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  •  -Cell Dysfunction and Insulin Resistance Produce Hyperglycemia in Type 2 Diabetes Dual Impairment Impaired insulin action (Insulin Resistance) Impaired insulin secretion (Impaired  -cell function) In adipose tissue resistant to the effects of insulin, there is increased lipolysis resulting in elevated level of plasma free fatty acids (FFA). Elevated FFA lead to an increase in hepatic glucose production and decrease in glucose uptake in the muscle. Impaired  -cell function and  -cell degranulation lead to a reduction in circulating insulin. This reduction in circulating insulin leads to hyperglycemia. Impaired insulin action or insulin resistance results in a decreased response to insulin in insulin sensitive tissues. In the liver, insulin resistance results in an increase in hepatic glucose production. Whether the impairment is to insulin secretion or action, the resulting hyperglycemia has a negative effect on muscle and adipose tissue by decreasing expression of GLUT4 which, in turn, limits glucose transport into insulin-sensitive tissues. Key words: Type 2 Defects Beta cell Insulin resistance
  • had anatomical evidence of significant atherosclerosis, albuminuria, left ventricular hypertrophy, or at least two additional risk factors for cardiovascular disease (dyslipidemia, hypertension, current status as a smoker, or obesity).
  • Mean duration of DM – 8 yrs
  • ½ w/o and ½ with clinical retinopathy
  • Glycosylated hemoglobin values were measured quarterly and fasting lipid levels, serum creatinine values, and other risk factors for cardiovascular disease were measured annually in a central laboratory. Microalbuminuria and albuminuria were defined by urinary albumin excretion of at least 40 mg in a 24-hour period and of at least 300 mg in a 24-hour period, respectively. Renal disease was defined by the development of a serum creatinine level of at least 2 mg per deciliter (177 µmol per liter) or the need for dialysis or kidney transplantation. Electrocardiograms were obtained and examined annually by readers who were unaware of patients' treatment assignments. During the EDIC follow-up study, the methods used in the DCCT were continued, but glycosylated hemoglobin was measured annually and fasting lipid levels and renal function were measured in alternate years.

Diabetes Step Care Approach Diabetes Step Care Approach Presentation Transcript

  • Diabetes: Step care approach to management Dr. B. K. Iyer CARDICARE
  • Diabetes: classification, diagnosis, management
    • Classification
    • Diagnosis
    • Treatment
    • Classification
    • Diagnosis
    • Treatment
    Diabetes classification – a relook
  • Classification
    • Type 1 diabetes
    • Type 2 diabetes
    • Other
      • Genetic defects of beta cell function
      • Genetic defects in insulin action
      • Diseases of the exocrine pancreas
      • Endocrinopathies
      • Drug/ chemical - induced
      • Infections
      • Uncommon forms of immune-mediated diabetes
      • Genetic syndromes sometimes associated with diabetes
    • Gestational diabetes mellitus
  • Type 1 diabetes
    • Type 1 diabetes is characterized by β-cell destruction, usually leading to absolute insulin deficiency.
      • Immune-mediated
      • Idiopathic
    * Diagnosis and Classification of Diabetes Mellitus. ADA 2009.
  • Type 1 diabetes - progression * Atkinson MA and Eisenbarth GS. Lancet 2001;358:221-229.
  • Type 1 diabetes – immune mediated
    • Absolute insulin deficiency
    • Usually due to autoimmune destruction of the pancreatic beta cells
      • Islet-cell antibodies (ICA) or
      • other autoantibodies
        • antibodies to glutamic acid decarboxylase [anti-GAD] and
        • anti-insulin)
  • Type 2 diabetes
    • Hyperglycemia
    • Insulin resistance
    • Relative insulin secretion/ response impairment
  • Type 2 diabetes - causes
    • Hyperglycemia in type 2 diabetes can be due to 2 causes:
    Pancreas Insulin Resistance Liver Hyperglycemia Islet  ­ Cell Degranulation; Reduced Insulin Content Muscle Adipose Tissue Decreased Glucose Transport & Activity (expression) of GLUT4 Increased Lipolysis ↑ Glucose Production ↓ Glucose Uptake Reduced Plasma Insulin Increased Glucose Output  ­ Cell Dysfunction Elevated Plasma FFA
  • Type 2 diabetes & declining β –cell function : UKPDS Dashed line = extrapolation from UKPDS data Lebovitz HE, Diabetes reviews, 1999;7: 139-153
    • Maturity–onset diabetes of the young (MODY)
    • 6 subtypes:
      • MODY 1 - Mutation in HNF-4-alpha (transcription factor), chromosome 20
      • MODY 2 - Mutation in glucokinase gene, chromosome 7
      • MODY 3 - Mutation in HNF-1-alpha (transcription factor), chromosome 12 (most common form)
      • MODY 4 - Mutation in insulin promoter factor-1 (IPF-1), chromosome 13
      • MODY 5 - Mutation in HNF-1-beta, chromosome 17
      • MODY 6 - Mutation in Neurogenic Differentiation Factor-1 (NEUROD1) , chromosome 2
    Other specific types of diabetes: Genetic defects in β -cell function
  • Other specific types of diabetes: Genetic defects in insulin action
    • Type A insulin resistance
    • Leprechaunism
    • Rabson- Mendenhall syndrome
    • Lipoatrophic diabetes
    • Others
  • Latent Autoimmune Diabetes in Adults (LADA)
    • Adult-onset diabetes with circulating islet antibodies but not requiring insulin therapy initially
    • Adults who should be considered for antibody testing*:
      • age of onset <50 years
      • acute symptoms
      • BMI <25 kg/m2
      • personal or family history of autoimmune disease
    * A clinical screening tool identifies autoimmune diabetes in adults. Fourlanos S; Perry C; Stein MS; Stankovich J; Harrison LC; Colman PG. Diabetes Care . 2006 May;29(5):970-5
  • Gestational DM
    • Any degree of impaired glucose tolerance with onset or first recognition during pregnancy
    • Gestational diabetes (GDM) occurs when pancreatic function is not sufficient to overcome the insulin resistance created by changes in diabetogenic hormones during pregnancy.
    • Most have impaired glucose tolerance that begins in pregnancy
    • Some have previous undiagnosed type 2 diabetes.
    • 10% have circulating islet cell antibodies
    • Classification
    • Diagnosis
    • Treatment
    Diabetes diagnosis
  • Diagnosis
    • Diabetes mellitus
    • Impaired fasting glucose (IFG)
    • Impaired glucose tolerance (IGT)
    • Gestational diabetes mellitus (GDM)
  • Diagnosis: Diabetes mellitus
    • Symptoms of diabetes (polydipsia, polyuria, unexplained weight loss) PLUS a random plasma glucose >200 mg/dL (11.1 mmol/L)
            • or
    • Fasting plasma glucose > 126 mg/dL (7.0 mmol / L) after overnight (at least 8 hours) fast
            • or
    • Two-hour plasma glucose> 200mg/dL (11.1 mmol / L) during a standard 75g oral glucose tolerance test
    Any of these criteria establishes the diagnosis but needs to be confirmed on a later day
  • Diagnosis: Impaired fasting glucose (IFG)
    • Fasting plasma glucose (FPG) < 100 mg/dl (5.6 mmol/l) = normal
    • FPG 100-125 mg/dl (5.6-6.9 mmol/l) = impaired fasting glucose (IFG)
    • Oral glucose tolerance test (OGTT) – glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water
    • 2-h post-load glucose < 140 mg/dl (7.8 mmol/l) = normal
    • 2-h post-load glucose 140 - 199 mg/dl (7.8 – 11.1 mmol/l) = impaired glucose tolerance (IGT)
    Diagnosis: Impaired glucose tolerance (IGT)
  • Diagnosis: Gestational Diabetes Mellitus (GDM)
    • Unequivocal hyperglycemia
    • (confirmed on a subsequent day)
    Fasting plasma glucose > 126 mg/dL (7.0 mmol/L) Random plasma glucose >200 mg/dL (11.1 mmol/L) OR 2. Diagnostic OGTT 100-g glucose load 7.8 140 3-h 8.6 155 2-h 10.0 180 1-h 5.3 95 Fasting mmol/l mg/dl
    • Classification
    • Diagnosis
    • Treatment – drugs in brief
    Diabetes: management
  • Treatment Treatment Lifestyle intervention Hypoglycaemic drugs
    • Weight loss
    • Increased exercise
    Oral hypoglycemic drugs Insulin & insulin analogs Others [incretins, pramlintide]
    • Biguanides
    • Sulfonylureas
    • Meglitinide analogs
    • Thiazolidinediones
    • α -Glucosidase Inhibitors
    • DPP-4 Inhibitors
  • Treatment: Oral Antihyperglycemic Drugs
  • Oral antihyperglycemic drugs: Biguanides
    • Metformin & Extended-release metformin now available
      • decrease hepatic glucose output
      • lower fasting glycemia
      • reduce HbA1c by 1.5%
    • adverse effects: lactic acidosis, gastro-intestinal disturbances
    AMPK - adenosine monophosphate-activated protein kinase, ACC - acteyl-CoA carboxylase, SREPB-1 - sterol-regulatory-element-binding-protein-1 Diagram adapted from Alice Y.Y. Cheng, I. George Fantus, 'Oral antihyperglycemic therapy for type 2 diabetes mellitus' Canadian Medical Association Journal 172(2),2005 pp213-226
  • Oral antihyperglycemic drugs: Metformin titration
    • Based on cost considerations, generic metformin is the first choice of therapy. A longer-acting formulation is available in some countries and can be given once per day.
    • The maximum effective dose is usually 850 mg twice per day, with modestly greater effectiveness with doses up to 3 g per day. GI side effects may limit the dose that can be used.
    • If GI side effects appear as doses advanced, can decrease to previous lower dose and try to advance dose at a later time.
    • After 5–7 days, if GI side effects have not occurred, advance dose to 850 or 1,000 mg before breakfast and dinner.
    • Begin with low-dose metformin (500 mg) taken once or twice per day with meals (breakfast and/or dinner).
  • Oral antihyperglycemic drugs: Sulfonylureas
    • 1st generation no longer used: Chlorpropamide Tolbutamide
    • 2nd generation : Glyburide, Glipizide, Glimepiride
      • enhance insulin secretion
      • lower HbA1c by 1.5 %
      • side effects: hypoglycemia, weight gain
  • Oral antihyperglycemic drugs: Meglitinide analogs
    • Repaglinide
    • Nateglinide
      • enhance insulin secretion (early-phase insulin release)
      • lower HbA1c by 0.1- 2.1 % (repaglinide) and by 0.2- 0.6% (nateglinide)
    • side effects: weight gain, hypoglycemia
    Black C, Donnelly P, McIntyre L et al. Meglitinide analogues for type 2 diabetes mellitus. Cochrane Database Syst Rev . 2007 Apr 18;(2):CD004654.  
  • Oral antihyperglycemic drugs: Thiazolidinediones (TZDs)
    • Rosiglitazone & Pioglitazone
      • peroxisome proliferator-activated receptor γ modulators (PPAR γ )
      • insulin sensitizers (increase the sensitivity of muscle, fat and liver to endogenous and exogenous insulin)
      • lower HbA1c by 0.5 - 1.4 %
    • adverse effects: weight gain, fluid retention
  • Oral antihyperglycemic drugs:  -Glucosidase Inhibitors
    • Acarbose
    • Miglitol
      • reduce the rate of digestion of polysaccharides in the proximal small intestine, primarily lowering post-prandial glucose levels
      • lower HbA1c by 0.5 – 0.8 %
    • side effects: increased gas production and gastro-intestinal symptoms
  • Oral antihyperglycemic drugs: DPP-IV inibitors
    • Sitagliptin : DPP-IV inhibitor
    • Dipeptidyl peptidase IV (DPP-IV) is a ubiquitous enzyme that deactivates a variety of bioactive peptides, including GIP and GLP-1
    • Used alone or in combination with metformin or TZDs
      • Reduces HbA1c by 0.5 – 0.7 %
    • Side effects: increased rate of respiratory infections, headaches
  • Other antihyperglycemic drugs: Incretins
    • Glucagon-like peptide 1 (GLP-1) agonist
    • Exenatide - active ingredient in Exenatide (Byetta) is a synthetic version of a protein present in the saliva of the Gila monster
  • Glucagon-like Peptide - 1
    • The majority of GLP-1 producing cells are in the terminal ileum and proximal colon.
    • GLP-1 levels in the blood increase rapidly after a meal.
    • Half-life is very short, approximately one minute.
    • GLP-1 binding to its G-protein coupled receptor on ß-cells increases glucose stimulated insulin secretion
    • GLP-1 infused into healthy subjects decreases gastric emptying, causes a sensation of satiety, and decreases appetite.
    • Effects:
      • enhances insulin secretion
      • limits postprandial hyperglycemia.
  • Other antihyperglycemic drugs: Incretins [Exenatide]
    • Added to metformin or sulfonylureas will reduce HbA1c by 0.4-0.6 %
    • Side effects:
      • nausea (dose-depended, declines with time)
      • acute pancreatitis (some necrotizing or hemorrhagic pancreatitis cases reported as well)
  • Incretin Effect Figure 1. Insulin levels following oral vs IV glucose administration in healthy individuals. Despite identical glucose concentrations, plasma insulin levels peaked much earlier and were greater in response to an oral vs IV dose of glucose. Figure 2. Insulin levels following oral vs IV glucose administration in patients with type 2 diabetes. The markedly reduced early peak of insulin after oral glucose, along with the smaller differences in insulin levels in response to oral and IV glucose doses, illustrate the diminished incretin effect. Data extrapolated from Perley, et al. @ http://www.byettahcp.com/hcp/hcp_incretin_effect.jsp
  • Antihyperglycemic drugs: Others
    • Pramlintide (Symlin)
      • synthetic analog of amylin
      • Delays gastric emptying, suppresses glucagon secretion, decreases appetite
      • Associated with weight loss (1 - 1.5 kg over 6 months)
      • Used only in conjunction with insulin treatment
      • ↓ HbA1c by 0.5- 0.7 %
      • Side effects: nausea, gastro-intestinal symptoms
  • Amylin
    • Stored in insulin secretory granules in the ß-cells
    • Co-secreted with insulin
    • Decreases glucagon
    • Satiety signal?
    • Decreases GI motility
  • Available insulin preparations * Onset and duration are rough estimates. They can vary greatly within the range listed and from person to person ** Human insulin is made by recombinant DNA technology
  • Summary of antidiabetic interventions as monotherapy Injections, three times/day dosing, frequent GI side effects, expensive, little experience Weight loss 0.5–1.0 Pramlintide Three times/day dosing, expensive Short duration 1–1.5† Glinides Injections, frequent GI side effects, expensive, little experience Weight loss 0.5–1.0 Exenatide Frequent GI side effects, three times/day dosing, expensive Weight neutral 0.5–0.8 α-Glucosidase inhibitors Other drugs Fluid retention, weight gain, expensive Improved lipid profile 0.5–1.4 TZDs Weight gain, hypoglycemia Inexpensive 1.5 Sulfonylureas Injections, monitoring, hypoglycemia, weight gain No dose limit, inexpensive, improved lipid profile 1.5–2.5 Insulin Step 2: additional therapy GI side effects, rare lactic acidosis Weight neutral, inexpensive 1.5 Metformin Fails for most in 1st year Low cost, many benefits 1–2 Lifestyle to decrease weight     and increase activity Step 1: initial Disadvantages Advantages Expected decrease in A1C (%) Interventions
    • Classification
    • Diagnosis
    • Treatment – goals
    Diabetes: management
  • Glycemic goals: non-pregnant adults with diabetes
    • Key concepts in setting glycemic goals
    • HbA1c is the primary target for glycemic control
    • HbA1c < 7.0%
    • Preprandial capillary plasma glucose 70-130 mg/dl (3.9-7.2 mmol/l)
    • Peak postprandial capillary plasma glucose < 180 mg/dl (< 10.0 mmol/l)*
    * Postprandial measurements should be made 1-2 h after the beginning of the meal, generally peak levels in patients with diabetes. Standards of Medical Care in Diabetes–2009. ADA Position Statement. Diabetes Care ;32:S13-S61.
  • Glycemic goals: non-pregnant adults with diabetes
    • Goals should be individualized based on:
      • duration of diabetes
      • age/life expectancy
      • comorbid conditions
      • known CVD or advanced microvascular complications
      • hypoglycemia unawareness
      • individual patient considerations
    • More or less stringent glycemic goals may be appropriate for individual patients
    • Postprandial glucose may be targeted if HbA1c goals are not met despite reaching preprandial glucose goals
    * Postprandial measurements should be made 1-2 h after the beginning of the meal, generally peak levels in patients with diabetes. Standards of Medical Care in Diabetes–2009. ADA Position Statement. Diabetes Care ;32:S13-S61.
  • Glycemic goals - pregnant adults with diabetes
    • Women with GDM
    • Maternal capillary glucose concentrations:
      • preprandial:≤95 mg/dl (5.3 mmol/l) and either
      • 1-h postmeal: ≤140 mg/dl (7.8 mmol/l)
    • Women with preexisting diabetes who become pregnant
    • Maternal capillary glucose concentrations:
      • premeal, bedtime, and overnight: 60-99mg/dl
      • Peak postprandial: 100-129 mg/dl
      • HbA1c <6.0%
  • Road map to achieve glycaemic goals: Naive to type 2 therapy
    • Classification
    • Diagnosis
    • Treatment – step care approach
    Diabetes: management
  • ADA Treatment Algorithm Algorithm for the metabolic management of type 2 diabetes; Reinforce lifestyle interventions at every visit and check A1C every 3 months until A1C is <7% and then at least every 6 months. The interventions should be changed if A1C is ≥7%. a)Sulfonylureas other than glybenclamide (glyburide) or chlorpropamide. b)Insufficient clinical use to be confident regarding safety.
  • ADA Treatment Algorithm Algorithm for the metabolic management of type 2 diabetes. Reinforce lifestyle intervention at every visit. *Check A1C every 3 months until <7% and then at least every 6 months. +Although three oral agents can be used, initiation and intensification of insulin therapy is preferred based on effectiveness and expense.
  • ADA Treatment Algorithm Initiation and adjustment of insulin regimens. Insulin regimens should be designed taking lifestyle and meal schedule into account. The algorithm can only provide basic guidelines for initiation and adjustment of insulin. See reference 90 for more detailed instructions. aPremixed insulins not recommended during adjustment of doses; however, they can be used conveniently, usually before breakfast and/or dinner, if proportion of rapid- and intermediate-acting insulins is similar to the fixed proportions available. bg, blood glucose.
  • ADA Treatment Algorithm Initiation and adjustment of insulin regimens. Insulin regimens should be designed taking lifestyle and meal schedule into account. The algorithm can only provide basic guidelines for initiation and adjustment of insulin. See ref. 71 for more detailed instructions. +Premixed insulins are not recommended during adjustment of doses; however, they can be used conveniently, usually before breakfast and/or dinner if proportion of rapid- and intermediate-acting insulins is similar to the fixed proportions available. bg, blood glucose.
  • ADA Treatment Algorithm Initiation and adjustment of insulin regimens. Insulin regimens should be designed taking lifestyle and meal schedule into account. The algorithm can only provide basic guidelines for initiation and adjustment of insulin. See ref. 71 for more detailed instructions. +Premixed insulins are not recommended during adjustment of doses; however, they can be used conveniently, usually before breakfast and/or dinner if proportion of rapid- and intermediate-acting insulins is similar to the fixed proportions available. bg, blood glucose.
  • Clarifications on the watch list
    • Insulin therapy in outpatient and inpatient settings
    • Glycemic control and inpatient outcomes
    • Does a perfect eating plan exist?
    • Medical Nutrition Therapy for Diabetes
    • Review goals and outcomes of Medical Nutrition Therapy [MNT]
    • Discuss basic recommendations for MNT
    • Review specific recommendations for patient population groups
  • Road Maps to Achieve Glycemic Control in Type 2 Diabetes Mellitus ACE/AACE Diabetes Road Map Task Force
  •  
  • Evidence
  • ACCORD
    • 10,251 patients with DM2
    • Mean age – 62.2 yrs
    • Baseline A1C – 8.1%
    • Intensive glucose
    • control vs. standard
    • control
    • Median f/up 3.5 yrs
    • primary outcome:
      • nonfatal myocardial infarction
      • nonfatal stroke
      • death from CV causes
    The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358:2545-2559 * P-value < 0.05 10% 7.2% 6.9% Primary outcome 24%* 4.6% 3.6% Non-fatal MI ↑ 22%* 4.0% 5.0% Death from any cause 7.5% 6.4% A1C 1.5% 2.7% Severe hypoglycemia RR reduction Standard Intensive
  • ACCORD
    • Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial
    • Designed primarily to examine the effects of glycemic control, lower than had previously been achieved, on CVD in subjects with long-standing diabetes
    • 10,250 adults (mean age 62 years) with a median diabetes duration of ten years and at high risk for cardiovascular disease (diagnosed with CVD or two risk factors in addition to diabetes)
    • Intensive treatment group with the aim of achieving A1C of < 6 % or a standard treatment group with a A1C goal of 7.0 to 7.9 %.
    • After 3.5 years, the intensive arm was halted due to a higher number of total deaths: 257 deaths in subjects assigned to intensive therapy versus 203 deaths in patients assigned to standard treatment group.*
    • The primary outcome (a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes) occurred in 352 and 371 patients in the intensive and standard therapy groups, respectively (HR 0.90, 95% CI 0.78-1.04).
    ACCORD * hazard ratio, 1.22; 95% CI, 1.01 to 1.46; P=0.04
    • Preliminary information : extensive analyses have not identified a specific cause for the excess mortality in the intensive treatment group.
    • Subjects in the intensive group rapidly achieved target A1C values and experienced a greater number of severe hypoglycemic events (annualized rate of 3.1 versus 1.0 percent) and more weight gain (mean 3.5 versus 0.4 kg at three years) than the standard group (median A1C 7.5 percent).
    ACCORD
  • ADVANCE
    • 11,140 patients with DM2
    • Mean age – 66 yrs
    • Baseline A1C - 7.5%
    • Intensive glucose
    • control vs. standard control
    • Median f/up 5 yrs
    • 1º end-points: major macro- and micro vascular events
    The ADVANCE Collaborative Group. N Engl J Med 2008;358:2560-2572 * P-value < 0.05 21%* 5.2% 4.1% New/worsening nephropathy 14% * 10.9% 9.4% Major microvascular 7.3% 6.5% A1C 6% 10.6% 10.0% Major macrovascular 9% * 25.7% 23.7% New onset microalbuminuria RR reduction Standard Intensive
  • ADVANCE
    • Mean glycated hemoglobin level was lower in the intensive- control group (6.5%) than in the standard-control group (7.3%)
    • Intensive control
      • reduced the incidence of combined major macrovascular and microvascular events (18.1% vs 20.0% with standard control; hazard ratio 0.90, 95% confidence interval (CI), 0.82 to 0.98; p=0.01)
      • reduced the incidence of major microvascular events (9.4% vs 10.9%; hazard ratio, 0.86; 95% CI, 0.77 to 0.97; p=0.01)
    • This occurred primarily because of a reduction in the incidence of the nephropathy (4.1% vs 5.2%; hazard ratio, 0.79; 95% CI, 0.66 to 0.93; p=0.006) with NO effect on retinopathy (p=0.50)
    • NO significant effects of the type of glucose control for:
      • major macrovascular events (hazard ratio with intensive control 0.94; 95% CI, 0.84 to 1.06; p=0.32)
      • death from CV causes (hazard ratio with intensive control 0.88; 95% CI, 0.74 to 1.04; p=0.12)
      • death from any cause (hazard ratio with intensive control 0.93; 95% CI, 0.83 to 1.06; p=0.28)
    ADVANCE
  • ADVANCE
    • Intensive control that resulted in HbA1c of 6.5% yielded a 10% relative reduction in the combined outcome of major macrovascular and microvascular events , primarily as a consequence of a 21% relative reduction in nephropathy
  • DCCT
    • 1441 patients with DM1
    • Age: 13-39
    • No history of cardiovascular disease
    • IIT vs. conventional IT for 6.5 yrs
    • 1º prevention group:
      • Retinopathy
      • Neuropathy
      • Nephropathy
    The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977-986 * P-value < 0.05 76%* 4.7 per 100 pt-yr 1.2 per 100 pt-yr New retinopathy 68%* 9.8 per 100 pt-yr 3.1 per 100 pt-yr Clinical neuropathy 34 %* 3.4 per 100 pt-yr 2.2 per 100 pt-yr Microalbuminuria 9.1% 7.4% A1C 41% 0.8 per 100 pt-yr 0.5 per 100 pt-yr Macrovascular disease RR reduction Standard Intensive
    • 93% of DCCT patients f/up for additional 11 yrs
    • At the end of the DCCT:
      • the conventional-treatment group intensive treatment
      • (all participants returned to
      • their own health care
      • providers for diabetes care)
    • No hx of cardiovascular disease
    • IIT vs. conventional IT for 6.5 yrs
    • 1 º prevention group:
      • Retinopathy
      • Neuropathy
      • Nephropathy
    EDIC Epidemiology of diabetes interventions and Complications (EDIC, 1994- 2006) follow-up study 75%* 21% 6% Progressive retinopathy 57%* 25 11 Non-fatal MI CVA, death from CVD 46%* 2.0% 0% Cr>2.0 42%* 0.8% per 100 pt-yr 0.38 per 100 pt-yr Major CV events 38 %* 17% 9% Microalbuminuria 7.8% 7.9% A1C RR reduction Standard Intensive Year 11th of EDIC
  • EDIC
    • Goal : examine the longer term effects of the original DCCT interventions (applied to cardiovascular, retinal and renal complications)
    • Discovered the long term “imprinting” effects (metabolic memory) of the previous intensive and standard treatments
    • Established (first time) the role of intensive therapy and chronic glycemia with regard to atherosclerosis
    (DCCT/EDIC Research Group. Epidemiology of Diabetes Interventions and Complications (EDIC). Design, implementation, and preliminary results of a long-term follow-up of the Diabetes Control and Complications Trial cohort. Diabetes Care 1999; 22: 99- 111.
  • United Kingdom Prospective Diabetes Study (UKPDS)
    • 3867 patients with newly diagnosed DM2
    • Randomized to conventional-therapy group (diet alone) or intensive-therapy group : sulfonylurea (chlorpropamide, glibenclamide, glipizide) or insulin
    • Metformin added to sulfonylurea if optimal control not achieved
    • Insulin initiated if combination of oral agents was ineffective
    Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998 Sep 12;352(9131):837-53.
  • United Kingdom Prospective Diabetes Study (UKPDS)
    • Drugs added to conventional group if symptoms of hyperglycemia or FPG>270 mg/dl
    • Goal of therapy: FPG<108 mg/dl
    • Microvascular and Macrovascular complications examined
    • 11 percent reduction in A1C ( 7.0% vs. 7.9%)
    • 25 percent risk reduction in microvascular disease (P = 0.001)
      • defined as renal failure, death from renal failure, retinal photocoagulation, or vitreous hemorrhage
    UKPDS: results
  • UKPDS: results
    • No reduction in macrovascular disease
    • More hypoglycemic episodes and weight gain in the intensive therapy group
  • 10 year follow-up of intensive glucose control in type 2 diabetes
    • United Kingdom Prospective Diabetes Study (UKPDS)- 4209 patients in conventional or intensive therapy
    • Post-trial monitor – 3277 patients followed up:
      • first 5 years: annual UKPDS clinic visits (no attempts to maintain previously assigned therapy)
      • years 6 – 10: annual questionnaires
    10 year follow-up of intensive glucose control in type 2 diabetes. R Holman et al. NEJM 2008;359:1577-89
  • 10 year follow-up of intensive glucose control in type 2 diabetes
    • Results
    • HbA1c: differences between groups in were lost after the first year
    • Sulfonylurea-insulin group:
      • any diabetes-related end point- relative risk reduction persisted at 10 years (9%, p=0.04)
      • microvascular disease - relative risk reduction persisted at 10 years (24%, p=0.001)
      • myocardial infarction - risk reduction emerged over time (15%, p=0.01)
      • death from any cause - risk reduction emerged over time (13%, p=0.007)
    • Metformin group:
      • any diabetes-related end point - significant risk reductions persisted (21%, p=0.010)
      • myocardial infarction - significant risk reductions persisted (33%, p=0.005)
      • death from any cause - significant risk reductions persisted (27%, p=0.002)
    10 year follow-up of intensive glucose control in type 2 diabetes. R Holman et al. NEJM 2008;359:1577-89
  • Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes
    • 1791 military veterans with suboptimal response to therapy for type 2 DM
    • mean age: 60.4 years
    • Mean number of years since diagnosis with diabetes: 11.5
    • 40% had already had one CV event
    • 2 groups
      • intensive glucose control
      • standard glucose control
    • Goal: absolute reduction of 1.5 percentage points in HbA1c in intensive treatment group compared to the standard treatment
    • Primary outcome: time from randomization to first major CV event
    Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes. Duckworth W et al. NEJM 2009;360:129-139
  • Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes
    • Follow-up: 5.6 years
    • Primary outcome occurred in 264 patients in the standard treatment group vs 235 patients in the intensive therapy group (HR: 0.88; 95%CI, 0.74 to 1.05; p=0.14)
    • Median glycated hemoglobin levels were 8.4% in the standard therapy group vs 6.9% in the intensive-treatment group.
    • Rate of adverse events were 17.6% in the standard therapy group and 24.1% in the intensive therapy group (p=0.05).
    • Hypoglycemia (most common side effect) occurred significantly more in the intensive treatment group than in the standard treatment group (p<0.001)
  • Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes
    • Results
    • NO significant difference between the 2 groups in any component of the primary outcome (the time from randomization to a major CV event) or in the rate of death from any cause.
    • NO difference between the 2 groups was observed for microvascular complications
    • Note! Correction: progression of microalbuminuria favors intensive therapy group (9.1% vs. 13.8 % in a standard group, P=0.04).*
    • * N ENGL J MED 361;10, September 3, 2009
  • Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes. Gæde P, M.D., D.M.Sc., Lund-Andersen H, M.D., D.M.Sc., Parving H, M.D., D.M.Sc., and Pedersen O, M.D., D.M.Sc. N Engl J Med . 2008 Feb 7;358(6):580-91. 160 patients with type 2 diabetes mellitus and persistent microalbuminuria Intensive, target-driven treatment Conventional multifactorial treatment Followed for a mean of 5.5 years Targets: - HbA1c < 6.5% - fasting serum total cholesterol < 175 mg/dl (4.5 mmol/l) - fasting serum triglyceride < 150 mg/dl (1.7 mmol per liter) - blood pressure: systolic <130 mm Hg, diastolic < 80 mm Hg.
  • Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes: End points
    • Primary end point :
      • time to death from any cause
    • Secondary end points:
      • death from cardiovascular causes
      • a composite of cardiovascular disease events (death from cardiovascular causes, nonfatal stroke, nonfatal myocardial infarction, coronary-artery bypass grafting, percutaneous coronary intervention or revascularization for peripheral atherosclerotic arterial disease, and amputation because of ischemia)
    • Tertiary end points:
      • incident diabetic nephropathy
      • development or progression of diabetic retinopathy or neuropathy
  • Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes: Results
    • Intensive group
    • 24 patients died (30%) vs 40 patients (50%) in the conventional treatment group (hazard ratio for death in the intensive group vs conventional group: 0.54; 95% confidence interval, 0.32 to 0.89; p=0.02)
  • Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes: Results
    • Lower risk of death from cardiovascular causes (HR 0.43; 95% CI, 0.19 to 0.94; p=0.04) compared to conventional treatment group
    • Lower risk of cardiovascular events (HR 0.41; 95% CI, 0.25 to 0.0.67; p<0.001) vs conventional treatment group
    • 1 patient had progression to end-stage renal disease vs 6 patients in the conventional treatment group (p=0.04)
    • Fewer patients required retinal photocoagulation (relative risk, 0.45; 95% CI, 0.23 to 0.86; p=0.02) compared to the other group
  • Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes
    • Meta-analysis
    • Searches
      • published literature,
      • FDA website,
      • GlaxoSmithKline clinical trial registry
    • Inclusion criteria
      • study duration > 24 weeks,
      • use of a control group not receiving rosiglitazone,
      • availability of outcome data for myocardial infarction and death from cardiovascular causes
    • Included: 42 trials (out of 116 potentially relevant trials)
    • Tabulated all occurrences of myocardial infarction and death from any cardiovascular causes
    • Mean age of subjects: 56 years
    • Mean baseline HbA1c: 8.2%
    S.E. Nissen, M.D., and K. Wolski, M.P.H. Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes. NEJM 2007; 356:2457-2471
  • Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes
    • Results
    • Myocardial infarction: OR=1.43 in the rosiglitazone group compared with the control group (95% CI, 1.03 to 1.98; p=0.03)
    • Death from cardiovascular causes: OR=1.64 in the rosiglitazone group compared with the control group (95% CI, 0.98 to 2.74; p=0.06)
    S.E. Nissen, M.D., and K. Wolski, M.P.H. Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes. NEJM 2007; 356:2457-2471
  • Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy ADOPT - A Diabetes Outcome Progression Trial
    • Evaluate rosiglitazone, metformin and glyburide as initial treatment for recently diagnosed type 2 diabetes
    • Double-blind, randomized, controlled clinical trial
    • 4360 patients enrolled
    • Median treatment time: 4.0 years
    Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. S E Kahn et al. NEJM 2006;355:2427-43
  • Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy
    • Outcomes
    • Primary outcome: time to monotherapy failure (FPG> 180 mg/dl) for rosiglitazone, as compared to metformin or glyburide
    • Secondary outcomes: FPG levels, glycated hemoglobin, insulin sensitivity, and beta-cell function
  • Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy
    • Results
    • 5 years cumulative incidence of monotherapy failure: 15% with rosiglitazone, 21% with metformin, 34% with glyburide. This represents a risk reduction of 32% for rosiglitazone as compared with metformin and 64% as compared with glyburide (p<0.01 for both)
    • Risk of cardiovascular (CV) events: glyburide was associated with lower CV risk than rosiglitazone (p<0.05) and risk was similar between the rosiglitazone group and metformin group
    • Rosiglitazone was associated with more weight gain and edema than either glyburide or metformin; less hypoglycemia than glyburide and less GI effects than metformin (p<0.001 for all)
    • Rosiglitazone was associated with a higher rate of fractures in women
  • Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD)
    • Design
    • To evaluate long-term impact of rosiglitazone on cardiovascular outcomes and blood glucose control, compared to the conventional medications metformin and sulfonylureas
    • 338 centers in 23 countries,
    • 5.5 years duration
    • randomized 4447 people with type 2 diabetes who were already taking metformin or sulfonylurea alone
  • Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD)
    • 4447 people with type 2 diabetes with mean HbA1c: 7.9%, who were already taking metformin or sulfonylurea alone
    1. Add-on rosiglitazone 2. Combination of metformin and sulfonylurea Goal: HbA1c: 7.0 or less If HbA1c >8.5 Add a third oral glucose-lowering agent Add insulin
  • Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD)
    • On the composite outcomes of cardiovascular death, stroke and heart attack the result was slightly but not statistically significant in favor of rosiglitazone
    • Rosiglitazone was shown to be superior in controlling blood glucose than older metformin and sulfonylurea therapies
    • Found a double risk for heart failure
    • Found an increased risk of arm and lower leg fractures in women
  • Angioplasty Revascularization Investigation in Type 2 Diabetes (BARI 2D) study
    • Evaluated the cardiovascular treatment approach compared to a diabetes control approach in persons with type 2 diabetes and stable coronary artery disease to reduce deaths or deaths and cardiovascular events (MI, stroke) combined
    • 2368 people with stable heart disease and type 2 diabetes
    • 5 years average follow up
    A Randomized Trial of Therapies for Type 2 Diabetes and Coronary Artery Disease.The BARI 2D Study Group. NEJM , 360:2503-2515
  • Angioplasty Revascularization Investigation in Type 2 Diabetes (BARI 2D) study
    • Prompt bypass surgery or angioplasty does NOT lower mortality risk compared to drug therapy in people with type 2 diabetes and stable heart disease.
    • No difference in mortality risk between drugs that reduce insulin resistance and drugs that provide insulin
  • Angioplasty Revascularization Investigation in Type 2 Diabetes (BARI 2D) study
    • No increase in heart attacks was observed in the rosiglitazone group
    • Prompt CABG had significantly better outcomes when compared to medical treatment alone when CV events were considered in addition to death (non-fatal MI)
    • Among the subgroup of patients pre-identified as candidates for CABG, the subgroup that received prompt surgery had fewer heart attacks or strokes compared to those receiving intensive medical therapy alone