Recent Developments in the World of Diabetes

Ali A. Rizvi, MD

Department of MedicineDivision of Endocrinology, Diabetes, and Metabolism

University of South Carolina School of Medicine

July 22, 2009

Evolution of Diabetes TechnologyEvolution of Diabetes Technology and Treatments: Timeline and Treatments: Timeline

Insulin Injections

Urine Test Strips

• Glucose Sensors• Insulin Analogs• New Oral agents

Artificial Pancreas:“Closing the Loop”

1999197819221900s 1977

Urine Tasting

1776

Glucose Meters

Insulin Pumps

• REAL- Time monitoring• Incretin-based Therapies• Inhaled Insulin

The Diabetes and Obesity Epidemic

Bewildering and empowering for clinicians and patients

The epidemic of….The epidemic of….

Diabetes, “Pre-diabetes” and Diabetes, “Pre-diabetes” and the Metabolic Syndromethe Metabolic Syndrome

What lies beneathWhat lies beneath

• Impaired fasting glucose: 100 – 125 mg/dl

• Impaired glucose tolerance: 2-hour OGTT value of 140-199 mg/dl

• Insulin resistance and Metabolic Syndrome

• Progression to diabetes halted with lifestyle changes (DPP study)

We will review…

Know current and evolving methods of glucose testing and monitoring

Be familiar with results of recent studies regarding diabetes and its complications

Apply an evidence-based approach to the treatment of diabetes in the office and hospital setting

Discuss thorny questions (debates) – controversial or unresolved

Meters with Built-in Data Analysis

Meter Downloads and

Data Management Systems

Computer software and Data management systems for office download of data for print-out and pattern analysis

The Sugar DebatesValue of SMBG for patients with diabetes

Farmer et al, BMJ 2007

• Established in insulin-treated patients• Not proven in patients who are on lifestyle

management or oral agents and reasonably well-controlled

• Most useful if used as feedback to make meaningful changes in therapy: review, respond, and use the data for improvement“If you cannot measure it, you cannot improve it” - Lord Kelvin

Minimally Invasive, Continuous Glucose Monitoring (CGM)

• Professional CGM for Physician Use: very frequent glucose readings – every 5 minutes, or 288 readings a day

• Worn for 3 days, with a tiny sensor inserted beneath the skin

• Downloaded and analyzed by the physician in the office

31 yr old type 2 DM on multiple daily insulin injections, switched to pump 3 months prior to pregnancy, 2 months after pump A1c 6.7, 2 months after CGM A1c 5.7%

Pre-Conception Planning with CGM

U.K. Study: Murphy et al. Changes in the Glycemic Profiles of Women with Type 1 (140 profiles) and Type 2 Diabetes (40 profiles) during pregnancy. Diabetes Care Nov 2007 (time spent in hyper- and hypoglycemia and risk of nocturnal hypoglycemia)

The MiniMed Paradigm REAL-Time System with MiniLink Sensor •A tiny glucose sensor C that is worn for up to three days at a time•Easily inserted using an automatic insertion device•Glucose sensor data is sent continuously to a MiniLink™ REAL- Time Transmitter D, •Transmitter sends the glucose data to the insulin pump A•REAL-Time Readings, Alarms, Trend Arrows, Trend Graphs

A System of Continuous Glucose Monitoring and “Sensor-Augmented” Pump

Real-Time “Personal” CGM for Patient Use

Reports from the web-based CareLink™ Personal Software

Personal CGMs

Continuous Glucose Monitoring and Intensive Treatment of Type 1 Diabetes New Engl J Med October 2, 2008

• 322 patients, majority pump users followed for 26 weeks

• Better control in adults (>24 yrs) A1c decrease -0.53%

• Improvement related to duration of use

• No difference in rates of severe hypoglycemia

• Identify barriers to effectiveness of CGM in children and adolescents

A1c Derived Average Glucose (ADAG) Study and eAG

Translating the A1c assay into estimated average glucose Diabetes Care, August 2008

• Increased accuracy of HbA1c in reflecting the true average glycemia

• Results reported as A1c-derived average glucose (in mmol and mg/dl) or “estimated average glucose”, eAG

A1C eAG

% mg/dlmmol

/l

6 126 7.0

6.5 140 7.8

7 154 8.6

7.5 169 9.4

8 183 10.2

8.5 197 11.0

9 212 11.8

9.5 226 12.6

10 240 13.4

The sugar debates: A1c for the diagnosis of diabetesInternational Expert Committee Report on the Role of A1c Testing to

Diagnose Diabetes: Joint Recommendations from IDF, EASD, and ADA

ADA Scientific Sessions, New Orleans, June 2009

Advantages of A1c vs. FPG or OGTT:• better indicator of overall glycemic exposure • good for predicting complications• less variability, unaffected by outside factors like stress • not a timed test, requires no fasting; more convenient• ≥6.5% seems to be a reasonable cut-point to avoid over-

diagnosis. An A1c 6 – 6.5% indicates high risk for developing diabetes

Genetics of type 2 diabetes: the advent of genome-wide association scans (GWAS)

• Two dozen genetic susceptibility variants (“SNPs”) identified since February 2007

• Some may have monogenic potential

• Explains only 5-10% of the genetic basis. Genotype information does not improve upon traditional diabetes predication tools

• May predict risk of complications, and

response to commonly-prescribed diabetes medication classes (genetic profiling and personalized medicine)

Insulin Analogues compared with Human Insulins: Action Profiles

0 1 2 53 4 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Plasmainsulinlevels

Regular 6–8 hours NPH 12–20 hours

Hours

LONG-ACTING: Glargine 24 hours Detemir 20 hours

RAPID-ACTING: Aspart, glulisine, lispro 4–5 hours

Multiple Daily Insulin Injections: Vial and Syringe

Insulin Pens:The Pen is Mightier than the Syringe…

A different method of insulin delivery: Insulin Pumps

Insulin Delivery Devices

0600 0800 18001200 2400 0600

Time of day

20

40

60

80

100 B L D

Basal-Bolus Insulin Treatmentwith Insulin Analogues

B=breakfast; L=lunch; D=dinner

Glargine or Detemir

Lispro, glulisine, or aspart

Normal pattern

U/mL

Analog Basal-BolusPros and Cons…

• A “physiologic” concept of insulin administration that m

• Better “designer” insulins that mimic normal pancreatic release

• Less hypoglycemia, esp. at night• Improved methods to deliver them• Expensive!• Cancer risk with glargine? Diabetologia June 2009

Premixed InsulinsHuman Premixes

Humulin 70/30, Novolin 70/30

Analog Premixes these are‘biphasic’ insulin formulations

Humalog Mix 75/25, Novolog Mix 70/30

Humalog Mix 50/50, Novolog Mix 50/50

• Convenient (type 2 diabetes)

• Lack flexibility of ratio and dosing

“Most patients with type 2 diabetes who fail to achieve adequate glucose control with oral agents are likely to need

combination insulin therapy in the long run”Final Results: IDF, Montreal, October 2009

The Sugar DebatesHow best to initiate insulin in type 2 diabetes?

New Engl J Med, October 2007

The ongoing “4-T” study

Pancreas

Enhanced Insulin

secretion

Liver

Food

Suppressed post-prandial glucagon Decreased Glucose Output

GLP-1 release

Diabetes is a Multi-System Disorder:

“The Incretin Effect”

Increased Satiety

GLP-1 and other gut hormones released in

response to food: “entero-insular axis”

This ability is reduced or lost in type 2 diabetes

Slowed gastric emptying

“Incretin-mimetics” – exenatide (Byetta)• Synthetic mimetic and agonist of GLP-1• Approved in combination with oral agents• Weight loss or weight-neutral• May cause nausea and vomiting• A1c reduction of 0.5 – 2.0%• In development: LA exenatide, liraglutide

Heloderma Suspectum

DPP-4 Inhibitors: sitagliptin (Januvia)• Prevents degradation of endogenous GLP-1

• Oral monotherapy and in combination

• Weight-neutral: A1c reduction of 0.5 – 1%

• In development: vildagliptin

Optimal Use of Oral agents• Early combination therapy!• Generic metformin: inexpensive, long safety

record (>50 yrs), reduced total mortality and CV events in UKPDS. Push to ≥2 grams per day, continue with insulin

• Sulfonylureas: use glimepiride or glipizide (both are generic) preferentially

• TZDs: contraindicated in heart failure, fluid retention esp. when combined with insulin, recent controversy and warning re: coronary artery disease

• Bile-acid Sequestrant Colesevelam (Welchol): only approved Rx for both hyperlipidemia and diabetes

Approach to Management of Hyperglycemia in Type 2 Diabetes:Algorithm for the Initiation and Adjustment of Therapy

Joint Consensus Statement from ADA and EASD Diabetes Care, October 2008

The Sugar DebatesRelationship between Glucose and

Cardiovascular Disease

• Does hyperglycemia predispose to macrovascular complications?

• Does glucose control help to prevent or reduce cardiovascular events?

Pathophysiologic and Epidemiologic Data Relationship between A1c and CVD/all-cause mortality is continuous, significant, and independent of classical risk

factors, even in persons without known diabetes

EPIC-NORFOLK Study Each 1% increase in A1c above 5% was associated with a 21% increase in CV events. Ann Intern Med, Sept 2004

Harvard School of Public Health Study on Global CVD mortality: 21% of IHD and stroke deaths attributable to glucose above 90 mg/dl worldwide. Danaei et al, Lancet, Nov 2006

HUNT study 20 year f/u of newly diagnosed diabetes. 20% increase in IHD mortality per 1% increment in A1c. Eur Heart J, Feb 2009

“Metabolic Memory” “Legacy Effect”Continued reduction of risk from previous good control

DCCT-EDIC Study – type 1 diabetes

New Engl J Med, December 2005

UKPDS 10-year follow up – type 2 diabetes

New Engl J Med, October 2008

ACCORDNEJM, June 2008

ADVANCENEJM, June 2008

VADTNEJM, Dec 2008

No. of participants 10,251 11,140 1791Participant age ,years 62 66 60Participants – male, % 62 58 97Duration of diabetes at study entry 10 8 11.5A1C at Baseline, % 8.1 7.2 9.4With prior CV event, % 35 32 40Duration of follow-up, years 3.4 5.0 6Endpoint A1C, % 6.4 vs. 7.5 6.4 vs. 7.0 6.9 vs. 8.4Death from any cause, % 5.0 vs. 4.0 8.9 vs. 9.6 NADeath from CV event, % 2.6 vs. 1.8 4.5 vs. 5.2 2.1 vs. 1.7Nonfatal MI, % 3.6 vs. 4.6 2.7 vs. 2.8 6.1 vs. 6.3Major/severe hypoglycemia, % 10.5 vs. 3.5 2.7 vs. 1.5 21.1 vs. 9.7Weight gain, kg 3.5 vs. 0.4 0.0 vs. -1.0 NACurrent status Ongoing Ongoing -

Summary of Recent Trials of Intensive Glycemic Control and Cardiovascular Disease

Early vs. Late Glucose Control in Type 2 Diabetes

• Good glucose control early in the disease when atherosclerotic complications have not yet developed, and

• Co-morbid risk factors are better addressed and easily managed

…is likely to be beneficial in the long-term (primary and secondary intervention)

It pays to be aggressive early in the disease!

Beware of overly-aggressive, intensive therapy in older patients with long-standing diabetes after years of poor control…

• when underlying vascular problems have manifested, and

• autonomic neuropathy, defective glucose counter-regulation, and hypoglycemia unawareness have supervened

….can be harmful and does not add much beyond management of other traditional risk factors (too much, too late).

Higher A1c’s have to be accepted!

Early vs. Late Glucose Control in Type 2 Diabetes

No “One Size Fits All”

• More research before we impose complex glucose control interventions that overwhelm the patients’ capacity to cope medically, psychologically, and financially

• Treatment burden, cost, and harm of serious hypoglycemia, with uncertain benefits in some patients

• Hba1c as a performance model (>8% as indicator of inadequate care

Multifactorial therapy to reduce Multifactorial therapy to reduce macrovascular risk: macrovascular risk: Steno-2 Trial

Debunking the “gluco-centric” view New Engl J Med, 2003, 2008

Multifactorial intervention aimed at multiple risk factors, behavior modification and pharmacologic therapy in type 2 diabetes:

hyperglycemia hypertension diabetic dyslipidemia microalbuminuria / use of ACE-inhibitors aspirin

A 53% reduction in all cardiovascular endpoints and microvascular complications compared with conventional therapy

Management of CAD in people with Diabetes; the BARI 2D study

New Engl J Med June 2009 Previous trials (BARI and meta-analyses) had shown survival

benefit with CABG that persisted at 10 yrs• BARI 2D: international multicenter trial of 2368 patients with both diabetes and CAD; 2 x 2 factorial design • No difference in primary end-point (death) with prompt revascularization (CABG or PCI) vs. medical therapy• CABG pts had fewer cardiac events (nonfatal MI)• For most patients with less severe CAD, optimal medical therapy rather than any intervention is an excellent 1st-line strategy• When revascularization is indicated, bypass is the preferred approach

2009 American Diabetes Association (ADA) Recommendations for Adults with Diabetes: Importance of Multi-factorial Therapy

Diabetes Care, January 2009

 

Hemoglobin A1c < 7.0% * In Pregnancy < 6.5% Pre-meal plasma glucose 90-130 mg/dlPostprandial plasma glucose < 180 mg/ml Blood Pressure < 130/80 mmHg In nephropathy < 125/75 mmHg

LDL < 100 mg/dlPatients above age 40 years: use statin therapy to achieve LDL reduction of 30-40% In overt CVD LDL goal of <70 using high-dose statins “is an option”HDL > 40 mg/dlTriglycerides < 150 mg/dl -*AACE and EASD <6.5%

-Goals should be individualized. Less intensive glycemic targets may be indicated if there is frequent or severe hypoglycemia

Patient-Centered Care:The Team Approach

• Partner with the patient: do not scold or scare!• A mutually respectful and trusting patient-provider relationship• Use and collaborate with diabetes education programs: team management!• “Refresher Courses” are often necessary• Frequent communication is key

education monitoring communication early insulin multifactorial therapy

Glucose Control in the Hospital, Inpatient Outcomes, and Cost of Care

A challenge and an opportunity to favorably impact patient care

• Open-heart surgery – Portland Diabetic Project 1987-2005

• Acute coronary events – DIGAMI 1 1995-99 and DIGAMI 2 Eur Heart J 2005

• Surgical ICU – Leuven trial 1 N Engl J Med 2001

• Medical ICU – Leuven trial 2 N Engl J Med 2006

The Sugar DebatesWhat are the Optimal Glucose Targets in

Hospitalized patients?

• Controversial – experts divided into various camps

• Labor-intensive, risk of hypoglycemia

Inzucchi S: New Engl J Med, 2006

Intensive versus Conventional Glucose Control in Critically Ill Patients

The NICE-SUGAR Study Investigators , New Engl J Med, March 2009

• Multicenter, international study of 6104 ICU patients. IV insulin used to achieve a BG target of 81 to 108 (115) in the intensive group and 144 to 180 (144) in the conventional group.

• 3% increase in primary end point, death at 90 days (27.5%, vs. 24.9%, a 10% higher relative mortality). A significantly higher rate of severe hypoglycemia in the intensive-control group (6.8% vs. 0.5%).

Optimal Glucose Targets in Hospital Patients:

The American Diabetes Association-American College of Endocrinology Consensus Statement based on the results of NICE-SUGAR

Diabetes Care, May 2009

Critically ill patients

• Use IV insulin in the majority of patients in the ICU setting

• A starting threshold of no higher than 180 mg/dL

• Maintain glucose levels between 140 and 180 mg/dL

• Greater benefit may be realized at the lower end of this range

• Targets less than 110 mg/dL are NOT recommended

Noncritically ill patients

• Recommendations are based on “clinical experience and judgment”

• Premeal glucose targets should generally be <140 mg/dL

• Random glucose values <180 mg/dL

Protocol Implementation: a multidisciplinary effort

Take–Home Messages• Minimally-invasive, REAL-TIME glucose monitoring • eAG, and A1c for diagnosis of diabetes• “Pre-diabetes”, metabolic syndrome, genetics of diabetes• Individualize outpatient glucose targets based on type of

patient and risk-benefit ratio. General A1c goal is <7%• Multifactorial therapy to reduce CVD and mortality early in

the disease• Medical therapy as good as revascularization • Early use of metformin and combination oral agents • Incretin-based therapies• Intensive insulin therapy, basal-bolus, and “smart pumps”• Inpatient targets: ICU 140-180, non-critical care 110-180• Communication, education, re-education!