Managing Diabetes and Metabolic syndrome 2008 Treatment Perspectives by Professor Dr Intekhab Alam D epartment of Medicine PGMI, Khyber Medical University.
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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
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