Pre-diabetes. Pharmacological Approaches to Delay Progression to Diabetes

Transcription

1 Pre-diabetes Pharmacological Approaches to Delay Progression to Diabetes

2 Overview Definition of Pre-diabetes Risk Factors for Pre-diabetes Clinical practice guidelines for diabetes Management, including medications

3 Pre-diabetes Impaired Fasting Glucose (IFG) FPG: mmol/L (100mg/dL- 125mg/dL) Impaired Glucose Tolerance mmol/L ( mg/dL) A1c: % Diabetes diagnosis A1c 6.5% FPG 7.0mmol/L 2hr PP 11.1mmol/L American Diabetes Association. Standards of Care. 2013; 36: S11-S66

4 Why Prevention? Costs Morbidity Hypertension Dyslipidemia CHD Mortality

5 Why Prevention? ADA (2007) estimated the cost of diabetes to be US$174 Billion annually Jamaica: Ward & Grant (2005) public hospital costs for diabetic patients estimated as JA$222 million in 2002 (approximately US$2.6M) NHF spent JA$459 million on its 94,978 diabetic members (~US$5.37M) in 2010 Patients paid JA$848.4 million (~US$9.93M) With a prevalence rate of 7.9% ~ 213,300 Jamaicans are estimated to have diabetes (diagnosed & undiagnosed)?? JA$1.9 billion or ~US$22 million

6 Why Prevention? Consequences of hyperglycemia-induced activation of PKC. Brownlee M Diabetes 2005;54: Copyright 2011 American Diabetes Association, Inc.

7 Why Prevention? The morbidity associated with diabetes accounts for: 25% of dialysis patients 50% of non-traumatic leg/foot amputations Leading cause of the onset of blindness Ref: MOH, 2001 report

8 Prevalence of Co-morbid disease in a sample of recently diagnosed diabetic patients up to 12 months after diagnosis. (DM: Diabetes; Htn: hypertension; Chol: dyslipidemia; CVD: cardiovascular disease). 2% 3% 4.5% 6% 27% 13% 17% 48% 50% 65% 36% 27%

9 Percent Controlled (<7.8mmol/L) Why Prevention? Percentage of sample population who attained acceptable glycaemic control (<7.8mmol/L) within drug treatment groups at one year and ~ three years after diagnosis % p < 0.01 p < % 62% 41% 44% 20 0 SU SU & Glu SU & Met Met only Anti-diabetic Drug Gruops At one year At end-point

10 Pre-diabetes Risk Factors Obesity (BMI 25kg/m 2 ) Abdominal or visceral fat Dyslipidemia Hypertension > 45 yrs Physical inactivity Race Delivery of baby > 9lbs GDM Polycystic Ovarian Syndrome Acanthosis nigricans History of CVD

11 Role of A1c as a guide Low intra-individual variability Zhang et al (2010) %: < 9% incidence over 5 yrs %: 9-25% %: 25-50% Ackerman et al., (2011) A1c 5.7% : 41.3% risk for DM 13.3% risk for HTN Zhang, X, Gregg EW, Williamson DF et al. Diabetes Care (2010); 33:

12 A1c and Incidence of Diabetes

13 Prevention tools

14 Lifestyle Modification Diabetes Prevention Program Research Group Lifestyle Weight reduction goal of 7% Exercise (150mins/wk)

15 Effect of weight, exercise and medication adherence in groups 50% 24wks 24wks; yrs

16 Diabetes Prevention Program Research Group Placebo Lifestyle Metformin Diabetes incidence 11% 4.8% 7.8% Caloric intake -249kcal -450kcal (p<0.0001) -296 kcal Fat intake 0.8% 6.6% 0.8% Lifestyle : 58% reduction in diabetes incidence vs placebo Metformin: 31% reduction vs placebo Metformin less cost-effective than lifestyle but cost-saving

17 Incidence of diabetes from DPP study 28% 21.7% 14.4%

18 Diabetes Prevention Program Research study

19 Diet SOP projects??? Mix of carbohydrate, protein & fat Reduced fat intake?alcohol Precautions to prevent hypoglycemia Production of ketones, cholesterol & fatty acids Meal planning

20 Meal Planning Oats Diabetes: 6-week consumption can significantly decrease blood glucose, 24-hour plasma glucose and insulin in type 2 diabetes Evidence suggests 50 grams of oats daily, (25 grams of soluble fiber), may be more effective than the 24 grams recommendation by ADA

21 Oats Mechanism for Reduction in Blood Glucose Increases food viscosity to delay absorption Leading to decrease in peak post-prandial glucose levels Reduces insulin levels Reduces appetite Reduces/Stabilizes blood glucose levels

22 Meal Planning Hypercholesterolemia Oats, oat bran, and other soluble fibers can moderately reduce total and LDL cholesterol when consumed as part of a diet low in saturated fat grams of oat products such as oatmeal and oat bran, ( grams of beta-glucan or soluble fiber) shown to significantly lower total and LDL cholesterol levels. Reduction of 0.13mmol/L in TC Reduction of 0.3mmol/L in LDL

23 Oats Mechanism in dyslipidemia Binds to bile acids (BA) Reduction in enterohepatic circulation of bile acids Increases conversion of cholesterol to BA s Up-regulation of LDL receptors Reduced micelle formation Fermentation produces short chain fatty acids Contains alpha tocotrienols Inhibits Hydroxymethylglutaryl coenzyme A (HMG Co-A)

24 Meal Planning What you eat and how much you eat! Food Substitution

25 Special Considerations Linking Pathophysiology of Disease with Drug Action Disease progression* Therapy Insulin Resistance β-cell failure Dysregulated hepatic glucose production Metformin; TZD;DPP-4 Metformin; SU; Glinides;GLP-1; DPP-4 Metformin Post-prandial hyperglycaemia Acarbose, Glinides; Amylin; DPP-4; Metformin * Ref: Dagogo-Jack & Santiago in Arch Int Med 1997; 157:

26 Special Considerations Drug Effectiveness & Patient Factors Drug HbA1c Lipids Weight Hypoglycemia Metformin - ++ SU TZD - - Glinides DPP-4 -/ - - GLP α-glu I GI effects DPP-4 inhibitors increase β-cell mass, decrease gastric emptying, decrease appetite, increase satiety, neuro-protection, increase Na + excretion, increased osteoblasts Ref: Ann Int Med 2011; 154: ; Ann Int Med 2007; 147: ; Diabetes Care 2007; 30: ; Diabetologia 2012; 55:

27 Mechanism of action of Metformin Metformin activates AMP-dependent protein kinase (AMPK), the cellular energy sensor Activation of AMPK Suppresses some ATP dependent processes, e.g. gluconeogenesis, protein, fatty acid and cholesterol synthesis Inhibits transcription of gluconeogenesis genes in the liver Increases glucose uptake in skeletal muscle Increases insulin sensitivity Reduces hyperinsulinemia associated with insulin resistance Fatty acid oxidation is induced along with reduced expression of lipogenic enzymes Very little effect on blood glucose in normoglycemic states

28 a-glucosidase Inhibitors Acarbose Mechanism Inhibition of a-glucosidase enzyme to reduce hydrolysis of complex carbs Delay glucose absorption

29 ADA-EASD Position Statement: Management of Hyperglycemia in T2DM PATIENT FACTORS Age: Older adults - Higher CVD burden - Reduced GFR - Co-morbid conditions - At risk for adverse events from poly pharmacy - More likely to be compromised from hypoglycemia Less ambitious targets Increase HbA1c target if tighter targets not easily achieved Focus on drug safety Diabetes Care 2012;35: Diabetologia 2012;55:

30 ADA-EASD Position Statement: Management of Hyperglycemia in T2DM PATIENT FACTORS Weight - Greater risk for T2DM - Majority of T2DM patients overweight / obese - CV risk: Dyslipidemia, hypertension Treatment options - Intensive lifestyle program - Metformin Diabetes Care 2012;35: Diabetologia 2012;55:

31 ADA-EASD Position Statement: Management of Hyperglycemia in T2DM PATIENT FACTORS Sex/ethnic/racial/genetic differences - African descendants, Native Americans, Pacific Islanders - Latinos: more insulin resistance - East Asians: more beta cell dysfunction - Women who delivered > 9lb baby - POS Diabetes Care 2012;35: Diabetologia 2012;55:

32 ADA-EASD Position Statement: Management of Hyperglycemia in T2DM PATIENT FACTORS Co-morbidities - Coronary Disease - Heart Failure - Renal disease Metformin: CVD benefit (UKPDS) Avoid hypoglycemia? SUs & ischemic preconditioning? Pioglitazone & CVD events? Effects of incretin-based therapies - Liver dysfunction Diabetes Care 2012;35: Diabetologia 2012;55:

33 ADA-EASD Position Statement: Management of Hyperglycemia in T2DM PATIENT FACTORS Co-morbidities - Coronary Disease - Heart Failure - Renal disease - Liver dysfunction Metformin: May be used unless condition is unstable or severe Avoid TZDs? Effects of incretin-based therapies Diabetes Care 2012;35: Diabetologia 2012;55:

34 ADA-EASD Position Statement: Management of Hyperglycemia in T2DM PATIENT FACTORS Co-morbidities - Coronary Disease - Heart Failure - Renal disease - Liver dysfunction Increased risk of hypoglycemia Metformin & lactic acidosis Caution with SUs (esp. glyburide) DPP-4-i s dose adjust for most Avoid exenatide if GFR < 30 Diabetes Care 2012;35: Diabetologia 2012;55:

35 ADA-EASD Position Statement: Management of Hyperglycemia in T2DM PATIENT FACTORS Co-morbidities - Coronary Disease - Heart Failure - Renal disease - Liver dysfunction Most drugs not tested in advanced liver disease Pioglitazone may help steatosis Insulin best option if disease severe Diabetes Care 2012;35: Diabetologia 2012;55:

36 Summary: Clinical Practice Guidelines Patient empowerment Target weight loss of 7% in obese patients Increase physical activity to 150mins/wk Follow-up counselling Metformin if A1c %; < 60yrs, hx of GDM Annual monitoring Screening for modifiable risk factors for CVD

37 Thank you!!!