM in the                 elderly is challenging      Risk factors                  Geriatric         ...
The Consequences of Hypoglycaemia                                                        Hospitalisation                  ...
ADVANCE – Association of severe hypoglycemia         with the risk of an adverse clinical outcome or                      ...
The risk of severe hypoglycaemia: post hoc                  epidemiological analysis of the ACCORD study                  ...
Antidiabetic agents and risk of                                     hypoglycemia                            High risk     ...
Vildagliptin in the very elderly T2DM patients                               ∆ HBA1c                                      ...
The A1C and ABCD of glycaemia managementin T2DM: a physician’s personalized approachAGEBODY WEIGHTCOMPLICATIONDURATION
The A1C and ABCD of glycaemia managementin T2DM: a physician’s personalized approachAGEBODY WEIGHTCOMPLICATIONDURATION
Frequency distribution of BMI and waist                   circumference in T2DM patients. The Pisa                        ...
Frequency distribution of BMI and waist                   circumference in T2DM patients. The Pisa                        ...
Frequency distribution of BMI and waist                   circumference in T2DM patients. The Pisa                        ...
Frequency distribution of BMI and waistcircumference in T2DM patients. The Pisa Diabetes                      Survey
Baseline BMI is associated with increased    CV mortality in treatment trials*                                            ...
Pooled between-group differences in bodyweight with monotherapy and combination               therapies.         Bennett W...
Effect of noninsulin antidiabetic drugsadded to metformin on glycemic control             Phung OJ et al JAMA 2010 ; 303:1...
T2DM treatment – a composite endpoint       ↓=BMI       ↑BMI       ↓HYPOs       ↑HYPOs                        Efficacy    ...
The A1C and ABCD of glycaemia managementin T2DM: a physician’s personalized approachAGEBODY WEIGHTCOMPLICATIONSDURATION
The A1C and ABCD of glycaemia managementin T2DM: a physician’s personalized approachAGEBODY WEIGHTCOMPLICATIONSDURATION
The Renal Insufficiency And Cardiovascular Events (RIACE) Italian multicentre study                           eGFR <60 ml/...
Tolerability and efficacy of vildagliptin in T2DM         patients with moderate or severe renal                       ins...
Tolerability and efficacy of vildagliptin in T2DM               patients with moderate or severe renal                    ...
Most prescribed medications in diabetis        persons – ARNO 2010                              Atorvastatin (s)          ...
Interaction of DPP4 Inhibitors with Cytochrome                     p450                                Vildagliptin       ...
UKPS 23: Risk Factors for CHD    HbA1c (%)                                           Age (yrs) Systolic BP (mmHg)         ...
Metformin: a multitasking medication                                                           FA                        ...
AMI, stroke, CHF and all-cause mortality in elderlymedicare patients treated with pio- or rosiglitazone               Bone...
Potential cardiovascular protective  properties of incretin-based therapies                 INCRETIN-BASED THERAPY  METABO...
Ongoing pre- and post-approval outcome                studies           Source: clinicaltrials.goc and sponsor’s web sites
The A1C and ABCD of glycaemia managementin T2DM: a physician’s personalized approachAGEBODY WEIGHTCOMPLICATIONSDURATION
The A1C and ABCD of glycaemia managementin T2DM: a physician’s personalized approachAGEBODY WEIGHTCOMPLICATIONDURATION
The lesson of the intervention trials                Reducing hypoglycemia                Reducing hypoglycemia           ...
Association between A1C and adherence                              8.8                              8.0           Adjusted...
Insulin sensitivity and secretion in individuals with          different degrees of glucose tolerance with ( ) and        ...
Sulfonylurea-induced beta-cell     apoptosis in cultured human islets          Solvent        Repaglinide 0.01 µM         ...
VERIFYVildagliptin Efficacy in combination with metfoRmIn For earlY treatment of T2DM                 Circa 2000 mostly dr...
VERIFYVildagliptin Efficacy in combination with metfoRmIn For earlY treatment of T2DM                             Other ob...
The A1C and ABCD of glycaemia managementin T2DM: a physician’s personalized approachAGEBODY WEIGHTCOMPLICATIONDURATION    ...
The evolving complexity of T2DM pathogenesis      accounts for treatment evolution             Islet b-cell               ...
The evolving complexity of T2DM pathogenesis      accounts for treatment evolution             Islet b-cell               ...
A roadmap for selecting antihyperglycemic          agents for treatment of Type 2 diabetes*potential β-cell protection?   ...
ConclusionWhile we await for effective and safepreventative approaches we mustappreciate that pharmacologicintervention to...
Glucose lowering management inType 2 diabetes - the way forward
Glucose lowering management inType 2 diabetes - the way forward                B       C                                  ...
The A1C and the diabetes alphabetFoot care         Quality of lifeGuidelines        Risk of CV diseaseHypoglycemia      St...
The A1C and the diabetes alphabetFoot care         Quality of lifeGuidelines        Risk of CV diseaseHypoglycemia      St...
The A1C and the diabetes alphabetFoot care         Quality of lifeGuidelines        Risk of CV diseaseHypoglycemia      St...
The A1C and the diabetes alphabetFoot care         Quality of lifeGuidelines        Risk of CV diseaseHypoglycemia      St...
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Personalizzazione della terapia del Diabete Mellito - Gastrolearning®

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Gastrolearning VII lezione
Personalizzazione della terapia del Diabete Mellito - Prof. S. Del Prato (Università di Pisa)
www.gastrolearning.it

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  • Using the UKPDS follow-up data [6], Yudkin et al. calculated the NNT for 10 years to prevent one myocardial infarction or stroke to be 29.4 [1]. This number relates to the sulfonylurea– insulin group. In the metformin group, the corresponding NNT is 14. Moreover, the 10 year NNT to prevent one death was 29 in the sulfonylurea–insulin and 14 in the metformin group.
  • Overview of anti-hyperglycemic therapy in T2DM (Figure 2.) What follows are variations of this figure to help guide the clinician in choosing agents which may be most appropriate under certain situations: to avoid weight gain, to avoid hypoglycemia, and to minimize costs.
  • Total 43% &gt;60 32,5
  • Patients with normoalbuminuric stages 3-5 CKD had lower rate of cardiovascular disease than those with albuminuric stages 3-5 CKD but higher rate than subjects with stages 1-2 CKD.
  • Similar incidence of hypoglycemia in Vilda and Pbo patients with severe RI Slightly higher incidence of hypoglycemia in Vilda vs. Pbo patients with moderate RI Lower HbA1c in Vilda patients compared to Pbo Majority of patients with hypoglycemia (&gt;90%) had background insulin
  • Vildagliptin increases pancreatic beta cell mass in neonatal rats Histological and morphometric analysis of pancreatic islets from neonatal rats (n =6/group/timepoint) that were treated once daily with vehicle or vildagliptin (60 mg/kg) for 19 days from day 2 to day 20 and pancreatic tissues were analyzed 24 h after the last dose. All bar graphs at the left panel show quantitation of A. BrdU-positive cells per insulin-positive islet area (1X10 5 μ M); B. Apoptag-positive cells per insulin-positive islet area (1X10 5 μM); and C. Beta cell mass (mg). The middle and right panels show photomicrographs of histological representation of A. BrdU-immuno-positive, B. Apoptag-immuno-positive islet cells at day 7 and C. insulin-immuno-positive islet cells at day 21 from vehicle and vildagliptin treated rats. Arrows indicate the positively stained cells. Values are expressed as the mean ± S.E.M., *P&lt;0.05; **P&lt;0.01. These data show that the DPP-4 inhibitor vildagliptin increased pancreatic beta cell mass through enhanced beta cell replication and reduced apoptosis. The increased beta cell mass was sustained for 12 days after vildagliptin washout. This study demonstrates that DPP-4 inhibitors can elicit beneficial effects on beta cell turnover that could help to prevent or retard the progression of type 2 diabetes. Reference Duttaroy A. et al. European Journal of Pharmacology. 2011; 650: 703–707
  • Personalizzazione della terapia del Diabete Mellito - Gastrolearning®

    1. 1. National and global trends indiabetes prevalence 1980-2008 2008, N= 347 millions 1980, N= 153 millions Danaei G et al Lancet 2011; 378:31
    2. 2. National and global trends indiabetes prevalence 1980-2008 Effective preventive interventions are needed, andhealth systems should prepareto detect and manage diabetes and its sequelae Danaei G et al Lancet 2011; 378:31
    3. 3. National and global trends indiabetes prevalence 1980-2008 Effective preventive interventions are needed, andhealth systems should prepareto detect and manage diabetes and its sequelae Danaei G et al Lancet 2011; 378:31
    4. 4. National and global trends indiabetes prevalence 1980-2008 Effective preventive interventions are needed, andhealth systems should prepareto detect and manage diabetes and its sequelae Danaei G et al Lancet 2011; 378:31
    5. 5. Macrovascular and microvascular complications occur frequently in people with diabetes Macrovascular Microvascular Prevalence (% patients) Heart Chest CHD CHF Stroke Kidney Foot Eye attack pain ComplicationsCHD = Coronary heart diseaseCHF = Congestive heart failure Deshpande AD, et al. Phys Ther 2008;88:1254
    6. 6. Hazard ratios for major causes of death, according to baseline levels of fasting glucoseThe Emerging Risk Factors Collaboration. N Engl J Med 2011;364:829-841
    7. 7. ACCORD, ADVANCE & VADT – Effect ofintesive treatment on glycemic control ACCORD VADT ADVANCE
    8. 8. Effect of intensive glucose control in T2DM patients Primary Outcome Mortality HR 95% CI P HR 95% CI PVADT 1 0.87 0.73-1.04 NS VADT 1 1.0650.801-1.416 NSACCORD 2 0.90 0.78-1.04 NS ACCORD 2 1.22 1.01-1.46 0.04ADVANCE 30.94 0.84-1.06 NS ADVANCE 30.93 0.83-1.06 NS 0.5 1.0 2.0 0.5 1.0 2.0 W. Duckworth et NEJM 2009;359:156; 2The ACCORD Study Group NEJM 2008;358:2545; 1 3 The ADVANCE Collaborative Group N EJM 2008,358:2560
    9. 9. Failure to observe reduction in macrovascular events in ACCORD, ADVANCE, and VADT• Wrong sample size …major CV risk factors already intensively treated factors already• Wrong drug …insulin and insulin providing drugs and insulin drugs• Wrong hypothesis …glycemia is not a major CV risk factor• Wrong patient population …advanced ATS in long standing T2DM patients T2DM
    10. 10. VADT in the context of the “natural history” of Type 2 diabetes Generate a Generate a Drive risk for Drive risk for negative negative complications complications “legacy” “legacy” HbA1c (%) TIME (years since diagnosis)Del Prato S. Diabetologia 2009;52:1219
    11. 11. Long-Term Effects of Intensive Glucose in Newly Diagnosed Type 2 Diabetic Patients Intensive (SU/Ins) vs. Conventional glucose control HR (95%CI) HR (95%CI) NNT 29.4 for 10 yrs* Intensive (metformin) vs. Conventional glucose control HR (95%CI) NNT HR (95%CI) 14 for 10 yrs*Holman RR et al. N Engl J Med. 2008;359:1577–1589 *De Vries JH Diabetologia. 2011;54:705–706
    12. 12. The lesson of the intervention trials• Aim at near-normal glycemic• Aim at near-normal glycemic control control• Adopt an uncompromised• Adopt an uncompromised • Intensify CV risk factor Rx • Intensify CV risk factor Rx therapeutic insistence • Assess risk:benefit ratio METABOLIC – HEMODYNAMIC ALTERATIONS therapeutic insistence • Assess risk:benefit ratio• Consider pathophysiological• Consider pathophysiological • Individualize therapy • Individualize therapy Dysglycemia basis (insulin resistance and β- basis (insulin resistance and β- Diabetes • Consider anti- • Consider anti- cell dysfunction) cell dysfunction) hyperglycemic vs. hyperglycemic vs.• Individualize therapy hypoglycemic agents Relative Risk• Individualize therapy hypoglycemic agents• Treat promptly all CV risk• Treat promptly all CV risk factors factors CVD 1.0 Plasma Glucose
    13. 13. Management of Hyperglycemia in Type 2 Diabetes: A Patient- Centered Approach Diabetes Care – Diabetologia June 2012
    14. 14. Glycaemic targets in diabetes. The ADA/AHA position statement A1c <7.0% A1cA1c >7.0% • >7.0% • Short duration of diabetes • History of severe • Long life expectancy hypoglycemia • No significant • Limited life expectancy cardiovascular disease • Long-standing diabetes • Advanced micro- and MAY GAIN ADDITIONAL macrovascular MICROVASCULAR BENEFIT AS WELL complications AS MACROVASCULAR PROTECTION Patient’s phenotype B =body weight BSkyler J, et al Diabetes Care 2009;32:187
    15. 15. Beyond the ADA/EASD algorithm
    16. 16. The A1C and ABCD of glycaemia management in T2DM: a physician’s personalized approach Age Age MIDDLE MIDDLE ELDERL ELDERL YOUNG YOUNG AGE AGE Y Y Complications* or Complications* or Disease duration Disease duration >10yrs >10yrs – – + + – – + + – – + + A1c target 6.5- 6.5- 7.0- 7.0- A1c target <6.0 <6.0 <6.5 <6.5 <6.5 <6.5 <7.0 <7.0 7.0 7.0 8.0 8.0 A1c at A1c at <9.0% <9.0% >9.0 >9.0 diagnosis diagnosis Initial Initial Metformi Metformi Consider Consider therapy therapy n n insulin insulin*Micro- and macrovascular complications Pozzilli P …. Del Prato S Diabetes Metab Res Rev 2010; 26:239
    17. 17. Effect of noninsulin antidiabetic drugs added to metformin on glycemic control -0,8Phung OJ et al JAMA 2010; 303:1410
    18. 18. The A1C and ABCD of glycaemia managementin T2DM: a physician’s personalized approachAGEBODY WEIGHTCOMPLICATIONDURATION
    19. 19. The A1C and ABCD of glycaemia managementin T2DM: a physician’s personalized approachAGEBODY WEIGHTCOMPLICATIONDURATION
    20. 20. Glycaemic control and all-cause mortality – A U shaped curve? 100 90 Age at baseline (years) 80 70 60 50 40Currie JE et al Lancet 2010; 375:481
    21. 21. Glycaemic control and all-cause mortality – A U shaped curve? 100 90 Age at baseline (years) 80 70 60 50 40Currie JE et al Lancet 2010; 375:481
    22. 22. Glycaemic control and all-cause mortality – A U shaped curve?Currie JE et al Lancet 2010; 375:481
    23. 23. High prevalence of T2DM in the elderly population 20 17.6 18 16 14.9 Prevalence (%) 14 12 10 7.9 8 6 4 2.1 2 0.2 0 12–19 20–39 40–59 60–74 ≥75 Age (years)National Health and Nutrition Examination Survey (NHANES) 2005–2006. T2DM=type 2 diabetes mellitus.Adapted from Cowie CC, et al. Diabetes Care. 2009;32:287–294.
    24. 24. The management of T2DM in the elderly is challenging Risk factors Geriatric syndromes Ageing Depression Diabetes Disability complications Comorbidity Malnutrition Increased Urinary Hyperglycaemia incontinence mortality Hypoglycaemia Falling Lack of Cognitive social support impairment Ageing, diabetic microvascular and macrovascular complications, hyperglycaemia, hypoglycaemia, multiple morbidity and lack of social support are risk factors for the geriatric syndromesT2DM=type 2 diabetes mellitus.Araki A, Ito H. Geriatr Gerontol Int. 2009;9:105–114.
    25. 25. The Consequences of Hypoglycaemia Hospitalisation Coma 3 costs4 Cardiovascular Death2,3 complications3 Weight gain by Increased risk defensive eating5 of dementia1 HYPOGLYCAEMIA Loss of Reduced consciousness3 quality of life7 Increased risk Increased risk of car accident6 of seizures31 Whitmer RA, et al. JAMA. 2009;301:1565–1572; 2Bonds DE, et al. BMJ. 2010;340:b4909; 3 Barnett AH. Curr Med Res Opin. 2010;26:1333–1342; 4Jönsson L, et al. Value Health . 2006;9:193–198; 5Foley JE, Jordan J. Vasc Health Risk Manag .2010;6:541–548; 6Begg IS, et al. Can J Diabetes. 2003;27:128–140; 7McEwan P, et al. Diabetes Obes Metab . 2010;12:431–436.
    26. 26. ADVANCE – Association of severe hypoglycemia with the risk of an adverse clinical outcome or deathZoungas S. et al N Engl J Med 2010;363:1410
    27. 27. The risk of severe hypoglycaemia: post hoc epidemiological analysis of the ACCORD study Miller ME et al . BMJ 2010;340: b5444 C D B C P<0.0001 A P=0.01 P=0.03 P<0.03 P<0.0001 P<0.0001 P<0.0001 Diabetes duration BMI Serum creatinine (years) (kg/m ) 2 (µmol/l)*History of peripheral neuropathy (yes vs. no); **per 1 year increase
    28. 28. Antidiabetic agents and risk of hypoglycemia High risk Low risk   Insulin therapy1 1   Metformin6 6   Sulphonylureas2 2   a-glucosidase inhibitors7 7   Glinides (less than SUs)1,3 1,3   Thiazolidinediones6,8 6,8   Drug-drug interaction can   GLP-1 agonists9 9 potentiate hypoglycemia4,5 4,5   DPP-4 inhibitors10-12 10-12 1. Henderson JN, et al. Diabet Med. 2003;20:1016; 2. Bolen S, et al. Ann Intern Med. 2007;147:386; 3. Kahn SE, et al. N Engl J Med. 2006;355:2427; 4. Krentz AJ, Bailey CJ. Drugs. 2005;65:385; 5. Prandin® (repaglinide) package insert. Novo Nordisk; June 2006; 6. Kahn SE, et al. N Engl J Med. 2006;355:2427; 7. Cefalu WT. Nature. 2007;81:636; 8. Bolen S, et al. Ann Intern Med . 2007;147:386; 9. DeFronzo RA, et al. Diabetes Care. 2005;28:1092;10. Stonehouse A. Curr Diabetes Rev 2008;4:101; 11. Aschner P et al. Diabetes Care. 2006; 29:2632; 12. Rosenstock J et al. Diabetes Obes Metab 2008;10:376.
    29. 29. Vildagliptin in the very elderly T2DM patients ∆ HBA1c ∆ Body Weight Achieving A1c ≤7.0 Hypoglycemia Age ≥75 yr (MonoRx, N=62; Add-on, N=25) Age <75 yr (MonoRx, N=2303; Add-on, N=910)Schweizer A et al. Diabetes Obes Metab 2011; 13:55
    30. 30. The A1C and ABCD of glycaemia managementin T2DM: a physician’s personalized approachAGEBODY WEIGHTCOMPLICATIONDURATION
    31. 31. The A1C and ABCD of glycaemia managementin T2DM: a physician’s personalized approachAGEBODY WEIGHTCOMPLICATIONDURATION
    32. 32. Frequency distribution of BMI and waist circumference in T2DM patients. The Pisa Diabetes Survey Women (n.918) Men (n. 680) 200 200 160 160 BMI CountCount 120 120 m±sd: 80 80 28.7±8.2 range: 16-52 40 40 0 0 15 20 25 30 35 40 45 50 55 15 20 25 30 35 40 45 50 55 200 200 160 160 Count 120 WaistCount 120 80 m±sd:106.0±12.3 80 range: 70-156 40 40 0 0 60 80 100 120 140 160 60 80 100 120 140 160
    33. 33. Frequency distribution of BMI and waist circumference in T2DM patients. The Pisa Diabetes Survey Women (n.918) Men (n. 680) 200 200 160 160 BMI CountCount 120 120 m±sd: 80 80 28.7±8.2 range: 16-52 40 40 0 0 15 20 25 30 35 40 45 50 55 15 20 25 30 35 40 45 50 55 200 200 160 160 Count 120 WaistCount 120 80 m±sd:106.0±12.3 80 range: 70-156 40 40 0 0 60 80 100 120 140 160 60 80 100 120 140 160
    34. 34. Frequency distribution of BMI and waist circumference in T2DM patients. The Pisa Diabetes Survey Women (n.918) Men (n. 680) 200 200 160 160 BMI CountCount 120 120 m±sd: 80 80 28.7±8.2 range: 16-52 40 40 0 0 15 20 25 30 35 40 45 50 55 15 20 25 30 35 40 45 50 55 200 200 160 160 Count 120 WaistCount 120 80 m±sd:106.0±12.3 80 range: 70-156 40 40 0 0 60 80 100 120 140 160 60 80 100 120 140 160
    35. 35. Frequency distribution of BMI and waistcircumference in T2DM patients. The Pisa Diabetes Survey
    36. 36. Baseline BMI is associated with increased CV mortality in treatment trials* 0.40 (logarithmically transformed)MentelHenzel-Odds Ratio 0.32 0.24 0.16 0.08 0.00 -0.08 -0.16 -0.24 -0.32 -0.40 27.2 27.7 28.2 28.7 29.2 29.7 30.2 30.7 31.2 31.7 32.2 BMI at baseline (Kg/m2) *UKPDS Group. Lancet 1998;352:837; UKPDS Group Lancet 1998;352:854; Darmandy JA et al Lancet 2005;366:1279; ADVANCE Collaborative Group. N Engl J Med 2008;358:2560; ACCORD Study Group. N E ngl J Med 2008;358:2545. Duckworth et al N Engl J Med 2009;360:129. Mannucci E. et al Nutr Metab Cardiovasc Dis. 2009 May 7. [Epub ahead of
    37. 37. Pooled between-group differences in bodyweight with monotherapy and combination therapies. Bennett WL et al Ann Intern Med. 2011;154:602-613.
    38. 38. Effect of noninsulin antidiabetic drugsadded to metformin on glycemic control Phung OJ et al JAMA 2010 ; 303:1410
    39. 39. T2DM treatment – a composite endpoint ↓=BMI ↑BMI ↓HYPOs ↑HYPOs Efficacy Efficacy
    40. 40. The A1C and ABCD of glycaemia managementin T2DM: a physician’s personalized approachAGEBODY WEIGHTCOMPLICATIONSDURATION
    41. 41. The A1C and ABCD of glycaemia managementin T2DM: a physician’s personalized approachAGEBODY WEIGHTCOMPLICATIONSDURATION
    42. 42. The Renal Insufficiency And Cardiovascular Events (RIACE) Italian multicentre study eGFR <60 ml/min Both Albuminuria 100 80 60 Percent 40 20 0 ≤45 46-60 61-75 >75 n. 113 (21.4%) n. 1,067 (26.8%) n. 3,100 (37.0%) n. 1,628 (56.4%) n. 528 n. 3,986 n. 8,374 n. 2,885 RIACE Study Group, unpublished data
    43. 43. Tolerability and efficacy of vildagliptin in T2DM patients with moderate or severe renal insufficiencya Number of patients ≥65 years with moderate RI were 113 (vildagliptin) and 102 (placebo) and with severe RI were 64 (vildagliptin) and 46 (placebo).AEs=adverse events; RI=renal impairment; SAEs=serious adverse events; vilda=vildagliptin. Lukashevich V et al Diabet Obes Metab 2011;13:942
    44. 44. Tolerability and efficacy of vildagliptin in T2DM patients with moderate or severe renal insufficiency Moderate RI Severe RI Mean Change from Between-treatment Mean Change from Between-treatment Baseline to End Point Difference vs Placebo Baseline to End Point Difference vs Placebo N= 157 128 N= 122 95 BL= 7.86 7.79 BL= 7.69 7.65 Adjusted Mean Change fromAdjusted Mean Change from Baseline in HbA1c (%) * Baseline in HbA1c (%) * Vildagliptin 50 mg once daily Placebo *P <0.0001 vs placebo. Full analysis set. BL=baseline; HbA1c=haemoglobin A1c; RI=renal impairment; T2DM=type 2 diabetes mellitus. Lukashevich V et al Diabet Obes Metab 2011;13:942
    45. 45. Most prescribed medications in diabetis persons – ARNO 2010 Atorvastatin (s) Atorvastatin (s) Metoprolol (s) Metoprolol (s) Rosuvastatin (s) Rosuvastatin (s) Warfarin (s) Warfarin (s) Simvastatin (s) Simvastatin (s) Diltiazem (s) Diltiazem (s) Carbamazepine  Carbamazepine Phenobarbital  Phenobarbital Phentoyn  Phentoyn Clarithromycin  Clarithromycin Phluoxetine  Phluoxetine Erythromycin  Erythromycin Midazolam (s) Midazolam (s) Fluconazole  Fluconazole Ketoconazole  Ketoconazole Rifampicin  Rifampicin Dexamethasone  Dexamethasone Diclofenac Diclofenac (s) – substrate;  – inhibitor;  –cythocrome p-450 inducer
    46. 46. Interaction of DPP4 Inhibitors with Cytochrome p450 Vildagliptin Sitagliptin SaxagliptinSubstrate for CYP3A4 No Low Yes CYP3A5 No No Yes CYP2C8 No Very low NoDose proportion Yes Yes YesMeal effect No No NoDrug interaction No No YesDose reduction with No No Yes (2.5 mg)CYP3A4 inhibitors Scheen A J. Diabetes, Obesity and Metabolism 2010; 12:648–658
    47. 47. UKPS 23: Risk Factors for CHD HbA1c (%) Age (yrs) Systolic BP (mmHg) LDL-cholesterol mmol/l) Turner RC et al BMJ 316:823-828, 1999
    48. 48. Metformin: a multitasking medication  FA  Insulin action   Insulin sensitivity  glucose   LDL production   body weight   PAI-1 Metformin  Insulin action  β-cell function • antioxidant effects • neutralisation of AGE  Insulin   adhesion molecule secretion*   differentiation of inflammatory cells into macrophages  lipolysis   improved microcirculation* Indirectly through reduced glucotoxicity or GLP-1 enhancement; ** Independently of glycemic lowering ?
    49. 49. AMI, stroke, CHF and all-cause mortality in elderlymedicare patients treated with pio- or rosiglitazone Bone fracture! Heart failure! Graham at al., JAMA 2007; 304:411
    50. 50. Potential cardiovascular protective properties of incretin-based therapies INCRETIN-BASED THERAPY METABOLIC EFFECTS CV EFFECTS Glycemic control  Endothelial function= Body weight  Anti-ischemic effect Blood pressure  Angiogenesis CV risk factors  Myocardial  lipid profile  lipid profile metabolism  inflammation  inflammation  Cardiac function
    51. 51. Ongoing pre- and post-approval outcome studies Source: clinicaltrials.goc and sponsor’s web sites
    52. 52. The A1C and ABCD of glycaemia managementin T2DM: a physician’s personalized approachAGEBODY WEIGHTCOMPLICATIONSDURATION
    53. 53. The A1C and ABCD of glycaemia managementin T2DM: a physician’s personalized approachAGEBODY WEIGHTCOMPLICATIONDURATION
    54. 54. The lesson of the intervention trials Reducing hypoglycemia Reducing hypoglycemia Preventing body weight Preventing body weight METABOLIC – HEMODYNAMIC ALTERATIONS gain gain Dysglycemia   Diabetes Increase adherence Increase adherenceRelative Risk Reduce clinical inertia Reduce clinical inertia CVD 1.0 Plasma Glucose
    55. 55. Association between A1C and adherence 8.8 8.0 Adjusted A1c (%) 7.2 6.4 5.6 -0.15% per 10% increase in adherence -0.15% per 10% increase in adherence 4.8 4.0 0 10 20 30 40 50 60 70 80 90 100 Adherence(%)Adjusted for Baseline A1C and the ODM Regimen* Rozenfeld Y. Am J Manag Care. 2008;14: 71
    56. 56. Insulin sensitivity and secretion in individuals with different degrees of glucose tolerance with ( ) and without ( ) family history for T2DM HOMA IR β-index Log [pmol insulin.120min-1 .m-2] NGT IGT DM NGT IGT DM NGT, normal glucose tolerance; IGT, impaired glucose tolerance; IR, insulin resistanceDel Prato S, Marchetti P, Bonadonna RC. Diabetes 2002; 51 (Suppl 1):S109
    57. 57. Sulfonylurea-induced beta-cell apoptosis in cultured human islets Solvent Repaglinide 0.01 µM Control GLP-1–treated cells Day 1 Nateglinide 10 µM Glibenclamide 0.1 µM Day 3 Day 5Maedler K, et al. J Clin Endocrinol Metab . 2005;90:501 Farilla L et al. E ndocrinology . 2003;144:5149
    58. 58. VERIFYVildagliptin Efficacy in combination with metfoRmIn For earlY treatment of T2DM Circa 2000 mostly drug-naïve T2DM patients HbA1c 6.5% to 7.5% 1:1 randomization 5-year follow-up Multinational double-blind, parallel group study To test the hypothesis whether early treatment combination with VILDA-MET will result in lower treatment failure rate or in lower rate of loss in glycemic control (HbA1c) over time than with MET alone.
    59. 59. VERIFYVildagliptin Efficacy in combination with metfoRmIn For earlY treatment of T2DM Other objectives include evaluation of rate of fasting plasma glucose (FPG) progression over time, change in HbA1c over time, time to insulin initiation, development or progression of micro- and macrovascular complications, changes in body weight, HOMA-B/IR, health status, safety and tolerability Insulin secretion rate relative to glucose (ISR/G) oral glucose insulin sensitivity (OGIS) microalbuminuria tests retinal photography with microaneurism counts
    60. 60. The A1C and ABCD of glycaemia managementin T2DM: a physician’s personalized approachAGEBODY WEIGHTCOMPLICATIONDURATION tiologyE ducation conomy
    61. 61. The evolving complexity of T2DM pathogenesis accounts for treatment evolution Islet b-cell DPP4-I DPP4-I DPP4-I DPP4-I GLP-1 agonists GLP-1 agonists GLP-1 agonists GLP-1 agonists GK agonists GK agonists Bile acid sequestrants Bile acid sequestrants TZDs Increased TZDs GPRs, IL-receptor GPRs, IL-receptor Dual/Pan PPARs Dual/Pan PPARsImpaired Lipolysis antagonist antagonist Decreased 11βHSD-I 11βHSD-IInsulin Secretion Incretin Effect Islet a-cell DPP4-I DPP4-I GLP-1 agonists GLP-1 agonists SGLT2-I SGLT2-I Glucagon receptor Glucagon receptor antagonist antagonist Increased Increased Glucose Glucagon Reabsorption Secretion TZDs TZDs Metformin Metformin Dual/Pan PPARs Dual/Pan PPARs GK agonists GK agonists Metformin Metformin Glucagon receptor Glucagon receptor antagonists antagonists Bromocriptin Bromocriptin Increased HGP Decreased Glucose Neurotransmitter Dysfunction Uptake
    62. 62. The evolving complexity of T2DM pathogenesis accounts for treatment evolution Islet b-cell DPP4-I DPP4-I DPP4-I DPP4-I GLP-1 agonists GLP-1 agonists GLP-1 agonists GLP-1 agonists GK agonists GK agonists Bile acid sequestrants Bile acid sequestrants TZDs Increased TZDs GPRs, IL-receptorImpaired GPRs, IL-receptor Dual/Pan PPARs Dual/Pan PPARs Lipolysis antagonist antagonist Decreased 11βHSD-I 11βHSD-IInsulin Secretion Incretin Effect Islet a-cell DPP4-I DPP4-I GLP-1 agonists GLP-1 agonists SGLT2-I SGLT2-I Glucagon receptor Glucagon receptor antagonist antagonist Increased Increased Glucose Glucagon Reabsorption Secretion TZDs TZDs Metformin Metformin Dual/Pan PPARs Dual/Pan PPARs GK agonists GK agonists Metformin Metformin Glucagon receptor Glucagon receptor antagonists antagonists Bromocriptin Bromocriptin Increased HGP Decreased Glucose Neurotransmitter Dysfunction Uptake
    63. 63. A roadmap for selecting antihyperglycemic agents for treatment of Type 2 diabetes*potential β-cell protection? Adapted from Drucker DJ et al Diabetes Care 2010; 33:428
    64. 64. ConclusionWhile we await for effective and safepreventative approaches we mustappreciate that pharmacologicintervention together with lifestylemodification:•Can provide strict and long-term glycemic control•This may not necessarily ensure clear cut benefitsin term of long-term complications, unless•Proper therapy is initiated early in the course ofthe disease•Individualized early intervention can be moreeffective though not necessarily simpler
    65. 65. Glucose lowering management inType 2 diabetes - the way forward
    66. 66. Glucose lowering management inType 2 diabetes - the way forward B C D A E Etiology Complications Education Body Diabetes Age Economy Weight Duration
    67. 67. The A1C and the diabetes alphabetFoot care Quality of lifeGuidelines Risk of CV diseaseHypoglycemia StatinsInsulin Treat-to-targetLiver steatosis UrgencyMonitoring ValidationOrganization WPrevention Y Z
    68. 68. The A1C and the diabetes alphabetFoot care Quality of lifeGuidelines Risk of CV diseaseHypoglycemia StatinsInsulin Treat-to-targetLiver steatosis UrgencyMonitoring ValidationOrganization Win against diabetesPrevention Y Z
    69. 69. The A1C and the diabetes alphabetFoot care Quality of lifeGuidelines Risk of CV diseaseHypoglycemia StatinsInsulin Treat-to-targetLiver steatosis UrgencyMonitoring ValidationOrganization Win against diabetesPrevention You are the specialists Z
    70. 70. The A1C and the diabetes alphabetFoot care Quality of lifeGuidelines Risk of CV diseaseHypoglycemia StatinsInsulin Treat-to-targetLiver steatosis UrgencyMonitoring ValidationOrganization Win against diabetesPrevention You are the specialists ZZZZZZZZZZZZZZZZZZZZ ZZ

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