Diabetes

Peter Goulden, MD, FRCP

Division of Endocrinology & Metabolism

University of Arkansas for Medical Sciences, Little Rock, AR

• To review key areas of diabetes management

• To discuss oral agents and insulin

• Review recent ADA update to lipid goals, htn management and glycemic targets

• To present board style questions covering diabetes management issues

Objectives

• Background

• Type 1 & Type 2 diabetes – goal setting

• Treatment Options

• Complications

• Summary

Outline of the talk

Diabetes Care 2012;35:1364–1379

Diabetologia 2012;55:1577–1596

(Adapted with permission from: Ismail-Beigi et al. Ann Intern Med 2011;154:554)

GAD and ICA may be useful in distinguishing Type 1 & Type 2 diabetes

Also C peptide

Who to screen

In clinic, patients with type 1 or type 2 diabetes require:

• blood pressure measurement and foot inspection at every visit

• hemoglobin A1c measurement every 3 (type 1 diabetes) to 6 (type 2 diabetes) months

• urinalysis for microalbuminuria yearly

• ophthalmologic examination yearly

• lipid measurement yearly

• comprehensive foot examination (with monofilament) yearly

• Background

• Type 1 & Type 2 diabetes – goal setting

• Treatment Options

• Complications

• Summary

Outline of the talk

Glycemic Goals (ADA 2015)

Diabetes Prevalence* by Age Group

Arkansas & United States, 2011

6.6

11.8

19.621.2

5.2

9.5

16.0

20.8

0.0

5.0

10.0

15.0

20.0

25.0

35-44 45-54 55-64 65+

Perc

en

t

Arkansas United States

*Question: Have you ever been told by a doctor that you have

diabetes?

Source: CDC Behavioral Risk Factor Surveillance System.

Glycemic Goals in adults > 65

Legacy Effect of Early Intensive Glucose ControlAfter median 8.5 years post-trial follow-up

1. UKPDS 33 Lancet 1998 352: 837–853

2. Holman RR N Engl J Med 2008 59:1577-1589

Aggregate Endpoint 19971 20072

Any diabetes-related endpoint ARR: 0.0051 0.0041

RRR: 12% 9%

P: 0.029 0.040

Microvascular disease ARR: 0.0028 0.0032

RRR: 25% 24%

P: 0.0099 0.001

Myocardial infarction ARR: 0.0027 0.0028

RRR: 16% 15%

P: 0.052 0.014

All-cause mortality ARR: 0.001 0.0035

RRR: 6% 13%

P: 0.44 0.007ARR = Absolute Risk Reduction per patient

year ,

RRR = Relative Risk Reduction, P = Log Rank

Conventional

Intensive

2005 – EDIC – Early aggressive

management has long term benefits

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

Years from Study Entry

0.00

0.02

0.04

0.06

0.08

0.10

0.12

Cu

mu

lati

ve I

ncid

en

ce

Risk reduction 57%

95% CI: 12% to 79%

P = 0.02

DCCT/EDIC N Engl J Med 2005: 353:2643-2653.

The Ominous Octet

Diabetes and hypertension

Diabetes and lipid lowering

Diabetes and antiplatelets

Goals in inpatients – critically ill

• Insulin therapy should be initiated for treatment of persistent hyperglycemia starting at a threshold of no greater than 180 mg/dL (10 mmol/L).

• Once insulin therapy is started, a glucose range of 140–180 mg/dL (7.8–10 mmol/L) is recommended for the majority of critically ill patients. A

• More stringent goals, such as 110–140 mg/dL (6.1–7.8 mmol/L), may be appropriate for selected patients, as long as this can be achieved without hypoglycemia. C

Goals in inpatients – noncritically ill

• If treated with insulin, generally premeal blood glucose targets of 140 mg/dL with random blood glucose 180 mg/dLare reasonable, provided these targets can be safely achieved.

• More stringent targets may be appropriate in stable patients with previous tight glycemic control.

• Less stringent targets may be appropriate in those with severe comorbidities. C

• A basal plus correction insulin regimen is the preferred treatment for patients with poor oral intake or who are taking nothing by mouth (NPO).

• An insulin regimen with basal, nutritional, and correction components is the preferred treatment for patients with good nutritional intake. A

Inpatients – some general points• A plan for preventing and treating hypoglycemia

should be established for each patient. • Episodes of hypoglycemia in the hospital should be

documented in the medical record and tracked. E• Consider obtaining an A1C in patients with diabetes

admitted to the hospital if he result of testing in the previous 3 months is not available. E

• Consider obtaining an A1C in patients with risk factors for undiagnosed diabetes who exhibit hyperglycemia in the hospital. E

• Patients with hyperglycemia in the hospital who do not have a prior diagnosis of diabetes should have appropriate follow-up testing and care documented at discharge.

• Background

• Type 1 & Type 2 diabetes – goal setting

• Treatment Options

• Complications

• Summary

Outline of the talk

MNT Study

Population/ Type of Study

Number of interventions(study length)

Nutrition TherapyIntervention

A1C and other outcomes from MNT Interventions

UKPDS 1990 & 2000

n=3044Adults withT2DM/RCT

3 at 1 month intervals (3 months)

Reduce Energy(50% carb, 20% protein, 30% fat)

A1c ↓ 1.9% All p <0.001Weight ↓ 4.5kgTC ↓ 7.8mg/dLLDL ↓ 7.8 mg/dLTG ↓ 28.4 mg/dL

Delahanty1993

n=623 T1DM/Observationalstudy

Quarterly visits during DCCT (9 years; average 4.1 years)

Intensive MNT; Exchange lists;carbohydratecounting

A1C: ↓ 0.9% p<0.001

Franz 1995 n=179Adults with T2DM/RCT

3 within first 6 weeks (6 months)

Individualized MNT A1C ↓ 0.9% (4 year T2DM) All p <0.001A1C ↓ 1.9% (Newly diag T2DM) All p <0.001Weight ↓ 1.4kg p<0.001TC

DAFNEStudy Group2002

n=169 individuals with T1DM/RCT

5 day course (follow up at 6 months)

Group MNTAdvanced carbohydrate counting; insulin to carbohydrate ratios

A1C: ↓ 1.0% (p<0.001)↑ Dietary Freedom (p<0.001)Overall Quality of Life (p<0.01)

MNT Study Population/ Type of Study

Number of interventions(study length)

Nutrition TherapyIntervention

A1C and other outcomes from MNT Interventions

Miller2002

n=90 adults with T2DM/RCT

Age > 65

10 weekly sessions (1 year)

10-week intervention information processing, learning theory, and Social Cognitive Theory to meet the needs of older adults

Nutrition Education, emphasis on food labelling

A1C ↓ 0.5%(p<0.001)

Ziemer 2003 n=648 adults with T2DM/RCT

4 initial at 1, 2 and 4 weeks (6 months)

Healthy Food Choices andexchange lists

A1C: ↓ 1.9% (p<0.0001)Tg : ↓ 35.5mg/dL (p<0.0001)HDL chol ↑ 2.3 mg/dL(p<0.005)

Rickheim2002

n=170 individuals with newly diagnosed T2DM/RCT

4 initial, 3 weeks, 3 months, 6 months

Carbohydrate Counting/Portion control

A1C: ↓ 2.0%(p<0.001)

Huang 2010 n=154 adults with T2DM/RCT

Individualized sessions with RD every 3 months

Nutritioneducation; ↓ energy intake; portion control

A1C: ↓ 0.7%(in subjects with baseline A1C > 7% (p=0.007)

108-144mg/dL

145-180mg/dL

181-216mg/dL

217-252mg/dL

>253mg/dL

Losing Weight & Diabetes

Exercise

Exercise and Blood Glucose

Class Mechanism Advantages Disadvantages Cost

Biguanides(Metformin)

• Activates AMP-kinase• Hepatic glucose production

• Extensive experience• No hypoglycemia• Weight neutral• ? CVD events

• Gastrointestinal• Lactic acidosis• B-12 deficiency• Contraindications

Low

SUs / Meglitinides

• Closes KATP channels• Insulin secretion

• Extensive experience• Microvascular risk

• Hypoglycemia• Weight gain• Low durability• ? Ischemic preconditioning

Low

TZDs • Activates PPAR-g• Insulin sensitivity

• No hypoglycemia• Durability• TGs, HDL-C • ? CVD events (pio)

• Weight gain• Edema / heart failure• Bone fractures• ? MI (rosi)• ? Bladder ca (pio)

High

a-GIs • Inhibits a-glucosidase• Slows carbohydrate absorption

• No hypoglycemia• Nonsystemic• Post-prandial glucose• ? CVD events

• Gastrointestinal• Dosing frequency• Modest A1c

Mod.

Table 1. Properties of anti-hyperglycemic agentsDiabetes Care 2012;35:1364–1379

Diabetologia 2012;55:1577–1596

Class Mechanism Advantages Disadvantages CostDPP-4inhibitors

• Inhibits DPP-4• Increases GLP-1, GIP

• No hypoglycemia• Well tolerated

• Modest A1c • ? Pancreatitis• Urticaria

High

GLP-1 receptor agonists

• Activates GLP-1 receptor• Insulin, glucagon• gastric emptying• satiety

• Weight loss• No hypoglycemia• ? Beta cell mass• ? CV protection

• GI• ? Pancreatitis• Medullary ca• Injectable

High

Amylin mimetics

• Activates amylinreceptor• glucagon• gastric emptying• satiety

• Weight loss• Post-prandial glucose

• GI• Modest A1c • Injectable• Hypo w/ insulin• Dosing frequency

High

Bile acid sequestrants

• Binds bile acids• Hepatic glucose production

• No hypoglycemia• Nonsystemic• LDL-C

• GI• Modest A1c• TGs• Dosing frequency

High

Dopamine-2agonists

• Activates DA receptor• Modulates hypothalamic control of metabolism• Insulin sensitivity

• No hypoglycemia• ? CVD events

• Modest A1c•

Dizziness/syncope• Nausea• Fatigue

High

• Ideally add current doses

• For insulin naïve• 0.3 units/kg/day for patients who are lean, on hemodialysis, frail and elderly,

insulin-sensitive, or at risk for hypoglycemia;• 0.4 units/kg/day for a patient at normal weight;• 0.5 units/kg/day for overweight patients; and• 0.6 units/kg/day or more for patients who are obese, on high-dose steroids or

insulin-resistant.

• Between 40% and 50% of that total dose should be administered as basal,

Total daily dose (Basal + Bolus)

• Weight (lb) = kg × 0.2 =Units

• 2.2

• Weight-based dosing: 0.2 Units/kg per day

• OR

• Start with 10 Units per day of basal insulin

Lantus

• Suggested guidelines for beginning dose: 0.2 unit/kg/day

• Morning• Give two thirds of daily insulin SC• Ratio of regular insulin to NPH insulin 1:2

• Evening• Give one third of daily insulin SC• Ratio of regular insulin to NPH insulin 1:1

NPH

Premix insulin

• Recommended dose

• Start 10 units predinner

• Add subsequent prebreakfast dose based on patient's needs, or

• Start 10 units prebreakfast and predinner

• Titration

• Prebreakfast dose: Adjust based on predinner/evening glucose values

• Predinner dose: Adjust based on prebreakfast/morning glucose values

• Do not increase dose if hypoglycemia (<70 mg/dL) or symptoms are present

Premix insulin adjustment

• Example 1 unit to cover 15g of carbohydrate

• 500 Rule (500 for analogs, 450 for regular)• Works in T1DM• Divide 500 by total daily dose of insulin to calculate the IC

ratio

• Fixed bolus – works well with structured constant meals

Insulin Carb ratio

• Defined as the effect of 1 unit of insulin on the blood glucose• Average = 1:50 ie 1 unit will drop glucose 50mg/dL• Utilized in correction scales

• The 1500 Rule estimates the point drop in mg/dL for every unit of Regular insulin taken.

• The 1800 Rule estimates the point drop in mg/dL for every unit of rapid-acting insulin taken.

Insulin Sensitivity

Hypoglycemia unawareness describes the presence of severely low plasma glucose levels that occur without warning symptoms followed by sudden loss of consciousness. Treat immediately with rapid-acting carbohydrates or a glucagon injection fo lowed by food. Reducing the insulin dose and allowing the average plasma glucose to increase for several weeks mat lead to improvement

Changing insulin – a daily review

Advances in technology

Remote Monitoring Tools

Technology can be overwhelming

• Background

• Type 1 & Type 2 diabetes – goal setting

• Treatment Options

• Complications

• Summary

Outline of the talk

1993 – DCCT & A Paradigm Shift

For every 1%

reduction in HbA1c

REDUCED RISK*

1%

UKPDS 35. BMJ 2000;321:405-412

UKPDS: What can a 1% drop in A1c achieve

Deaths from diabetes

Heart attacks

Microvascular complications

Amputation or death from

peripheral vascular disease

*p<0.0001

Renal -Screening

Renal - management

Eyes

Feet

Key points

Complication Agents used

Neuropathy Improved glycemic control

Patient education

Drug therapy: pregabalin,duloxetine, venlafaxine, amitriptyline,gabapentin, valproate, andother opioids (morphine sulfate, tramadol,oxycodone controlled release)

Nephropathy Glycemic controlACE or ARB. Target BP <130/80 ifappropriate

Retinopathy Prevent with excellent blood glucose andblood pressure control, ACE inhibitors, andsmoking cessation

• Background

• Type 1 & Type 2 diabetes – goal setting

• Treatment Options

• Complications

• Summary

Outline of the talk

Diabetes Care 2012;35:1364–1379

Diabetologia 2012;55:1577–1596

(Adapted with permission from: Ismail-Beigi et al. Ann Intern Med 2011;154:554)

Summary

• Goal setting key – realistic and evidence based

• Avoid clinical inertia

• Be aware of causes of hypoglycemia (common exam question)

• Screen for and manage complications

Thank-you

Incretin mimetics