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2003 CDA Clinical Practice Guidelines

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1 2003 CDA Clinical Practice Guidelines
J. Robin Conway M.D. Diabetes Clinic Smiths Falls, ON

2 Worldwide rates of diabetes mellitus: predictions
80 70 60 50 40 30 20 10 Prevalence (millions) Year 1995 2000 2025 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 North America Europe Southeast Asia World Health Organization Canadian Diabetes Association, 1998 website.


4 2 Million Canadians Have Diabetes Mellitus
Frequency of diagnosed and undiagnosed diabetes and IGT, by age (U.S. data - Harris) 1.5 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 1.5 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:

5 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.

6 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 Que screening >2 Risk Factors 79% tested % Diabetes % IGT or IFG % No Treatment Advice Leiter et al. Diabetes Care 2000 Strychar I et al. Cdn J Diab 2003(abs)

7 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 Harris S et al. Cdn Fam Phys 2003

8 Cardiovascular Risk Sask Smiths Falls Statin 19.9% 70% ACE 48.9% 91%
ASA % % Brown L et al. Cdn J Diab 2003(abs) Nozek L et al. Cdn J Diab 2003(abs) Conway R et al. Cdn J Diab 2003(abs)

9 Burden of Poor Control - Cost
The socioeconomic buden of diabetes can be documented in different ways: Burden of poor control established by assessing the relationship between glycemic control and diabetes health care cost Example of such a study is given above where Gilmer et al. Estimated the cost to health plans associated with different levels of glycemic control Lack of control in diabetes has a socioeconomic burden for all stakeholders in health care

10 2003 CDA Guidelines Early Aggressive Screening
FPG every 3yrs over age 40 High Risk Groups Relatives of Diabetics Aboriginals & Hispanics PCOS Schizophrenics Dyslipidemia

All individuals should be evaluated annually for Diabetes risk on the basis of history, clinical and demographic criteria. Screening for Diabetes using a fasting plasma glucose should be performed every 3 years for individuals over 40 years of age. More frequent or earlier testing with either a fasting plasma glucose or OGTT in people with additional risk factors for Diabetes,

12 PREVENTION Pre diabetes
OGTT should be considered if BMI>25 and FPG between 5.7 & 7 to identify IGT or Diabetes With IGT a program of lifestyle mod that includes wt loss & exercise to prevent T2D With IGT treatment with Metformin or Acarbose should be considered.

13 DIAGNOSIS FBS >7 mmol/L + symptoms RBS >11 mmol/L + symptoms
PREDIABETES IFG FBS mmol/L IGT 2 hr PC glucose on OGTT If FBS > 5.7 mmol/L do OGTT

14 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 *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

15 Monitoring A1c every 3 months
Self Monitor Glucose, interpret results,alter food choices, physical activity, frequency of testing & medications Type 1 should test at least 3 times a day Type 2 should test at least daily Type 1 in acute illness should test ketones if glucose >14 mmol/L

16 Exercise 150 minutes of moderate intensity aerobic exercise over 3 nonconsecutive days of the week or if willing 4 hrs/week Encourage resistance exercise 3 times/week

17 Nutrition Nutrition Counselling Canada Food Guide
For PPG control Amnt & source of CHO, Glycemic Index Sucrose to 10% Cal Discuss Alcohol Intensive Insulin do CHO counting

18 Goals in Diabetes FBS<7, PC<11, A1c<7% BP <130/80
TC/HDL <4, LDL <2.5, Trig <1.5 ACR <2 Male, <2.8 Female

19 Drugs in Type 2

20 Need for Combination Therapy in UKPDS
% of Patients Slide 37 Speaker notes: 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. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321(7258):

21 Pathophysiology of Type 2 Diabetes
Decreased insulin secretion Loss of ‘first-phase’ insulin secretion Increased insulin resistance, resulting in: Decreased glucose and fat uptake Increased free fatty acid release Increased hepatic glucose output Slide 17 Speaker notes: The pathophysiology of type 2 diabetes thus involves decreased insulin secretion, loss of the first phase secretion of insulin, and increased insulin resistance. Resistance to insulin results in increased fatty acid release and hepatic glucose output, as well as decreased uptake of glucose and fatty acids by target tissues such as muscle.

22 UKPDS: Long-term Glucose Control
9 Conventional 8 HbA1c (%) Intensive 7 Slide 16 Speaker notes: 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:

23 Progressive Loss of -cell Function in UKPDS
20 40 60 80 100 1 2 3 4 5 6 7 -cell function (%) Years from randomization Non obese Obese -cell function (%) Slide 15 Speaker notes: 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

24 Stages of Type 2 Diabetes in Relationship to ß-cell Function
Type 2 Diabetes is Characterized by Insulin Resistance and Progressive ß-cell Failure 100 75 50 25 Stages of Type 2 Diabetes in Relationship to ß-cell Function Beta Cell Function (%) Impaired glucose tolerance Postprandial hyperglycemia Type 2 diabetes phase I Type 2 diabetes phase III Type 2 diabetes phase II In Type 2 diabetes, there is both an impairment of beta cell (ß-cell) function and an impairment of insulin action. Impaired ß-cell function results in a decrease in insulin secretion whereas impaired insulin action results in insulin resistance.1 REFERENCE: 1. Lebovitz HE. Insulin secretagogues: old and new. Diabetes Review. 1999; 7(3): Years from Diagnosis 50% of ß-cell function is already lost at diagnosis Elevated PPG occurs before diagnosis Lebovitz HE. Diabetes Review 1999;7(3):

25 Impaired Insulin Secretion in Type 2 Diabetes
Time 6 am 10 am 2 pm 6 pm 10 pm 2 am 800 600 400 200 Insulin secretion (pmol/min) Type 2 diabetes healthy The difference in insulin secretion between type 2 diabetes and healthy individuals can be found in a specific defect of loss of 1st-phase insulin secretion. As a result, plasma glucose levels are higher in type 2 diabetes both under fasting conditions and in response to meals. Adapted from Polonsky KS et al. N Engl J Med 1996; 334: 777.

26 Type 2 Diabetes: Underlying Defects
Pathophysiology Type 2 Diabetes: Underlying Defects Insulin resistance  Beta-cell function Type 2 diabetes Other defects:  lipolysis release of NEFA  hepatic glucose production The main pathologic defects in diabetes are peripheral insulin resistance and defective beta-cell secretory function. Insulin resistance occurs when cells do not respond efficiently to insulin. Insulin resistance (and impaired insulin secretion) are initiator abnormalities for diabetes. As insulin resistance develops, more insulin is produced by the beta-cells in the pancreas to compensate. This leads to hyperinsulinemia. Eventually, beta-cell dysfunction develops and thus adequate blood glucose control cannot be maintained. Increased lipolysis with release of NEFA (non-esterified fatty acid) or free fatty acids and increased hepatic glucose production are also present. Adapted from Matthaei et al. Endocrine Reviews 2000;21: Adapted from Frayn. Br J Nutr 2000;83(suppl 1): S71-S77.

27 Type 2 Diabetes - Dual Impairment
Insulin Secretion Impaired insulin secretion from pancreatic ß-cells A sluggish and inadequate response to the glucose load imposed by meals Characteristic only of Type 2 diabetes 100% of patients have impaired secretion at diagnosis Approx. 84% have insulin resistance Also associated with other metabolic conditions Insulin Resistance Type 2 diabetes is characterized by beta cell dysfunction Type 2 diabetes is by far the most common form of diabetes and usually arises because of impaired pancreatic beta cell function causing impaired insulin secretion in response to a glucose load.1,2 Type 2 diabetes may also result from insulin resistance Insulin resistance occurs when normal levels of insulin are produced but fail to exert their usual biological actions. Insulin resistance also develops as a result of elevated blood glucose levels, and hyperglycemia itself may impair insulin mediated glucose transport i.e. insulin resistance is a consequence of glucose toxicity.1,2 Insulin resistance is a risk factor for type 2 diabetes, however, not all people with insulin resistance develop diabetes.3 REFERENCES: 1. Lebovitz HE. Insulin secretagogues: old and new. Diabetes Review. 1999; 7(3): 2. Polonsky KS, Given BD, Hirsh LJ, et al. Abnormal patterns of insulin secretion in non-insulin-dependent diabetes mellitus. The New England Journal of Medicine 1988;318: 3. Bonora E, et al. Prevalence of insulin resistance in metabolic disorders: The Bruneck Study. Diabetes 1998; 47: Lebovitz HE. Diabetes Review. 1999; 7(3): Polonsky KS, et al. NEJM 1988;318: Bonora E, et al. Diabetes 1998;47:

28 Issues to be Addressed when Selecting Agents
Degree of -cell deficiency Magnitude of insulin resistance Extent of fasting hyperglycemia Magnitude of postprandial hyperglycemia Slide 38 Speaker notes: When selecting agents, clinicians need to be aware of four key parameters: The degree of beta-cell deficiency The presence and magnitude of insulin resistance The severity of fasting hyperglycemia, and The severity of postprandial hyperglycemia. Each of these parameters may differ in importance between individual patients.

29 Epidemiological Evidence Linking PPG with Cardiovascular Disease

30 CHD Risk and Type 2 Diabetes
Db- No diabetes; Db+ Diabetes; MI- No prior MI; MI+ prior MI Several studies have shown the risk that having type 2 diabetes confers on overall cardiovascular mortality. For example, Haffner et al. compared the 7-year incidence of MI (fatal and nonfatal) among 1373 non-diabetic subjects with the incidence among 1069 diabetic subjects, from a Finnish population-based study The 7-year incidence rates of MI, stroke and death from CV were reported. Haffner found a similar incidence of cardiovascular disease (MI, stroke, death— diagonal-striped column 2 and 3 in each group) between the known risk factor of prior MI and diabetes after adjustment for other cv risk factors (smoking hypertension, LDL, HDL, total cholesterol and triglycerides). This study supports the rationale for treating CV risk factors aggressively in diabetes patients. Stroke CV death MI p<0.001 for prior MI vs. no MI and diabetes vs. no diabetes calculated with Cox proportional-hazards models, adjusted for age and sex Haffner SM et al. N Engl J Med 339: , 1998

31 2-hour PPG, Not FPG, Predicted All-cause Mortality
2.5 2.0 1.5 1.0 0.5 0.0 Hazard ratio ³11.1 Recognizing that overall glycemic control, A1C is comprised of both PPG and FPG, DECODE tried to determine the relationship between fasting plasma glucose (American Diabetes Association) versus 2-hour plasma glucose and the risk of cardiovascular disease and mortality. As PPG levels increased, moving up along the z-axis, the hazard ratio increased dramatically The increase in risk was not as great as you increased FPG, shown across the x-axis DECODE clearly demonstrated that CV mortality was more closely associated with two-hour PPG than with FPG. n= 25,364 people in 13 European population- or occupational-based studies. 1,275 of these people had a previous diagnosis of diabetes. 18,048 men, 7316 women aged 30+; Mean follow-up: 7.3 yrs 2-hr PPG was associated with a 73% increased risk of all-cause mortality independently of fasting glucose levels (DECODE, 1999). A two-hour glucose level of ≥11.1 mmol/L more than doubled the risk of death Thus, the DECODE study clearly demonstrated that CV mortality was more closely associated with two-hour glucose than with fasting glucose levels. DECODE study group. Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria. Lancet 1999;354:617–621. Graph from Table 3, p. 619. 7.8 –11.0 2-hour PPG, 75g OGTT (mmol/L) <7.8 < – ³7.0 Fasting plasma glucose (mmol/L) Adjusted for age, centre, sex Adapted from DECODE Study Group. Lancet 1999;354:617.

32 Epidemiological Evidence Linking High PPG* with CVD Risk & Mortality
DECODE, High PPG is associated with increased risk of death, independent of FPG Pacific and Indian Ocean, High PPG with normal FPG doubles the risk of mortality Funagata Diabetes Study, IGT, but not IFG, is a risk factor for CVD Whitehall, Paris, Helsinki Study Men in upper 2.5% of PPG distribution had significantly higher CHD mortality The Rancho-Bernardo Study, PPG more than doubles the risk of fatal CVD and heart disease in older adults Diabetes Intervention Study, PPG (1-hr post-breakfast), but not FPG, is associated with CHD This slide summarizes a number of studies showing that elevated PPG* (2-hr PPG after 75g OGTT except where indicated) is a significant risk factor in the development of macrovascular diabetic complications The recent DECODE study indicated that using FPG concentrations alone, without 2-hr PPG to screen for diabetes, would not identify individuals at increased risk of death associated with hyperglycemia. Similarly the Pacific and Indian Ocean study determined that isolated 2 hour post-challenge hyperglycemia at least doubles the risk of mortality and that this is not detected using FPG alone. In the Funagata diabetes study, the new US category of impaired fasting glucose (IFG) (fasting plasma glucose of between mmol/L) was found not to be a risk factor for cardiovascular disease (CVD) but impaired glucose tolerance, (plasma glucose concentration of mmol/L 2 hours after a 75 g glucose dose) was. In the Whitehall, Paris, Helsinki study, men in the upper 20% and 2.5% of the 2-hour post meal glucose distribution were found to have a higher risk of all-cause mortality or cardiovascular associated mortality, respectively. The failure of fasting glucose alone to identify older adults at high risk for CVD was highlighted in the Rancho-Bernardo study, while in older women, 2-hour post meal hyperglycemia ≥11.1 mmol/L and FPG < 7 mmol/L doubled the risk of fatal CVD. In the Diabetes intervention study, 1-hr PPG (post-breakfast) was associated with increased risk of coronary heart disease and mortality. NOTE: Possible criticism of these studies is that they did not all include diagnosed type 2 diabetes patients *2-hour PPG after 75g OGTT, except where indicated 1DECODE Study Group. Lancet 1999;354:617. 2Shaw JE et al. Diabetologia 1999;42:1050. 3Tominaga M et al. Diabetes Care 1999;22:920. 4Balkau B et al. Diabetes Care 1998;21:360. 5Barrett-Connor E et al. Diabetes Care 1998;21: Hanefeld M et al. Diabetologia 1996;39:1577.

33 Intervention Studies to Control PPG and its Effect on CV Disease
Manzella 20051 Type 2 Repaglinide had greater PPG lowering and a significantly greater improvement in endothelial function and a decline in oxidative stress compared to glyburide Esposito 20042 After 12 months, CIMT regression (decrease of > mm) was observed in 52% of the repaglinide group vs 18% in the glyburide group (p<0.01). Hanefeld 20043 Acarbose reduced relative risk of myocardial infarction by 64% (p=0.012) and any CV event 35% (p=0.0061) Chiasson 20034 IGT Acarbose reduced relative risk of CV events by 49% and new cases of hypertension by 34% compared to placebo Recent intervention studies using agents that targeted PPG and their effect on CV markers and outcomes. Manzella month, randomized, cross-over, parallel-group study. Investigators blinded to treatment. Repaglinide 1 mg BID. Glyburide 5 mg bid. The main beneficial effect seems to be mediated by Nitric oxide as this beneficial effect was blocked by NO inhibitors, l-NMMA Note: Greater FPG lowering with repaglinide - the changes in endothelial function may be due to glucose lowering Esposito type 2 drug-naïve RPG n=88, glyburide n=87. A multivariate analysis was performed with CIMT as the dependent variable and FPG, glucose peaks, A1C, IL-6, IL-18, and CRP were the independent variables. The model explained 60% variability in the change of CIMT with changes in glucose peak (28% p=0.002). Context to CIMT changes: DCCT/EDIC N Engl J Med 2003; 358: 23. mean progression of intima-media thickness was significantly less in the intensive therapy between year 6 and year one vs. conventional therapy: vs (difference 0.014mm) p=0.01; REGRESS Pravastatin 40 mg/day: mm/year vs. placebo ( p=0.0085) mean change after 2 years, combined mean intima media thickness of femoral and carotid arteries; Statin studies also showed a reduction in coronary events by 20-40%. Esposito also included patients (8% of total) who were on statins. This study did not look at postprandial lipids Hanefeld 2004 Meta-analysis of 7, randomized, placebo-controlled studies in type 2 DM patients randomized to acarbose (n=1248) or placebo (n=932) over > 1 year. Acarbose reduced RR: Myocardial infarction 64% (p=0.012); Any CV event 35% (p=0.0061); These CV benefits are in addition to risk reduction by concomitant CV therapy. Note: data from published information as well as Bayer database Chiasson Patients with IGT randomized to placebo (n=715) or acarbose 100 mg TID (n=714). Multicentre, double-blind, placebo-controlled, randomized trial followed up for a mean of 3.3 (SD 1.2) years. 49% relative risk reduction in CV events; hazard ratio [HR] 0.51; 95% CI % relative risk reduction in new cases of hypertension HR 0.66; 95% Confidence interval , p= Notes: 24% discontinued prematurely; 19% discontinued due to adverse effects (GI); studied in IGT not diabetes; 49% relative risk reduction corresponded to 2.5% absolute risk reduction. The absolute numbers of events is 12 cases of MI in placebo group and 1 case in the acarbose group 1. Chiasson et al. JAMA 2003; 290: Hanefeld M, et al. Eur Heart J 2004;25(1): Esposito K et al. Circulation 2004; Manzella D et al. Diabetes Care 2005; 28(2): 366.

34 Sites of Action of Currently Available Therapeutic Options
LIVER MUSCLE ADIPOSE TISSUE PANCREAS GLUCOSE PRODUCTION Biguanides Thiazolidinediones PERIPHERAL GLUCOSE UPTAKE Thiazolidinediones (Biguanides) Sites of Action o f 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. INSULIN SECRETION Sulfonylureas Meglitinides Insulin INTESTINE GLUCOSE ABSORPTION Alpha-glucosidase inhibitors Sonnenberg, Kotchen Curr Opin Nephrol Hypertens 1998;7:551-5.

35 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.

36 Timeline for Therapy in Type 2 Diabetes
Metformin/Thiazolidinediones Lifestyle Insulin Secretagogues IGT Diabetes Fasting Blood Glucose Postprandial Blood Glucose Insulin Resistance Endogenous Insulin Avg Dx 6.5 yrs Normal Blood Glucose Normal Insulin Explain each component (line) as it is animated. Type 2 diabetes begins with insulin resistance (impaired glucose tolerance), which is linked to macrovascular disease. Beta cell function accelerates to compensate, however, it eventually begins to deteriorate, resulting in insulin deficiency and elevated glucose. In response to deteriorating beta cell function and subsequent loss of first-phase insulin response, postprandial glucose increases, which is associated with the initiation of macrovascular complications. While fasting glucose levels remain normal during the initial stages of this cycle. They eventually rise, initiating the development of microvascular complications. Main Message(s) While physicians often look at fasting glucose as an indication of control, we can see that the postprandial glucose is the initial driver of hyperglycemia and microvascular complications. Because beta cell deterioration is progressive and persistent, all patients who live long enough will eventually need insulin therapy. With the increasing prevalence of type 2 diabetes among younger adults, we will see many patients living with diabetes for many years. Years Modified from graphic developed by the IDC

37 Canadian Diabetes Association
2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada

38 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)

39 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

40 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 L I F E S T Y L E Biguanide alone or in combination with 1 of: 1 or 2† antihyperglycemic agents from different classes 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 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

41 L I F E S T Y L E Biguanide alone or in combination with 1 of:
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 If not at target L I F E S T Y L E Add a drug from a different class or Use insulin alone or in combination with: 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 * 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.

42 Expected A1C Lowering with Oral Monotherapy
Metformin Repaglinide*# Sensitizers (pioglitazone, rosiglitazone) Sulfonylureas# (glyburide, gliclazide, glimepiride) 1 – 1.5 % Acarbose* Nateglinide*# Orlistat 0.5 – 0.8 % #oral insulin secretagogue *targets PPG Adapted from Table 1. CDA 2003 Clinical Practice Guidelines, Can J Diabetes 2003; 27(Suppl 2): S38.

43 Insulin Secretagogues: Mechanisms of Action
Treatment Insulin Secretagogues: Mechanisms of Action 1. Intestine: glucose absorption 2. Muscle and adipose tissue: glucose uptake Insulin resistance Blood glucose 4. Liver: hepatic glucose output The main mechanism by which the insulin secretagogues exert their therapeutic effect is to increase insulin production by stimulating the beta-cells of the pancreas in a similar way to glucose itself. 3. Pancreas: Insulin secretion Sulfonylureas  insulin secretion Insulin resistance Lebovitz HE. Joslin’s Diabetes Mellitus, Ch. 29,

44 Antihyperglycemic Agents
Acarbose Nateglinide Repaglinide Rapid-acting insulin analogues Postprandial hyperglycemia 12.5 10.0 glucose (mmol/l) 7.5 5.0 Metformin Sulfonylureas TZD’s Basal insulin In order to achieve overall glycemic control, it is important to target both FPG and PPG. Pharmacological agents that target PPG more specifically are highlighted in red. Graph adapted from Riddle MC. Evening insulin strategy. Diabetes Care. 1990;13: The 24-hour plasma glycemic pattern typical of healthy individuals is indicated by the lower border of the blue area, and that of patients with mild type 2 diabetes is indicated by the upper border of the red area. The red area shows the part of the glycemic abnormality of diabetes accounted for by excessive postprandial hyperglycemia related to meals, while the blue area shows the part due to elevated basal glycemia. Basal hyperglycemia 0600 1200 1800 2400 0600 hours Adapted from Riddle et al. Diabetes Care. 1990;13:

45 Attributes of Meglitinides Gluconorm (repaglinide) Starlix (nateglinide)
Increases early-phase insulin release Physiologic response to meals (rapid onset and elimination) Significant improvement in key blood glucose parameters (PPG, FPG, and HbA1c) Low risk of hypoglycemia Weight neutral Slide 43 Speaker notes: GlucoNorm, the first of a new class of insulin secretagogues called meglitinides, works by increasing early insulin release. This is an important advantage for the control of PPG. Its rapid onset of action and elimination mimics the normal physiologic response to meals. Because its dosing is coupled to meals, it is compatible with variations in lifestyle. Key studies have shown that GlucoNorm significantly improves PPG, FPG and HbA1c. This agent is not associated with significant weight gain, and offers a lower risk of severe hypoglycemia than sulfonylureas—an attractive safety feature if a meal is missed, delayed or decreased in size. Finally, it should be noted that meglitinides such as GlucoNorm do not actually inhibit insulin synthesis. These compounds have minimal interaction with cardiac and smooth muscle potassium ATPase channels.

46 Hypoglycemia: Why is it Important?
Annually, about % of patients on oral agents have hypoglycemia Under-recognized and under-reported Substantial impact: Social embarrassment Emotional toll – “found dead in bed” Work restrictions (e.g. operating machinery) Devastating to elderly patients Slide 21 Speaker notes: The information in the next few slides is based on the Canadian Diabetes Association’s upcoming guidelines on hypoglycemia. It has been estimated that each year, perhaps 5-20% of patients taking oral anti-hyperglycemic medications will experience a hypoglycemic episode. This is likely to be an underestimate, given that the condition is under-recognized and under-reported. Hypoglycemia has a huge social, occupational and emotional impact; it can be devastating to frail elderly patients.

47 Adding Repaglinide to Restore Mealtime Insulin Secretion
If A1C ≥8% 1 mg or mg with meals If repaglinide is 1st line or A1C <8%, start 0.5 mg with meals Double the dose every week until target achieved Maximum mealtime dose (4mg); Maximum daily dose (16mg) Mealtime dosing of repaglinide is simple; one meal, one dose. No meal, no dose. Adding repaglinide to metformin at mealtime or to rosiglitazone is convenient and easy to remember. REFERENCE: 1. GlucoNorm® Product Monograph, Novo Nordisk Canada Inc., 2005. GlucoNorm® Product Monograph, Novo Nordisk Canada Inc., 2005.

48 Basal/Bolus Treatment Program with Rapid-acting and Long-acting Analogs
Breakfast Lunch Dinner Aspart Aspart Aspart or or or Lispro Lispro Lispro Plasma insulin Glargine or Detemir 4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00 Time

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