Managing Diabetes and
Metabolic syndrome
2008 Treatment Perspectives
by
Professor Dr Intekhab Alam
Department of Medicine
PGMI, Khyber Medical University
Lady Reading Hospital, Peshawar.
Dual defect of type 2 diabetes: treating
a moving target
Insulin
Resistance
Type 2
Diabetes
Insulin
Concentration
b-cell
Dysfunction
b-cell Failure
Insulin
Resistance
Euglycaemia
Normal
IGT ± Obesity
Diagnosis of
type 2 diabetes
Progression of
type 2 diabetes
DeFronzo et al. Diabetes Care 1992;15:318-68
% of population
IGT is driving the worldwide
diabetes pandemic
50
45
40
35
30
25
20
15
10
5
0
20-44
IGT
Undiagnosed
type 2 diabetes
Diagnosed
type 2 diabetes
45-54
55-64
65
Age (years)
Harris. Consultant. 1997;37 Suppl:S9
Type 2 Diabetes : Tip of the Iceberg
Stage III
Diabetes
Stage II
Impaired glucose
tolerance
Stage I
Normal glucose
tolerance
Macroangiopathy
Microangiopathy


Postprandial
Plasma glucose 
Glucose production 
Glucose transport 
Insulin secretory deficiency
Lipogenesis 
Obesity
Waist-hip ratio
Atherogenesis
Hyperinsulinaemia
Insulin Resistance
Tg 
HDL 
Hypertension
Diabetes Genes
“Genetics loads the gun
But the environment pulls the trigger”
Joslin, 1927
Principles of Diabetes Care
Life Style
Exercise
•
Diet
•
Hypertension
Isulin Secretagogues
Sulfonylureas
•
Hyperlipidaemia
Meglitinides
•
•
•
•
Insulin Sensitizers
Microalbuminuria
Metformin
Thiazolidenediones
Incretin mimetics
Glycosidase Inhibitors
◄
•
•
Insulin
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, SYSTEuro, HOT).
OBESITY COMORBIDITY
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
• Reduced red cell aggregability
• Improved fibrinolytic capacity
Blood clotting
indices
Physical
complications
Ovarian function
5 – 10 kg
>5%
• Improved back and joint pain
• Improved lung function
• Decreased breathlessness
• Reduced frequency of sleep apnoea
• 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
Principles of Diabetes Care
Life Style
Diet
Exercise
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!
Principles of Diabetes Care
Life Style
Exercise
Diet
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 2hour blood glucose irrespective of the
FPG level
2.5
Hazard ratio
2.0
1.5
1.0
11.1
0.5
7.8–11.0
<7.8
0.0
<6.1
6.1–6.9
7.0
Fasting plasma glucose (mmol/l)
Adjusted for age, centre, gender
DECODE Study Group. Lancet 1999;354:617–621
Knowledge from UKPDS and DECODE
UKPDS1
DECODE2
Hyperglycaemia
Postprandial
peaks
Total load
(HbA1c)
Macroangiopathy
Microangiopathy
Acute
glucose toxicity
Chronic
glucose toxicity
Tissue
damage
Diabetes
complication
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 for
Improving 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: Ellenberg and Rifkin’s Diabetes Mellitus. 5th ed. 1997:513-552.
Consequences of Insulin Resistance
Insulin resistance interferes with
the insulin signal...
Insulin
Pancreas
Liver
…hepatic glucose
output increases
Fat
FFA output
increases
Reaven. Physiol Rev 1995;75:473-483.
Muscle
...and glucose uptake in
fat and muscle
decreases
Insulin resistance exposes patients to.....
Excessive
calorific intake
Obesity
Insulin Resistance
Inherited
genetic
susceptibility
Hyperinsulinemia
Dyslipidaemia
Raised TG
Raised LDL-C
Lowered HDL-C
Hypertension
Atherosclerosis
Reduced nitric
oxide production
Raised
inflammatory
markers
Modified from Reaven G. In: LeRoith D, et al, eds.
Diabetes Mellitus: A Fundamental and Clinical Text. 2000;Philadelphia, PA: LWW pp604-614.
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
Principles of Diabetes Care
Life Style
Exercise
•
Diet
•
Hypertension
Isulin Secretagogues
Sulfonylureas
•
Hyperlipidaemia
Meglitinides
•
•
•
•
Insulin Sensitizers
Microalbuminuria
Metformin
Thiazolidenediones
Incretin mimetics
Glycosidase Inhibitors
◄
•
•
Insulin
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 - 1998
Traditional 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
HOT
4S
UKPDS UKPDS UKPDS
Metformin SU/Ins Captopril Felodipine SimvaAtenolol
Aspirin
statin
n=1501
n=202
n=753 n=3867 n=1148
Diabetes-related deaths (%) 42
HOPE
Ramipril
n=3577
10
32
67
36
37
All-cause mortality (%)
36
6
18
43
43
24
All MI (%)
39
16
21
51
55
22
Fatal MI (%)
50
6
28
-
-
-
All stroke (%)
41
(+)11
44
30
62
33
Fatal stroke (%)
25
(+)17
58
-
-
-
10.7
10.7
8.4
3.8
5.4
4.5
Follow-up (years)
Thiazolidinediones
Pioglitazone
Rosiglitazone
THIAZOLIDINEDIONES
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
THE PPAR FAMILY OF
NUCLEAR RECEPTORS
LIGAND
RECEPTOR
FIBRATES
PPAR α
THIOZOLIDINEDIONES
PPAR γ
FATTY ACIDS
PPAR δ
EFFECT
LIPOPROTEIN
EXPRESSION
PEROXISOME LIPID SYNTHESIS
PROLIFERATION
CARBOHYDRATE
METABOLISM
PPARg Increases Glucose Disposal:
Potential Site of Action
SITES OF ACTION OF ORAL ANTIDIABETIC
AGENTS
Delay
Carbohydrate absorption
Acarbose
Stimulate Impaired
Insulin secretion
Reduce excessive
Hepatic glucose output
TZD’s 20%
Metformin 80%
TZD’s
80%
Reduce
Hyperglycemia
Sulfonylureas
Metformin
20%
Reduce peripheral
Insulin resistance
THIAZOLIDINEDIONES
DURATION OF ACTION
24-30 Hours
SIDE EFFECTS
Hepatotoxicity
Weight gain
Fluid retention
Anemia
CONTRAINDICATIONS
Liver disease
Heart Failure (NYHA class 3 &4)
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
HbA1c at week 26 (% points)
1
1
0.6
Placebo (n=25)
7.5mg (n=27)
15mg (n=26)
30mg (n=26)
45mg (n=21)
0.5
0.5
0
0
0
-0.5
-0.5
-1
-0.6
-0.8 *
*
-1
-1.5
-1.5
-2
-2
-1.9
*
-2.5
Change from baseline
Baseline mean HbA1c: 9.5%
*p<0.05 vs baseline
†p<0.05 vs placebo
-0.6
-1.4 -1.3
+ +
-2.5
-3
-2.6
Difference from placebo+
adapted from: Aronoff S, et al., Diabetes Care 2000;23:1605-1611.
Pioglitazone + Sulphonylurea Study
Mean Changes in FPG at Endpoint
 FPG at week 16 (mmol/L)
Placebo + SU (n=182)
Plo 15mg + SU (n=179)
Plo 30mg + SU (n=186)
1
0.5
0.3
0
-0.5
-1
-1.5
-2
-1.8
-2.5
-3
-2.9
-3.5
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 + Metformin Study
Mean Changes in FPG at Endpoint
 FPG at week 16 (mmol/L)
Placebo + Met (n=157)
Plo 30mg + Met (n=167)
1
0.5
0
-0.5
-0.3
-1
-1.5
-2
-2.5
-2.4
-3
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 + Met
Einhorn D, et al. Clin Ther 2000;22:1395-1409.
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
Pioglitazone
0
Rosiglitazone
-6%
-10
Mean
change -20
in TG
(mg/dL) -30
-13.3
-23%
P = 0.041 vs. baseline
-40
-50
-60
-55.2
P <0.001 vs. baseline
Pioglitazone vs.
Rosiglitazone:
P <0.001
Mean Change in Total Cholesterol
Pioglitazone
6
4
Mean 2
change 0
in TC
(mg/dL) -2
-4
-6
-8
-10
Rosiglitazone
4.8
2%
P = 0.011 vs. baseline
-4%
-8.5
P <0.001 vs. baseline
Pioglitazone vs.
Rosiglitazone:
P <0.001
Mean Change in HDL-C
Pioglitazone
3.0
Rosiglitazone
2.7
2.5
Mean 2.0
change
in HDL-C 1.5
(mg/dL)
1.0
6%
0.5
Pioglitazone vs.
Rosiglitazone:
P = 0.064
-0.3%
0.0
-0.5
P <0.001 vs. baseline
-0.1
P = 0.924 vs. baseline
Mean Change in LDL-C
Pioglitazone
Rosiglitazone
6
3.6
4
Mean
2
change
in LDL-C 0
(mg/dL)
-2
3%
P = 0.030 vs. baseline
-4%
-4
-6
-5.1
P = 0.002 vs. baseline
Pioglitazone vs.
Rosiglitazone:
P <0.001
Conclusions
pioglitazone
rosiglitazone
• Blood lipid levels changed
more favorably with
pioglitazone than with
rosiglitazone
• Changes in HbA1c and
weight gain were
equivalent
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 gestational
diabetes with her first pregnancy at age 21
presents with frequent urination, thirst, weight
loss and a random glucose of 250. She has an
IUD 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
Alb/Cr
Cr
LFT’s
CBC
TSH
Fasting Insulin
C-peptide
b-HCG
9.2
0.010
0.6
WNL
WNL
2.3
3.5
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