CONTROLLO GLICEMICO NEL PAZIENTE CON DMT2: E' SUFFICIENTE HbA1C? Contrario. Antonio Ceriello a,b

Transcription

1 CONTROLLO GLICEMICO NEL PAZIENTE CON DMT2: E' SUFFICIENTE HbA1C? Contrario Antonio Ceriello a,b

2 Excessive Glucose Fluctuations With Same A1C Values 400 Mean A1C = 6.7% Glucose Concentration (mg/dl) :00 AM 4:00 AM 8:00 AM 12:00 PM 4:00 PM 8:00 PM 12:00 AM 24-h CGMS glucose sensor data in 9 subjects with type 1 diabetes Type 1 diabetes (N = 9) CGMS = Continuous Glucose Monitoring System

3 EVIDENCE IN TYPE 1 DIABETES Kilpatrick reported: - that glycemic instability is not a predictor of microvascular complications in patients from the DCCT (Diabetes Care 2006; 29: ). - that mean daily glucose as well as pre and postprandial hyperglycaemia are predictors for cardiovascular disease in the same cohort (Diabetologia 2008; 51: ). - more recently, that HbA1c instability is a predictor of microvascular complications in the same patient cohort (Diabetes Care 2008; 31: ).

4 Variability of blood glucose and CV mortality in Type 2 diabetes Survival rate (10 Yr) 0.9 Variability of fasting glucose 0.8 Group 1 (8.5%) 0.7 Group 2 (14.8%) 0.6 Group 3 (27.7%) Time (years) Verona Diabetes Study Muggeo M et al. Diabetes Care 2000;23:45-50

5 Time-dependent variation of fasting plasma glucose is a strong predictor of all-cause and cause-specific mortality in patients with Type 2 diabetes mellitus: The Taichung Diabetes Study METHODS: A computerized database of all patients with type 2 diabetes aged 30 years and over (n = 5008) enrolled in the Diabetes Care Management Program of China Medical University Hospital before 2007 was used in a time-dependent Cox proportional hazard regression model. Lin CC et al. Am J Med 2012 ;125:416.e9-18.

6 Time-dependent variation of fasting plasma glucose is a strong predictor of all-cause and cause-specific mortality in patients with Type 2 diabetes mellitus: The Taichung Diabetes Study CONCLUSIONS: Time-dependent variation of FPG was a strong predictor of allcause, expanded, and nonexpanded cardiovascular diseaserelated mortality in patients with type 2 diabetes, suggesting that glucose variation may become a measure in clinical practice for the goal in the management of these patients. Lin CC et al. Am J Med 2012 ;125:416.e9-18.

7 Four pathways of hyperglycaemic damage Glucose Polyol pathway: depletes NADPH, resulting in decreased nitric oxide and glutathione and increased ROS concentrations Fructose-6-P Hexosamine pathway: increased production of N-acetyl glucosamine alters signalling pathways, leading to induction of transcription factors Glyceraldehyde-3-P NAD + PARP GAPDH NADH O 2 1,3-diphosphoglycerate PKC pathway: results in bloodflow abnormalities, capillary occlusion and proinflammatory gene expression AGE pathway: end products alter intracellular signalling, activate inflammatory pathways and promote extracellular fibrosis Brownlee. Nature 2001;414:813 20; Giardino et al. J Clin Invest 1994;94:110 7; Abordo et al. Immunol Lett 1997;58:139 47; Charonis et al. Diabetes 1990;39:807 14

8 Urinary excretion rates of isoprostanes (pg/mg creatinine) P < ± 85 Age matched control N = ± 206 Type 2 diabetic patients N = 21 Monnier et al. JAMA 2006; 295:

9 Glycaemia (mg/dl) (SD=62mg/dl) pm am pm am pm Principle of MAGE assessment (from Molnar et Service)

10 Postprandial spikes and glucose swings linked to oxidative stress generation Factor FPG (fasting glucose plasma) Mean glucose level HbA 1C Fasting plasma insulin level MAGE (mean amplitude of glycaemic excursions) AUCpp (area under curve attributable to PPG) Total Cholesterol HDL-C LDL-C Triglycerides Free fatty acids Multiple regression analysis (P value) NS NS NS NS <0.001 = NS NS NS NS NS Monnier et al. JAMA 2006; 295:

11 Effect of GV on FMD and oxidative stress 27 patients with type 2 diabetes 15mmol/L mmol/L 5-15mmol/L Ceriello et al Diabetes 2008 ; 57:

12 Impact of glycemic and blood pressure variability on surrogate measures of cardiovascular outcomes in type 2 diabetic patients CONCLUSIONS: An impaired GV and BP variability is associated with endothelial and cardiovascular damage in short-term diabetic patients with optimal metabolic control. Oxidative stress is the only independent predictor of increased LV mass and correlates with glucose and BP variability. D. Flaviani et al. Diabetes Care 2011: 34:

13 Characterizing Glucose Exposure for Individuals with Normal Glucose Tolerance Using Continuous Glucose Monitoring and Ambulatory Glucose Profile Analysis R.S. MAZZE, E. STROCK, D. WESLEY, S. BORGMAN, B. MORGAN, R. BERGENSTAL and R. CUDDIHY DIABETES TECHNOLOGY & THERAPEUTICS 2008 ;10:

14 The modal day and the AGP depict 3,628 continuous glucose readings measured for 30 days. The modal day shows each data point graphed without regard to date. The AGP replaces the individual data points with five smoothed frequency curves, which represent the underlying glycemic pattern. (accounting for outlier values). The statistical summary (shown separately, but contained in the AGP report) is customizable. Center solid line is the median, next two outer solid lines (25th and 75th percentiles) represent the IQR, the dotted lines depict the 10th and 90th percentiles

15 Defining glucose variability Hypoglycaemic events Postprandial glucose excursions Minor fluctuations in blood glucose levels

16 The Contribution of Glucose Variability to Asymptomatic Hypoglycemia in Persons with Type 2 Diabetes Louis Monnier, Anne Wojtusciszyn, Claude Colette and David Owens CONCLUSIONS: As the risk of asymptomatic hypoglycemia increases in the presence of increased glucose variability, avoidance of excess glucose fluctuations should be an important consideration for either reducing or preventing the risk of hypoglycemia in type 2 diabetes. Diabetes Technology & Therapeutics 2011; 13:

17 J Clin Invest 2007; 117:

18 Hypoglycemia followed by Hyperglycemia or Normoglycemia Controls: 2 h Hypo + 2 h Hyperglycemia Type 1: 2 h Hypo + 2 h Normoglycemia Type 1: 2 h Hypo + 2 h Hyperglycemia Ceriello A et al. Diabetes 2012;61:2993-7

19 Hypoglycemia followed by Hyperglycemia with or without Vit. C Controls: 2 h Hypo + 2 h Hyper and Vit C Controls: 2 h Hypo + 2 h Hyper Type 1: 2 h Hypo + 2 h Hyper and Vit C Type 1: 2 h Hypo + 2 h Hyper Ceriello A et al. Diabetes 2012;61:2993-7

20 Reducing average glycaemia without reducing variability may be dangerous Reduction in average glycaemia without reducing glucose variability is indicated by downward shift of the glucose profile from the upper panel to the lower panel This results in increased occurrence and severity of hypoglycaemic episodes Kovatchev et al. J Diabetes Sci Technol 2009;3:

21 2012

22 REDUCTION OF OXIDATIVE STRESS AND INFLAMMATION BY BLUNTING DAILY ACUTE GLUCOSE FLUCTUATIONS IN PATIENTS WITH TYPE 2 DIABETES: ROLE OF DIPEPTIDYL PEPTIDASE-4 INHIBITION Study design PROBE design: Prospective, randomized, open-label parallel group with a blinded-endpoint from May 2010 to June 2011 Vildagliptin 50 mg twice daily (n=43) Week -3 Day 1 Week 6 Week 12 Screening Active treatment Active treatment Visit 0 -Clinical evaluations -Physical examination -Routine analyses -HbA1c Visit 1 -Physical examination -Routine analyses -HbA1c -CSMG Visit 2 -Clinical evaluations -Physical examination -Routine analyses Visit 3 -Physical examination -Routine analyses -HbA1c -CSMG Sitagliptin 100 mg/day (n=47) Rizzo MR et al. Diabetes Care 2012;35:

23 Vildagliptin resulted a greater increase in active GLP-1 levels during prandial and interprandial periods Vildagliptin 50 mg bid + Metformin (n=45) Sitagliptin 100 mg qd + Metformin (n=45) *p<0.05 vs sitagliptin Vildagliptin has provided better glycemic control than sitagliptin Rizzo MR et al.. Diabetes Care 2012;35:

24 Vildagliptin supresses glucagon levels more than sitagliptin during prandial and interprandial periods Vildagliptin 50 mg bid + Metformin (n=45) Sitagliptin 100 mg qd + Metformin (n=45) *p<0.05 vs vildagliptin Vildagliptin has provided better glycemic control than sitagliptin Rizzo MR et al.. Diabetes Care 2012;35:

25 Vildagliptin is associated with a significant decline in MAGE versus sitagliptin 25

26 INFLAMMATORY AND OXIDATIVE STRESS PARAMETERS AFTER SITAGLIPTIN or VILDAGLIPTIN 3,00 2,80 2,60 2,40 2,20 2,00 1,80 1,60 1,40 1,20 1,00 BASELINE IL-6 IL-6 (pg/ml) (pg/ml) + + * AFTER 12 WEEKS 125,00 120,00 115,00 110,00 105,00 100,00 95,00 IL-18 (pg/ml IL-18 (pg/ml) + * SITA VILDA 90,00 BASELINE AFTER 12 WEEKS TNFα TNFa (pg/ml) (pg/ml) PCR PCR mg/dl (mg/dl) 2,55 2,50 2,45 2,40 2,35 2,30 2,25 BASELINE + + AFTER 12 WEEKS 1,50 1,30 1,10 0,90 0,70 0,50 0,30 0,10-0,10 BASELINE AFTER 12 WEEKS *p<0,05 Sita vs Vilda + p<0,05 V3 vs V1 Rizzo MR et al. Diabetes Care 2012;35:

27 INFLAMMATORY AND OXIDATIVE STRESS PARAMETERS AFTER SITAGLIPTIN or VILDAGLIPTIN 0,80 + 0,70 0,60 0,50 0,40 0,30 0,20 0,10 0,00 Nitrotyrosine (µmol/l) ( Nitrotyrosine (µmol/l) + * + BASELINE AFTER 12 WEEKS *p<0,05 Sita vs Vilda + p<0,05 V3 vs V1 Rizzo MR et al. Diabetes Care 2012;35:

28 Blood glucose fluctuations have been found to be relevant to the progression of atherosclerosis in patients with type 2 diabetes and to be more detrimental for the development of atherosclerosis than the sustained hyperglycemia. Whether the effects of glycemic excursion reduction may have clinical implication in term of prevention of the progression of atherosclerosis and cardiovascular events is unknown.

29 Decreased carotid atherosclerotic process by control of daily acute glucose fluctuations in diabetic patients treated by DPP-IV inhibitors In the study, after 3 months therapy, in absence of change in lipid profile, BMI and systolic blood pressure, a significant reduction in IMT was observed in both sitagliptin and vildagliptin groups with a greater decrease in vildagliptin group. Barbieri M et al, Atherosclerosis 2013

30 Decreased carotid atherosclerotic process by control of daily acute glucose fluctuations in diabetic patients treated by DPP-IV inhibitors D Interestingly, change in IMT significantly correlated with reduction of daily glucose excursions but not with indexes of chronic sustained hyperglycemia such as HbA1c or with postprandial glucose excursions. The greatest effect on IMT observed in vildagliptin, could be explained by the more pronounced ability of vildagliptin to reduce daily glucose excursions and inflammation and oxidative stress. Barbieri et al, Atherosclerosis 2013

31 GRACIAS THANK YOU GRAZIE