Diabetes:

Diagnosis, Classification, Management Controversies and News

Leonid Poretsky, MD Chief, Division of Endocrinology and Metabolism Director, Gerald J. Friedman Diabetes Institute Gerald J. Friedman Chair in Endocrinology Professor of Medicine, Albert Einstein College of Medicine

Bianca Alfonso, MD Endocrinology Fellow, Year 1 Marina Krymskaya, ANP, CDE Diabetes Nurse Educator Jill Gregory Medical Illustrator

Diabetes Care Enhancement Initiative

 

Team: Leonid Poretsky, MD; Agustin Busta, MD; Morton Davidson, MD; Marina Krymskaya, RN, NP; Jason Park, MD; Carmen Schmidt, RN; Daniel Steinberg, MD; Goal: Improvement of diabetes care for both inpatients and outpatients throughout the Beth Israel System. The first event of the Initiative Grand Rounds on June 16th, presented by Dr. Silvio E. Inzucchi,of Yale University: Successful Management of Inpatient Hyperglycemia. The Initiative includes educational and clinical components. Plan Educational aspects:
   

To include physicians, nurses, house staff, patients and their significant others; The series of lectures, grand rounds, in-service events to be planned; The discharge kit with general and individualized instructions to be developed and piloted; Educational video materials for inpatient TV to be selected/created and used throughout BIMC; review of all existing diabetes protocols for general wards; review of current PRIZM orders; review of current diabetes-related protocols in CCU, MICU, CT ICU, SICU; jointly with GMA, develop program for house staff Open for suggestions. Please direct any comments to Marina Krymskaya at Mkrymska@chpnet.org or 212-420-2062

Clinical aspects:
  

Quality Improvement:
 

Diabetes: diagnosis, classification, management

      

Definition Epidemiology Classification Diagnosis Treatment Evidence Treatment goals

Diabetes: diagnosis, classification, management

      

Definition Epidemiology Classification Diagnosis Treatment Evidence Treatment goals

Definition


Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both.* The name 'diabetes mellitus' derives from: Greek: 'diabetes' siphon or to pass through Latin: 'mellitus' honeyed or sweet**

* Diagnosis and Classification of Diabetes Mellitus. ADA 2009. ** http://science.jrank.org/pages/2044/Diabetes-Mellitus.html

Diabetes: diagnosis, classification, management

      

Definition Epidemiology Classification Diagnosis Treatment Evidence Treatment goals

Epidemiology
     

20.8 million Americans (7% of US population) About 10% have Type 1 DM 14.6 million diagnosed 6.2 million remain undiagnosed 41 million have pre-diabetes Lifetime risk for developing DM (Type 1 or 2) is 33 % in males and 39% in females for individuals born in 2000 Up to 45% of newly diagnosed cases of DM in US children and adolescents are type 2

AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007;13(Suppl 1) 2007

Diabetes: diagnosis, classification, management

      

Definition Epidemiology Classification Diagnosis Treatment Evidence Treatment goals

Classification
  
1. 2. 3. 4. 5. 6. 7. 8.

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
 

A. Immune-mediated B. Idiopathic Type 1 diabetes is characterized by -cell destruction, usually leading to absolute insulin deficiency.*

* Diagnosis and Classification of Diabetes Mellitus. ADA 2009.

Atkinson MA and Eisenbarth GS. Lancet 2001;358:221-229.

Type 1 diabetes mellitus 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 [antiGAD] and anti-insulin)

Type 2 diabetes


Hyperglycemia Insulin resistance Relative impairment in insulin secretion.

F-cell dysfunction and insulin resistance produce hyperglycemia in type 2 diabetes Insulin Resistance
Increased Lipolysis

F-Cell Dysfunction
Pancreas Liver

Elevated Plasma FFA Glucose Uptake

Islet F-Cell Degranulation; Reduced Insulin Content Increased Glucose Output Reduced Plasma Insulin

Glucose Production

Muscle

Adipose Tissue

Hyperglycemia

Decreased Glucose Transport & Activity (expression) of GLUT4

Other specific types of diabetes Genetic defects of beta cell function

Maturityonset diabetes of the young (MODY) 6 subtypes

Maturity: Onset diabetes of the young (MODY)



 

 

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 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
Definition  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 mellitus 10% have circulating islet cell antibodies

Diabetes: diagnosis, classification, management

      

Definition Epidemiology Classification Diagnosis Treatment Evidence Treatment goals

Diagnosis
   

Diabetes mellitus Impaired fasting glucose (IFG) Impaired glucose tolerance (IGT) Gestational diabetes mellitus (GDM)

Diagnosis: Diabetes mellitus

1.

2.

3.

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)

Diagnosis: Impaired glucose tolerance (IGT)



Oral glucose tolerance test (OGTT) glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water 2-h postload glucose < 140 mg/dl (7.8 mmol/l) = normal 2-h postload glucose 140 - 199 mg/dl (7.8 11.1 mmol/l) = impaired glucose tolerance (IGT)

Diagnosis: Gestational Diabetes Mellitus (GDM)

Fasting plasma glucose > 126 mg/dL (7.0 mmol/L)

1. Unequivocal hyperglycemia
(confirmed on a subsequent day) Random plasma glucose >200 mg/dL (11.1 mmol/L)

OR
100-g glucose load
mg/dl Fasting 1-h 2-h 3-h 95 180 155 140 mmol/l 5.3 10.0 8.6 7.8

2. Diagnostic OGTT

Diabetes: diagnosis, classification, management

      

Definition Epidemiology Classification Diagnosis Treatment Evidence Treatment goals

Treatment


Lifestyle intervention Hypoglycemic drugs

  

oral hypoglycemic drugs insulin and insulin analogs others (incretins, pramlintide)

Treatment: Lifestyle Interventions



Weight loss Increased exercise

Treatment: Oral Antihyperglycemic Drugs

     

Biguanides Sulfonylureas Meglitinide analogs Thiazolidinediones E-Glucosidase Inhibitors DPP-4 Inhibitors

Treatment: Oral Antihyperglycemic Drugs

Oral antihyperglycemic drugs: Biguanides

 

Metformin (Glucophage) Extended-release metformin (Glucophage-XR) decrease hepatic glucose output lower fasting glycemia reduce HbA1c by 1.5% adverse effects: lactic acidosis, gastrointestinal disturbances

   

Oral antihyperglycemic drugs: Metformin

AMPK - adenosine monophosphate-activated protein kinase, ACC - acteyl-CoA carboxylase, SREPB-1 - sterolregulatory-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

Treatment: Oral Antihyperglycemic Drugs

Oral antihyperglycemic drugs: Sulfonylureas



1st generation : Tolbutamide (Orinase), Tolazamide (Tolinase), Acetohexamide (Dymelor), Chlorpropamide (Diabinese) 2nd generation : Glyburide (DiaBeta, Glynase) Glipizide (Glucotrol), Glimepiride (Amaryl) enhance insulin secretion lower HbA1c by 1.5 % side effects: hypoglycemia, weight gain

  

Treatment: Oral Antihyperglycemic Drugs

Oral antihyperglycemic drugs: Meglitinide analogs

 

Repaglinide (Prandin) Nateglinide (Starlix) enhance insulin secretion (early-phase insulin release) lower HbA1c by 0.1- 2.1 % (repaglinide) and by 0.20.6% (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.

Treatment: Oral Antihyperglycemic Drugs

Oral antihyperglycemic drugs: Thiazolidinediones (TZDs)

 

Rosiglitazone (Avandia) Pioglitazone (Actos) peroxisome proliferator-activated receptor modulators (PPAR ) 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

 

Treatment: Oral Antihyperglycemic Drugs

Oral antihyperglycemic drugs: E-Glucosidase Inhibitors

 

Acarbose (Precose) Miglitol (Glyset) reduce the rate of digestion of polysaccharides in the proximal small intestine, primarily lowering postprandial glucose levels lower HbA1c by 0.5 0.8 % side effects: increased gas production and gastrointestinal symptoms

 

Oral antihyperglycemic drugs: DPP-IV inibitors

 

Sitagliptin (Januvia) : DPP-IV inhibitor Dipeptidyl peptidase IV (DPP-IV) is a ubiquitous enzyme that deactivates a variety of bioactive peptides, including GIP and GLP-1

Oral antihyperglycemic drugs Sitagliptin (Januvia)



Used alone or in combination with metformin or TZDs Reduces HbA1c by 0.5 0.7 % Side effects: increased rate of respiratory infections, headaches

"Januvia" by Byron Rubin



Sculpture was installed at the West Point Pennsylvania Merck location.

Other antihyperglycemic drugs: Incretins

 

Exenatide (Byetta) glucagon-like peptide 1 (GLP-1) agonist

Antihyperglycemic drugs: Exenatide (Byetta)

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 being very short, approximately one minute. GLP-1 binding to its G-protein coupled receptor on -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.

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: Exenatide (Byetta)



active ingredient in Exenatide (Byetta) is a synthetic version of a protein present in the saliva of the Gila monster

Antihyperglycemic drugs: Exenatide (Byetta)



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)

Antihyperglycemic drugs: Exenatide (Byetta)

Antihyperglycemic drugs: Others



Pramlintide (Symlin)


synthetic analog of amylin

Amylin


   

Stored in insulin secretory granules in the cells Co-secreted with insulin Decreases glucagon Satiety signal? Decreases GI motility

Antihyperglycemic drugs: Pramlintide (Symlin)



  

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 Reduces HbA1c by 0.5 - 0.7 % Side effects: nausea, gastro-intestinal symptoms

Antihyperglycemic drugs: Pramlintide (Symlin)

AVAILABLE INSULIN PREPARATIONS

Product (Manufacturer) Rapid Acting (Onset 15-30 min, duration hrs 3-4) Insulin Analog Aspart - Novolog (Novo Nordisk) Lispro - Humalog (Lilly) Glulisine Apidra (Aventis) Short Acting (Onset 0.5-1 hr, duration hrs 5-7)* Human Insulin Novolin R (Rugular) (Novo Nordisk) Humulin R (Regular) (Lilly) Purified Insulin Regular Iletin II (Lilly) Human** Human** Pork Analog** Analog** Form Product (Manufacturer) Analog Mix Humalog 75/25 Mix Novolog Mix 70/30 (combination of fast and intermediate acting insulin with action similar to that of Humalog 75/25 mix) Insulin for Special Use Buffered Insulin (for pumps) Humulin BR Refills for Novolin Pen Novolin R PenFill Novolin N PenFill Novolin 70/30 PenFill Novolog Mix 70/30 PenFill Prefilled Pens Novolin R Novolin N Novolin 70/30 Novolog Novolog Mix 70/30 Humalog Humalog Mix 75/25 Humalog Mix 50/50 Humulin N Apidra Form Analog** Analog**

Human** Human** Human** Analog** Human** Human** Human** Analog** Analog** Analog** Analog** Analog** Human** Analog**

Intermediate Acting (Onset 1-4 hrs, duration hrs 18-24)* Human Insulin Novolin N (NPH) (Lilly) Humulin N (NPH) (Lilly) Humulin L (Lente) (Lilly) Purified Insulin NPH Iletin III (Lilly) Long Acting (Onset 4-6 hrs, duration hrs 24-34)* Human Insulin Humulin Ultralente (Lilly) Basal Peakless Insulin Glargine-Lantus (Aventis) Detemir Levemir (Novo Nordisk) Mixed Insulins 70/30 Insulin Novolin 70/30 (Novo Nordisk) Humulin 70/30 (Lilly) Humulin 50/50 (Lilly) Humalog 50/50 Human** Human** Human** Analog** Human** Human** Human** Pork

Human** Analog** Analog**

* 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

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 rapidand intermediate-acting insulins is similar to the fixed proportions available. bg, blood glucose.

Diabetes: diagnosis, classification, management

      

Definition Epidemiology Classification Diagnosis Treatment Evidence Treatment goals

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:


Intensive A1C Primary outcome Death from any cause Non-fatal MI Severe hypoglycemia

Standard

RR reduction

6.4% 6.9% 5.0% 3.6% 2.7%

7.5% 7.2% 4.0% 4.6% 1.5%

* P-value < 0.05

10% 22%* 24%*

 

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

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 %.

ACCORD


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).
* hazard ratio, 1.22; 95% CI, 1.01 to 1.46; P=0.04

ACCORD


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).

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 1 end-points: major macro- and micro vascular events

Intensive A1C

Standard

RR reduction

6.5%

7.3% 10.9% 5.2% 25.7% 10.6% 14% * 21%* 9% * 6%

Major microvascular 9.4% New/worsening nephropathy New onset microalbuminuria Major macrovascular

4.1% 23.7% 10.0%

* P-value < 0.05

The ADVANCE Collaborative Group. N Engl J Med 2008;358:2560-2572

ADVANCE


Mean glycated hemoglobin level was lower in the intensivecontrol 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)

ADVANCE


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


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 1 prevention group:
  

Intensive

Standard

RR reduction

A1C New retinopathy Microalbuminuria Clinical neuropathy Macrovascular disease

7.4% 1.2 per 100

pt-yr

9.1% 4.7 per

100 pt-yr

76%* 34%* 68%* 41%

2.2 per 100

pt-yr

3.4 per
100 pt-yr

3.1 per 100

pt-yr

9.8 per
100 pt-yr

Retinopathy Neuropathy Nephropathy

0.5 per 100

pt-yr

0.8 per
100 pt-yr

* P-value < 0.05

The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977-986

EDIC
 

 

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 prevention group:  Retinopathy  Neuropathy  Nephropathy

Year 11th of EDIC A1C Microalbuminuria Cr>2.0 Progressive retinopathy Major CV events

Intensive 7.9% 9% 0% 6% 0.38 per 100 pt-yr 11

Standard 7.8% 17% 2.0% 21% 0.8% per 100 pt-yr 25

RR reduction 38%* 46%* 75%* 42%*

Non-fatal MI CVA, death from CVD

57%*

Epidemiology of diabetes interventions and Complications (EDIC, 1994- 2006) follow-up study

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

UKPDS: results


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


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 follow2008;359:1577-

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) 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)

Metformin group:


 

10 year follow-up of intensive glucose control in type 2 diabetes. R Holman et al. NEJM 2008;359:1577-89 follow2008;359:1577-

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

160 patients with type 2 diabetes mellitus and persistent microalbuminuria

Intensive, target-driven treatment

Conventional multifactorial treatment

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.

Followed for a mean of 5.5 years

Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes. Gde 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.

Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes: End points

1. Primary end point:  time to death from any cause 2. 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) 3. 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 study duration > 24 weeks, use of a control group not receiving rosiglitazone, availability of outcome data for myocardial infarction and death from cardiovascular causes

Inclusion criteria
  

 

 

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 2006;355:2427-

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

Diabetes: diagnosis, classification, management

      

Definition Epidemiology Classification Diagnosis Treatment Evidence Treatment goals

Glycemic goals: non-pregnant adults with diabetes

     

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)* Key concepts in setting glycemic goals HbA1c is the primary target for glycemic control 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 Diabetes2009. 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 Maps to Achieve Glycemic Control In Type 2 Diabetes Mellitus

ACE/AACE Diabetes Road Map Task Force
Chairpersons
Paul S. Jellinger, MD, MACE, Co-Chair Jaime A. Davidson, MD, FACE, Co-Chair

Task Force Members

Lawrence Blonde, MD, FACP, FACE Daniel Einhorn, MD, FACP, FACE George Grunberger, MD, FACP, FACE Yehuda Handelsman, MD, FACP, FACE Richard Hellman, MD, FACP, FACE Harold Lebovitz, MD, FACE Philip Levy, MD, FACE Victor L. Roberts, MD, MBA, FACP, FACE

2008 AACE. All rights reserved. No portion of the Roadmap may be altered, reproduced or distributed in any form without the express permission of AACE. Revision April 2008

www.medscape.com/viewarticle/559463

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.

Coming Attractions
Insulin therapy in outpatient and inpatient settings Glycemic control and inpatient outcomes
Agustin Busta,MD Assistant Professor Albert Einstein College of Medicine 2009

Coming Attractions

Medical Nutrition Therapy for Diabetes Does a perfect eating plan exist?

Jennifer Regester, RD, CDN

Coming Attractions
Medical Nutrition Therapy
  

Review goals and outcomes of MNT Discuss basic recommendations for MNT Review specific recommendations for patient population groups

Coming Attractions
What Do I Eat?

Discuss lifestyle changes including diet and exercise Review basic nutrition recommendations and how to give nutrition advice Provide follow-up resources

Coming Attractions
Diabetes Technology Update


Glucose Monitoring Systems

- Glucose Meters - CGMS

Insulin Delivery Modes

Syringes Insulin Pens Jet Injectors Insulin Pumps

Marina Krymskaya, ANP, CDE

Coming Attractions
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