Targeting the Targets

Type II Diabetes

Richard NabhanSenior Consultant PhysicianCardiologist & Diabetologist

Fellow of the Royal College of PhysiciansM.B.Ch.B, D.T.M&H, M.R.C.P (UK), F.R.C.P (London)

Life Style Medical Centre 04/11/06

CASE PRESENTATION

Ms. Fatima, Age 48, is a Banker, & a mother with (4) children

She is known to be Diabetic > 5 Years Inadequately controlled with Glyburide 20

mg/day Her mother & Aunt are Diabetic (DM2) She appeared to her GP for CONTROL

• BMI = 32 Kg/ m2 • WC = 39”• BP = 139/ 87 mmHg• FBS = 230 mg/dl• HBA1C = 10.6%

Case Facts

Findings• Total Cholesterol = 235 mg/dl• HDL-C = 51 mg/dl• LDL-C = 126 mg/dl• Triglyceride = 282 mg/dl• B urea = 21 mg/dl• S creat. = 1.1 mg/dl

Signs were not noticed by GP

1. Family History of Type II DM2. Central Obesity3. High FBS inspite of Mono therapy (OAD)

4. High HBA1C – Uncontrolled Diabetes

5. Dyslipidemia6. BP – Not optimal

GP response . . .

Risk FactorsRisk FactorsAre there any Risk Factors for Diabetes related complications?

He added metformin 500 mg titrated to 2000 mg/day to be seen after 3/12

Questioning the GP’s response?Questioning the GP’s response?

1. Was this the Best response ?2. What is the weapon used by Diabetes to attack its victims ?3. Which is best …

a. To address Glycemic Control ONLY ?b. To keep the patients’ vital arteries open ?

4. Did she need further screening for target organ damage ?

5. Did she need Theraputic Lifestyle Change (TLC) ?6. Did the patient need Diabetic & Dietetic education ?7. Should the GP have advised self-monitoring of her Blood Sugar & BP ?

Benefits of SMBG

Useful tool for control & therapy of all diabetics Ability to detect Hyperglycemia & Hypoglycemia at odd times

as well May uncover eating disorders & other issues related to stress,

diet & exercise Better administration & correlation of insulin dosages (less

guessing) Reassures for the fear of Hypoglycemia especially at night

My policy is to give my patients Note Book to record each High or Low sugar readings & explain why it happened & what measure

to be taken to AVOID this abnormal reading in the future.

With my advice & criticism, the patient will be able to obtain a good Glycemic Control by self adjustment

The Golden ABC Goals for Diabetic Management

HBA1C < 7%FBS < 110 mg/dlPPS < 140 mg/dl

Cholester

ol

Blood Pressure

A 1C

Systolic < 130 mmHgDiastolic < 80 mmHg

LDL-C < 100 mg/dlHDL-C > 40 mg/dl (men)HDL-C > 50 mg/dl (women)Triglyceride < 150 mg/dl

A for

B for

C for

Some Facts from (UKPDS)

Benefits from Lowering HBA1C – ONLY 1% reduction in HBA1C results in:

21% risk reduction from DM related End Points 21% risk reduction from DM related Deaths 14% risk reduction from MI 37% risk reduction from Microvascular complications

MY ADVICE . . . Trust FBS for Reducing High HBA1C > 8%Trust PPBS for Reducing Lower HBA1C < 8%

Lessons to Learn from Fatima’s Case

1. TLC – Diet, Loss of weight & Exercise Lowers…

BP, Cholesterol, Triglyceride, & improves Glycemic controlThe Cheapest form of treatment

2. Referral to • Diabetic Educator • Dietician (food facts)

3. Instructions on how to self monitor her Blood Sugar & BP ( SMBG was a must )

4. Optimizing her BP to prevent vascular events

5. Attending the atherogenic dyslipidemia a must

Strongly advisable

Observations from Fatima’s case

Appropriate control Appropriate control of :of :

1. Body weight

2. BP

3. Lipid Level

Significantly reduces CV events

Clustering of elements of Metabolic Clustering of elements of Metabolic SyndromeSyndrome

1. Abdominal Obesity

2. Elevated BP

3. Atherogenic Dyslipidemia

4. Insulin resistanceAchanthosis Nigricans

Reduce High BP

You reduce the risks of

WHEN & HOW to reduce BP

SBP (130 – 139)

DBP (80 – 89)Lifestyle modification for 3 months

SBP ≥ 140 mmHg Should receive ACE &/or ARB + TLC (must)

For resistant cases you may add (Polypharmacy) diuretics, CCB, betablockers & on top of that TLC

TLC is a common denominator in all forms of treatment & prevention

1. CVD2. Micro Vascular Complications

- Retinopathy- Nephropathy

3. Stroke & All Diabetic End Points

Points to Remember in DM2 with HTN

1. Increase in pulse pressure, increases CV morbidity

2. Lack of nocturnal dipping of BP, increase risks of renal & CVD

3. Orthostatic hypotension & lack of auto regulation of blood pressure increases pressure within target organs

4. Hyperinsulinemia & insulin resistance increase sympathetic drive thus contributing to hypertension

Dyslipidemia in DM2

1. Dyslipidemia is associated with progression of CVD… retinopathy … & nephropathy …

2. Pre-existing CVD + LDL-C > 100 mg/ dlOR

No CVD + LDL-C > 135 mg/ dl

Starts with intensive TLC till LDL becomes < 100 mg/ dl

3. Patients with High C-Reactive Protein (CRP), LDL-C should be < 70 mg/dl

4. If TLC is inadequate, starts STATIN as your first line in treatment of dyslipidemia

5. Second line treatment – cholesterol absorption inhibitors, fibrates, nicotinic acid

Never

forget

The Golden Rule in DM2

DM2 is a CVD equivalent

thus

STATIN therapy is a MUST

when starting treatment for all DM2

Increasing HDL Cholesterol & lowering Triglyceride

1. Adequate Glycemic Control improves Triglyceride profile.

2. Difficult to obtain targets but . . .

INTENSIVE TLC ± Nicotinic Acid ± Fibrate ± High STATIN dozes

May improve

the levels

Thinning Agents

Aspirin (an anti-platelet stickiness agent) stood the test of time as primary or secondary preventive measure of CV events, even in Diabetics.

ALWAYS remind patients on Aspirin to watch their stool for black colour.

Clopidogrel is another anti-platelet agent which maybe used with Aspirin in high risk patients or when Aspirin is contra indicated.

It is a MUST with stents for at least 9/12

Back to Fatima’s Case

After 3/12 on max doze of Metformin and Glyburide, Fatima’s sugars’ level were still high.

HBA1C=9.6 , FBS=208 mg/dl, BP=134/90

Her son who is a medical student did a test for urinary microalbumin which was high.

Her GP was unhappy about this interference.

He added Glitazon (insulin sensitizer) to the previous combination

Any comments about this consultation?

Patient failed to obtain glycemic control inspite of max. doze of two OADs?

Could this mean exhaustion of beta cells?

Could this make exogenous insulin as a likely option?

Did the GP behave nicely with her son?

Could she have obtained better results if the GP was more experienced in Diabetology?

Every 5 years beta cell functions decline by 50%

Ignoring Microalbuminurea

Is microalbuminurea an early sign of diabetic nephropathy ?

Does it increase CV risks ?

Why was it ignored by the GP ?

Can it be reversed at an early stage ?

Could microalbuminurea be prevented ?

Screening for Diabetic Nephropathy

TEST WHEN NORMAL RANGEBlood Pressure

Each office visit < 130/80 mmHg< 120/75 mmHg

if Nephropothy is present

Urinary microalbumin

DM2: Annually beginning at diagnosis

< 30 mg/day

DM1: Annually, 5 years post-diagnosis

< 30 mg/day

1.1. Hypertension Control Hypertension Control

2. Glycemic Control2. Glycemic Control

3. Restrict Dietary Protein 3. Restrict Dietary Protein

Treatment of Diabetic Nephropathy

- Preprandial plasma glucose 90-120 mg/dl- A1C < 7 %- Peak postprandial plasma glucose < 140 mg/dl- Self-monitoring of blood glucose (SMBG)- Medical Nutrition Therapy

2. Glycemic Control 2. Glycemic Control

A. Antihypertensive agents1. Angiotensin-converting enzyme (ACE) inhibitorscaptopril, enalapril, lisinopril, benazepril, fosinopril, ramipril,

quinapril, perindropil, trandolapril, moexipril

2. Angiotensin receptor blocker (ARB) therapycandesartan, irbesartan, losartan, telmisartan, valsartan,

esprosartan

3. Beta blockerB. TLC including salt free diets

1. Hypertension Control <130/80 mmHg1. Hypertension Control <130/80 mmHg

Prevention of Diabetic Nephropathy

• Maintain BP < 130/80 mmHg …BUT if microalbuminurea appears, then BP should be < 120/75 mmHg

• Maintain HBA1C < 7%

• Maintain FBS < 90 -120 mg/dl PPBS < 140 mg/dl

Points to learn from Fatima at this stageThis is an appropriate stage to intervene & educate Fatima about . . .1. Progression of the disease2. OAD control is for short periods only3. She should be prepared for insulin therapy 4. We should stress on TLC, (Diet, weight loss, exercise)

Should have started SMBG for Glycemic Control Should have controlled her BP & Dyslipidemia Should have referred her to a Diabetic Educator Should have a comprehensive Dietary Evaluation:

Carb management, Reduced sodium & protein intake

P L E A S E R E M E M B E R

Useful Facts on Beta Cell Function

Therapy of DM2 begins with TLC -/+ 1 or more OAD

DM2 is characterized by progressive ßcell impairment Every 5 years ßcell score 50% decline in function Even minimal elevation in FBS may result from profound

reduction and ßcell function DM2 can have normal FBS but elevated PPBS Both FBS and PPBS increase as a result of ßcell failure

thus oral agents (AODs) can help for a limited time. Eventually ßcell deteriorates to the degree of needing

exogenous insulin

Understanding Endogenous Insulin

After glucose challenge 2 spikes of insulin secretions appears:

It inhibits glucose production from liver allowing to take up 40 -50% of glucose from circulation after absorption of glucose from ingested carbs in the gut

In DM2 , this phase is absent, thus Blood Sugar is high

A. Early spike 10 minutes after Glucose challenge

B. Late spike 2 hours after glucose challenge The second spike of insulin drives any glucose not taken by liver into

muscle and adipose tissue. In DM2 insulin resistance lies mainly in muscle thus exercise might help

to drive glucose out of the circulation into muscle to liberate energy

Exercise is the cheapest way to lower your glucose

OAD Agents

2. Drugs that helps the action of insulinBiguanidesAcarboseTZDs (Glitazones)…insulin sensitizers

Major classes have different sites and mechanisms of action, thus can work synergistically in combination

1. Drugs that helps the secretion of insulin

SulphonylureaMeglitinides

Fatima’s Progress

BP = 162/88 Total Cholesterol = 213 mg/dlBMI = 33 kg/m2 HDL–C = 44 mg/dlW.C. = 40 kg/m2 LDL–C = 136 mg/dlFBS = 208 mg/dl Triglyceride = 224 mg/dlHBA1C = 9.1% Microalbuminurea = 240 mg/dl

(4) months later she walked in for stomach pain….Upon evaluation, the findings were:

GP decided to stop sulphonyleurea and glitazone & add Biphasic insulin (premix) 70/30

bd to metformin

What could you have done if you were the GP ?

1. Address Nephropathy ACE ± ARB + STATIN + Glycemic control + Dietry advice on carb, protein, salt + TLC

2. SMBG & Insulin education

3. Biphasic Insulin commonly used but never lowers HBA1C to < 8%

4. Did not address atherogenic dyslipidemia

Starting Insulin in DM2

If HBA1C remains > 7% inspite of max. OAD, then Insulin should be started

Early Insulin therapy may preserve Beta cell function

Insulin + Metformin is cheaper than triple OADs

Barriers to Insulin Therapy

Hypglycemia is the biggest

barrier to tight Glycemic Control

weight gain contributes to Insulin

resistance & CV risk factors

Again with Fatima

After 4 months, she visited ER after experiencing ? Hypoglycemia (c/o tingling of feet + blurred vision)

She blamed Insulin for them, thus stopped Insulin Did few FBS, but all were > 200 mg/dl HBA1C = 8.8% Microalbuminurea = 320 mg Gained 6 kg, denied having problems with eating Being a Mother, Wife and a Banker, makes dietary compliance difficult She watches sugar, but not total carb intake Plenty of orange juice because it contains vitamin C (to prevent illness) Does not use sweeteners because they cause cancer

How could we have helped at this stage

At the point of starting insulin . . . Education on Insulin starting from action, types, . . . up to

negotiating erratic controlSMBGPre & Post prandial - - - to bed timeHow to adjust the dozesKeep a note book to record hyper and hypoglycemia

recordingsShe should also be asked to record how and why it

happened & by learning this fact, she will be able to correct the diviations on her own

Education on Dietary facts, benefits of loss of weight, benefits of exercise

Close touch with the Diabetic Educator & Dietician

Monitoring BP, and means to lower it

Prevention of progression of nephropathy

Correcting Dyslipidemia

Make sure we can translate TLC slogan into actual practice

Continued…

How to make Insulin Therapy workConventional insulin therapy consist of using premixed

regimens (regular and NPH)

Often too rigid inconsistent with eating (3) or more meals resulting an alternating excessive and insufficient insulin levels, thus increasing chances of hypoglycemia, and compromising glycemic control

Hypoglycemia leads to poor compliance or discontinuation of Insulin

Pre-mixes are effective in lowering glucose levels from 300 mg/dl to 200 mg/dl ONLY

Our Goal To mimic physiological insulin secretion to control

FBS, and PPBS

Therapy needs: Long acting basal insulin that suppresses glucose

production between meals & overnight Short acting prandial component that addresses PPBS

Our realistic Goal an HBA1C level as close to normal

without inducing unacceptable side effects

Adding Basal Insulin to OAD

1. Continue OAD at same doze to ensure adequate control of PPG excursions

2. Add a single dose of pre-mix (70/30) insulin in the eve, or NPH, or Glargine Insulin at bed time

3. Address FBS to keep it under 120

This is an effective approach to achieve Glycemic Target