Diabetes mellitus: An update

D. HuntMarch 2010

Significance of diabetes mellitus

• 5% of the population has diagnosed diabetes

• prevalence increases with age:20 - 44: 1%45 - 65: 5%> 65: 10%

• the true prevalence of diabetes is estimated to be twice the prevalence of diagnosed diabetes

Frequency of diagnosed and undiagnosed diabetes and IGT, by age (U.S. data - Harris)

0

5

10

15

20

25

30

35

40

20-34 35-44 45-54 55-64 65-74

% ofpopulation

IGTUndiagnosed diabetesDiagnosed diabetes

Harris. Diabetes Care 1993;16:642-52.

Significance of diabetes mellitus

Eye Disease

Type 1: 25% after 15 yearsType 2: 4% - 12% after 15 years

Diabetes is the leading cause of adult-onset blindness

Kidney Disease

Type 1: 30% after 15 yearsType 2: 20% after 15 years

Diabetes is the leading cause of end-stage renal disease

Foot complications

Loss of foot sensation > foot ulcers and infections > foot amputations

Amputation rate: 2 - 30/1000 patient-years

Diabetes is the leading cause of non-traumatic amputation

Haffner Am J Cardiol 1999;84:11J-4J.

Framingham study: diabetes and CAD mortality at 20-year follow-up

Cardiovascular Disease Risk is Increased 2 to 4 Times

17.4

8.5

17.0

3.602468

101214161820

Annual CAD Deaths per 1,000

Persons

Men Women

Diabetics Nondiabetics

Blood glucose control reduces the risk of diabetic

complications, especially microvascular complications

UK Prospective Diabetes UK Prospective Diabetes StudyStudy

UK Prospective Diabetes Study

20-year Interventional Trial from 1977 to 1997:

5,102 patients with newly-diagnosed DM2

Median follow-up 10.0 years, range 6 to 20 years

Results presented in 1998

Microvascular EndpointsMicrovascular Endpoints

p=0.0099

0%

10%

20%

30%

0 3 6 9 12 15

% o

f pa

tient

s w

ith a

n ev

ent

Years from randomisation

Intensive

Conventional

Risk reduction 25%(95% CI: 7% to 40%)

renal failure or death, vitreous haemorrhage or photocoagulation346 of 3867 patients (9%)

Myocardial InfarctionMyocardial Infarction

0%

10%

20%

30%

0 3 6 9 12 15

% o

f pa

tient

s w

ith a

n ev

ent

Years from randomisation

Intensive

Conventional

p=0.052

Risk reduction 16%(95% CI: 0% to 29%)

fatal or non fatal myocardial infarction, sudden death573 of 3867 patients (15%)

UK Prospective Diabetes Study

20-year Interventional Trial from 1977 to 1997 5,102 patients with newly-diagnosed DM2

Median follow-up 10.0 years, range 6 to 20 years

Results presented in 1998

10-year Post-Trial Monitoring from 1997 to 2007 Annual follow-up of the survivor cohort

Clinic-based for first five years

Questionnaire-based for last five years

Median overall follow-up 17.0 years, range 16 to 30 years

Post-Trial Changes in HbA1c

UKPDS resultspresented

Microvascular Disease

Intensive (SU/Ins) vs. Conventional glucose control

(photocoagulation, vitreous haemorrhage, renal failure)

HR (95%CI)

Myocardial Infarction(fatal or non-fatal myocardial infarction or sudden death)

Intensive (SU/Ins) vs. Conventional glucose control

All-cause Mortality

Intensive (SU/Ins) vs. Conventional glucose control

HR (95%CI)

After median 8.5 years post-trial follow-up

Aggregate Endpoint 1997 2007

Any diabetes related endpoint RRR: 12% 9% P: 0.029 0.040

Microvascular disease RRR: 25% 24% P: 0.0099 0.001

Myocardial infarction RRR: 16% 15% P: 0.052 0.014

All-cause mortality RRR: 6% 13% P: 0.44 0.007

RRR = Relative Risk Reduction, P = Log Rank

Legacy Effect of Earlier Glucose Control

After median 8.8 years post-trial follow-up

Aggregate Endpoint 1997 2007

Any diabetes related endpoint RRR: 32% 21% P: 0.0023 0.013

Microvascular disease RRR: 29% 16% P: 0.19 0.31

Myocardial infarction RRR: 39% 33% P: 0.010 0.005

All-cause mortality RRR: 36% 27% P: 0.011 0.002

RRR = Relative Risk Reduction, P = Log Rank

Legacy Effect of Earlier Metformin Therapy

• Despite an early loss of glycemic differences, a continued reduction in microvascular risk and emergent risk reductions for MI and death were observed during 10 years of post-trial follow-up

UKPDS Conclusions

Pharmacologic Management of Type 2 Diabetes

• If glycemic targets are not achieved within 2 to 3 months of lifestyle management, pharmacotherapy should be initiated.

• Timely adjustments should be made to attain target A1C within 6 to 12 months.

• In patients with marked hyperglycemia (A1C ≥ 9.0%), pharmacotherapy should be initiated concomitantly with lifestyle management, and consideration be given to either combination therapy or insulin.

Management of hyperglycemia in type 2 diabetes

A1C >9.0% Symptomatic with metabolic decompensation

A1C <9.0%

Initiate pharmacotherapy immediately without waiting for effect from lifestyle interventions:

• Consider initiating metformin concurrently with another agent from a different class or

• Initiate insulin

Initiate metformin Initiate insulin ± metformin

If not at target

L

I

F

E

S T Y L E

Clinical Assessment

Lifestyle intervention (initiation of nutrition therapy and physical activity)

Oral agents:(agents listed in alphabetical order)

Class A1C Hypoglyc. Advantages Disadvantages

Alpha-glucos. inhibitor

↓ Rare Improved postprandial control weight neutral

GI side effects

Incretin: DPP-4 inhib.

↓ - ↓↓

Rare Improved postprandial control; weight neutral

New agents (unknown long-term safety)

Insulin ↓-↓↓↓

Yes No dose ceiling Weight gain

Meglitinides

Sulfonylureas

↓ - ↓↓

↓↓

Yes

Yes

Improved postprandial controlNewer sulfonylureas (gliclazide) are associated with less hypoglycemia than glyburide

Requires TID to QID dosing

Weight gain

*less hypoglycemia in the context of missed meals

TZD ↓ ↓ Rare Durable monotherapy

6-12 weeks for maximal effectEdema, rare CHF, fractures in females

↓ = < 1.0% decrease in A1C

↓ ↓ = 1.0–2.0% decrease in A1C

↓ ↓ ↓ = >2.0% decrease in A1COral agents beyond metformin

If not at target

• Add another drug from a different class; or • Add bedtime basal insulin to other agent(s); or• Intensify insulin regimen

Timely adjustment to and/or addition of antihyperglycemic agents should be made to attain target

A1C within 6 to 12 months

Canadian Diabetes Association 2008 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada; Canadian Journal of Diabetes: 2008 Vol:32 Supplement

Natural History of Type 2 Diabetes

Normal Impaired glucosetolerance

Type 2 diabetes

Time

Insulinresistance

Insulinproduction

Glucoselevel

b-celldysfunction

Henry. Am J Med 1998;105(1A):20S-6S.

b cell function in type 2 diabetic patients

Natural deterioration of Natural deterioration of bb-cell function-cell function

Years after diagnosis

b-cell

fun

cti

on

Insulin

Type Starts Peaks Duration

Lispro

Aspart

Glulisine

5-10 min 0.5-1 hrs 3.5 hrs

Regular

Toronto

30 min 2-4 hrs 6-8 hrs

N/NPH 1-2 hrs 6-10 hrs 16-24 hrs

Detemir - 6 – 8 hrs Up to 24 hrs

Glargine 1.5 hrs None Up to 24 hrs

Insulin regimens – Type 2 DM

Many different potential regimens!

– Oral + hs insulin (basal)– Oral + AM insulin (basal)– Pre-mixed insulin with breakfast and

supper– Short-acting with meals + bedtime basal

Holman RR. NEJM 2009;361:1736-47

Aims

First Phase

One-year head-to-head comparison of the efficacy of three different types of analogue insulins, when given in addition to dual oral antidiabetic therapy:

Biphasic insulin

Prandial insulin

Basal insulin

Patient Disposition

235Assigned to

biphasic insulin(biphasic aspart)

234Assigned to basal

insulin(detemir)

239Assigned to

prandial insulin(aspart)

34 Discontinued

45 Discontinued51Discontinued

201 (86%)Completedthree years

189 (81%)Completedthree years

188 (79%)Completedthree years

Overall, 18.4% of patients did not complete three years No difference in proportions between groups (p=0.15) No difference in baseline characteristics between those who

completed or did not complete three years follow up

Transition to a Complex Insulin Regimen

* Intensify to a complex insulin regimen in year one if unacceptable hyperglycaemia

708 T2DMon dual

oral agents

Add biphasic insulin*twice a day

Add prandial insulin*three times a day

R

First Phase

Add basal insulin*once (or twice) daily

Add prandial insulinat midday

Add basal insulinbefore bed

Second Phase

Add prandial insulinthree times a day

From one year onwards, if HbA1c levels were >6.5%, sulfonylurea therapy was stopped and a second type of insulin was added

Demographic CharacteristicsBiphasic

N=235PrandialN=239

BasalN=234

Male 68% 64% 61%

White Caucasian 94% 90% 93%

*Diabetes duration (yrs) 9 (6-12) 9 (6-14) 9 (6-12)

Taking sulfonylurea 98% 100% 99%

Taking metformin 96% 95% 97%

Age (years) 61.7±8.9 61.6 ±10.5 61.9±10.0

Body mass index (kg/m2) 30.2 ±4.8 29.6 ±4.5 29.7 ±4.6

HbA1c (%) 8.6 ±0.8 8.6 ±0.8 8.4 ±0.8

*interquartile range No significant differences between groups

Glycaemic targets and Insulin Injections

Fasting and pre-meal: 4.0-5.5 mmol/l (72-99 mg/dl)

Two-hours post meal: 5.0-7.0 mmol/l (90-126 mg/dl)

6 6 1212 624186 6 1212 624186 6 1212 62418

Biphasic

Basal

Prandial*

* Twice a day if required

Complex Insulin Regimens

Proportion eligible for a second type of insulin per protocol

Proportion taking two types of insulin

Insulin Doses Over 3 YearsMedian±95% confidence interval

Biphasic±prandial

Prandial±basal

Basal±prandial

Total Daily Insulin Doses at 3 YearsMedian±95% confidence interval

HbA1c Values Over 3 YearsMedian±95% confidence interval

Biphasic±prandial

Prandial±basal

Basal±prandial

Overall6.9%

(6.8 to 7.1)

Primary Outcome: HbA1c at 3 YearsMedian±95% confidence interval

Body Weight over 3 YearsMedian±95% confidence interval

Biphasic±prandial

Prandial±basal

Basal±prandial

Increase in Body Weight Over 3 YearsMean±1SD

Hypoglycaemia

Categorised as

Grade 1- Symptoms only with glucose (if measured) ≥3.1 mmol/l (≥56 mg/dl)

Grade 2- Symptoms plus glucose <3.1 mmol/l (<56 mg/dl)

Grade 3- Third party assistance required

Grade 2 or 3 Hypoglycaemia Over 3 Years

Biphasic±prandial

Prandial±basal

Basal±prandial

Grade 2 or 3 Hypoglycaemia Over 3 Years

Allpatients

Patients withHbA1c ≤6.5%

Overview of Main Results

Biphasic Prandial Basal

Fewer hypoglycaemic episodes ++ + +++Less weight gain + + ++Less increase in waist circumference

+ + ++

4T trial

Three quarters of patients added a second insulin Those commencing therapy with a basal or prandial

insulin more often achieved glycaemic targets than patients commencing with a biphasic insulin

Patients commencing therapy with basal insulin had fewer hypoglycaemic episodes and less weight gain

These findings provide clear evidence in people with type 2 diabetes to support starting insulin therapy with a once a day basal insulin, and then adding

a mealtime insulin if glycaemic targets are not met

Beyond Glycemic Control

Blood pressure control

Lipid therapy

Microvascular complication screening and management

Blood Pressure Control Study

UK Prospective Diabetes StudyUK Prospective Diabetes Study

Randomisation

on antihypertensive therapyn = 421

not on antihypertensive therapyn = 727

avoid ACE inhibitor : Beta blockern = 390

34%

less tight blood pressure controlaim : BP < 180/105 mmHg

ACE inhibitorn = 400

35%

Beta blockern = 358

31%

tight blood pressure controlaim : BP < 150 / 85 mmHg

randomisation

1148 hypertensive patients

Blood Pressure : Tight vs Less Tight Control

60

80

100

140

160

180

0 2 4 6 8

mm

Hg

Years from randomisation

cohort, median values

Less tight control Tight control

Any diabetes-related endpoints

0%

10%

20%

30%

40%

50%

0 3 6 9

% o

f pa

tient

s w

ith e

vent

s

Years from randomisation

Tight blood pressure control (758)

Less tight blood pressure control (390)

risk reduction24% p=0.0046

Diabetes-related deaths

0%

5%

10%

15%

20%

0 3 6 9

% o

f pa

tient

s w

ith e

vent

s

Years from randomisation

Tight blood pressure control (758)

Less tight blood pressure control (390)

risk reduction32% p=0.019

Any DM-related endpoint 24% p=0.0046

Diabetes-related deaths 32% p=0.019

Stroke 44% p=0.013

Microvascular disease 37% p=0.0092

Heart failure 56% p=0.0043

Retinopathy progression 34% p=0.0038

Deterioration of vision 47% p=0.0036

Blood Pressure Control Study

Blood Pressure Study

ACCORDACCORD

ACCORD Study Group. NEJM 2010

ACCORD BP TrialACCORD BP Trial

ACCORD Study Group. NEJM 2010

4,733 patients with DM2; high CVS risk

SBP 130 – 180

Randomized to target SBP <140 v. <120

Primary outcome: nonfatal MI, nonfatal CVA; CVS death

Follow-up: 4.7 years; 95% complete

Baseline Characteristics

<120 <140

N 2362 2371

Age 62 62

% females 48% 48%

Hx CVS event 34% 33%

SBP 139.0 139.4

Duration DM 9 10

GHb (%) 8.4 8.3

ACCORD BP TrialACCORD BP Trial

ACCORD Study Group. NEJM 2010

Achieved SBP: 119 v. 133

Antihypertensive medications: 3.4 v. 2.3

ACCORD BP TrialACCORD BP Trial

ACCORD Study Group. NEJM 2010

Achieved SBP: 119 v. 133

Antihypertensive medications: 3.4 v. 2.3

Primary outcome:

Nonfatal MI, nonfatal CVA, CVS death (%/year):

1.9% v. 2.1%; HR 0.88 (0.73 – 1.06, p=0.20)

ACCORD BP Trial: OutcomesACCORD BP Trial: Outcomes

ACCORD Study Group. NEJM 2010

Nonfatal MI, nonfatal CVA, CVS death (%/year):

1.9% v. 2.1%; HR 0.88 (0.73 – 1.06, p=0.20)

Total mortality: 1.3% v. 1.2%, p=0.55

CVS death: 0.5% v. 0.5%

Stroke: 0.3% v. 0.5%, p=0.01

ACCORD BP Trial: ConclusionACCORD BP Trial: Conclusion

ACCORD Study Group. NEJM 2010

Targeting a SBP < 120, as compared to a SBP < 140, does not improve CVS outcomes in patients with DM2 at high risk of CVS events

Lipid Therapy Study

ACCORDACCORD

ACCORD Study Group. NEJM 2010

ACCORD Lipid TrialACCORD Lipid Trial

ACCORD Study Group. NEJM 2010

5,518 patients with DM2; high CVS risk

LDL 1.5 – 4.6; HDL < 1.4; TG < 8.5

All patients received open label simvastatin

Randomized to fenofibrate (160 mg) v. placebo

Primary outcome: nonfatal MI, nonfatal CVA; CVS death

Follow-up: 4.7 years

Baseline Characteristics

Fenofibrate Placebo

N 2765 2753

Age 62 62

% females 31% 31%

Hx CVS event 36% 37%

LDL 2.6 2.6

HDL 1.0 1.0

TG 2.1 2.1

ACCORD Lipid TrialACCORD Lipid Trial

ACCORD Study Group. NEJM 2010

Achieved LDL: 2.1 v. 2.1

Achieved HDL: 1.1 v. 1.0

Achieved TG: 1.7 v. 1.9

ACCORD Lipid TrialACCORD Lipid Trial

ACCORD Study Group. NEJM 2010

Achieved LDL: 2.1 v. 2.1

Achieved HDL: 1.1 v. 1.0

Achieved TG: 1.7 v. 1.9

Primary outcome:

Nonfatal MI, nonfatal CVA, CVS death (%/year):

2.2% v. 2.4%; HR 0.92 (0.79 – 1.08, p=0.32)

• Total mortality: 1.5% v. 1.6%, p=0.33

ACCORD Lipid Trial: OutcomesACCORD Lipid Trial: Outcomes

ACCORD Study Group. NEJM 2010

Pre-specified subgroups:

Sex:

Men: 11.2% v. 13.3%

Women: 9.1% v. 6.6%, p=.01

Dyslipidemia (HDL<0.9, TG > 2.3):

Dyslipidemia patients: 12.4% v. 17.3%

Non-dyslipidemic patients: 10.1% v. 10.1%, p=.057

ACCORD Lipid Trial: ConclusionsACCORD Lipid Trial: Conclusions

ACCORD Study Group. NEJM 2010

Routine fenofibrate therapy, in addition to simvastatin, does not improve CVS outcomes in patients with DM2 at high risk of CVS events

Addition of fenofibrate to simvastatin may benefit patients with significant dyslipidemia

• Glycemic control

• BP control

• Lipid management

Conclusions