1. Options for Diabetes 2003 CDA Clinical Practice Guidelines ORAL AGENTS
J. Robin Conway M.D.
Diabetes Clinic - Smiths Falls, ON
Kingston April

2. Prevalence (millions)
Worldwide rates of diabetes
mellitus: predictions 80 70 60 50 40 30 20 10
Prevalence (millions)
Why is Diabetes such an important disease?
Because the predictions are that in the next 25 years, the number of Diabetics in North America will double
Year
1995
2000
2025
North America
Europe
Southeast
Asia
World Health Organization
Canadian Diabetes Association, 1998 website.

3. 2 Million Canadians Have Diabetes Mellitus
Frequency of diagnosed and undiagnosed diabetes and IGT, by age (U.S. data - Harris)
2 Million Canadians Have Diabetes Mellitus
According to data from the Heart and Stroke Foundation of Canada, overall, 4% of Canadian men and 5% of women report having diabetes mellitus, that is 2 million Canadians.1 They report an increasing prevalence of diabetes with age, ranging from 1-3% in the youngest (15-34 years) to 9-12% in the oldest (55-74 years) age groups.1
The true prevalence may be double that of self-reported diabetes, based on this U.S. study by Harris, which showed that 50% of adults with diabetes have not been diagnosed.2 The high incidence of impaired glucose tolerance (IGT) in the population is also a consideration. Although the data in this graph are from the U.S., the prevalence data for Canada are very similar.
Type 2 (noninsulin dependent) diabetes accounts for up to 95% of cases, while type 1 (insulin dependent) diabetes is much less frequent, affecting about 5-10% of the population with diabetes.2,3 By 1995, an estimated 110 million individuals worldwide had been diagnosed with diabetes, and the WHO projects this will double by the year
References: 1. Heart and Stroke Foundation of Canada. Heart Disease and Stroke in Canada, Ottawa, Canada, Harris MI. Undiagnosed NIDDM: Clinical and public health issues. Diabetes Care 1993;16: Plosker GL, Faulds D. Troglitazone. Drugs 1999;57(3): Turner NC, Clapham JC. Insulin resistance, impaired glucose tolerance and non-insulin-dependent diabetes, pathologic mechanisms and treatment: current status and therapeutic possibilities. Prog Drug Res 1998;51:33-94.
Harris. Diabetes Care 1993;16:

4. Cardiovascular Disease Risk is Increased 2 to 4 Times
Framingham study: diabetes and CAD mortality at 20-year follow-up
Cardiovascular Disease Risk is Increased 2 to 4 Times
Physicians managing patients with diabetes are well aware of the significant relationship between diabetes and cardiovascular disease. Morbidity and mortality from cardiovascular disease is 2- to 4-fold higher than in age- and sex-matched individuals without diabetes.1-3 Twenty-year follow-up mortality data from the Framingham study emphasizes the significantly increased risk of CAD mortality in individuals with type 2 diabetes.
Men and women with diabetes are more likely to experience silent ischemia and myocardial infarction (MI) and the outcome of an infarction is worse than in individuals without diabetes. After an acute MI, people with diabetes are at greater risk for congestive heart failure, recurrent infarction, arrhythmias and have lower overall survival rates.3 About 75% to 80% of individuals with diabetes die from coronary artery, cerebrovascular or peripheral vascular diseases.2
References: 1. Haffner SM. Epidemiology of insulin resistance and its relation to coronary artery disease. Am J Cardiol 1999;84:11J-4J. 2. Edmonds M. Dyslipidemia in diabetes mellitus. Can J CME 1997;Aug: Meltzer S, et al clinical practice guidelines for the management of diabetes in Canada. CMAJ 1998;159(Suppl):S1-29.
Haffner Am J Cardiol 1999;84:11J-4J.

5. The burden of Diabetes
87% of Type 2 Diabetes is managed in Primary Care
Diascan Study: 23.5% of patients in our office have diabetes
Quebec screening >2 Risk Factors, 79% tested % Diabetes , 13% IGT or IFG % No Treatment Advice
Leiter et al. Diabetes Care 2000
Most Type 2 Diabetes is managed in primary care settings. About 7 or 8% of the population have diabetes (50% undiagnosed) and almost twice this number have Impaired Glucose Tolerance or “Pre-Diabetes”. The DIASCAN study by Dr. Leiter from Toronto has shown that close to ¼ of all patients presenting in a family physicians office have diabetes (though they may not know it). The Quebec study by Strychar shows that we could improve our treatment.
Strychar I et al. Cdn J Diab 2003(abs)

6. T2DM in Family Practice 84% of patients had A1c in past year
Average A1c 7.9% (goal<7%)
88% had BP check
48% had lipid profiles
28% tested for microalbuminuria
15% had foot exams
A study by Dr. Stewart Harris from London, Ont shows that our treatment of Diabetes could be improved, Av A1c is well above the goal of <7% and although most patients have had BP check and lipid profile, we are doing poorly in identifying microvascular complications.
Harris S et al. Cdn Fam Phys 2003

7. Organization and Delivery of Care
Diabetes should be organized using a DHC (Diabetes Healthcare) team approach
People with diabetes should be offered initial and ongoing needs-based diabetes education
The role of diabetes nurse educators and other DHC team members should be enhanced in cooperation with the physician

8. Structured care ACLS ATLS Seattle Defibrillator Experience
GREACE Study
It has been repeatedly demonstrated that a structured care approach improves outcomes. The CDA recommends a multidisciplinary approach to Diabetes Care, following a structured care algorithm means that all members of the care team are singing from the same hymn book.

9. Structured Care VS Usual Care
Patients received atorvastatin 10 mg/d (titrated up to 80 mg/d) to reach the NCEP LDL-C goal
Specialist care unit with a strict protocol to achieve NCEP LDL-C target
Treatment from a physician of pt’s choice
All patients had access to any necessary medications, including statins
Included lifestyle modifications (diet and exercise) as well as lipid-lowering medications
Structured
Care:
The GREACE study is a good example of a multidisciplinary structured care approach.
The difference between Structured Care and Usual Care is explained more fully in this slide.
Patients in the structured care group were supervised in a specialist care unit and followed a strict protocol to try to achieve the NCEP LDL cholesterol goal for secondary prevention. Atorvastatin was initiated at a dosage of 10 mg/d. If the NCEP LDL cholesterol goal was not reached within 6 weeks, the dose of atorvastatin was increased to 20 mg/d. With evaluations every 6 weeks, the dose of atorvastatin was titrated up to a maximum of 80 mg/d depending on patient response.
Treatment of patients in the usual care group was at the physician’s discretion and could include lifestyle modifications (diet and exercise) as well as lipid-lowering medications, including atorvastatin.
Usual
Care:
Αthyros VG et al. Curr Med Res Opin. 2002;18:

10. Reduction in Relative Risk of Primary Endpoints
The reductions in relative risk of primary end points for structured care compared with usual care after 3 years of treatment are highlighted in this slide.
Total mortality was decreased by 43% (P=0.0021), coronary mortality by 47% (P=0.0017), nonfatal MI by 59% (P=0.0001), and stroke by 47% (P=0.034) in patients treated with structured care using atorvastatin compared with usual care.
P=0.034
P=0.0021
P=0.0017
P=0.0001
P=0.0032
P=0.0011
P=0.021
Αthyros VG et al. Curr Med Res Opin. 2002;18:

11. Target for most patients
Recommended targets for glycemic control*
A1C**
(%)
FPG/preprandial PG
(mmol/L)
2-hour postprandial PG
(mmol/L)
Target for most patients
7.0
Normal range
(considered for patients
in whom it can be
achieved safely)
6.0
The 2003 Canadian Diabetes Association Clinical Practice Guidelines have clearly set out targets for glycemic control.
*Treatment goals and strategies must be tailored to the patient, with consideration given to individual risk factors.
†Glycemic targets for children 12 years of age and pregnant women differ from these targets. Please refer to “Other Relevant Guidelines” for further details.
**An A1C of 7.0% corresponds to a laboratory value of Where possible, Canadian laboratories should standardize their
A1C values to DCCT levels (reference range: to 0.060). However, as many laboratories continue to use a different
reference range, the target A1C value should be adjusted based on the specific reference range used by the laboratory that
performed the test. As a useful guide: an A1C target of 7.0% refers to a threshold that is approximately 15% above the upper limit of normal.
A1C = glycosylated hemoglobin
DCCT = Diabetes Control and Complications Trial
FPG = fasting plasma glucose
PG = plasma glucose

12. Physical Activity and Diabetes
As always, the cornerstones of Type 2 Diabetes treatment are Exercise
For people who have not previously exercised regularly and are at risk of CVD, an ECG stress test should be considered prior to starting an exercise program
Testing is particularly important before, during
and for many hours after exercise.

13. Nutrition Therapy People with diabetes should:
Receive nutrition counseling by a registered dietitian
Receive individualized meal planning
Follow Canada’s Guidelines for Healthy Eating
People on intensive insulin should also be taught to adjust the insulin for the amount of carbohydrate consumed
And Diet

14. Drugs in Type 2 www.diabetesclinic.ca
When these measures are insufficient to achieve control, we start drug therapy. In order to give the most appropriate treatment we need to understand what is going on in the diabetic (the pathophysiology of the disease).

15. UKPDS: Long-term Glucose Control9
Conventional 8
HbA1c (%)
Intensive 7
From the UKPDS we learned the progressive nature of Type 2 Diabetes. Irrespective of treatment with Sulphonylurea, Glyburide or Insulin, glycemic control deteriorated over time.
This slide shows the deterioration of glycemic control that was associated with the loss of beta-cell function over time.
ULN = Upper Limit of Normal
UKPDS Group. U.K. prospective diabetes study 33. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. U.K. Prospective Diabetes Study Group. Lancet 1998;352:
ULN = 6.2% 6 3 6 9 12 15
Years of treatment
UKPDS Study Group, Lancet, 1998;352:

16. UKPDS demonstrated loss of glycemic control with all agents studied9 8
(%)
Conventional
Glyburide
Chlorpropamide
Metformin
Insulin
A1C 7
UKPDS showed that as type 2 diabetes progresses, monotherapy with traditional agents fails to maintain glycemic control.
Of 1,704 overweight (>120% ideal bodyweight) patients with newly-diagnosed type 2 diabetes recruited to the study, 753 were included in a randomised trial of conventional therapy (diet alone, n = 411) versus intensive blood glucose control with metformin.
A secondary analysis comparing the 342 patients allocated metformin with 951 overweight patients allocated intensive blood-gluose control with chlorpropamide (n = 256), glibenclamide (n = 277), or insulin (n = 409) found that over 10 years, median HbA1c was 7.4% in the metfromin group, compared with 8.0% in the conventional group. The patients assigned intensive control with sulfonylurea or insulin had similar HbA1c to the metformin group.
UK Prospective Diabetes Study Group. UKPDS 34. Lancet 1998; 352:854–865.
Upper limit of
normal = 6.2% 6
Overweight patients Cohort, median values 2 4 6 8 10
Years from randomization
UK Prospective Diabetes Study Group. UKPDS 34. Lancet 1998; 352:854–865.

17. Progressive Loss of -cell Function in UKPDS20 40 60 80
100 1 2 3 4 5 6 7
-cell function (%)
Years from randomization
Non obese
Obese
-cell function (%)
The reason for this deterioration of A1c was the progressive loss of beta cell function over time despite treatment with the agents available at that time.
The United Kingdom Prospective Diabetes Study (UKPDS) illustrated the loss of beta-cell function in type 2 diabetes over time.
However, it is critical to note that the slopes of the deterioration are very similar in the conventionally- and intensively-treated groups. This powerful observation implies that diabetes eventually follows a deteriorating course, regardless of the treatment.
The progressive loss of beta-cell function is a key component of the pathophysiology of type 2 diabetes.
UKPDS Group. U.K. prospective diabetes study 16. Overview of 6 years' therapy of type II diabetes: a progressive disease. U.K. Prospective Diabetes Study Group. Diabetes 1995;44:
Conventional
Sulphonylurea
Metformin
Mean age at baseline 53 yrs.
UKPDS 16: Diabetes 1995; 44:1249–1258

18. Natural History of Type 2 Diabetes
Lifestyle
Metformin/Thiazolidinediones
Insulin
Secretagogues
In order to have the best success with our treatment programs it is important to understand the Natural History of Type 2 Diabetes
Prior to the manifestation of the metabolic defects that lead to type 2 diabetes, fasting and postprandial insulin levels are similar and constant. In the majority of patients that go on to develop type 2 diabetes, increasing insulin resistance leads to compensatory increases in circulating insulin, which prevents an increase in glucose levels. As time progresses, the insulin resistance reaches a peak and stabilizes while the compensatory increase in insulin continues to prevent fasting glucose levels from becoming abnormal.
Impaired Glucose Tolerance (IGT): However, at some point in time, either due to early -cell dysfunction or due to a natural limit of -cell capacity, challenge of this delicate balance with a glucose load may demonstrate that, although fasting glucose levels remain normal, postprandial glucose levels become abnormal as a limitation in insulin response is reached.
Type 2 Diabetes: Following the onset of -cell dysfunction, insulin levels can no longer overcome insulin resistance, and fasting and postprandial glucose levels increase progressively over time.
Lifestyle intervention is effective from the early stages of insulin resistance right through to pancreatic exhaustion and in the DPS and DPP was the most effective treatment in preventing the progression from Impaired Glucose Tolerance to Diabetes. Metformin (DPS), Acarbose (STOP NIDDM), Orlistat (XENDOS) and Troglitazone (TRIPOD & DPP) have shown value in delaying or preventing the progression from IGT to Diabetes. Rosiglitazone in prevention is currently being studied in the DREAM trial.
After the diagnosis of Type 2 Diabetes, Metformin is effective to reduce hepatic glucose production. In the early stages of Diabetes, the predominant problem is insulin resistance and the Thiazolidenediones directly address this.
Diabetes always has an element of insulin deficiency and the insulin secretagogues, either the sulphonylureas or Repaglinide & Nateglinide will increase insulin production by the pancreas but as the beta cell progressively declines, these drugs become less effective and as insulin deficiency becomes more pronounced, exogenous insulin is needed.
References: 1. Henry RR. Type 2 diabetes care: the role of insulin-sensitizing agents and practical implications for cardiovascular disease prevention. Am J Med 1998;105(1A):20S-6S.
Henry. Am J Med 1998;105(1A):20S-6S.

19. Sites of Action of Currently Available Therapeutic Options
LIVER
ADIPOSE TISSUE
MUSCLE
PANCREAS
GLUCOSE PRODUCTION
Biguanides
Thiazolidinediones
PERIPHERAL
GLUCOSE UPTAKE
Thiazolidinediones
(Biguanides)
INSULIN SECRETION
Sulfonylureas
Meglitinides
Insulin
Sites of Action of Currently Available Therapeutic Options
The major metabolic defects in type 2 diabetes that lead to glucose elevation are: decreased glucose transport and utilization in muscle and adipose tissue, increased glucose production by the liver, and decreased insulin secretion by the pancreas.
Sulfonylureas and meglitinides (repaglinide) treat hyperglycemia by stimulating pancreatic insulin secretion.1 Administration of insulin is also a choice to increase circulating insulin levels in response to a failing beta-cell function. Biguanides increase the sensitivity of the liver to circulating insulin, thereby helping to reduce the level of excess glucose produced by that organ.2 Thiazolidinediones (TZDs) are PPAR- activators, which act at a number of sites to lower blood glucose levels.2,3 They also improve hepatic insulin sensitivity, thereby decreasing the excess glucose production by the liver. TZDs are more commonly recognized for their action in increasing insulin sensitivity in muscle and adipose tissue peripherally. This improves the utilization of glucose by these organs. Biguanides, in high doses, also have some mild effect on increasing peripheral glucose utilization. To decrease the rapid influx of carbohydrate from ingested food, alpha-glucosidase inhibitors are used to slow the digestion of starches and the absorption of glucose.2
References: 1. Meltzer S, et al clinical practice guidelines for the management of diabetes in Canada. CMAJ 1998;159(Suppl):S Sheen AJ. Drug treatment of non-insulin-dependent diabetes mellitus in the 1990s. Drugs 1997;54: Sonnenberg GE, Kotchen TA. New therapeutic approaches to reversing insulin resistance. Curr Opin Nephrol Hypertens 1998; 7:551-5.
INTESTINE
GLUCOSE ABSORPTION
Sonnenberg, Kotchen Curr Opin Nephrol
Hypertens 1998;7:551-5.
Alpha-glucosidase inhibitors

20. Combination Antihyperglycemic Therapy
Addition, rather than substitution recommended
Agents from other classes should be added
Diff sites of action
Diff MOA
Combination Antihyperglycemic Therapy
In general, when monotherapy is failing, addition and not substitution of another oral agent is usually required to improve metabolic control.1,2 Selecting an agent of a different class is recommended.
Sulfonylurea and metformin: proven effective, this combination tends to be one of the most potent in terms of lowering glycosylated hemoglobin concentrations. Metformin will blunt the weight gain associated with a sulfonylurea
Sulfonylurea and acarbose: Used together these agents can reduce both fasting and postprandial glucose values. Acarbose will also blunt the weight gain.
Metformin and acarbose: have been used together successfully without excessive GI side effects. Metformin significantly affects FBG values and acarbose will reduce postprandial values. These agents do not cause weight gain when used alone or in combination.
Sulfonylurea, metformin and acarbose: This combination has been used in clinical practice in Europe. The mechanisms of action compliment each other to improve glucose control and avoid exogenous insulin therapy.
Thiazolidinediones have been investigated in several combinations, which will be discussed later in the presentation.
References: 1. Edelman SV. Type II diabetes mellitus. Adv Intern Med 1998;43: Meltzer S, et al clinical practice guidelines for the management of diabetes in Canada. CMAJ 1998;159(Suppl):S1-S29.

21. Individualized Treatment
Metformin for overweight patients
If control not achieved add another agent
If A1c >9 start with 2 agents
Consider early insulin for hyperglycemia
Bedtime intermediate insulin (NPH)
The 2003 CDA Guidelines, rather than advocating a step wise approach, suggest individualized treatment according to the predominant problem and recognizing that none of the oral agents will improve A1c more than 1.5%, it is suggested that if A1c is greater than 9%, we should start with combination therapy. If the patient has severe hyperglycemia or is metabollicaly decompensated the we should start with insulin as part of the treatment.

22. antihyperglycemic agent
Clinical assessment and initiation of nutrition and physical activity
Mild to moderate hyperglycemia (A1C <9.0%)
Marked hyperglycemia (A1C 9.0%)
Overweight
(BMI 25 kg/m2)
Non-overweight
(BMI 25 kg/m2)
2 antihyperglycemic agents
from different classes †
Basal and/or
preprandial insulin
biguanide
insulin sensitizer*
insulin secretagogue
insulin
alpha-glucosidase
inhibitor
Biguanide alone or in
combination with 1 of:
1 or 2† antihyperglycemic
agents from different
classes
L I F E S T Y L E
insulin sensitizer*
insulin secretagogue
insulin
alpha-glucosidase
inhibitor
biguanide
insulin sensitizer*
insulin secretagogue
insulin
alpha-glucosidase
inhibitor
If not at target
If not at target
If not at target
If not at target
The treatment algorithm for hyperglycemia looks complicated, bu in fact each of the arms is very similar.
Add a drug from a different class or
Use insulin alone or in combination with:
Add an oral
antihyperglycemic agent
from a different
class of insulin*
Intensify insulin
regimen or add
biguanide
insulin secretagogue
insulin sensitizer*
alpha-glucosidase inhibitor
biguanide
insulin
secretagogue**
insulin sensitizer*
alpha-glucosidase
inhibitor
Timely adjustments to and/or additions of oral antihyperglycemic agents
and/or insulin should be made to attain target A1C within 6 to 12 months

23. antihyperglycemic agent
Clinical assessment and initiation of nutrition and physical activity
Mild to moderate hyperglycemia (A1C <9.0%)
Marked hyperglycemia (A1C 9.0%)
Overweight
(BMI 25 kg/m2)
Non-overweight
(BMI 25 kg/m2)
2 antihyperglycemic agents
from different classes †
Basal and/or
preprandial insulin
biguanide
insulin sensitizer*
insulin secretagogue
insulin
alpha-glucosidase
inhibitor
Biguanide alone or in
combination with 1 of:
1 or 2† antihyperglycemic
agents from different
classes
L I F E S T Y L E
insulin sensitizer*
insulin secretagogue
insulin
alpha-glucosidase
inhibitor
biguanide
insulin sensitizer*
insulin secretagogue
insulin
alpha-glucosidase
inhibitor
If not at target
If not at target
If not at target
If not at target
Add an oral
antihyperglycemic agent
from a different
class of insulin*
Add a drug from a different class or
Use insulin alone or in combination with:
Intensify insulin
regimen or add
biguanide
insulin
secretagogue**
insulin sensitizer*
alpha-glucosidase
inhibitor
biguanide
insulin secretagogue
insulin sensitizer*
alpha-glucosidase inhibitor
Timely adjustments to and/or additions of oral antihyperglycemic agents
and/or insulin should be made to attain target A1C within 6 to 12 months

24. Mild to moderate hyperglycemia (A1C <9.0%)
Overweight (BMI 25 kg/m2)
Biguanide alone or in combination with 1 of:
insulin sensitizer*
insulin secretagogue
insulin
alpha-glucosidase inhibitor
L I F E S T Y L E
If not at target
Add a drug from a different class or
Use insulin alone or in combination with:
biguanide
insulin secretagogue
insulin sensitizer*
alpha-glucosidase inhibitor
The algorithm is in fact fairly simple, if we look at the first treatment path, the obese diabetic we start with Metformin then add an insulin sensitizer, then an insulin secretagogue then insulin.
Timely adjustments to and/or additions of oral antihyperglycemic agents
and/or insulin should be made to attain target A1C within 6 to 12 months
When used in combination with insulin, insulin sensitizers may increase the risk of edema or CHF. The combination
of an insulin sensitizer and insulin is currently not an approved indication in Canada.

25. Pharmacotherapy Metformin Insulin Sensitizer (TZD)
Insulin Secretagogue
Insulin
Alpha-glucosidase inhibitor
Anorexiant*
If not at target
Add an agent from another class
The order of agents is essentially the same, Metformin, TZD, Insulin Secretagogue, Insulin, Acarbose and Orlistat

26. Pharmacotherapy Treat the Predominant problem
Each Drug will lower A1c 1-1.5% (Acarbose & Orlistat 0-5%)
Start with Metformin in Obese or High FBS
Combination therapy if A1c >9%
Early Insulin if decompensated
Consider TZD
The key is to consider where the patient is on the curves of glucose, Insulin Resistance & Insulin production and tailor treatment to treat the predominant problem.

27. HbA1C in Diet-Treated Patients Effects of Various Medications
(Difference from Placebo)
HbA1C (%)
This graph demonstrates the decrement of HbA1C (compared to placebo) in previously diet treated patients for a variety of diabetes medications.
It can be seen that the degree of improvement in HbA1C is largest with the insulin secretagogues (eg, repaglinide and glipizide-GITS) and the biguanide (metformin), which show reductions of the order of 1.5% to 2% or more.
In comparison, the thiazolidinediones (eg, troglitazone) and alpha-glucosidase inhibitors (eg, acarbose) show reductions of the order of 0.5% to 1.0%.
Repaglinide
Metformin
Glyburide
Glitazone
Acarbose
FDA approved Prescribing Information for various OADs

28. Oral Agents for Type 2 Diabetes
Combination at less than maximal doses result in more rapid improvement of blood glucose
Counsel patients about hypoglycemia prevention and treatment
Again shown in this table from the CDA.
SMBG is recommended at least once daily
Canadian Diabetes Association 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Cdn J Diabetes 2003; 27 (suppl 2)

29. Pharmacologic Management of Type 2 Diabetes
Add anti-hyperglycemic agents if:
Diet & exercise therapy do not achieve targets after 2-3 month trial or
newly diagnosed and has an A1C of  9
A1C
& BMI
Suggested starting agent
< 9%
BMI  25
Biguanide alone or in combination
BMI < 25
1 or 2 agents from different classes
 9% --
2 agents from different classes or insulin basal and/or preprandial
So in summary, if A1c is below 9% we start with one agent, in the obese patient this agent should be Metformin.
If A1c is greater than 9% we start with 2 agents from different classes. The important thing is to titrate aggressively to reach glycemic targets (A1c <7%) within 6-12 months.
Intensify to reach targets in 6-12 months

30. Need for Combination Therapy in UKPDS
% of Patients
We need to recognize that most patients will require combination therapy.
Because diabetes follows a deteriorating course, most patients will eventually require combination therapy.
In the UKPDS, at the 3-year point, 50% of patients required combination therapy to maintain glycemic control at previous levels; at the 9-year point, 75% of patients needed a combination regimen.
Turner RC, Cull CA, Frighi V et al. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group. JAMA 2000 Jun 2;281(21);

31. Dose-Response Curve Metformin30 20 10
500
1000
1500
2000
2500
0.5
1.0
1.5
2.0
Dose
GI Distress Patients (%)
Reduction vs. placebo, HbA 1c
(%)
In considering our dosages of hypoglycemic medications we need to keep in mind that generally we get 75% of the maximum therapeutic effect with 50% of the maximum therapeutic dose and that doses higher than the maximum therapeutic dose not only provide no additional benefit but may give less effective control. In addition the incidence of side effects increases dramatically at higher doses.
Overall we are often better to give sub maximal doses of several agents than to persist in trying to increase the dose. (Despite what ODB may think).
Metformin
Dose-response curve showing GI related effects
Riddle M. Combining sulfonylureasand other oral agents. Am J of Med2000; 108(6A):15S-22S .

32. Mechanisms To Lower Glucose
Decrease glucose production: biguanides (or thiazolidinediones)
Increase muscle glucose uptake: thiazolidinediones (or biguanides)
Stimulate insulin secretion: repaglinide or sulfonylureas
Retard carbohydrate absorption: alpha-glucosidase inhibitors
Correct insulin deficiency: insulin or insulin analogues
There are several mechanisms by which glucose levels can be lowered. Various medications are available which act upon these different mechanisms.

33. Biguanides: mechanism of action
1. Intestine: glucose absorption
2. Muscle and adipose tissue: glucose uptake Metformin  glucose utilization
Blood glucose
Insulin resistance
4. Liver: hepatic glucose output Metformin ¯ HGO 
Let us take a moment to consider the mechanism of action of the drugs we hav e available for treatment of Diabetes.
The first drug is Metformin which acts primarily by decreasing hepatic glucose output.
Insulin resistance
3. Pancreas: insulin secretion

34. Metformin – Advantages –
Corrects a primary pathophysiologic impairment: hepatic glucose production
High initial response rate
Long record of relative safety
No weight gain or modest weight loss
Advantageous lipid profile
Advantages of metformin include:
Insulin sensitivity improved
High initial response rate
Long-term safety
Modest weight loss or no weight gain
Beneficial effects on lipid profile.

35. Metformin – Disadvantages –
GI side effects on initiation
Must be held prior to, and after, radiologic studies using intravascular iodinated contrast media
Risk of lactic acidosis: caution in
impaired renal function
impaired hepatic function
pharmacologically treated CHF
alcoholism
Disadvantages of metformin include:
Gastrointestinal symptoms (eg, diarrhea, nausea, vomiting, abdominal bloating, flatulence, anorexia) are the most common adverse effects experienced. However, these symptoms usually diminish with continued treatment.
Metformin must be held prior to, and after, radiologic studies using intravascular iodinated contrast media.
If metformin accumulates during treatment, there is a risk of lactic acidosis. Therefore, metformin should be used cautiously in patients with impaired renal function, impaired hepatic function, pharmacologically treated congested heart failure, or alcoholism.

36. Metformin Dosage
mg/day, no benefit over 2000 mg/day. Divide dose into twice daily. Tablets of 500 & 850 mg. 500 mg fully covered by ODB, 850 mg (Glucophage) not covered.
Start low and titrate up slowly to avoid GI side effects
The dose of Metformin is from mg/day but as we saw in a previous slide we get 75% of the maximal effect with 1500 mg of drug, doses over 2000 mg should not be used as they may cause worsening of efficacy. GI side effects are common and may be avoided by slowly titrating the dose over a few weeks. Some brands of generic seem more prone to the side effects. While the 500 mg tabs are fully covered by ODB, the 850 mg tabs (Glucophage) are not.

37. Thiazolidinediones: mechanism of actions
Blood glucose
Muscle and
adipose tissue  insulin resistance  glucose uptake
The Thiazolidenediones or Glitazones act primarily by decreasing insulin resistance by increasing glucose uptake in fat and muscle cells.
Liver  insulin resistance
 hepatic glucose production
Pancreas
demand for insulin secretion
ß-cell insulin content

38. Thiazolidinediones – Advantages –
Corrects a primary pathophysiologic impairment: insulin resistance
Possible once-daily dosing
Improves Lipids, Lower serum triglyceride
May be used in renal insufficiency
Advantages of thiazolidinediones include:
Lowers blood glucose by improving target cell response to insulin.
Possible once-daily dosing.
Lowers serum triglycerides.
Dose adjustment in renal insufficiency is unnecessary with some thiazolidinediones.

39. Thiazolidinediones – Disadvantages –
Delayed action (onset: 3 wks, full effect: wks)
Variable response in monotherapy
Weight gain
Increased LDL-cholesterol (short-term)
Few long-term studies
Disadvantages of thiazolidinediones include:
Rare cases of severe, idiosyncratic, hepatocellular injury have been reported with troglitazone, some of which have been fatal.
Initial benefits may not be seen until 3 weeks of therapy with full effect expected in 10 weeks to 12 weeks.
There is a variable response seen when used as monotherapy, both in terms of degree of response and differences among agents.
Patients may experience weight gain.
Although serum triglycerides are lowered, LDL-cholesterol is increased (short-term).
Long-term side effects are unknown.

40. Thiazolidenedione Dosage
Pioglitazone (Actos), dosage range mg
Tablets of 15, 30 & 45 mg
Rosiglitazone (Avandia) dose range 2-8 mg Tablets of 2, 4, 8 mg
May take 3 weeks to 3 mo to see effect
ODB Section 8 with failure of max dose Metformin & Glyburide

41. Sulfonylureas: mechanism of action
1. Intestine: glucose absorption
2. Muscle and adipose tissue: glucose uptake
Insulin resistance
Blood glucose 
4. Liver: hepatic glucose output
Sulphonylureas act priomarily by stimulating insulin secretion from the pancreas, they are effective only if the pancreas is producing sub maximal amounts of insulin and as beta c ell deterioration progresses they become progressively less effective.
3. Pancreas: Insulin secretion Sulfonylureas insulin secretion
Insulin resistance

42. Sulfonylureas – Advantages –
Improve a primary pathophysiologic impairment: insulin secretion
Physiologic route of insulin delivery
High initial response rate
No lag period before response
Advantages of sulfonylureas include stimulation of insulin secretion, physiologic route of insulin delivery, and rapid onset of action.

43. Sulfonylureas – Disadvantages –
Hypoglycemia
may be prolonged or severe
Weight gain
Drug interactions (especially 1st generation)
Hyponatremia (with chlorpropamide)
Cannot use if allergic to sulfa compounds
Disadvantages of sulfonylureas include:
Prolonged or severe hyperglycemia is possible.
Patients may experience weight gain.
Must be cautious of drug interactions especially with 1st generation drugs.
Chlorpropamide has been shown to cause hyponatremia.
Should not use if allergic to sulfa compounds.

44. Sulphonylureas Dosage
Glyburide (Diabeta)dose range mg, split into twice daily. Tablets of 2.5 and 5 mg Full ODB Coverage
Gliclazide (Diamicron) dose range mg a day, divided into 2 doses. Diamicron MR 30 mg from 1-4 tablets, once daily ODB section 8 if hypoglycemia on Glyburide
Glimepiride (Amaryl) dose mg OD Tabs 0.5, 1 , 2, 4 mg. No ODB coverage

45. MEGLITINIDES New Class of Insulin Secretagogues
Physiologic Reasons
Insulin secretion must be closely coupled to fluctuations in plasma glucose with little or no lag time
Prevents early postprandial hyperglycemia
Prevents late postprandial hypoglycemia
Insulin secretion should not be stimulated when plasma glucose is low
One of the problems with the sulphonylureas is the fact that they continuously stimulate the pancreas and may be inappropriate in individuals with erratic meal times and frequently cause late postprandial hypoglycemia. What we need is a secretagogue that causes insulin secretion in a glucose dependant manner.

46. Why is there a Need for New Classes of Insulin Secretagogues?
Pharmacologic Reasons
Chronic sulfonylurea treatment causes desensitization of ß-cell insulin secretion
High “secondary failure” rate with sulfonylureas
The sulphonylureas become less effective over time because the chronic stimulation of the beta cell causes desensitization of the beta cell which leads to secondary failure.

47. Therapeutic Need, 1988
“In general, older patients have more renal failure and cardiovascular and hepatic problems, as well as a tendency to skip meals and snacks. For this reason, it is best to choose an agent with relatively short duration of action, which is less likely to cause profound hypoglycemia.”
Particularly in older patients, a short acting secretagogue may cause less hypoglycemia.
Physician’s Guide to Non-Insulin-Dependent (Type II) Diabetes. Diagnosis and Treatment (Second Edition) p.39. ADA-CEP 1984,1988.

48. Meglitinides Efficacy Summary
Rapid response
Decline in 24-hr mean BG ( mmol/L) within 1 week
Good clinical response
Improves glucose control D HbA1C ~ % (vs placebo)
Glycemic control
Documented HbA1C reductions sustained over 1 year
Dose response
Reductions in mean glucose seen at mg ac
Synergistic
Incremental improvements when used in combination with metformin
The efficacy of the meglitinides; repaglinide and nateglinide is shown in its rapid demonstration of effect. Significant decline in mean blood glucose from 2.2 mmol/L to 4.4 mmol/L is seen in less than one week.
Significant differences in control are seen when repaglinide is compared to placebo. In studies evaluating individuals treated for 24 weeks up to 1 year, the average decline of hemoglobin A1C (HbA1C ) was 1.6% to 2.1%.
The effect on glycemic control was demonstrated in trials lasting more than 1 year.
With Repaglinide an escalation of effect is seen over a range of 0.5 mg to 4 mg with meals. Note that the dosing is with meals. It is not bid, tid, qid, etc.
Nateglinide is given as 120 mg with each meal.
Repaglinide and Nateglinide have a synergistic effect when used in combination with metformin.

49. Meglitinides Dosage
Repaglinide (Gluconorm) 0.5 to 4 mg with each meal. Tablets of 0.5, 1.0 and 2 mg ODB Section 8 requires hypoglyhcemia on Glyburide
Nateglinide (Starlix) 120 mg with each meal ODB No Coverage

50. Insulin – Disadvantages –
Hypoglycemia
Weight gain
Need for injections
Non-physiologic route of administration (peripheral)
Patient and physician non-acceptance
Disadvantages of insulin include:
Hypoglycemia may result in certain situations, particularly with increased activity or prolonged interval between food intake.
Patients may experience weight gain as glycemic control is improved.
Delivery by injection may be less acceptable by patient and physician.

51. Alpha-Glucosidase inhibitors mechanism of action
1. Intestine: glucose absorption
2. Muscle and
adipose tissue: glucose
uptake
Insulin resistance
Blood glucose 
4. Liver: hepatic
glucose output
The Alpha Glucosidase Inhibitor Acarbose (Prandase), impairs absorption of glucose in the early part of the small intestine. Since the glucose is ultimately absorbed further down the intestine, it doesn’t act as a blocker (like Orlistat does with fat) but rather it delays absorption and allows more time for the failing pancreas to deal with the prandial glucose.
Insulin resistance
3. Pancreas: insulin secretion
Amatruda, Diabetes Mellitus, 1996.

52. Alpha-Glucosidase Inhibitors – Advantages –
Good safety profile
No weight gain or modest weight loss
Dose coupled to meals
Advantages of alpha-glucosidase inhibitors include:
Good safety profile
No weight gain and or modest weight loss
Dosing with meals.

53. Alpha-Glucosidase Inhibitors - Disadvantages -
Modest effect on fasting plasma glucose and HbA1C
Flatulence, gastrointestinal side effects
Cannot treat hypoglycemia with sucrose, maltose, or starch
use glucose, fructose, or lactose
Disadvantages of alpha-glucosidase inhibitors include:
Modest effect on fasting plasma glucose and hemoglobin A1C (HbA1C).
Flatulence is the most common adverse event seen with these agents. Other gastrointestinal effects such as diarrhea and abdominal pain also are common.
Limited options allowed for treatment of hypoglycemia.

54. Acarbose Dosage
Acarbose (Prandase) dose mg with the first bite of each meal High index of side effects, start low (25 mg OD) and titrate up gradually.
Not very effective for hyperglycemia 0.5% A1c reduction.
ODB Coverage on LU
Acarbose needs to have the dosage gradually titrated up to avoid GI side effects. Tablets are taken with the first bite of each meal. The effect on A1c is modest. It is effective in Pre-Diabetes and for reactive hypoglycemia. Approved by ODB on limited use.

55. Anorexiants Dosage
Orlistat (Xenical) 120 mg tabs, one with the first bite of each meal. Inhibits 30% of dietaryt fat absorpton needs to be used with a low fat diet. Lifestyle counseling essential. Prevented Diabetes in XENDOS study.
ODB Section 8 with failure of Metformin & SU in the obese patient
Sibutramine (Meridia) dose 10 or 15 mg caps OD. No ODB Coverage
The anorexiants have an adjunctive role in the obese patient. Orlistat is approved for the treatment of Type 2 Diabetes but is only modestly effective with the potential to decrease A1c by only 0.5%. There is a high incidence of GI side effects and patients require nutritional counseling to adopt a low fat diet. Section 8 ICR may be granted by ODB. Orlistat has been shown on the XENDOS trial to reduce progression of IGT to Type 2 Diabetes.
Sibutramine is not approved for the treatment of Type 2 Diabetes but may be modestly effective in the obese diabetic

56. Type 2 Diabetes Key Concepts
Dual impairment:
ß-cell function: insulin secretion
insulin action: insulin resistance
“Glucose toxicity” aggravates both impairments
Multiple mechanisms to correct hyperglycemia
Most patients require combination therapy
Key concepts of type 2 diabetes include:
In type 2 diabetes there is an impairment of ß-cell function resulting in reduced insulin secretion and an impairment of insulin action with subsequent insulin resistance.
Hyperglycemia causes further aggravation of ß-cell function impairment and insulin action impairment.
Glucose can be lowered by various mechanisms.
Most patients require combination therapy sooner or later to achieve goal.

57. Combination Therapy Summary
The magnitude of the diabetic epidemic dictates more aggressive approaches to treatment
Evidence clearly suggest that early intensive treatment results in significant decrease in complications
To reduce macrovascular disease more strict glucose control might be needed (HbA1c <6%)
In summary, the magnitude of the diabetic epidemic means that unless good diabetic control can be achieved, there will be a deluge of complications that are costly in both individual and societal terms. This situation dictates a more aggressive approach to treatment.
We have reviewed some studies that form part of a growing body of evidence for the value of initiating intensive therapy early.
We know that microvascular complications can be significantly reduced. To reduce macrovascular disease as well, it is possible that very strict glycemic control—HbA1c levels < 6%—might be required. This question is being addressed by studies that are already underway.
In order to achieve very tight levels of control, combination therapy will need to be introduced early, and the components will need to be tailored to the patient’s particular metabolic defects. In some patients, insulin formulations that target PPG may be the only route to optimal control.

58. In Conclusion Prevalence of type 2 diabetes is increasing dramatically
Majority of patients are diagnosed and treated by the family physician
New paradigm: need to be much more aggressive early in the treatment of these patients utilizing dual therapies
Hypoglycemia can be managed through proper treatment choices and lifestyle management
Glucose is a continuous progressive risk factor for cardiovascular disease
Slide 50
Speaker notes:
In conclusion, the prevalence of type 2 diabetes mellitus is increasing at a dramatic and alarming rate. Most patients with diabetes will be diagnosed and treated by family physicians.
A new paradigm dictates that in order to avoid complications and deterioration of glycemic control, early and aggressive therapy will be required. Almost inevitably, this will involve the use of oral combination regimens.
If patients and physicians are aware of it, hypoglycemia can be managed with judicious choices of agents and by appropriate lifestyle management.
Finally, the plasma glucose level is a continuous and progressive risk factor for cardiovascular disease, even at levels that fall below the definitions of diabetes. Very tight glycemic control that includes targeting of PPG therefore has the potential to reduce macrovascular complications such as CV events.

59. QUESTIONS?