Managing Diabetes and Metabolic syndrome 2008 Treatment Perspectives

by

Professor Dr Intekhab AlamDepartment of Medicine

PGMI, Khyber Medical UniversityLady Reading Hospital, Peshawar.

InsulinResistance

Type 2 Diabetes

-cellDysfunction

InsulinResistance

Hyperglycaem

ia

InsulinConcentration

Insulin Action

Euglycaemia

-cell Failure

Normal IGT ± Obesity Diagnosis oftype 2 diabetes

Progression oftype 2 diabetes

Dual defect of type 2 diabetes: treating a moving target

DeFronzo et al. Diabetes Care 1992;15:318-68

Harris. Consultant. 1997;37 Suppl:S9

IGT

Undiagnosedtype 2 diabetes

Diagnosedtype 2 diabetes

504540353025201510

5020-44 45-54 55-64 65

Age (years)

% o

f p

op

ula

tio

n

IGT is driving the worldwide diabetes pandemic

Type 2 Diabetes : Tip of the Iceberg

Stage IIImpaired glucosetolerance

Stage IIIDiabetes

Stage INormal glucosetolerance

Macroangiopathy

Microangiopathy

AtherogenesisHyperinsulinaemiaInsulin Resistance

PostprandialPlasma glucose

Glucose production Glucose transport

Insulin secretory deficiency

Lipogenesis Obesity

Waist-hip ratio

Tg HDL

Hypertension

Diabetes Genes

“Genetics loads the gunBut the environment pulls the trigger”

Joslin, 1927

Life Style

Diet

Exercise

Principles of Diabetes Care

Isulin Secretagogues

Sulfonylureas

Meglitinides

Insulin SensitizersMetformin

Thiazolidenediones

Incretin mimetics

Hyperlipidaemia

Hypertension

Microalbuminuria

Insulin•

•

•

•

••

•

◄Glycosidase Inhibitors

•

Pramlintide•

Treatment of the Metabolic Syndrome in Overweight or Obese Patients

• Weight loss induced by diet and increased physical activity is the cornerstone of therapy

• Weight loss induced by drug therapy can also improve specific features of the metabolic syndrome

• Bariatric surgery is the most effective weight loss therapy for extremely obese subjects and improves all features of the metabolic syndrome

Treatment of Metabolic Syndrome in Patients with Diabetes

• 80-85% of diabetic subjects in North America and Europe have the metabolic syndrome

• However, most subjects with the metabolic syndrome do not have diabetes

• Statin therapy has been shown to be effective in diabetic subjects (4S, HPS, CARE, CARDS).

• Treatment of Hypertension is also crucially important in diabetic subjects (UKPDS, SYST-Euro, HOT).

OBESITY CO-MORBIDITY WEIGHT LOSS BENEFIT OF WEIGHT LOSS

Mortality 10 kg • >20% fall in total mortality• >30% fall in diabetes-related deaths• Fall in obesity-related cancer deaths

Diabetes 10 kg • Fall in 50% fasting glucose

Blood pressure 10 kg • Fall of 10 mmHg systolic• Fall of 20 mmHg diastolic

Blood lipids 10 kg • Fall of 10 % total cholesterol• Fall of 15% LDL• Fall of 30% triglycerides• Increase of 8% HDL

Blood clotting indices

• Reduced red cell aggregability• Improved fibrinolytic capacity

Physical complications

5 – 10 kg • Improved back and joint pain• Improved lung function• Decreased breathlessness• Reduced frequency of sleep apnoea

Ovarian function >5% • Improved ovarian function

Goal for Glycemic Control

• HbA1C less than 7% (6.5%?)

• Fasting sugars less than 110

• Two-hour postprandial sugars

less than 140

• Blood pressure less than 130/80 (125/75 if renal impairment)

KEY CONCEPTS IN SETTING GLYCEMIC CONTROL

Goals should be individualized

Certain populations(children, pregnant women,elderly) require special considerations

Less intensive glycemic goals for patients with frequent hypoglycemia

Postprandial goals may be targeted if A1C goals are not met despite reaching pre-prandial glucose goals

Life Style

Diet Exercise

Principles of Diabetes Care

How much?

•2½ hours weekly or 30 min a day for 5 days a wk

•Moderate exertion like brisk walk, light exercise….

•Increase activity rather than stressing on exercise.

Exercise!

Life Style

DietExercise

Principles of Diabetes Care

Outline•Maintain Ideal Body Weight.

Maximum 25 (men) 24 (women)

•“Limit” total fat

•“Limit” free sugars

“From an excess of FAT diabetes begins&

from an excess of FAT diabetics die.”

Take Home Messages

“if you love them don’t stuff them”

Don’t allow your children to get obese.

Eat less and remain healthy.

Physical activity or exercise doesn’t play a great role in weight loss.

It is possible to remain slim after overeating but it is not possible to get obese without overeating.

Relative risk for death increases with 2-hour blood glucose irrespective of the

FPG level

<6.1 6.1–6.9 7.0

11.1

7.8–11.0

<7.8

Fasting plasma glucose (mmol/l)

2-hour plasma glucose(mmol/l)

2.5

2.0

1.5

1.0

0.5

0.0

Haz

ard

rat

io

Adjusted for age, centre, genderDECODE Study Group. Lancet 1999;354:617–621

Knowledge from UKPDS and DECODE

Hyperglycaemia

Tissue damage

Diabetescomplication

Total load (HbA1c)

Chronicglucose toxicity

Microangiopathy

UKPDS1

Postprandial peaks

Acuteglucose toxicity

Macroangiopathy

DECODE2

DECODE: Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe, HbA1c: haemoglobin A1c, UKPDS: UK Prospective Diabetes Study

1. Stratton IM, et al. BMJ 2000;321:405–12.2. DECODE. Diabetes Care 2003;26:688–96.

Postprandial Glucose Monitoring Take-home messages

• Epidemiological data supports relationship between postprandial glycemia and mortality including cardiovascular mortality.

• Outcomes trials show benefit of reducing HbA1c for microvascular and macrovascular disease with no threshold for glycemic control

• Emerging evidence that targeting postprandial glucose reduces adverse outcomes

Pharmacological Therapy

Matching pathophysiology to pharmacology

Type 2 Diabetes Standard “Stepped” Approach to

Treatment

• Step1: Education, Diet, Exercise & SMBG• Step2: Oral Antidiabetic Agents (Monotherapay)• Step3: Oral Antidiabetic Agents

“Combination therapy”.• Step4: Bedtime NPH or Glargine + Daytime OAD• Step5: BID Split / Mixed Insulin• Step6: Multiple daily Injections

Targeting Insulin Resistance:

A Strategy forImproving Glycemic Control

in Type 2 Diabetes

Insulin Resistance: Definition

Condition in which greater than normal amounts of insulin are required to produce

a normal biological response

Olefsky JM. In: Olefsky JM. In: Ellenberg and Rifkin’s Diabetes MellitusEllenberg and Rifkin’s Diabetes Mellitus. 5th ed. 1997:513-552.. 5th ed. 1997:513-552.

Consequences of Insulin Resistance

Pancreas

...and glucose uptake in fat and muscle

decreases

Insulin

Insulin resistance interferes with the insulin signal...

…hepatic glucose output increases

Liver Fat Muscle

Reaven. Physiol Rev 1995;75:473-483.

FFA output increases

Insulin resistance exposes patients to.....

Modified from Reaven G. In: LeRoith D, et al, eds. Diabetes Mellitus: A Fundamental and Clinical Text. 2000;Philadelphia, PA: LWW pp604-614.

.

Excessive calorific intake

ObesityInsulin Resistance

Inherited genetic

susceptibility

Hyperinsulinemia

Hypertension Atherosclerosis

Dyslipidaemia

Raised TG

Raised LDL-C

Lowered HDL-CReduced nitric

oxide production

Raised

inflammatory

markers

Insulin Resistance and Type 2 Diabetes

• 40% of older people are insulin resistant mostly secondary to obesity and inactivity (important in prevention and treatment)

• 20% of the elderly have type 2 diabetes• 8.5% of all adults have type 2 diabetes• 90% of diabetics are managed in

primary care

One Approach to Selecting Medication for Type 2 Diabetics

Check a fasting insulin C-peptide level• If high or high-normal use an insulin

sensitizer – biguanine or glitazone or a combination of the two

• If low or low-normal use an insulin secretagogue

Consider changing patients who were put on insulin before the new oral diabetes medications to insulin sensitizers

Life Style

Diet

Exercise

Principles of Diabetes Care

Isulin Secretagogues

Sulfonylureas

Meglitinides

Insulin SensitizersMetformin

Thiazolidenediones

Incretin mimetics

Hyperlipidaemia

Hypertension

Microalbuminuria

Insulin•

•

•

•

••

•

◄Glycosidase Inhibitors

•

Pramlintide•

Insulin sensitizers

BIGUANIDES

THIAZOLIDINEDIONES.

BIGUANIDES

Metformin

First Line Drug for Type 2 Diabetes

Biguanides (Metformin)

• Decreases hepatic glucose output• Increases insulin sensitivity• Decreases LDL and triglycerides• Decreases C-reactive protein• Causes weight loss or stabilization• No risk of hypoglycemia• Causes nausea, cramps and diarrhea• Lactic acidosis rare (contraindications –

CHF, renal impairment, age greater than 80)

UKPDS - 1998Traditional glycemic control (secretagogues)reduced microvascular complications • Retinopathy -29%• Nephropathy -33%• Neuropathy -40%But not macrovascular complications• MI’s -16%• Stroke +11%• Deaths -6%

UKPDS 1998

Metformin decreased macrovascular

complicatons (lower insulin levels)

• MI -39%

• Coronary Deaths -50%

• Diabetes Related

Deaths -42%

• All Cause Mortality -36%

Risk reductions from intervention studies in type 2 diabetes

Clinical Outcomes

Diabetes-related deaths (%)

All-cause mortality (%)

All MI (%)

Fatal MI (%)

All stroke (%)

Fatal stroke (%)

Follow-up (years)

UKPDSSU/Ins

n=3867

10

6

16

6

(+)11

(+)17

10.7

UKPDSCaptoprilAtenololn=1148

32

18

21

28

44

58

8.4

HOPERamipril

n=3577

37

24

22

-

33

-

4.5

HOTFelodipine

Aspirinn=1501

67

43

51

-

30

-

3.8

4SSimva-statinn=202

36

43

55

-

62

-

5.4

UKPDSMetformin

n=753

42

36

39

50

41

25

10.7

Thiazolidinediones

PioglitazoneRosiglitazone

MECHANISM OF ACTION

Peroxisome Proliferator Acivated Receptor-gamma

(PPAR-γ) agonists.

Expression of number of genes

↑glucose transporter expression(GLUT 4)

↓FFA

↓hepatic gluconeogenesis

↑differentiation of preadipocytes into adipocytes

THIAZOLIDINEDIONES

THE PPAR FAMILY OF NUCLEAR RECEPTORS

LIGAND

PPAR α PPAR δPPAR γRECEPTOR

EFFECT

FIBRATES THIOZOLIDINEDIONES FATTY ACIDS

LIPOPROTEIN EXPRESSION

PEROXISOME PROLIFERATION

LIPID SYNTHESIS CARBOHYDRATE METABOLISM

PPAR Increases Glucose Disposal:

Potential Site of Action

SITES OF ACTION OF ORAL ANTIDIABETIC AGENTS

DelayCarbohydrate absorption

Acarbose

Reduce Hyperglycemia

Stimulate ImpairedInsulin secretion

Sulfonylureas

Reduce excessive Hepatic glucose output

TZD’s 20%

Metformin 80%

TZD’s80%

Metformin20%

Reduce peripheralInsulin resistance

DURATION OF ACTION

24-30 Hours

SIDE EFFECTS

Hepatotoxicity

Weight gain

Fluid retention

Anemia

CONTRAINDICATIONSLiver diseaseHeart Failure (NYHA class 3 &4)

THIAZOLIDINEDIONES

Indications

As an adjunct to diet & exercise to improve glycemic control in patients with type 2 diabetes.

Indicated as monotherapy

Also indicated for use in combination with a sulfonylurea, metformin or insulin.

Insulin Sensitizers Do More Than Just Lower Glucose

• Improve lipid (TZDs >> Metformin)– Decrease TG, Increase HDL, Increase LDL – bigger particle

• Lower CRP (TZD > Metformin)• Lower PAI-1 (TZD & Metformin)• Decrease intra abdominal fat (TZD)• ? Protect beta cell (TZD)• Prevent restenosis after stenting.

Fixed-Dose Monotherapy Study Change in HbA1c at Endpoint

0.6

0

-0.8*

-0.6*

-1.9*

-2.5

-2

-1.5

-1

-0.5

0

0.5

1

-0.6

-1.4+

-1.3+

-2.6+-3

-2.5

-2

-1.5

-1

-0.5

0

0.5

1 Placebo (n=25)

7.5mg (n=27)

15mg (n=26)

30mg (n=26)

45mg (n=21)

HbA1c at week 26 (% points)

Change from baseline Difference from placebo

Baseline mean HbA1c: 9.5%*p<0.05 vs baseline†p<0.05 vs placebo

adapted from: Aronoff S, et al., Diabetes Care 2000;23:1605-1611.

0.3

-1.8

-2.9-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

0.5

1

FPG at week 16 (mmol/L)

Mean Change from baseline

Baseline mean FPG placebo: 13.1 mmol/L, pioglitazone: 13.5mmol/L *p=0.05 vs baseline †p=0.05 vs placebo +SU

Kipnes MS, et al. Am J Med 2001;111:10-17.

Pioglitazone + Sulphonylurea StudyMean Changes in FPG at Endpoint

Placebo + SU (n=182)

Plo 15mg + SU (n=179)Plo 30mg + SU (n=186)

-0.3

-2.4-3

-2.5

-2

-1.5

-1

-0.5

0

0.5

1

Pioglitazone + Metformin StudyMean Changes in FPG at Endpoint

FPG at week 16 (mmol/L)

Mean Change from baseline

Baseline mean FPG:placebo 14.4 mmol/L, pioglitazone 14.0 mmol/L *p<0.05 vs baseline †p<0.05 vs placebo + MetEinhorn D, et al. Clin Ther 2000;22:1395-1409.

Placebo + Met (n=157)

Plo 30mg + Met (n=167)

Pioglitazone:

Favorable effects on serum lipids

Study Objective

To evaluate the impact of pioglitazone and rosiglitazone on lipid profiles and glycemic control in patients with type 2 diabetes

pioglitazone

rosiglitazone

Mean Change in Triglyceride

Mean change in TG

(mg/dL)

-60

-50

-40

-30

-20

-10

0

Pioglitazone vs. Rosiglitazone:

P <0.001

-55.2P <0.001 vs. baseline

-23%-13.3

P = 0.041 vs. baseline

-6%

Pioglitazone Rosiglitazone

Mean Change in Total Cholesterol

Mean change

in TC (mg/dL)

Pioglitazone Rosiglitazone

Pioglitazone vs. Rosiglitazone:

P <0.001

-10

-8

-6

-4

-2

0

2

4

6

-8.5

-4%

P <0.001 vs. baseline

4.8

2%

P = 0.011 vs. baseline

Mean Change in HDL-C

Mean change in HDL-

C (mg/dL)

-0.5

0.0

0.5

1.0

1.5

2.0

2.5

3.0

Pioglitazone Rosiglitazone

Pioglitazone vs. Rosiglitazone:

P = 0.064

2.7

6%

P <0.001 vs. baseline -0.1

-0.3%

P = 0.924 vs. baseline

Mean Change in LDL-C

Mean change in LDL-C (mg/dL)

Pioglitazone Rosiglitazone

-6

-4

-2

0

2

4

6

Pioglitazone vs. Rosiglitazone:

P <0.001 -5.1

-4%

P = 0.002 vs. baseline

3.6

3%

P = 0.030 vs. baseline

Conclusions

• Blood lipid levels changed

more favorably with

pioglitazone than with

rosiglitazone

• Changes in HbA1c and

weight gain were

equivalent

pioglitazone

rosiglitazone

Pioglitazone. A new armament against Type 2 DM

An insulin sensitizer that reduces insulin

resistance Provides excellent glycemic control Less risk of Hypoglycemia Improves lipid profile Reduces the risk of CVD.Indicated as mono therapy as well as in

combination with Metformin, Sulfonylureas &

Insulin

Non Glycemic Goals:Treat All Cardiovascular Risks Factors

Aggressively• Smoking

• Hypertension– BP less than 130/80

• Lipids– LDL Cholesterol < 100 mg/dl

• LDL less than 70 mg/dl in “high risk” cases– HDL cholesterol > 40 mg/dl– Triglycerides < 150 mg/dl

• Aspirin

Case History

30 y.o. woman with a history of gestationaldiabetes with her first pregnancy at age 21presents with frequent urination, thirst, weightloss and a random glucose of 250. She has anIUD in place. Her BMI is 33. BP is 140/80.Is this enough information to diagnose

diabetes? What other tests would you order?

Test Results• HbA1C 9.2• Alb/Cr 0.010• Cr 0.6• LFT’s WNL• CBC WNL• TSH 2.3• Fasting Insulin

C-peptide 3.5HCG Neg

What will you do now?

• Educate your patient about diabetes and set goals together for her care

• Diabetic diet counseling and a weight loss program

• Educate her in use of a glucometer.

• Devise exercise program for physical fitness.

Anything else?

• Refer to ophthalmologist

• Do microfilament check for neuropathy

• See frequently to reinforce diet, exercise, home glucose monitering

• Start Metformin.

• Treat BP with ACEI if remains over 130/80

Eight Months Later

Despite modest weight loss and compliance with her medications your patient still has a HbA1C of 8.0. Her blood pressue is 120/75 and her Alb/Cr is 0.012. LFT’s remain normal.

What would you do now?

Second Oral Medication

Add a

• Glitazone or

• Sulfonylurea

Summary

• Type 2 diabetes affects many organs• Type 2 diabetes changes over time• Diabetes treatment changes over time• Medications can now be selected to work

where the problem is• Combinations of medications, because they

work at different sites, in the body usually work better than monotherapy