9 EARLIER INTERVENTION • 2006 Consensus statement from the ADA and EASD –“Our consensus is that an HbA1c of ≥7 should serve as a call to action to initiate or change therapy…” –“If lifestyle intervention and maximal tolerated dose of metformin fail to achieve or sustain glycaemic goals, another medication should be added within 2–3 months of the initiation of therapy or at any time when HbA1c goal is not achieved”EASD=European Association for the Study of Diabetes.Nathan DM et al. Diabetologia. 2006;49:1711–1721; International Diabetes Federation. 2005:1–79.
10 EARLIER INTERVENTION • 2005 Global Guideline by IDF –“Begin with metformin unless evidence or risk of renal impairment, titrating the dose over early weeks to minimise discontinuation due to gastro-intestinal intolerance” –“Step up doses, and add other glucose- lowering drugs, at frequent intervals until blood glucose control is at target levels”EASD=European Association for the Study of Diabetes.Nathan DM et al. Diabetologia. 2006;49:1711–1721; International Diabetes Federation. 2005:1–79.
Improved 24-hour glucose profile in 23T2DM Placebo + metformin (n=13) Sitagliptin 50 mg b.i.d. + metformin (n=15) Breakfast Lunch Dinner 240 Dose 1 Dose 2 7:30 18:30 Difference in 24-hour weighted LS mean glucose: 220 –32.8 mg/dL (–1.82 mmol/L) p<0.001 200Glucose (mg/dL) 180 160 140 120 100 8:00 13:00 19:00 0:00 7:30 Day 1 Day 2 Time Adapted from Brazg RL et al. Poster presented: at American Diabetes Association; June 10–14, 2005; San Diego, Calif.
ADA and IDF Guidelines: Treatment Goals for HbA1c, FPG, and PPG Normal ADA IDF Parameter Level Goal Goal FPG, mg/dl <110 90–130 <100 (mmol/L) (<6.1) (5.0–7.2) (<5.5) PPG, mg/dl <140 <180 <140 (mmol/L) (<7.8) (<10.0) (<7.8) HbA1c 4%–6% <7%* <6.5%*Reference to a nondiabetic range of 4.0% to 6.0% using a DCCT-based assay.ADA=American Diabetes Association; IDF=International Diabetes Federation.American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41; International Diabetes Federation. 2007:1–32. 24Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:1427–1483.
Diabetes-Related Complications Relative Risk N=3642 EVERY 1% REDUCED RISK reduction in HbA1c (P<0.0001) Diabetes- related deaths Myocardial infarctions 1% Microvascular complications Amputations or deaths from peripheral vascular disordersUKPDF=United Kingdom Prospective Diabetes Study.Data adjusted for age, sex, and ethnic group, expressed for white men aged 50–54 years at diagnosis and with mean duration of diabetes of 10 years.Stratton IM et al. UKPDS 35. BMJ 2000;321:405–412. 25
THE LANCET Vol 363 April 3, 2004
Asymptomatic :missing the boat of opportunity fordiabetic complications• Retinopathy: often not symptomatic• Incipient Diabetic nephropathy is diagnosable• Fatty liver not symptomatic• Ischemic heart disease: diabetics “silent AMI”• „Silent Stroke”
Modern living and the diabetic:circadian-metabolic link• Major lifestyle modifications:• 24 hour society• Extended working hours• Night work; sleep-wake cycle abnormal phase relationship• Shift of eating hours towards late night• Shift work and increased prevalence of obesity
SHIFT WORK AND SLEEP LOSS• Shift workers get less sleep on average during the week than regular day workers• 49% of shift workers average 6.5 hours of sleep per night.• When the subjects ate and slept approx 12 hours out of phase from their habitual times their levels of Leptin decreased, post-meal sugars increased.
Circadian Clocks & obesity andDiabetes Endocrine News June 2011• Timing of AMI and cardiovascular events (including thrombosis and AMI) peak in the morning• Disorders of lipid absorption, lipogenesis and lipolysis display circadian rhythm• Impaired nocturnal blood pressure: due to autonomic dysfubction
Shift work and sleep: Novel riskfactors for obesity and DM• When subjects ate and slept approx. 12 hours out of phase from their habitual times, – their levels of satiety hormone leptin decreased, – post-prandial glucose responses higher – Shift workers experience shift misalignment
Shift work• The desynchronised schedule causes insulin resistance and impaired insulin secretion• Ghrelin and adiponectin (produced in GIT and adipose tissue) display diurnal expression rhythms
SHIFT WORKERS• Sleep after night shift almost always involves sleep loss. Rarely exceeds 6 hours;49% average 6.5hours of sleep per night Proc. Natl Acad sci U.S.A. 2009;106: 4453-4458
Genetic Mice models• MICE given access to a high fat diet during the light phase (their normal resting period ) gain more weight than mice with access to the same diet only during the dark phase (active period).
LIFESTYLE AND HEALTH• Disturbance in circadian clock system : promotes weight gain• Extended work shifts; increased risk of weight gain or metabolic syndrome• Animal studies : circadian misalignment promotes obesity and glucose intolerance
References:• Mahmoud et al JACC Cardiovas Interv, 2011, 4:183-190• Paschos GK, Fitzgerald GA Circadian clocks and vascular function Circ Res. 2010; 106:833-841