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SHIELD Study Diabetes Update 03/29/17 Objectives for this talk • Background and goals of treatment • Drug therapy • Appropriate use of insulin Objectives for this talk • Background and goals of treatment • Drug therapy • Appropriate use of insulin Pathogenesis of DM: Summary • Type 1 – Inability to secrete insulin – Presents abruptly, but not always. Can be of slow onset, more often in older patients. • Type 2 – Insulin resistance – Impaired (not absent) ability to secrete insulin – Type 2 diabetes worsens with time. What comes first in type 2 DM? • Still debated. • Insulin resistance is present early. • Worsening likely due to loss of ability to compensate for insulin resistance by secreting more insulin What do we want to achieve? Tangible goals Surrogate goals • Prevent worsening of • Low A1c diabetes • Good BP • No long-term complications • Well controlled lipids • CV health • Low inflammatory markers • Good quality of life • Normal creatinine • Minimal highs and lows • Normal liver function tests • Avoid healthcare costs • Normal body mass • Ability to carry out physical activity Some important diabetes treatment trials DCCT/EDIC sites PERCENT OF SUBJECTS IN MEAN HbA1c CATEGORIES 30 Combined Cohort 25 PP Int Con EE 20 RR CC 15 EE NN 10 TT 5 0 <6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5 11.0 11.5 12.0 12.0+ MEAN HbA1cHbA1c Glycemic Intervention and Development of Complications in Type 1 Diabetes DCCT: Intensive vs Conventional Therapy New-Onset Complication RRR Retinopathy 76% Nephropathy* 54% Neuropathy 60% *Urinary albumin excretion 300 mg/24 h. DCCT Research Group. N Engl J Med. 1993;329:977. Relationship between Glycemia and Complications DCCT Retinopathy 250 200 43% reduction In risk for every 10% 150 Event decrease in HbA1c Rate per 100 1000 Pt-Y 50 0 5 6 7 8 9 10 11 12 5.5 6.5 7.5 8.5 9.5 10.5 11.5 Current Mean HbA1c (%) DCCT/EDIC data over 31 years First of any predefined CVD outcome Risk reduction with intensive therapy was 30% (p = 0.016) Cumulative incidence of cardiovascular outcomes in the conventional treatment and intensive treatment groups during up to 30 years of DCCT/EDIC treatment and follow-up. Diabetes Care Ahead of Print, published online February 9, 2016 Summary UKPDS results • Intensive blood-glucose control by either sulfonylureas or insulin substantially decreases the risk of microvascular complications, but not macrovascular disease, in patients with type 2 diabetes. • Metformin monotherapy (obese patients) resulted in greater reduction in risk of any diabetes related event and decreased the risk of MI • BP controlled reduced micro and macrovascular complications Data from DCCT/EDIC and UKPDS • UKPDS • DCCT – 10 years after UKPDS, – Nine years after DCCT, follow-up showed at 15% incidence of CV events decrease in MI in intense was reduced 57% in treatment group initially on former intensive patients sulfonylurea or insulin; and 33% in more obese treated – Younger age at onset (13- initially with metformin. 39) with no known CVD – Mortality also reduced 13 and 27% respectively Nathan DM, et. al. NEJM 353:2643, 2005 Holman RR, et. al. NEJM 359, 1577, 2008 Glycemic control and macrovascular disease in ACCORD, ADVANCE, and VADT Large randomized trials directed at the effect of glycemic control on cardiovascular risk in type 2 diabetes in participants at high risk for vascular events. ACCORD ADVANCE VADT # subjects 10,251 11,140 1,791 Average age 62 66 60 A1c control 6.4 vs 7.5 % 6.4 vs 7.0 % 6.9 vs 8.4 % Primary results No decrease in No decrease in No decrease in cardiovascular events. cardiovascular risk cardiovascular risk Increased cardiovascular Reduced risk of mortality with intensive nephropathy Rx * The excess mortality in the ACCORD study was in subjects in the intensive group who did not achieve targeted control (higher A1c values in spite of efforts to lower glucose. Epidemiologic Relationships Between A1C and All-Cause Mortality During a Median 3.4-Year Follow-up of Glycemic Treatment in the ACCORD Trial DIABETES CARE, VOLUME 33, NUMBER 5, MAY 2010 These analyses implicate factors associated with persisting higher A1C levels, rather than low A1C per se, as likely contributors to the increased mortality risk associated with the intensive glycemic treatment strategy in ACCORD. Implications of major Rx trials • Target of 7.0 % HbA1c still considered valid • More aggressive treatment may need to be implemented early with cautious approach with more advanced diabetes and cardiovascular disease • Overly persistent efforts to lower glucose in patients at risk for macrovascular events may not be warranted • Strong evidence for microvascular benefits of glucose control • Type 2 DM worsens with time. Can we prevent this? ADA Treatment Goals for Glycemic Control General goal for non-pregnant adults HbA1c < 7.0% (normal < 5.7%) Pre-meal 80-130 mg/100 ml Peak post-meal < 180 mg/100 ml (measure 1-2 h after start of meal) More stringent for selected Individuals • short duration of diabetes As close to normal as • treatment with lifestyle or metformin only possible without significant • long life expectancy hypoglycemia • no significant cardiovascular disease. Less stringent for some patients • hypoglycemia unawareness HbA1c < 8.0 • limited life expectancy • co-morbidity • long hx DM with minimal complications where control has been historically difficult American Diabetes Association: Standards of Care (Diabetes Care 40, Suppl. 1, Jan. 2017) Online www.diabetes.org/ Objectives for this talk • Background and goals of treatment • Drug therapy • Appropriate use of insulin Metformin • Near universal acceptance as initial drug therapy in absence of contraindication (e.g. renal failure, hypoxia) or intolerance • Decrease hepatic glucose release and increases muscle glucose uptake • Beneficial effects on weight and lipids • Lack of hypoglycemia when used alone • Generic drug with long history of use worldwide (over 50 yr) • Evidence from several studies supports a reduction in CV events, improved carotid IMT • UKPDS showed a significant reduction in MI and cardiac and all cause mortality by 39, 50, and 36% respectively when administered to obese patients (weight > 120% of ideal). Metformin: mechanism of action • There is clear consensus that metformin reduces hepatic gluconeogenesis • But how it does that is still unclear – evidence for: – Impair (alter) mitochondrial function at complex I – Noncompetitively inhibits the redox shuttle enzyme mitochondrial glycerophosphate dehydrogenase (mGPD), resulting in an altered hepatocellular redox state, reduced conversion of lactate and glycerol to glucose – Activates AMPK leading to reduction of gluconeogenic gene transcription. Increased glucose transport in muscle and β- oxidation of fatty acids. – Other ? Severe hyperglycemia Insulin Initial Pharmacologic treatment Contraindication or Metformin intolerance to metformin) Goal achieved Goal not achieved Add second drug Another drug What drug ? Sulfonylureas • Mechanism of action: ↑ β-cell insulin secretion by activating potassium channels • Glipizide, Glimepiride • Glyburide (glibenclamide) – more hypoglycemia, maybe adverse interactions with cardiac channels • Advantages: – Well tolerated – Low cost • Disadvantages: – Hypoglycemia – Weight gain – Sulfa allergy – May have low durability Sulfonylureas (CV effects) • UGDP (1970s) – increased CV mortality (controversial) • Retrospective and some prospective analyses of databases support increased risk • UKPDS, ADVANCE, ACCORD do not support increased CV risk Dipeptidyl peptidase -4 (DPP-4) inhibitors • Several available – Sitagliptin (Januvia) – Alogliptin (Nesina) – Saxagliptin (Onglyza) – Linagliptin (Tradjenta) (no renal adjustment) • Block degradation of endogenous GLP-1 • Not very effective in lowering A1c • Advantages – Little or no hypoglycemia • Disadvantages – Urticaria, angioedema – Pancreatitis risk DPP-4 inhibitors (CV effects) • Weight neutral • Decrease TG, may reduce hsCRP, may improve endothelial function, and improve reduce ischemia-reperfusion in animals, may decrease IMT (diabetes care Dec 2015 online) • Two large CV outcome trials in high risk patients (SAVOR-TIMI and EXAMINE) showed no difference in outcomes – Slight increase in hospitalization for CHF • TECOS trial – 14,671 patients to add either sitagliptin or placebo, no diff in CV events (839 vs. 851 – No difference in hospitalization for CHF GLP-1 agonists • Several drugs differing in duration of action – Exenatide (Byetta) Short-acting BID (needs renal adjustment) – Long acting exenatide (Bydureon) Weekly (needs renal adjustment) – Lixisenatide (Lyxumia) Intermediate-acting Daily – Liraglutide (Victoza) Long-acting Weekly – Dulaglutide (Trulicity) Long-acting Weekly – Albiglutide (Tanzeum) Long-acting Weekly • Activate GLP-1 receptors in pancreatic β -cell and nervous system • ↑ glucose-induced insulin secretion, ↓ glucagon, ↓ gastric emptying,↑ satiety – Decreased hepatic glucose production – Decreased post-prandial glucose • Durable up to at least 3 years, may increase β -cell mass • Mild weight loss • Disadvantages – Nausea, vomiting, or diarrhea – Pancreatitis risk – Medullary thyroid tumors GLP-1 agonists (CV effects) • Many favorable effects on CV risk factors: Decrease weight and visceral fat, decrease BP, increase urinary sodium, improved endothelial function, decrease TG, FFA levels • LEADER trial – Randomized double blind trial, 9340 subjects with type 2 diabetes at high risk for CV disease or with CV disease. – Assessed the effect of liraglutide, a GLP-1 receptor agonist, versus placebo
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