issues in diabetes care academic half-day february 2002 d. hunt

Issues in Diabetes Care

Academic Half-day

February 2002

D. Hunt

Outline

1. Significance of diabetes mellitus

2. Glycemic control: - evidence

- oral agents

- insulin

3. Blood pressure control

4. Nephropathy and microalbuminuria

5. Cases

Significance of diabetes mellitus

• 5% of the population has diagnosed diabetes• 10% Type 1; 90% Type 2• 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)

1.5 Million Canadians Have Diabetes Mellitus

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.

Proliferative retinopathy

Type 1: 25% after 15 years

Type 2: 4% - 12% after 15 years

Blindness: 10% - 15% of patients with proliferative retinopathy have severe visual loss within 2 years

Diabetes is the leading cause of adult-onset blindness

Nephropathy



Follow-up from the Multiple Risk Factor Intervention Trial:RR for end-stage renal disease: 9.0 (7.4 - 11.0)

Diabetes is the leading cause of end-stage renal disease

Neuropathy

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 mortalityat 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

Macrovascular disease

Multiple Risk Factor Intervention Trial:Follow-up of 350,000 screened patients

RR for cardiovascular death: 3.0

Swedish cohort study:Baseline age: 51 - 59Follow-up: 16 years

RR for cardiovascular death: 2.9 (2.3 - 5.6)

Glycemic control - Type 1 diabetes

The Diabetes Control and Complications Trial:– 1441 patients with Type 1 diabetes– intensive insulin therapy vs conventional therapy– follow-up 6.5 years

Early retinopathy: 24% vs 7%

Microalbuminuria:20% vs 13%

Neuropathy: 10% vs 3%

Glycemic control

Can these results be applied to people with Type 2 diabetes?

Potential benefits: Decreased microvascular disease

Potential adverse effects: Increased cardiovascular mortality with oral hypoglycemic agents and insulin

Does an intensive glucose Does an intensive glucose control policy reduce the risk control policy reduce the risk of complications for people of complications for people

with Type 2 diabetes?with Type 2 diabetes?

UK Prospective Diabetes StudyUK Prospective Diabetes Study

Randomisation of Treatment Policies

342 allocated to metformin

Conventional Policy30% (n=1138)

Intensive Policy70% (n=2729)

Sulphonylurean=1573

Insulinn=1156

Main Randomisationn=4209 (82%)

3867

Treatment Policies in 3867 patients

Conventional Policy

n = 1138

• initially with diet alone

• aim for near normal weightbest fasting plasma glucose < 15 mmol/Lasymptomatic

• when marked hyperglycaemia developsallocate to non-intensive pharmacological therapy

Treatment Policies in 3867 patientsIntensive Policy with sulphonylurea or insulin

n = 2729 • aim for

fasting plasma glucose < 6 mmol/Lasymptomatic

• when marked hyperglycaemia developson sulphonylurea add metforminmove to insulin therapyon insulin, transfer to complex regimens

Actual Therapy

Years from randomisation

1 2 3 4 5 6 7 8 9 10 11 120

20

40

60

80

100

pro

po

rtio

n o

f p

ati

en

ts

diet alone

1 2 3 4 5 6 7 8 9 10 11 12

intensivepharmacologicaltherapy

diet aloneadditional non-intensivepharmacological therapy

Intensive Policyaim for < 6 mmol/L

Conventional Policyaccept < 15 mmol/L

HbA1c cross-sectional, median values

06

7

8

9

0 3 6 9 12 15

HbA 1

c (%

)


Conventional

Intensive

6.2% upper limit of normal range

Any Diabetes Related EndpointAny Diabetes Related Endpoint

1401 of 3867 patients (36%)

First occurrence of any one of:

• diabetes related death

• non fatal myocardial infarction, heart failure or angina

• non fatal stroke

• amputation

• renal failure

• retinal photocoagulation or vitreous haemorrhage

• cataract extraction or blind in one eye

Any Diabetes Related Endpoint (cumulative )Any Diabetes Related Endpoint (cumulative )

0%

20%

40%

60%

0 3 6 9 12 15

% o

f pa

tient

s w

ith a

n ev

ent


Intensive (2729)

Conventional (1138)

Risk reduction 12%(95% CI: 1% to 21%)

p=0.029

1401 of 3867 patients (36%)

Diabetes Related DeathsDiabetes Related Deaths

414 of 3867 patients (11%)

Any of:

• fatal myocardial infarction or sudden death

• fatal stroke

• death from peripheral vascular disease

• death from renal disease

• death from hyper/hypoglycaemia

Diabetes Related Deaths (cumulative)

0%

10%

20%

30%

0 3 6 9 12 15

% o

f pa

tient

s w

ith a

n ev

ent


Intensive (2729)

Conventional (1138)

p=0.34

414 of 3867 patients (11%)

Microvascular Endpoints (cumulative)Microvascular Endpoints (cumulative)

p=0.0099

0%

10%

20%

30%

0 3 6 9 12 15

% o

f pa

tient

s w

ith a

n ev

ent


Intensive

Conventional


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

Myocardial Infarction (cumulative)Myocardial Infarction (cumulative)

0%

10%

20%

30%

0 3 6 9 12 15

% o

f pa

tient

s w

ith a

n ev

ent


Intensive

Conventional

p=0.052


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

Aggregate Clinical EndpointsAggregate Clinical Endpoints

Favoursconventional

0.5 1 2

0.88

0.90

0.94

0.84

1.11

0.75

0.029

0.34

0.44

0.052

0.52

0.0099

Any diabetes related endpoint

Diabetes related deaths

All cause mortality

Myocardial infarction

Stroke

Microvascular

RR p

Favoursintensive

Relative Risk& 95% CI

Progression of RetinopathyProgression of RetinopathyTwo step change in Early Treatment Diabetic Retinopathy Study (ETDRS) scale

1.03

0.83

0.83

0.79

0.78

0.017

0.012

0.015

0 - 3 years

0 - 6 years

0 - 9 years

0 - 12 years

RR p 0.5 1 2


Favoursconventional

Favoursintensive

MicroalbuminuriaMicroalbuminuriaUrine albumin >50 mg/L

0.89

0.83

0.88

0.76

0.67

0.70

0.24

0.043

0.13

0.00062

0.000054

0.033

Baseline

Three years

Six years

Nine years

Twelve years

Fifteen years

RR p 0.5 1 2


Favoursconventional

Favoursintensive

<

Glycemic control - UKPDSGlycemic control - UKPDS

Intensive blood glucose control reduces

the risk of diabetic complications, the

greatest effect being on microvascular

complications

Does metformin in overweight diabetic patients have any

advantages or disadvantages?


RandomisationRandomisation

Main Randomisation4209

Overweight1704

Non overweight2505

Conventional Policy411

Intensive Policy1293

Metformin342

Insulin or Sulphonylurea951

0.0

0.2

0.4

0.6

0 3 6 9 12 15

Pro

port

ion

of p

atie

nts

with

eve

nts


Conventional (411)

Intensive (951)

Metformin (342)


M v Ip=0.0034

overweight patients

M v C p=0.0023

0.0

0.1

0.2

0.3

0.4

0 3 6 9 12 15

Pro

port

ion

of p

atie

nts

with

eve

nts


Conventional (411)

Intensive (951)

Metformin (342)


M v Ip=0.11

overweight patients

M v C p=0.017

Myocardial Infarction

M v Ip=0.12

overweight patients

0.0

0.1

0.2

0.3

0.4

0 3 6 9 12 15

Pro

port

ion

of p

atie

nts

with

eve

nts


Conventional (411)

Intensive (951)

Metformin (342)

M v Cp=0.010

0.0

0.1

0.2

0.3

0 3 6 9 12 15

Pro

port

ion

of p

atie

nts

with

eve

nts


Conventional (411)

Intensive (951)

Metformin (342)

Microvascular endpoints

M v Ip=0.39

overweight patients

M v Cp=0.19

Metformin Comparisons

favours metformin

favours conventional

overweight patientsRR p

Any diabetes related endpointMetformin 0.68 0.0023

Diabetes Related deathsMetformin 0.58 0.017

All cause mortalityMetformin 0.64 0.011

Myocardial infarctionMetformin 0.61 0.01

RR (95% CI)

0.2 1 5

Metformin in Overweight Patients

• compared with conventional policy

32% risk reduction in diabetes-related endpoints p=0.002342% risk reduction in diabetes-related deaths p=0.01736% risk reduction in all cause mortality p=0.01139% risk reduction in myocardial infarction p=0.01

Natural History of Type 2 Diabetes

Normal Impaired glucosetolerance

Type 2 diabetes

Time

Insulinresistance

Insulinproduction

Glucoselevel

-celldysfunction

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

Meltzer et al CMAJ 1998;159(Suppl):S1-29.

Oral Antihyperglycemic Agents: Biguanides (metformin)

• Decreases hepatic glucose production• Enhances peripheral glucose uptake• Increased insulin sensitivity in the periphery

• HbA1c: 7.1% vs. 8.6% (US Metformin Study) 7.4% vs. 8.0% (UKPDS)

• Not associated with hypoglycemia• May promote weight loss

MUSCLELIVER


Oral Antihyperglycemic Agents: Biguanides (metformin)

• May cause GI side effects– Introduce slowly!

• Contraindicated in renal/hepatic insufficiency

• Lactic acidosis (0.03 cases/1000 patient years)

• Dose 250 – 500 mg BID/TID, to max of 2500 mg/d

MUSCLELIVER

Plosker, Faulds Drugs 1999;57:410-32. Balfour, Plosker Drugs 1999;57:921-30.

MUSCLE

ADIPOSE TISSUE

LIVER

Oral Antihyperglycemic Agents: Thiazolidinediones (TZDs)

• New class of oral agents

• Designed to increase insulin sensitivity

• Pioglitazone, rosiglitazone



Mechanism:• Activate the peroxisome proliferator-activated receptor gamma

(PPARγ) nuclear receptor• Expressed in adipose tissue, large colon, hematopoietic cells• Involved in efficient energy storage and adipogenesis• Activation of the gene in adipose tissue leads to:

– Apoptosis of larger fully differentiated adipocytes (insulin resistant)– Differentiation of pre-adipocytes into small metabolically active

adipose cells



Net effect:

• Increased insulin sensitivity

• Increased insulin-dependent glucose uptake

• Improved glycemic profile

• Reduction in triglyceride levels – Increased LPL activity



Effect on glycemic control when combined with other oral agents:

Pioglitazone:HbA1c: 0.8% - 1.3%

FBG: 2.1 – 3.2 mmol/L

Rosiglitazone: HbA1c: 1.0% – 1.2%

FBG: 2.4 – 2.9 mmol/L



Effect on lipid control when combined with other oral agents:

Pioglitazone:Triglycerides: decrease 20%

HDL: increase 10%

Thiazolidinediones

Side effects:- Edema/fluid retention - 4%- Congestive heart failure- Weight gain – 4.5 kg- Ovulation – polycystic ovarian syndromeContraindications:- Elevated liver function tests (>2.5 x upper limit of normal)- Class 2,3,4 heart failure- EdemaMonitoring: Liver function tests every 2 months for 1 year

Thiazolidinediones:Clinical aspects

• Dosing:– Pioglitazone: 15-45 mg daily– Rosiglitazone: 2-4 mg bid or 4-8 mg qd

• Half-life:– Pioglitazone: 16-24 h– Rosiglitazone: 3-4 h

• Initial effect: 2-4 weeks • Full effect: 8-12 weeks

Sites of Action of Currently Available Therapeutic Options

GLUCOSE ABSORPTION

GLUCOSE PRODUCTIONBiguanides

Thiazolidinediones

MUSCLE

PERIPHERAL GLUCOSE UPTAKE

Thiazolidinediones(Biguanides)

PANCREAS

INSULIN SECRETIONSulfonylureasMeglitinides

ADIPOSE TISSUE

LIVER

Alpha-glucosidase inhibitors

INTESTINE

Sonnenberg, Kotchen Curr Opin Nephrol Hypertens 1998;7:551-5.

Oral Antihyperglycemic Agents: Sulfonylureas

• Stimulate pancreatic insulin release

– First-generation: tolbutamide, chlorpropamide

– Second-generation: Glyburide, gliclazide

– HbA1c: 1 – 2%– Weight gain: 2 – 3 kg– Risk of severe hypoglycemia: 1 – 1.5%/year


PANCREAS

Oral Antihyperglycemic Agents: Meglitinides

• Stimulate pancreatic insulin release

– Repaglinide – Rapid onset and short duration of action– Lowers fasting and postprandial glucose levels– HbA1c: 1.5%– May cause hypoglycemia

Balfour, Faulds Drugs Aging 1998;13:173-80.

PANCREAS

Oral Antihyperglycemic Agents: Alpha-glucosidase inhibitors

• Slows gut absorptionof starch and sucrose

– Acarbose

– Attenuates postprandial increases in blood glucose levels

– GI side effects– Not associated with hypoglycemia or weight gain

Salvatore, Giugliano Clin Pharmacokinet 1996;30:94-106.

INTESTINE

Stepwise approach to type 2 diabetes

Nonpharmacologic therapy

Oral agent monotherapy

Oral agent combination therapy

Bedtime insulin and oral agents

Insulin 2–4 times/day

Goals of insulin therapy

• Achieve optimal glycemic control

• Minimize adverse effects:– Weight gain– Hypoglycemia– Inconvenience

Insulin action

Onset Peak Duration

(min) (hrs) (hrs)

Regular 15-60 2-4 5 - 8

NPH 2.5-3.0 5-7 13-16

Regular – with meals

NPH - basal

Limitations of Regular Human InsulinLimitations of Regular Human Insulin

• Slow onset of activity:– Should be given 30 to 45 minutes before meals

– Inconvenient for patients - less flexibility

• Insulin not peaking during peak absorption of food:– Inadequate post-prandial control

• Long duration of activity:– Lasts up to 8 hours

– Potential for late post-prandial hypoglycemia

– Need for additional snacks

Insulin action

Onset Peak Duration

(min) (hrs) (hrs)

Lispro 10-15 1-1.5 4-5

Regular 15-60 2-4 5 - 8

NPH 2.5-3.0 5-7 13-16

Objectives for the Development of Short-Acting Insulin Objectives for the Development of Short-Acting Insulin AnaloguesAnalogues

360

180

300

240

120

60

0

0 60 120 180 240 300 360 420

0

10

20

30

60

50

40

Humalog s.c.

Time (minutes)

Graph adapted from Pampanelli S et al. Diabetes Care, 1995: 18;11:1452-1459.

Insu

lin (

mg

/mL

)

Pancreatic insulin OGT

Regular insulin (–5 min.)

Regular insulin (–30 min.)

0

1

2

3

4

0 1 2 3 4 5 6

months

regular-lisprolispro-regular

Post-prandial Glucose Control in 772 Patients Post-prandial Glucose Control in 772 Patients with Type 2 Diabetes Mellituswith Type 2 Diabetes Mellitus

Anderson JH et al. Arch Int Med 1997;157:1249-55

2 hour pc blood glucose was significantly reduced with lispro

2 ho

ur p

ost p

rand

ial g

luco

se r

ise

(mm

ol/L

)

Hypoglycemia in 772 PatientsHypoglycemia in 772 Patientswith Type 2 Diabetes Mellituswith Type 2 Diabetes Mellitus

Anderson JH et al. Arch Int Med 1997;157:1249-55

• hypoglycemia reduced by 7.3% with lispro insulin ( 3.43 to 3.18 episodes/30 days/pt, p<0.02)

• severe hypoglycemia was rare

• overnight hypoglycemia reduced by 36% with lispro insulin (0.73 to 0.47 episodes/30 days/pt, p<.001)

Lispro Insulin in Type 1 Diabetes

• Systematic review – 8 trials

• Lispro insulin vs. regular insulin

• 2576 patients with type 1 diabetes mellitus

• Follow-up: 4 – 12 months

• Severe hypoglycemia: 3.1% vs. 4.4%, p=0.024

Brunelle RL Diabetes Care 1998;21:1726-31.

LisproLispro

– Allows patients to inject at time of meal

– Significantly reduces post-prandial blood glucose levels

– Reduces the incidence of hypoglycemia

– Can improve the HbA1c

– Offers improved flexibility and convenience

Pre-mixed InsulinPre-mixed Insulin

– Convenient

– Less injections per day

– Adjustments in basal and meal time insulin more difficult

– Preparations:

• 30/70 – 30% regular insulin/70% NPH insulin

• Other ratios available

• Mix25 – 25% lispro/75% NPH insulin

Insulin regimens

Many different potential regimens!

– Oral + hs insulin (NPH)– Oral + AM insulin (NPH)– Pre-mixed insulin with breakfast and supper– Short-acting with meals + bedtime NPH

– Pre-mixed with breakfast, short acting at supper, and bedtime HPH

Insulin regimens

All equivalent glycemic control.

Weight gain less with bedtime insulin.

Less hypoglycemia and weight gain with metformin (vs. glyburide)

Regime will depend on patient preferences and ability to achieve glycemic goals!

CDA Guidelines for Glucose Control

Normal Optimal Suboptimal Inadequate

Glycated Hb (% of ULN) HbA1C assay

<100

(0.04-0.06)

<115

(<0.07)

116-140

(0.07-0.084)

>140

(>0.084)

Preprandial glucose (mmol/L)

3.8-6.1

4-7

7.1-10

>10

Postprandial glucose (mmol/L)

4.4-7

5-11

11.1-14

>14

Meltzer et al CMAJ 1998;159(Suppl):S1-29. Gerstein HC et al CDA’s UKPDS Position Statement.

Blood Pressure Control Study


Blood Pressure Control Study

- to determine whether a tight blood pressure control policy can reduce morbidity and mortality in Type 2 diabetic patients

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


cohort, median values

Less tight control Tight control

mmHg baseline mean over 9 years

Less tight control 160 / 94 154 / 87

Tight control 161 / 94 144 / 82

difference 1 / 0 10 / 5

p n.s. <0.0001

ACE inhibitor 159 / 94 144 / 83

Beta blocker 159 / 93 143 / 81

difference 0 / 0 1 / 1

p n.s. n.s. / p=0.02

Mean Blood Pressure

Therapy requirement

1 2 3 4 5 6 7 80

20

40

60

80

100

% o

f pa

tient

s

LessTight Control Policy

1 2 3 4 5 6 7 8


None one two > two

Tight Control Policy

number of antihypertensive agents

Any diabetes-related endpoints

0%

10%

20%

30%

40%

50%

0 3 6 9

% o

f pa

tient

s w

ith e

vent

s


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


Tight blood pressure control (758)

Less tight blood pressure control (390)


Myocardial Infarction

0%

5%

10%

15%

20%

25%

0 3 6 9

% o

f pa

tient

s w

ith e

vent


Tight Blood Pressure Control (758)

Less Tight Blood Pressure Control (390)


Heart Failure

0%

5%

10%

15%

20%

25%

0 3 6 9

% p

atie

nts

with

eve

nt




risk reduction 56% p=0.0043

Stroke

0%

5%

10%

15%

20%

25%

0 3 6 9

% p

atie

nts

with

eve

nt





Microvascular endpoints

0%

5%

10%

15%

20%

25%

0 3 6 9

% p

atie

nts

with

eve

nt





Do ACE inhibitors or Do ACE inhibitors or Beta Blockers Beta Blockers

have any specific advantages have any specific advantages or disadvantages?or disadvantages?


Aggregate Clinical EndpointsAggregate Clinical Endpoints

1.10

1.27

1.14

1.20

1.12

1.29

0.43

0.28

0.44

0.35

0.74

0.30



All cause mortality

Myocardial infarction

Stroke

Microvascular

RR p 0.5 1 2


>

>

FavoursBeta blocker

FavoursACE inhibitor

Renal Disease in Diabetes

Blood pressure control

ACE - inhibition

Angiotensin receptor blockade

Diabetes:The Most Common Cause of ESRD

Primary Diagnosis for Patients Who Start Dialysis

Diabetes50.1%

Hypertension27%

Glomerulonephritis

13%

Other

10%

United States Renal Data System. Annual data report. 2000.

No. of patientsProjection95% CI

1984 1988 1992 1996 2000 2004 20080

100

200

300

400

500

600

700

r2=99.8%243,524

281,355520,240

No

. o

f d

ialy

sis

pat

ien

ts

(th

ou

san

ds)

Blood pressure control

• Decreases development of microalbuminuria• Decreases rate of decline in glomerular filtration rate

UKPDS: 29% RRR for microalbuminuriaAbsolute risk reduction: 8.2%

Meta-analysis of RCTs of diabetic nephropathy:• 10 mm Hg improvement – 0.18 ml/min/month

ACE-inhibition

• Role in patients with Type 1 diabetes and nephropathy– Prevent death, dialysis, and transplantation

• Role in patients with microalbuminuria– Reduce rate of diabetic nephropathy

• Role in patients with Type 2 diabetes at high risk of cardiac complications– Reduce risk of MI, stroke, and cardiovascular death

Type 1 Diabetes and nephropathy

Lewis and colleagues, 1993

• 409 patients

• Captopril vs. placebo

• Follow-up 3.5 years

• Outcome: Death, dialysis, renal transplant

• Placebo arm: 21%

• Captopril arm: 11%

Microalbuminuria

• Systematic review of randomized controlled trials

• Follow-up: >1 year

• RR for proteinuria: 0.35 (0.24 – 0.53)

• ARR 16.3% NNT 6

• No demonstrated effect on renal function

HOPE9297 patients: >55 years of age

- clinical vascular disease or diabetes mellitus + 1 other cardiovascular risk factor

- no history of heart failure

- randomly allocated to ramipril or placebo

- followed for a mean of 5 years

- outcome: MI, stroke, or CVS death

1137 patients: diabetes mellitus with no clinical manifestations of cardiovascular disease

HOPE

Results:

- ramipril arm: 14.1%

- placebo arm: 17.7%

Relative risk: 78% (95% CI 70% - 86%)

Consistent across all subgroups, including patients with diabetes and no CVS disease

MICRO-HOPE: ACEI Reduces the Risk of MI, Stroke, and CV Death in Patients With Diabetes

HOPE Study Investigators. Lancet. 2000;335:253.

Combined MI Stroke CV death

15.3

10.2

4.26.2

19.8

12.9

6.1

9.7

0

5

10

15

20

25

30Ramipril

Placebo

25% RRP=0.0004

22% RRP=0.01

33% RRP=0.0074

37% RRP=0.0001

Pri

ma

ry e

ve

nts

Angiotensin Receptor Blockers

• 3 recent publications

• Effect of angiotensin receptor blockers in patients with Type 2 diabetes mellitus and nephropathy or microalbubinuria

IRMA 2: IRbesartan MicroAlbuminuria Type 2 Diabetes Mellitus in Hypertensive Patients

• Irbesartan (150 mg and 300 mg) vs. other antihypertensive medications

– (excl ACEIs, ARBs, dihydropyridine Ca++ ch. blockers)

• 590 patients

• Hypertension, type 2 diabetes, and microalbuminuria

• Follow-up: 2 years

IRMA 2: Results

• Nephropathy rate:– 5.2% among patients treated with 300 mg irbesartan/day

– 9.7% among patients treated with 150 mg irbesartan/day

– 14.9% among those treated with conventional therapy (P=0.0004)

• Reduction in microalbuminuria to normal levels (33% vs 20%; P=0.006)

• BP control similar across study arms

IDNT: Irbesartan Type 2 Diabetic Nephropathy Trial

Patients: 1715 patients with NIDDM, HT, proteinuria (≥900 mg/24 h), serum creatinine 88 – 265 µmol/l

Treatment regimen: Irbesartan 300mg, amlodipine 10mg, or placebo (± conventional therapy); target BP 135/85

1 End points: Combined incidence of doubling of sCr, ESRD, and death

2 End points: cardiovascular events

Follow-up: 2.6 years

IDNT: Results• Incidence of the composite endpoint (CrX2, ESRD, death):

– Irbesartan: 32.6%– Amlodipine: 41.1%– Placebo: 39.0%

• Effects of irbesartan independent of effects on BP• No effect on mortality or cardiovascular outcomes

Patients: 1513 patients with NIDDM, nephropathy, serum creatinine 115 - 265

Treatment regimen: Losartan vs placebo (± conventional therapy)

1 End point: Combined incidence of doubling of sCr, ESRD, and death

2 End points: CV events, proteinuria

Follow-up: 3.4 years

RENAAL: Reduction of Endpoints in NIDDM With the AII Antagonist Losartan

RENAAL: Results• Incidence of the composite endpoint (CrX2, ESRD, death):

– Losartan: 43.5%– Placebo: 47.1%,– RRR 16%, p=0.02

• Effects of losartan independent of effects on BP• No effect on mortality or cardiovascular outcomes

Diabetes Clinical Cases

Case 1

60 y.o. ♂, mildly obese

• Inferior myocardial infarction 6 months ago

• Echocardiogram: mild left ventricular dysfunction

• Started on glyburide 5 mg bid post-discharge

• Fasting blood glucose values currently 8 – 10

Case 1 – Points for discussion

• High risk for cardiac complications– Aggressive risk factor modification

• Diet and exercise review

• Role for insulin

• Role for metformin - UKPDS

Case 2

50 y.o. ♀; Type 2 DM for 6 years; uses 30/70 bid

• Poor glycemic control despite increasing doses

• Persistently elevated fasting blood glucose values

• Progressive weight gain

• Lab: LDL 3.2

↑microalb/creat. ratio


• Often difficult to achieve optimal control with 30/70 bid– Insulin adjustment difficult– Nocturnal hypoglycemia and Somogyi effect common

• NPH action (hrs): Onset: 2.5-3.0 Peak: 5-7 Dur’n: 13-16

• ↑ LDL: Treat lipid abnormalities aggressively

• ↑ microalb/Cr ratio: 24-hour urine to confirm – If abnormal: optimize glycemic control + ACE - inhibitor

Case 3

40 y.o. ♀; Type 1 diabetes for 15 years

• Regular with meals (fixed doses) and NPH qhs

• Sub-optimal glycemic control; HbA1c 8.5%

• Frequent hypoglycemia

• BP 150/80

• Urine: 1+ proteinuria


• Lyspro insulin– Less post-prandial hyperglycemia– Less hypoglycemia

• Adjust insulin doses according to CHO content

• Probable nephropathy:– 24-hour urine; ACE-inhibition; aggressive BP control

Case 4

65 y.o. ♂; Type 2 diabetes for 7 years

• Glyburide 10 mg bid; metformin 1000 mg bid

• Fasting blood glucose values: 10 – 12

• Lipid profile: ↑ TG, ↓ HDL, normal LDL


• Diet and exercise review

• Consider insulin sensitizer– e.g. pioglitazone, rosiglitazone

Case 5

75 y.o. ♀; Type 2 diabetes for 12 years

• Main complaint: pain in feet at night

• Physical examination: callus formation, ↓ monofilament sensation


• Neuropathic pain:– Tricyclic antidepressant– Gabapentin– Capsaicin

• Foot care:– Education – inspection, walking barefoot– Footwear– Nail care

issues in diabetes care academic half-day february 2002 d. hunt

Documents

diabetes control

insulin slide

undiagnosed diabetes

patientyears diabetes

years type

times slide

hunt slide

diabetes mellitus harris