How can diabetes care and

outcomes be improved?

Heri Fadjari
March 18, 2010
 Practical management of T2DM

Use of evidence-based methods wherever possible

Individualization of treatment.
Adjusting dosage and timing of medications, and substituting one
agent for another based on individualized clinical judgment rather
than evidence from trials of large populations.
Metabolic target should be established, and treatment adjusted to
achieve this target. HbA1c (A1c) value of 7% or less
Sequential addition of therapies (rather than substitution of one for
another) as the metabolic disorders underlying T2DM progress over
time.
 Insulin Secretion in Non-Diabetics
and T2DM
800
700 Normal
Insulin Secretion (pmol/min)

Type 2 DM
600
500
400
300
200
100

06:00 10:00 14:00 18:00 22:00 02:00 06:00

Clock Time (Hours)
O'MEARA et al. Am. J. Medicine, 1990;89
 Type 2 diabetes

Characterized by chronic hyperglycemia

Associated with microvascular and macrovascular
complications
Generally arises from a combination
of insulin resistance and
-cell dysfunction
Glucotoxicity
Lipotoxicity

Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Department of Noncommunicable Disease Surveillance,
World Health Organization, Geneva 1999. Available at: http://www.diabetes.org.uk/infocentre/carerec/diagnosi.doc
Glucose and FFA homeostasis

Post-absorptive/fasting period
Glucose and FFA homeostasis

Postprandial period
Control of fatty acid uptake and release by adipose
tissue
lipid-induced insulin resistance in skeletal muscle
 What is insulin resistance?

Major defect in individuals with type 2 diabetes1

Reduced biological response to insulin13
Strong predictor of type 2 diabetes4
Closely associated with obesity5

IR

1American Diabetes Association. Diabetes Care 1998; 21:310314.

2Beck-Nielsen H & Groop LC. J Clin Invest 1994; 94:17141721. 3Bloomgarden ZT. Clin Ther 1998; 20:216231.
4Haffner SM, et al. Circulation 2000; 101:975980. 5Boden G. Diabetes 1997; 46:310.
 What is -cell dysfunction?

Major defect in individuals with type 2 diabetes

Reduced ability of -cells to secrete insulin in response to
hyperglycemia

DeFronzo RA, et al. Diabetes Care 1992; 15:318354.

Insulin resistance and -cell dysfunction are core
defects of type 2 diabetes

Genetic susceptibility,
obesity, Western lifestyle

-cell
Insulin
resistance IR dysfunction

Type 2 diabetes

Rhodes CJ & White MF. Eur J Clin Invest 2002; 32 (Suppl. 3):313.
How do insulin resistance and -cell dysfunction combine
to cause type 2 diabetes?
Normal IGT* Type 2 diabetes

Insulin Increased insulin

resistance resistance

Insulin Hyperinsulinemia,
secretion then -cell failure

Post-prandial
Abnormal
glucose
glucose tolerance

Fasting glucose
Hyperglycemia

*IGT = impaired glucose tolerance

Adapted from Type 2 Diabetes BASICS. International Diabetes Center (IDC), Minneapolis, 2000.
 How is insulin resistance measured?

Several methods exist, including:

continuous sampling of insulin/glucose1

gold standard, but impractical for large-scale use

single measure of insulin/glucose2

simple estimate from fasting insulin and glucose
useful for assessment on a larger scale

1Bergman RN, et al. Eur J Clin Invest 2002; 32 (Suppl. 3):3545.

2Matthews DR, et al. Diabetologia 1985; 28:412419.
 More than 80% of patients progressing to T2DM
are insulin resistant
Insulin sensitive;
low insulin secretion (16%)

Insulin sensitive;
good insulin secretion Insulin resistant;
(1%) low insulin secretion (54%)

83%
Insulin resistant;
good insulin secretion (29%)

Haffner SM, et al. Circulation 2000; 101:975980.

 Insulin resistance reduced response to circulating
insulin
Insulin
resistance IR

Liver Muscle Adipose

tissue

Glucose output Glucose uptake Glucose uptake

Hyperglycemia
 Overall, 75% of patients with
type 2 diabetes die from cardiovascular
disease

Gray RP & Yudkin JS. Cardiovascular disease in diabetes mellitus. In Textbook of Diabetes 2nd Edition, 1997. Blackwell Sciences.
Insulin resistance is as strong a risk factor for
cardiovascular disease as smoking

1.8

1.6

1.4

1.2

1.0

0.8

0.6
Age Smoking Total cholesterol: Insulin
HDL cholesterol resistance

Bonora E, et al. Diabetes Care 2002; 25:11351141.

 Insulin resistance is closely linked to cardiovascular
disease

Present in > 80% of people with

type 2 diabetes1

Insulin Approximately doubles the risk

resistance IR of a cardiac event2

Implicated in almost half of CHD

events in individuals with type 2
diabetes2

1Haffner SM, et al. Circulation 2000; 101:975980.

2Strutton D, et al. Am J Man Care 2001; 7:765773.
 Insulin resistance is linked to a range of
cardiovascular risk factors

Hyperglycemia

Dyslipidemia

Hypertension
Insulin
resistance
IR Damage to blood
vessels

Clotting abnormalities
Atherosclerosis
Inflammation

Metabolic syndrome
Zimmet P. Trends Cardiovasc Med 2002; 12:354362.
~90% of people with type 2
diabetes are overweight or
obese

World Health Organization, 2005. http://www.who.int/dietphysicalactivity/publications/facts/obesity

 How is -cell function measured?

-cell function is difficult to measure and most methods are

impractical for large-scale use1
Homeostasis model assessment (HOMA) provides a simple
estimate of -cell function2
Proinsulin:insulin ratio is sometimes used as a marker of -cell
dysfunction1

1Matthews DR, et al. Diabetologia 1985; 28:412419.

2Bergman RN, et al. Eur J Clin Invest 2002; 32 (Suppl. 3):3545.
 Why does the -cell fail?
Oversecretion of insulin to
compensate for insulin
resistance1,2

Glucotoxicity2 Lipotoxicity3

Chronic Pancreas High circulating free

hyperglycemia fatty acids

-cell dysfunction
1Boden G & Shulman GI. Eur J Clin Invest 2002; 32:1423.
2Kaiser N, et al. J Pediatr Endocrinol Metab 2003; 16:522.
3Finegood DT & Topp B. Diabetes Obes Metab 2001; 3 (Suppl. 1):S20S27.
 Glycemic control declines over time
Diet
Sulfonylurea or insulin
9
Median HbA1c (%)

6.2% upper limit of normal range

6
0
0 3 6 9 12 15
Years from randomization

UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:837853.

 Loss of -cell function occurs before diagnosis

100

80 Up to
Diagnosis 50%
-cell function (%)

60 loss

40

20

0
-10 -9 -8 -7 -6 -5 -4 -3 -2 -1 1 2 3 4 5 6
Time from diagnosis (years)

Holman RR. Diabetes Res Clin Prac 1998; 40 (Suppl.):S21S25.

 Oral antidiabetic agents:
do they target insulin resistance and
-cell dysfunction?
Barriers to achieving good glycemic control

Inadequate targeting of
underlying
pathophysiology
 Primary sites of action of oral antidiabetic agents

-glucosidase Sulfonylureas/
inhibitors meglitinides Biguanides Thiazolidinediones

Carbohydrate Insulin Glucose output Insulin

breakdown/ secretion Insulin resistance resistance
absorption

Kobayashi M. Diabetes Obes Metab 1999; 1 (Suppl. 1):S32S40.

Nattrass M & Bailey CJ. Baillieres Best Pract Res Clin Endocrinol Metab 1999; 13:309329.
 Sulfonylureas
and
Biguanides TZDs Nonsulfonylurea
Decrease Hepatic Decreased Secretagogues
Glucose Lipolysis Increase Insulin
Thiazolidinedinones Production Secretion
(TZDs) Adipose Tissue
Increase Glucose Liver
Increased Lipolysis
Uptake
Increased Glucose Pancreatic
Skeletal Muscle Production Beta Cells
Decreased Increased
Glucose Uptake Free Fatty
Lipotoxicity Lipotoxicity
Acids Defective
Insulin
Insulin Secretion
resistant

a-Glucosidase
Inhibitors
Delay Intestinal
Carbohydrate
Absorption Hyperglycemia

Small Intestine
Carbohydrate
Absorption
 Options for monotherapy

Sulfonylureas

Meglitinides

Biguanides

Thiazolidinediones

Alpha-
glucosidase
inhibitors
 Target Population

Sulfonylureas

Meglitinides

Recent type 2 DM Biguanides

diagnosis
Type 2 DM < 5yrs Thiazolidinediones
duration
Alpha-glucosidase
inhibitors
 Target Population

Sulfonylureas

Meglitinides

Recent type 2 DM Biguanides

diagnosis
Thiazolidinediones
Elevated PPG

Alpha-glucosidase
inhibitors
 Target Population

Sulfonylureas

Meglitinides

Overweight/obese Biguanides
Insulin resistant
Thiazolidinediones

Alpha-glucosidase
inhibitors
 Target Population

Sulfonylureas

Meglitinides

Biguanides
Insulin resistant
Thiazolidinediones
Overweight
Obese Alpha-
glucosidase
inhibitors
 Target Population

Sulfonylureas

Meglitinides

Elevated PPG Biguanides

Contraindications to
other agents Thiazolidinediones

Alpha-glucosidase
inhibitors
 Advantages

Sulfonylureas

Meglitinides

Rapid FPG Biguanides

reduction
Low cost Thiazolidinediones

Alpha-glucosidase
inhibitors
 Advantages

Sulfonylureas

Meglitinides

Risk of Biguanides
hypoglycemia
Short-acting
Thiazolidinediones
Meal-adjusted
dosing Alpha-glucosidase
inhibitors
 Advantages

Sulfonylureas

Meglitinides

No weight gain Biguanides

Risk of
hypoglycemia Thiazolidinediones

Alpha-glucosidase
inhibitors
 Advantages

Sulfonylureas

Meglitinides

Biguanides

Amount of insulin
Thiazolidinediones
Risk hypoglycemia

Alpha-glucosidase
inhibitors
 Advantages

Sulfonylureas

Meglitinides

Biguanides
Risk of hypoglycemia
Thiazolidinediones
Non systemic action

Alpha-glucosidase
inhibitors
 Disadvantages

Sulfonylureas

Meglitinides

Weight gain Biguanides

Risk of
hypoglycemia Thiazolidinediones

Alpha-glucosidase
inhibitors
 Disadvantages

Sulfonylureas

Meglitinides

High costs Biguanides

Frequent dosing
Thiazolidinediones

Alpha-glucosidase
inhibitors
 Disadvantages

Sulfonylureas

Meglitinides

GI side effects Biguanides

High costs
Rare lactic Thiazolidinediones
acidosis

Alpha-glucosidase
inhibitors
 Disadvantages

Sulfonylureas

Meglitinides

Biguanides
High cost
Weight gain
Slow onset of action Thiazolidinediones
Issue of liver toxicity
Alpha-glucosidase
inhibitors
 Disadvantages

Sulfonylureas

Meglitinides

Biguanides
High cost
GI side effects Thiazolidinediones

Alpha-glucosidase
inhibitors
 Total daily dose (mg) & dosing interval

Sulfonylureas

Meglitinides

Glyburide 1.25 to 20 QD or BID

Biguanides
Glyburide, micronized 0.75 to 12 QD or BID
Glipzide 2.5 to 40 QD or BID Thiazolidinediones
Glipizide, extended-release 2.5 to 20 QD
Glimepiride 1 to 8 QD
Alpha-glucosidase
Glibenclamide 2 to 4 OD or BD inhibitors
 Total daily dose (mg) & dosing interval

Sulfonylureas

Meglitinides

Biguanides
Nateglinide 180 to 360 TID
Repaglinide 1.5 to 16 TID or QID
Thiazolidinediones

Alpha-glucosidase
inhibitors
 Total daily dose (mg) & dosing interval

Sulfonylureas

Meglitinides

Biguanides

Metformin HCI 1,000 to 2,550 BID orThiazolidinediones

TID
Metformin, extended-release 1,000 to 2,000 QD or BID

Alpha-glucosidase
inhibitors
 Total daily dose (mg) & dosing interval

Sulfonylureas

Meglitinides
Rosiglitazone maleate 4 to 8 QD or BID
Biguanides
Pioglitazone HCI 15 to 45 QD
Thiazolidinediones

Alpha-glucosidase
inhibitors
 Total daily dose (mg) & dosing interval

Sulfonylureas

Meglitinides

Acarbose 150 to 300 TID Biguanides

Miglitol 150 to 300 TID
Thiazolidinediones

Alpha-glucosidase
inhibitors
 Monotherapy Pearls

All drugs except AGIs and nateglinide equally reduce HbA1c

Metformin usually best for obese- no weight gain
Non-SU secretagogues may be useful for irregular meals
Metformin and TZDs avoid hypoglycemia
 Clinical Efficacy of
Oral Hypoglycemic Agents
Class of hypoglycemic agents Reduction in Reduction in FPG
HbA1c (%) (mg per dl)
Sulfonylureas 0.8 to 2.0 60 to 70
Meglitinides 0.5 to 2.0 65 to 75
Biguanides 1.5 to 2.0 50 to 70
Thiazolidinediones 0.5 to 1.5 25 to 50
Alpha-glucosidase inhibitors 0.7 to 1.0 35 to 40
 Options for combination therapy

Sulfonylureas +
Biguanide or Biguanide +
Alpha-
Thiazolidinedione
Biguanide + glucosidase
or Alpha- inhibitor
glucosidase meglitinide
inhibitor
Biguanides + Triple combination therapy
Thiazolidinediones Sulfonylurea + biguanide +
Thiazolidinedione or
Sulfonylurea + biguanide +
alpha-glucosidase inhibitor

If therapeutic goals are not met using the above combinations;

switch to insulin +/- oral agent
 Insulin
made from the pancreas of pig or cow, or synthetically made
can be stored at room temperature for up to a month
do not expose to direct sunlight and keep away from heat
store unopened and insulin that will last longer than a month in
refrigerator
monitor expiration date
review SQ injection sites
rotate site to prevent lipodystrophy
begin teaching patient insulin administration immediately
make sure patient can see lines on syringe and read label
 Insulin
Short acting insulin
Humalog - onset in 15 minutes, peaks a in 3 hours and duration is 5
hours
Regular insulin (Actrapid, Humulin R) - onset is 30 minutes, peaks in 3
hours and duration is 6 hours
Semilente - onset 30-60 minutes, peaks 5-7 hours and duration is 12-
16 hours
Intermediate acting insulin
NPH- onset is 1-3 hours, peaks 8-12 hours and duration is 24 hours
lente - onset 1-3 hours,peaks 7-15 hours and duration is 24 hours
Long acting insulin
Ultralente-onset is 4 hours,peaks in 16-22 hours and the duration is
36 hours.
Lantus is new insulin given once a day and has no peak action.
Premixed insulin 70/30 (30% Regular, 70% NPH)
 Injection Sites

Deltoid-lateral surface of upper arms

Abdomen
Vastus lateralsis
Upper back
Upper buttocks

NOTE: Sites should be rotated to prevent lipodystrophy

 Insulin Reaction
Hypoglycemia
is the most common acute complication of diabetes
bG is usually less than 60 (too little circulating glucose)
Causes:
too much insulin or diabetes medication, too much exercise,
delayed or omitted food intake, alcohol consumption.
When in doubt treat !!!
S/S :
dizziness, trembling sensation, sweating, irritability, headaches,
blurred or double vision, pallor, palpitations, hunger.
will lead to confusion, LOC, seizures
 Insulin Reaction

Treatment
must immediately raise the glucose
simple carbohydrates juice, glucose tablets
followed by complex carbohydrates
glucagon preparation may be given
20-30 ml of 50% glucose solution (D50W)
treatment may have rebound effect
 Foot Care

Wash feet daily with warm water and mild soap and dry well. Avoid
hot water.
Make sure area between toes are dry, do not apply lotion to this
area.
Consult a podiatrist for tough toenails or corns that require cutting.
Inspect feet daily.
Wear properly fitting shoes.
Never soak feet or place heat on feet.
Do not go barefoot.
Avoid any constricting foot wear, socks, or hose.
 The dual action of thiazolidinediones reduces HbA1c

Insulin -cell
resistance IR
+ function

HbA1c

Lebovitz HE, et al. J Clin Endocrinol Metab 2001; 86:280288.

 Potential to prevent progression to T2DM
in at-risk women
Troglitazone reduced progression to type 2 diabetes by > 50%
Troglitazone* 400 mg/day
0.6
Placebo
0.5
Proportion with diabetes

0.4

0.3

0.2

0.1

0.0
0 10 20 30 40 50 60
Time on trial (months)
*Troglitazone is no longer available

Buchanan TA, et al. Diabetes 2002; 51:27962803.

 Can thiazolidinediones delay progression
from IGT to T2DM?
Placebo Rosiglitazone 8 mg/day
100
T2DM
11%

80
IGT
Subjects (%)

56%
60
IGT IGT IGT
100% 89% 100%
40

NGT
20 44%

0
Screening Week 12 Screening Week 12

Bennett SM, et al. Diabet Med 2004; 21:415422.

 Does decreasing insulin resistance decrease
macrovascular complications?
Sulfonylureas/insulin Metformin

Myocardial All-cause mortality Myocardial All-cause

infarction infarction mortality

21% 8% 39% 36%

Not significant Not significant Significant Significant

UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:854865.

Insulin sensitizers reduce cardiovascular events in
type 2 diabetes

12-month combined event rate (%) 60

50

40

30

20

10

0
Non-sensitizers Sensitizers

Kao JA, et al. J Am Coll Cardiol 2004; 43:37A.

The Global Partnership recommends:
Address the underlying pathophysiology, including treatment of
insulin resistance

Del Prato S, et al. Int J Clin Pract 2005; 59:13451355.

 Severe Hypoglycemia.
An episode requiring the assistance of another person to raise the plasma glucose
concentration resulting in resolution of symptoms, with or without a measured low
plasma glucose concentration.
Documented Symptomatic Hypoglycemia.
Symptoms consistent with hypoglycemia with a measured plasma glucose
concentration <70 mg/dL (3.9 mmol/L).
Asymptomatic Hypoglycemia. A measured plasma glucose concentration <70 mg/dL
(3.9 mmol/L) in the absence of symptoms.
Probable Symptomatic Hypoglycemia.
Typical symptoms of hypoglycemia without a measured plasma glucose
concentration.
Relative Hypoglycemia. Typical symptoms of hypoglycemia with a measured plasma
glucose concentration >70 mg/dL (3.9 mmol/L) but approaching that level. (Such
episodes occur in people with poorly controlled diabetes.)
 Factors contributing to destabilization of glycemic
control during intercurrent illness

Altered caloric and carbohydrate exposure

Altered physical activity
Drugs
Organ dysfunction
Trauma
Infection
Inflammation
 Putative physiologic and tissue targets
during critical illness
Coagulation pathway
Inflammatory pathway
- Proinflammatory transcription factors
- Gene products
(a) Adhesion molecules (ICAM-1, E-selectin)
(b) Matrix metalloproteinases
(c) PAI-1
(d) Other
Hepatic iNOS, plasma NO metabolites
 Putative physiologic and tissue targets
during critical illness
Endothelium
- Vessel wall inflammatory processes
- Vasomotor tone
Heart
Host defenses against infection
Fuel and energy metabolism
- Glucose, Free fatty acids
- Reactive oxygen species
- Nutritional status
Fluid and electrolyte balance
Association of infectious diseases with diabetes

Any infection RR 1.21

Pneumococcal bacteremia OR 1.9
Otitis externa RR 1.14
Invasive fungal sinusitis RR 1.38
Periodontal disease ?
Upper respiratory tract infection OR 1.05
Pneumonia RR 1.46
Tuberculosis RR 1.12
Enteric infection RR 1.50
Biliary infections RR 1.6
Peritonitis RR 1.94
Association of infectious diseases with diabetes

UTI RR 1.8
Pyelonephritis RR 1.9
GU infection RR 1.16
Necrotizing fasciitis OR 1.33
Cellulitis OR 1.81
Foot ulcers OR 7.6
Osteomyelitis OR 4.9
Septic Arthritis RR 1.72
Bacterial Meningitis RR 1.5
 Malignancies and the role of diabetes

Gastric cancer RR 2.29

Colon cancer RR 1.4
Pancreatic cancer RR 2.15
Endometrial cancer RR 2.41
Bladder cancer RR 2.46
Breast cancer HR 1.17
Esophagus RR 4.32
Hepatocellular Carcinoma HR 1.59
Prostate RR 1.02
Hematologic malignancy RR 0.90
Genesis of diabetic dyslipidemia