1. Back to Basics: Endocrinology Diabetes, Obesity, Metabolic Syndrome
Dr. Amel Arnaout

2. Which of the following statements is true?
Type 1 diabetes is not diagnosed after age 50
Type 2 diabetes is more strongly inherited than type 1 diabetes.
The incidence and prevalence of DM-1 is on the rise
Gestational diabetes does not increase the risk of developing diabetes in the future.
People with type 2 diabetes never get DKA

3. Answer
B and C

4. Diabetes in Canada: Prevalence of Diagnosed Diabetes by age and sex
Prevalence of diagnosed diabetes among individuals aged ≥ 1 year, by age group and sex, 2008/09
Overall Prevalence 30
6.4%
Females 25
7.2%
Males 20
Total
6.8%
Prevalence (%) 15 10
Source: Public Health Agency of Canada (July 2011); using 2008/09 data from the Canadian Chronic Disease Surveillance System (Public Health Agency of Canada). 5
Age group (years)
1-19
20-24
25-29
30-34
35-39
40-44
45-49
50-54
55-59
60-64
65-69
70-74
75-79
80-84
≥85
Canada
Prevalence increased with age. The sharpest increase occurred after age 40 years. The highest prevalence was in the year age group.
Public Health Agency of Canada. Diabetes in Canada: Facts and figures from a public health perspective. Ottawa, 2011.

5. Classification of Diabetes
Type
Definition
Type 1 Diabetes
Diabetes due to pancreatic beta destruction and prone to ketosis
Type 2 diabetes
Diabetes that ranges from insulin resistance with relative insulin deficiency to a predominant secretory defect with insulin resistance
Gestational
Diabetes
Mellitus
Glucose intolerance with onset or first recognition in pregnancy
Other types
Variety of uncommon diseases, genetic forms, or diabetes associated with drug use.

6. TYPE 2 Diabetes TYPE 1 Diabetes Proportion of diabetes cases
Pathogenesis
Endogenous insulin secretion
Need for insulin therapy
Age of onset
Body habitus
Genetic component
Symptoms at onset
Ketoacidosis
Long-term complications present at dx?
TYPE 1 Diabetes
10%
Beta cell destruction
(usually autoimmune)
Low or absent
Required for survival
Often <30 (but can occur at any age)
Usually lean
Smaller
Acute, severe
Yes No
TYPE 2 Diabetes
90%
Insulin resistance, relative insulin deficiency
Variable
Required in <50%, to improve control rather than for survival
Often >40 but even in kids
Often obese
Very large
Often mild, slow onset
Rare
Retinopathy ~20%, CVD relatively common

7. The pathophysiology of T2DM includes three main defects
Islet
α-cell produces excess glucagon
Pancreas
β-cell produces less insulin
1. Insulin deficiency
Excess glucagon
The pathophysiology of hyperglycemia in type 2 diabetes (T2DM) involves three main defects: (1) insulin deficiency due to insufficient pancreatic insulin release; (2) excess hepatic glucose output; and (3) insulin resistance (decreased glucose uptake) in peripheral tissues (including muscle and fat) and the liver.
Two pancreatic islet cell defects contribute to this pathology:
ß-cells produce insulin, which facilitates glucose entry into tissues. In T2DM, a decline in functional ß-cell mass causes insulin deficiency, which in turn contributes to hyperglycemia.
α-cells produce glucagon. Elevated glucagon levels promote increased hepatic glucose output.
In T2DM, excess glucagon and diminished insulin secretion drive hepatic glucose output and contribute to hyperglycemia.
Illustrations: ©2007 GCT II Solutions and Enterprises Ltd. O/A Headcan for unlimited reproduction rights in slide kits.
Muscle and fat
Hyperglycemia
Diminished insulin
Diminished insulin
Liver
2. Excess glucose output
3. Insulin resistance
Adapted from Buse JB, et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:1427–1483. Buchanan TA. Clin Ther. 2003;25[Suppl. B]:B32–B46. Powers AC. In: Harrison’s Principles of Internal Medicine. 16th ed. New York: McGraw-Hill, 2005:2152–2180. Rhodes CJ. Science. 2005;307:380–384.

8. Diabetes mellitus - complications
Diabetic Retinopathy
Leading cause of blindness in working-age adults1
Stroke
Cardiovascular Disease
Diabetic Nephropathy
Leading cause of end-stage renal disease2
Type 2 diabetes is indeed a serious disease. The speaker should point out that 80% of deaths are due to cardiovascular disease (CVD). Diabetes is the leading cause of blindness among working adults and the leading cause of end-stage renal disease. Diabetes is also the leading cause of non-traumatic amputations.
Diabetic Neuropathy
Leading cause of non-traumatic lower extremity amputations5
1. Fong DS et al. Diabetes Care 2003; 26(Suppl 1):S99-S Molitch ME et al. Diabetes Care 2003; 26 (Suppl 1):S94-S Kannel WB et al. Am J Heart 1990; 120: Gray RP and Yudkin JS. In: Textbook of Diabetes Mayfield JA, et al. Diabetes Care 2003; 26(Suppl 1):S78-S79.

9. Diabetes Complications: Macrovascular
DM is a major risk factor for cardiac disease
Acute MI occurs years earlier in those with DM
Heart disease accounts for approximately 50% of all deaths among people with diabetes in industrialized countries
REF: Diabetes in Ontario, An ICES Practice Atlas, 2002 pg5.96
REF: Diabetes in Ontario, An ICES Practice Atlas, 2002

10. Diabetes Complications: Cardiovascula disease
Several large epidemiological studies have found a strong relationship between
glucose level and subsequent coronary events, even at ‘pre-diabetes’ levels (IGT and IFG)
glucose levels that are only modestly elevated place patients at risk.
REF: Coutiho M. et al Diabetes Care 1999;22:
& DECODE Study Group. Arch Intern Med 2001;161:

11. Diabetes Complications: Peripheral vascular disease (Macro and microvascular disease)
Is the leading cause of non traumatic amputation
Increases the risk of amputation by 20 fold
those living in the north or in low income neighborhoods and those with poor access to physician services are at particular risk for amputation.
Page – Diabetes in Ontario, Practice Atlas, 200?
It is estimated that 4-10% of people with diabetes will develop a foot ulcer. In other words 80, ,000 Canadians with diabetes will be affected in their lifetime.
The numbers get even worse because statistics show that 14-24% of those persons with diabetes and foot ulcers will require amputation (either a partial foot amputation or a leg amputation) because the ulcer won't heal. Quality of life is another big concern because persons suffering from a foot ulcer are often reluctant to go out for fear of offending others with the odour. Routines are interrupted by the need for daily dressing changes, a situation that may mean waiting around for the visiting nurse. It is not surprising that foot ulcers are one of the biggest fears shared by persons with diabetes.
REF: Diabetes in Ontario, An ICES Practice Atlas, 2002

12. Diabetes Complications: Microvascular – Retinopathy
Is a leading cause of adult-onset blindness
Prevalence of diabetic retinopathy is ~ 70% in persons with type 1 and 40% with person with type 2 diabetes.
Neuropathy
REF: Diabetes in Ontario, An ICES Practice Atlas, 2002

13. Diabetes Complications: Microvascular - Nephropathy
Is the leading cause of ESRD
Increases the risk of developing ESRD by up to 13-fold
Diabetes in Ontario, Practice Atlas, 200?) pg 8.166
Refs: Meltzer S, et al CMAJ 1998; 159 (8 suppl):S1-S29, &
Parchman ML, et al Medical Care 2002; 40(2):

14. DM-2 Risk Factors Modifiable Risk Factors &
Physical Activity
Obesity
Diet
&
Non-Modifiable Risk Factors
Ethnicity
Family History
Age

15. Walking the dog demonstrates height of physical inactivity

16. Diabetes Risk Factors: Modifiable
BMI between out strips any of the relative risk factors of physical activity or diet….
However, physical activity and diet feed into BMI – it is a complex disease with complex and compounding risk factors
Source: Choi B, Shi F. Diabetologia 2001, 44:

17. The Epidemic: Ethnic Groups at High Risk for DM
Aboriginal
Latino
South Asian
Asian
African Descent

18. Prevention strategies
Primary Prevention
Prevent diabetes through reduction of modifiable risk factors in general population
Secondary Prevention
Screening those at high-risk for diabetes
Tertiary Prevention
Upon diagnosis of diabetes, prevention of complications morbidity, and mortality
SWB (blue) and Hunt (green)
Diabetes Blueprint
REF: Diabetes Blueprint

19. Primary Prevention Model
Goal
Reducing modifiable risk factors for diabetes
Target
General population & high-risk groups
Messages
Healthy lifestyle choices
Current Delivery Models of Primary Prevention
Population Health
Primary Care
CDA, Health Canada
Prevention Programs
NDSS/ADI/prevention and promotion
Health website education
Television Campaign
?other
Health Unit - Wellness Fair
week (schools)

20. Primary Prevention Model: Population Health – National
CDS
Health Canada
Health Canada
National level
NADA
REF: Health Canada

21. Secondary Prevention Goal Target Messages
Early identification of those with dysglycemia
Target
High-risk individuals and groups
Messages
Diabetes awareness
Current delivery model of secondary prevention relies on primary care

22. Secondary Prevention: Is It Effective?
Yes….
Patients diagnosed with IGT can be prevented from progressing to type 2 diabetes
58% reduction with lifestyle changes (DPP, DPS)
30% reduction with medication (DPP, Stop NIDDM)
Q&A of DPP
For a person with IGT, what is the risk of developing type 2 diabetes? As few as 1 to as many as 10 of every 100 persons with IGT will develop diabetes per year. The risk of getting diabetes rises as people become more overweight and more sedentary, have a stronger family history of diabetes, and belong to a racial or ethnic minority group. In the DPP, about 10 percent of participants in the placebo or standard group developed diabetes per year. The DPP interventions decreased the development of diabetes by 58 percent with intensive lifestyle interventions and by 31 percent with metformin.

23. Tertiary Prevention: Is it Effective?
Yes…
Strong evidence for tertiary prevention particularly for microvascular disease
DCCT, UKPDS
And for macrovascular as legacy effect (UKPDS and EDIC follow up studies)
How to translate this evidence into practice? …

24. Tertiary Prevention Goals
Glucose, blood pressure, and lipid control to reduce the development of complications
Complication screening for early identification and management
Prevention of diabetes once the diagnosis of IGT or IFG has been made
Lifestyle changes
Medications
Prevention of complications once the diagnosis of diabetes has been made
Glycemic control to reduce incidence of complications
Complication screening for early identification

25. OBESITY

26. Why are Obesity and Type 2 DM Increasing in Frequency?
More sedentary lifestyles
Worldwide changes in urbanization and nutrition
Aging population due to demographic growth rates (baby boomers) and increased life expectancy
Key Teaching Point: Slide is animated to have maximize fun impact of pictures
WHO reference:
Accessed March 2006.
IDF reference:
Information from Prevalence section under Facts and Figures tab.
Exact website:
and accessed March 16, 2006

27. Obesity The most common metabolic condition in industrialized nations
Statistics Canada: 48% of Canadians between ages yr are overweight (BMI>25), about 25% are obese
Associated with dyslipidemia, impaired glucose tolerance and insulin resistance
Risk factor for developing metabolic syndrome, type 2 Dm, cardiovascular disease
Huge economic costs

30. METABOLIC SYNDROME

31. Metabolic Syndrome A constellation of risk factors
Significantly increased CVD risks
Significantly increased risks for type 2 diabetes

32. Definition of Metabolic Syndrome – need central obesity plus 2 others for diagnosis

33. Clinical Features of the Metabolic Syndrome
Abdominal obesity
Hyperglycemia
Atherogenic dyslipidemia
Hypertension
Proinflammatory state
Prothrombotic state

34. Metabolic Syndrome
A common condition associated with increased cardiovascular disease risks
Treatment is aimed at lifestyle modification to achieve desirable body weight and reduce abdominal obesity
Multiple medical therapy may be required to achieve metabolic targets (lipids, glucose and BP)
Lifestyle modification benefits everyone!

35. DIABETES

36. Fasting = no caloric intake for at least 8 hours
Diagnosis of Diabetes
2013
FPG ≥7.0 mmol/L
Fasting = no caloric intake for at least 8 hours or
A1C ≥6.5% (in adults)
Using a standardized, validated assay, in the absence of factors that affect the accuracy of the A1C and not for suspected type 1 diabetes
2hPG in a 75-g OGTT ≥11.1 mmol/L
Random PG ≥11.1 mmol/L
Random= any time of the day, without regard to the interval since the last meal
Script:
Diabetes can be diagnosed by many different cut-offs. The biggest change from the previous set of guidelines is that HbA1c > 6.5% is part of diagnostic cut-off if a standardized validated assay is used with absence of other factors that affect A1c and not suspecting Dm. So FBG >7, A1c >6.5%, or 2h PG > 11.1 or random PG >11.1 can be used to used to diagnose diabetes.
Diagnosis of diabetes is based on thresholds of glycemia that are associated with microvascular disease
2hPG = 2-hour plasma glucose; FPG = fasting plasma glucose; OGTT = oral glucose tolerance test; PG = plasma glucose

37. Diagnosis of Prediabetes*
2013
Test
Result
Prediabetes Category
Fasting Plasma Glucose
(mmol/L)
Impaired fasting glucose (IFG)
2-hr Plasma Glucose in a 75-g Oral Glucose Tolerance Test (mmol/L)
7.8 – 11.0
Impaired glucose tolerance (IGT)
Glycated
Hemoglobin
(A1C) (%)
Prediabetes
* Prediabetes = IFG, IGT or A1C %  high risk of developing T2DM

38. Definitions of Impaired Fasting Glucose (IFG) and Impaired Glucose Tolerance (IGT) and Diabetes
8.5
Diabetes
7.5
6.9
IFG
IFG + IGT
Fasting Glucose (mmol/L)
6.5
6.1
5.6*
5.5
Normal
Glucose
IGT
Key Teaching Point:
There is a range of values for the lower limit glucose level for a diagnosis of IFG:
World Health Association (WHO) uses 5.6 mmol/L as the threshold for IFG when whole blood is used, 6.1 mmol/L if plasma. American Diabetes Association (ADA) uses 5.6 mmol/L as the threshold for IFG. Canadian Diabetes Association (ADA) uses 6.1 mmol/L as the threshold for IFG. The upper limit is 6.9 mmol/L for the ADA, the CDA, and the WHO.
ADA guidelines:
American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2006;29:S47.
WHO guidelines:
World Health Organization. Definition, diagnosis, and classification of diabetes mellitus and its complications: Report of a WHO Consultation. WHO/NCD/NCS/ Available online at Accessed March 2, 2006.
CDA guidelines:
Canadian Diabetes Association. Clinical practice Guidelines: Screening and Prevention. Can J Diabetes 2003;27(Suppl 2):S7.
4.5
3.5 3 4 6 8 10 12 14
7.8
11.1
2-h Post-load Glucose (mmol/L)
* 1. ADA Diabetes Care 2006;29(Suppl 1):S47,2. CDA Can J Diabetes 2003;27(Suppl 2):S7,
3.WHO NDC/NCS.99.2 accessed Mar from

39. Recognize pitfalls of A1C: conditions that can affect value
Factors affecting A1C
Increased A1C
Decreased A1C
Variable Change in A1C
Erythropoiesis
B12/Fe deficiency Decreased erythropoiesis
Use of EPO, Fe, or B12
Reticulocytosis
Chronic liver Dx
Altered hemoglobin
Fetal hemoglobin Hemoglobinopathies Methemoglobin
Altered glycation
Chronic renal failure
(use of EPO decreases A1C)
ASA, vitamin C/E
Hemoglobinopathies
↑ erythrocyte pH
Erythrocyte destruction
Splenectomy
Splenomegaly
Rheumatoid arthritis
HAART meds, Ribavirin
Dapsone
Assays
Hyperbilirubinemia
Carbamylated Hb
ETOH
Chronic opiates
Hypertriglyceridemia
Script:
While HbA1c is an excellent measure for diagnosis, it is essential to know conditions where the value may not adequate reflect true glycemic control and other measures such as fasting blood sugar or OGTT may be more helpful.
Important conditions where the rate of red blood cell turnover is significantly shortened or extended, or the structure of hemoglobin is altered, A1C may not accurately reflect glycemic status
This includes common conditions such as B12 and Fe deficiency that can falsely increase hbA1c and also increased red cell turn over states and factors that increase erthropoeisis such as use of EPO, Fe, B12 deficiency – which can falsely lower hbA1c.
So While HbA1c is convenient for patients understanding the factors that affect the accuracy of it’s ability to diagnose diabetes.
TT: point of slide is to teach practionners to recognize common pitfalls and conditions where HbA1c might not be an accurate measure to use for diagnosis.

40. Pros and Cons of Diagnostic Tests
Advantages
Disadvantages
FPG
Established standard
Fast and easy
Single Sample
Sample not stable
Day-to-day variability
Inconvenient to fast
Glucose homeostasis in single time point
2hPG in 75 g OGTT
Inconvenient, Unpalatable
Cost
A1C
Convenient
Single sample
Low day-to-day variability
Reflects long term [glucose]
$$$
Affected by medical conditions, aging, ethnicity
Standardized, validated assay required
Not used for age <18, pregnant women or suspected T1DM
Script:
While all 3 approaches predict microvascular disease and can be used for diagnosis, A1c may be a better predictor of macrovascular disease. The decision of which test to use for diabetes diagnosis is left to clinical judgment. Each diagnostic test has advantages and disadvantages
TT: Slide compares the advantages and disadvantages of the different tests.

41. Treatment of Diabetes – Target A1C

42. Individualizing A1C Targets
2013
Consider % if:
which must be balanced against the risk of hypoglycemia

43. DCCT n=1441 T1DM Intensive (≥ 3 injections/day or CSII) vs Conventional (1-2 injections per day)
N Engl J Med Sep 30;329(14):
The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group.
[No authors listed]
Abstract
BACKGROUND:
Long-term microvascular and neurologic complications cause major morbidity and mortality in patients with insulin-dependent diabetes mellitus (IDDM). We examined whether intensive treatment with the goal of maintaining blood glucose concentrations close to the normal range could decrease the frequency and severity of these complications.
METHODS:
A total of 1441 patients with IDDM--726 with no retinopathy at base line (the primary-prevention cohort) and 715 with mild retinopathy (the secondary-intervention cohort) were randomly assigned to intensive therapy administered either with an external insulin pump or by three or more daily insulin injections and guided by frequent blood glucose monitoring or to conventional therapy with one or two daily insulin injections. The patients were followed for a mean of 6.5 years, and the appearance and progression of retinopathy and other complications were assessed regularly.
RESULTS:
In the primary-prevention cohort, intensive therapy reduced the adjusted mean risk for the development of retinopathy by 76 percent (95 percent confidence interval, 62 to 85 percent), as compared with conventional therapy. In the secondary-intervention cohort, intensive therapy slowed the progression of retinopathy by 54 percent (95 percent confidence interval, 39 to 66 percent) and reduced the development of proliferative or severe nonproliferative retinopathy by 47 percent (95 percent confidence interval, 14 to 67 percent). In the two cohorts combined, intensive therapy reduced the occurrence of microalbuminuria (urinary albumin excretion of > or = 40 mg per 24 hours) by 39 percent (95 percent confidence interval, 21 to 52 percent), that of albuminuria (urinary albumin excretion of > or = 300 mg per 24 hours) by 54 percent (95 percent confidence interval 19 to 74 percent), and that of clinical neuropathy by 60 percent (95 percent confidence interval, 38 to 74 percent). The chief adverse event associated with intensive therapy was a two-to-threefold increase in severe hypoglycemia.
CONCLUSIONS:
Intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy in patients with IDDM.

44. Reduction in Retinopathy
Primary Prevention
Secondary Intervention
76% RRR
(95% CI 62-85%)
54% RRR
(95% CI 39-66%)
N Engl J Med Sep 30;329(14):
The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group.
[No authors listed]
Abstract
BACKGROUND:
Long-term microvascular and neurologic complications cause major morbidity and mortality in patients with insulin-dependent diabetes mellitus (IDDM). We examined whether intensive treatment with the goal of maintaining blood glucose concentrations close to the normal range could decrease the frequency and severity of these complications.
METHODS:
A total of 1441 patients with IDDM--726 with no retinopathy at base line (the primary-prevention cohort) and 715 with mild retinopathy (the secondary-intervention cohort) were randomly assigned to intensive therapy administered either with an external insulin pump or by three or more daily insulin injections and guided by frequent blood glucose monitoring or to conventional therapy with one or two daily insulin injections. The patients were followed for a mean of 6.5 years, and the appearance and progression of retinopathy and other complications were assessed regularly.
RESULTS:
In the primary-prevention cohort, intensive therapy reduced the adjusted mean risk for the development of retinopathy by 76 percent (95 percent confidence interval, 62 to 85 percent), as compared with conventional therapy. In the secondary-intervention cohort, intensive therapy slowed the progression of retinopathy by 54 percent (95 percent confidence interval, 39 to 66 percent) and reduced the development of proliferative or severe nonproliferative retinopathy by 47 percent (95 percent confidence interval, 14 to 67 percent). In the two cohorts combined, intensive therapy reduced the occurrence of microalbuminuria (urinary albumin excretion of > or = 40 mg per 24 hours) by 39 percent (95 percent confidence interval, 21 to 52 percent), that of albuminuria (urinary albumin excretion of > or = 300 mg per 24 hours) by 54 percent (95 percent confidence interval 19 to 74 percent), and that of clinical neuropathy by 60 percent (95 percent confidence interval, 38 to 74 percent). The chief adverse event associated with intensive therapy was a two-to-threefold increase in severe hypoglycemia.
CONCLUSIONS:
Intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy in patients with IDDM.
RRR = relative risk reduction CI = confidence interval
The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:

45. 57% risk reduction (P=0.02; 95% CI: 12–79%)
DCCT/EDIC: Early intensive therapy reduced the risk of nonfatal MI, stroke or death from CVD
0.12
0.10
0.08
0.06
0.04
0.02
0.00
57% risk reduction (P=0.02; 95% CI: 12–79%)
Conventional treatment
MI, stroke or CV death
N Engl J Med Dec 22;353(25):
Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes.
Nathan DM, Cleary PA, Backlund JY, Genuth SM, Lachin JM, Orchard TJ, Raskin P, Zinman B; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group.
Source
Abstract
BACKGROUND:
Intensive diabetes therapy aimed at achieving near normoglycemia reduces the risk of microvascular and neurologic complications of type 1 diabetes. We studied whether the use of intensive therapy as compared with conventional therapy during the Diabetes Control and Complications Trial (DCCT) affected the long-term incidence of cardiovascular disease.
METHODS:
The DCCT randomly assigned 1441 patients with type 1 diabetes to intensive or conventional therapy, treating them for a mean of 6.5 years between 1983 and Ninety-three percent were subsequently followed until February 1, 2005, during the observational Epidemiology of Diabetes Interventions and Complications study. Cardiovascular disease (defined as nonfatal myocardial infarction, stroke, death from cardiovascular disease, confirmed angina, or the need for coronary-artery revascularization) was assessed with standardized measures and classified by an independent committee.
RESULTS:
During the mean 17 years of follow-up, 46 cardiovascular disease events occurred in 31 patients who had received intensive treatment in the DCCT, as compared with 98 events in 52 patients who had received conventional treatment. Intensive treatment reduced the risk of any cardiovascular disease event by 42 percent (95 percent confidence interval, 9 to 63 percent; P=0.02) and the risk of nonfatal myocardial infarction, stroke, or death from cardiovascular disease by 57 percent (95 percent confidence interval, 12 to 79 percent; P=0.02). The decrease in glycosylated hemoglobin values during the DCCT was significantly associated with most of the positive effects of intensive treatment on the risk of cardiovascular disease. Microalbuminuria and albuminuria were associated with a significant increase in the risk of cardiovascular disease, but differences between treatment groups remained significant (P< or =0.05) after adjusting for these factors.
CONCLUSIONS:
Intensive diabetes therapy has long-term beneficial effects on the risk of cardiovascular disease in patients with type 1 diabetes.
Intensive treatment
Years since entry
DCCT/EDIC Study Research Group. N Engl J Med 2005;353:2643–2653. 45

46. UKPDS: N = 3867 T2DM 9 8 7 6 3 6 9 12 15 Conventional 7.9% A1C (%)
Lancet Sep 12;352(9131):
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group.
[No authors listed]
Erratum in
Lancet 1999 Aug 14;354(9178):602.
Abstract
BACKGROUND:
Improved blood-glucose control decreases the progression of diabetic microvascular disease, but the effect on macrovascular complications is unknown. There is concern that sulphonylureas may increase cardiovascular mortality in patients with type 2 diabetes and that high insulin concentrations may enhance atheroma formation. We compared the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial.
METHODS:
3867 newly diagnosed patients with type 2 diabetes, median age 54 years (IQR years), who after 3 months' diet treatment had a mean of two fasting plasma glucose (FPG) concentrations of mmol/L were randomly assigned intensive policy with a sulphonylurea (chlorpropamide, glibenclamide, or glipizide) or with insulin, or conventional policy with diet. The aim in the intensive group was FPG less than 6 mmol/L. In the conventional group, the aim was the best achievable FPG with diet alone; drugs were added only if there were hyperglycaemic symptoms or FPG greater than 15 mmol/L. Three aggregate endpoints were used to assess differences between conventional and intensive treatment: any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or non-fatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation [of at least one digit], vitreous haemorrhage, retinopathy requiring photocoagulation, blindness in one eye, or cataract extraction); diabetes-related death (death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia or hypoglycaemia, and sudden death); all-cause mortality. Single clinical endpoints and surrogate subclinical endpoints were also assessed. All analyses were by intention to treat and frequency of hypoglycaemia was also analysed by actual therapy.
FINDINGS:
Over 10 years, haemoglobin A1c (HbA1c) was 7.0% ( ) in the intensive group compared with 7.9% ( ) in the conventional group--an 11% reduction. There was no difference in HbA1c among agents in the intensive group. Compared with the conventional group, the risk in the intensive group was 12% lower (95% CI 1-21, p=0.029) for any diabetes-related endpoint; 10% lower (-11 to 27, p=0.34) for any diabetes-related death; and 6% lower (-10 to 20, p=0.44) for all-cause mortality. Most of the risk reduction in the any diabetes-related aggregate endpoint was due to a 25% risk reduction (7-40, p=0.0099) in microvascular endpoints, including the need for retinal photocoagulation. There was no difference for any of the three aggregate endpoints between the three intensive agents (chlorpropamide, glibenclamide, or insulin). Patients in the intensive group had more hypoglycaemic episodes than those in the conventional group on both types of analysis (both p<0.0001). The rates of major hypoglycaemic episodes per year were 0.7% with conventional treatment, 1.0% with chlorpropamide, 1.4% with glibenclamide, and 1.8% with insulin. Weight gain was significantly higher in the intensive group (mean 2.9 kg) than in the conventional group (p<0.001), and patients assigned insulin had a greater gain in weight (4.0 kg) than those assigned chlorpropamide (2.6 kg) or glibenclamide (1.7 kg).
INTERPRETATION:
Intensive blood-glucose control by either sulphonylureas or insulin substantially decreases the risk of microvascular complications, but not macrovascular disease, in patients with type 2 diabetes.(ABSTRACT TRUNCATED)
Intensive
7.0% 7 6 3 6 9 12 15
UKPDS Study Group. Lancet 1998:352:

47. UKPDS: decreased risk of diabetes-related complications associated with a 1% decrease in A1C
Observational analysis from UKPDS study data
Any diabetes-
related
endpoint
Diabetes-
related
death
All cause mortality
Peripheral vascular disease†
Micro-
vascular
disease
Myocardial
infarction
Cataract extraction
Stroke
Percentage decrease in relative risk corresponding to a 1% decrease in HbA1C
12%
14%
14% *
19% **
21%
21% ** **
UKPDS 35 was a prospective observational study to determine the relationship between exposure to hyperglycemia over time and the risk of macrovascular or microvascular complications in patients with type 2 diabetes who were participants in the UKPDS.
3,642 white, Asian Indian and Afro-Caribbean UKPDS patients who had HbA1c measured 3 months after their diabetes diagnosis and with complete data for potential confounders were included in the sub-analysis of relative risk. Reductions in the risk of microvascular and macrovascular complications that might be achieved by lowering HbA1c by 1% were estimated.
The incidence of clinical complications was found to be significantly associated with hyperglycemia. While any reduction in HbA1c is likely to reduce the risk of complications, the lowest risk was observed in those with HbA1c values in the normal range (< 6.0%). A 1% decrease in HbA1c was estimated to correspond with significant reductions in any diabetes-related endpoint, diabetes-related death, all cause mortality, myocardial infarction, stroke, peripheral vascular disease, microvascular disease and cataract extraction.
Stratton IM, et al. UKPDS 35. BMJ 2000; 321:405–412. ** **
37%
43%
†Lower extremity amputation or fatal peripheral vascular disease
*P = 0.035; **P < ** **
Adapted from Stratton IM, et al. UKPDS 35. BMJ 2000; 321:405–412.

48. Legacy Effect of Earlier Glucose Control
After median 8.5 years post-trial follow-up
Aggregate Endpoint
Any diabetes related endpoint RRR: 12% 9% P:
Microvascular disease RRR: 25% 24% P:
Myocardial infarction RRR: 16% 15% P:
All-cause mortality RRR: 6% 13% P:
N Engl J Med Oct 9;359(15): doi: /NEJMoa Epub 2008 Sep 10.
10-year follow-up of intensive glucose control in type 2 diabetes.
Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA.
Source
Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology, and Metabolism, Churchill Hospital, Headington, Oxford OX3 7LJ, United Kingdom.
Abstract
BACKGROUND:
During the United Kingdom Prospective Diabetes Study (UKPDS), patients with type 2 diabetes mellitus who received intensive glucose therapy had a lower risk of microvascular complications than did those receiving conventional dietary therapy. We conducted post-trial monitoring to determine whether this improved glucose control persisted and whether such therapy had a long-term effect on macrovascular outcomes.
METHODS:
Of 5102 patients with newly diagnosed type 2 diabetes, 4209 were randomly assigned to receive either conventional therapy (dietary restriction) or intensive therapy (either sulfonylurea or insulin or, in overweight patients, metformin) for glucose control. In post-trial monitoring, 3277 patients were asked to attend annual UKPDS clinics for 5 years, but no attempts were made to maintain their previously assigned therapies. Annual questionnaires were used to follow patients who were unable to attend the clinics, and all patients in years 6 to 10 were assessed through questionnaires. We examined seven prespecified aggregate clinical outcomes from the UKPDS on an intention-to-treat basis, according to previous randomization categories.
RESULTS:
Between-group differences in glycated hemoglobin levels were lost after the first year. In the sulfonylurea-insulin group, relative reductions in risk persisted at 10 years for any diabetes-related end point (9%, P=0.04) and microvascular disease (24%, P=0.001), and risk reductions for myocardial infarction (15%, P=0.01) and death from any cause (13%, P=0.007) emerged over time, as more events occurred. In the metformin group, significant risk reductions persisted for any diabetes-related end point (21%, P=0.01), myocardial infarction (33%, P=0.005), and death from any cause (27%, P=0.002).
CONCLUSIONS:
Despite an early loss of glycemic differences, a continued reduction in microvascular risk and emergent risk reductions for myocardial infarction and death from any cause were observed during 10 years of post-trial follow-up. A continued benefit after metformin therapy was evident among overweight patients. (UKPDS 80; Current Controlled Trials number, ISRCTN )
Holman R, et al. N Engl J Med 2008;359.

49. Therapeutic strategies for the management of type 2 diabetes.

50. L I F E S T Y 2013 AT DIAGNOSIS OF TYPE 2 DIABETES
Start lifestyle intervention (nutrition therapy and physical activity) +/- Metformin
A1C <8.5%
A1C 8.5%
Symptomatic hyperglycemia with metabolic decompensation
If not at glycemic target (2-3 mos)
Start metformin immediately
Consider initial combination with another antihyperglycemic agent
Initiate insulin +/-
metformin
Start / Increase metformin
If not at glycemic targets
Add an agent best suited to the individual:
Patient Characteristics
Degree of hyperglycemia
Risk of hypoglycemia
Overweight or obesity
Comorbidities (renal, cardiac, hepatic)
Preferences & access to treatment
Other
Agent Characteristics
BG lowering efficacy and durability
Risk of inducing hypoglycemia
Effect on weight
Contraindications & side-effects
Cost and coverage
Other
May start Metformin at the time of diagnosis
Change to 8.5% as threshold
Start metformin immediately as an option
Concept of individualizing therapy based on patient and agent characteristics
With that in mind, the next figure shows the characteristics of the agents ….
2013
See next page…

51. Oral Medications to Treat Type 2 Diabetes

52. Major Classes of Medications
1. Drugs that sensitize the body to insulin and/or control hepatic glucose production
2. Drugs that stimulate the pancreas to make more insulin
3. Drugs that slow the
absorption of starches
Thiazolidinediones
Biguanides
Sulfonylureas
Meglitinides
Alpha-glucosidase inhibitors
There are five major classes of oral diabetes medications: thiazolidinediones, biguanides, sulfonylureas, meglitinides, and alpha-glucosidase inhibitors. These five classes of medication operate in essentially three different ways.
Thiazolidinediones and biguanides decrease glucose production in the liver and increase insulin sensitivity in peripheral body tissues.
Sulfonylureas and meglitinides stimulate the pancreatic beta cells to make more insulin.
Finally, alpha-glucosidase inhibitors slow the absorption of starches in the gut, reducing the amount of glucose that enters the bloodstream.

53. New Class of Medications
Incretins
Derived from gut hormone GLP-1
Glucagon like peptide 1
There are five major classes of oral diabetes medications: thiazolidinediones, biguanides, sulfonylureas, meglitinides, and alpha-glucosidase inhibitors. These five classes of medication operate in essentially three different ways.
Thiazolidinediones and biguanides decrease glucose production in the liver and increase insulin sensitivity in peripheral body tissues.
Sulfonylureas and meglitinides stimulate the pancreatic beta cells to make more insulin.
Finally, alpha-glucosidase inhibitors slow the absorption of starches in the gut, reducing the amount of glucose that enters the bloodstream.

54. GLP-1 Effects in Humans: Understanding Glucoregulatory Role of Incretins
Speaker’s Notes
GLP-1 exerts two simultaneous effects on beta cells.
It enhances beta-cell response by stimulating glucose-dependent insulin secretion in response to the ingestion of food.
At the same time, it decreases the beta-cell workload by inhibiting gastric emptying and reducing glucagon secretion from the alpha cells of the pancreas.
The reduced glucagon levels in the portal circulation result in decreased stimulation of gluconeogenesis and glycogenolysis in the liver, leading in turn to decreased hepatic glucose output.
The central action of GLP-1 promotes satiety, reduces appetite, and decreases weight, and this again decreases the demands placed on the beta cells.
Adapted from Flint A, et al. J Chin Invest. 1998;101: ; Larsson H, et al. Acta Physiol Scand. 1997;160: ; Nauck MA, et al. Diabetologia. 1996;39: ; Drucker DJ. Diabetes. 1998;47:

55. Thiazolidinediones
Thiazolidinediones decrease insulin resistance by making muscle and adipose cells more sensitive to insulin. They also suppress hepatic glucose production.
Efficacy
Decrease fasting plasma glucose ~ mmol/L
Reduce A1C ~ %
6 weeks for maximum effect
Other Effects
Weight gain, edema
Hypoglycemia (if taken with insulin or agents that stimulate insulin release)
Contraindicated in patients with abnormal liver function or CHF
Improves HDL cholesterol and plasma triglycerides; usually LDL neutral
Medications in this Class: pioglitazone (Actos), rosiglitazone (Avandia),
Thiazolidinediones (TZDs) enhance insulin sensitivity in muscle and adipose tissue by binding to cell receptors,which leads to an increase in glucose transporter expression. TZDs encourage beta cells to respond more efficiently by lowering the amount of glucose and free fatty acids in the bloodstream, both of which are known to be detrimental to insulin secretion. Finally, these drugs reduce glucose production in the liver.
Clinical trials indicate that pioglitazone and rosiglitazone are slightly more effective at reducing A1C ( % reduction) than troglitazone (1.1% reduction).
Some of the beneficial side effects of thiazolidinediones include an increase in HDL cholesterol and reduction of triglyceride concentrations. This class of drugs has also been shown to lower blood pressure and decrease vascular inflammation in vitro. There are clinical studies underway to further examine the cardiovascular benefit to TZDs.
Some adverse effects of TZDs include weight gain, a potential increase in LDL cholesterol levels, and a possible increase in alanine aminotransferase levels (ALT). Because of the risk of weight gain, edema, and increased LDL cholesterol, thiazolidinediones are contraindicated in patients with advanced forms of congestive heart failure. Due to reported cases of liver failure and liver toxicity caused by the increase in ALT levels, TZDs are contraindicated in patients with abnormal liver function.
TZDs are the most expensive of the oral antidiabetic agents.

56. Biguanides
Biguanides decrease hepatic glucose production and increase insulin-mediated peripheral glucose uptake.
Efficacy
Decrease fasting plasma glucose mmol/L
Reduce A1C %
Other Effects
Diarrhea and abdominal discomfort
Risk of Lactic acidosis in those at risk (renal failure, CHF)
Cause small decrease in LDL cholesterol level and triglycerides
No specific effect on blood pressure
No weight gain, with possible modest weight loss
Contraindicated in patients with impaired renal function (eGFR<33 ml/min)
Medications in this Class: metformin (Glucophage), metformin hydrochloride extended release (Glumetza)
The mechanism of action of metformin is not entirely understood, but it's predominant effect is to suppress hepatic glucose production and to enhance insulin sensitivity in peripheral tissues (primarily muscle). It is unclear if insulin sensitivity occurs by metformin binding to cell receptors,which leads to an increase in glucose transporter expression, or whether insulin sensitivity is simply a secondary effect of the suppressed glucose production.
Metformin's ability to lower A1C and decrease fasting plasma glucose is similar to that of sulfonylurea drugs. However, the UKPDS showed that those who received metformin had less hypoglycemia and weight gain than those who received sulfonylureas.
Metformin must be avoided in patients with renal impairments, as those patients are at higher risk of experiencing lactic acidosis. However, metformin is an effective monotherapy and may be an ideal drug for overweight patients since it does not cause weight gain and has been seen to cause modest amounts of weight loss when first administered. Diarrhea and abdominal discomfort can be alleviated by changes in diet and slow increases in metformin dosage.

57. Sulfonylureas Sulfonylureas increase endogenous insulin secretion
Efficacy
Decrease fasting plasma glucose mmol/L
Reduce A1C by %
Other Effects
Hypoglycemia
Weight gain
No specific effect on plasma lipids or blood pressure
Generally the least expensive class of medication
Medications in this Class:
glyburide (DiaBeta), glimepiride (Amaryl), gliclizide (Diamicron)
Sulfonylureas (SUs) increase insulin secretion by binding to receptors on the surface of pancreatic beta cells, triggering a series of reactions which leads to insulin secretion.
Because SUs cause circulating insulin levels to increase, there is a risk of hypoglycemia. There is also some concern that increased insulin levels are associated with cardiovascular disease, however the UKPDS did not show a relationship between increased mortality and SU administration. Finally, there is concern that SUs will exhaust beta cell function by increasing insulin secretion. However, the decline in beta cell function is more likely caused by the disease itself, and not the use of SUs.
First generation sulfonylureas are just as efficacious as the second generation drugs, however the second generation may be more potent and safer than first. When diet and exercise fail, SUs are an effective monotherapy.

58. Meglitinides
Meglitinides stimulate insulin secretion (rapidly and for a short duration) in the presence of glucose.
Efficacy
Decreases peak postprandial glucose
Decreases plasma glucose mmol/L
Reduce A1C %
Other Effects
Hypoglycemia (although may be less than with sulfonylureas if patient has a variable eating schedule)
Weight gain
No significant effect on plasma lipid levels
Safe at higher levels of serum Cr than sulfonylureas
Medications in this Class: repaglinide (Gluconorm), nateglinide (Starlix)
The mechanism of action of repaglinide is similar to that of the sulfonylurea drugs: binding to beta cell receptors to stimulate insulin secretion. The major difference between the two drug classes is that meglitinides are shorter-acting, and are most effective when taken after meals in the presence of glucose.
Adverse effects include weight gain and hypoglycemia. An additional drawback to this drug is the dosing schedule since it must be taken with meals.

59. Alpha-glucosidase Inhibitors
Alpha-glucosidase inhibitors block the enzymes that digest starches in the small intestine
Efficacy
Decrease peak postprandial glucose mmol/L
Decrease fasting plasma glucose mmol/L
Decrease A1C %
Other Effects
Flatulence or abdominal discomfort
No specific effect on lipids or blood pressure
No weight gain
Contraindicated in patients with inflammatory bowel disease or cirrhosis
Medications in this Class: acarbose (Glucobay)
Alpha-glucosidase inhibitors (AGIs) work by blocking the enzyme in the small intestine that breaks down complex carbohydrates, alpha-glucosidase. By blocking this enzyme these drugs prevent starches from being absorbed into the bloodstream and in doing so lower blood glucose levels. AGIs are the only drug class used to treat type 2 diabetes that does not specifically target the pathology of the disease.
Because AGIs work in the digestive tract, they are more effective at lowering postprandial glucose levels than fasting plasma glucose levels. On average, AGIs are less effective at lowering A1c levels than biguanides or sulfonylureas.
What makes this class of drug attractive to patients and physicians is it's disassociation with weight gain and hypoglycemia. However, it is known to cause abdominal discomfort and diarrhea. AGIs are also rarely used as monotherapy because of their low efficacy.

60. 2013 guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca
Copyright © 2013 Canadian Diabetes Association

61. Insulin Therapy

62. Insulin Type (trade name)
Types of Insulin
Insulin Type (trade name)
Onset
Peak
Duration
Bolus (prandial) Insulins
Rapid-acting insulin analogues (clear):
Insulin aspart (NovoRapid®)
Insulin glulisine (Apidra™)
Insulin lispro (Humalog®)
min h
1 - 2 h
3 - 5 h h
Short-acting insulins (clear):
Insulin regular (Humulin®-R)
Insulin regular (Novolin®geToronto)
30 min
2 - 3 h
6.5 h
Basal Insulins
Intermediate-acting insulins (cloudy):
Insulin NPH (Humulin®-N)
Insulin NPH (Novolin®ge NPH)
1 - 3 h
5 - 8 h
Up to 18 h
Long-acting basal insulin analogues (clear)
Insulin detemir (Levemir®)
Insulin glargine (Lantus®)
90 min
Not applicable
Up to 24 h
(glargine 24 h,
detemir h)

63. Insulin Type (trade name)
Types of Insulin (continued)
Insulin Type (trade name)
Time action profile
Premixed Insulins
Premixed regular insulin – NPH (cloudy):
30% insulin regular/ 70% insulin NPH
(Humulin® 30/70)
(Novolin®ge 30/70)
40% insulin regular/ 60% insulin NPH
(Novolin®ge 40/60)
50% insulin regular/ 50% insulin NPH
(Novolin®ge 50/50)
A single vial or cartridge contains a fixed ratio of insulin
(% of rapid-acting or short-acting insulin to % of intermediate-acting insulin)
Premixed insulin analogues (cloudy):
30% Insulin aspart/70% insulin aspart protamine
crystals (NovoMix® 30)
25% insulin lispro / 75% insulin lispro protamine
(Humalog® Mix25®)
50% insulin lispro / 50% insulin lispro protamine
(Humalog® Mix50®)

65. Normal Pancreatic Function
Basal: Beta cells secrete small amounts of insulin
throughout the day.
Bolus: At mealtime, insulin is rapidly released in response to food.
Bolus Insulin
Basal Insulin
Ensure audience understands normal basal insulin secretion
Discussion points
The ideal insulin regimen should strive to match normal insulin secretion patterns.
This includes;
A basal component that covers basal glucose levels throughout the day.
Bolus components that cover glucose excursions due to meals.
Meal
Meal
Meal
Expected insulin changes during the day for individuals with a healthy pancreas.
*Insulin effect images are theoretical representations and are not derived from clinical trial data.

66. Action Profiles of Bolus & Basal Insulins
lispro/aspart 4–6 hours
BOLUS INSULINS
BASAL INSULINS
regular 6-10 hours
NPH 12–20 hours
detemir ~ 6-23 hours (dose dependant)
Plasma Insulin levels
glargine ~ hours
EDUCATIONAL TIP: Please note this slide is animated. Analogue insulins mimic normal physiology better than regular based insulins.
Also, note that detemir’s duration of action can vary depending on the dose given (curve shown above is for 0.4 units/kg). Insulin detemir is a long-acting basal human insulin analog with a relatively flat action profile. The mean duration of action of insulin detemir ranged from 5.7 hours at the lowest dose (0.1 units/kg.) to 23.2 hours at the highest dose (1.6 units/kg) (sampling period 24 hours). Plank J, et al. “A double-blind, randomized, dose-response study investigating the pharmacodynamic and pharmacokinetic properties of the long-acting insulin analog detemir.” Diabetes Care, 2005 May;28(5):
Hours
Note: action curves are approximations for illustrative purposes. Actual patient response will vary.
Mayfield, JA.. et al, Amer. Fam. Phys.; Aug. 2004, 70(3): 491
Plank, J. et.al. Diabetes Care, May 2005; 28(5):

67. BID NPH and Regular Insulin Therapy - Compared to Normal Physiology
Basal needs: NPH
Bolus needs: Regular
EDUCATIONAL TIP: Please note this slide is animated to discuss normal physiology of insulin action first, then basal, then mealtime
Discussion points
The ideal insulin regimen should strive to match normal insulin secretion patterns.
The combination of two injections of intermediate acting NPH insulin (to cover the basal requirements) mixed with short acting Regular insulin (to cover the bolus requirements) may be the best regimen a patient will accept. However, it does not mimic normal insulin physiology.
Meal
Meal
Meal
Expected insulin changes during the day
for individuals with a healthy pancreas.
*Insulin effect images are theoretical representations and are not derived from clinical trial data
Mayfield, JA. et al., Amer. Fam. Phys.; Aug. 2004, 70(3):

68. Multiple Daily Injections (MDI) – Strive to Mimic Normal Physiology
MDI insulin therapy addresses:
Basal needs: Glargine, Detemir
Bolus needs: Lispro, Aspart
EDUCATIONAL TIP: Please note this slide is animated to discuss normal physiology of insulin action first, then basal then mealtime.
Discussion points
"Insulin aspart or insulin lispro, in combination with adequate basal insulin, is preferred to regular insulin to achieve postprandial glycemic targets and improve A1C while minimizing the occurrence of hypoglycemia" (CDA Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Canadian Journal of Diabetes Dec, 2003;27(Suppl 2)
The ideal insulin regimen should strive to match normal insulin secretion patterns.
The combination of a long acting insulin to cover the basal dose with rapid acting insulin to cover the bolus doses may be the best regimen by which to mimic the normal secretion of insulin.
Meal
Meal
Meal
Expected insulin changes during the day
for individuals with a healthy pancreas.
*Insulin effect images are theoretical representations and are not derived from clinical trial data.

69. Insulin Regimens Type 2
Usually – a single bedtime injection of basal insulin added to OAD.
Occasionally - twice daily injections of basal insulin with OAD.
Twice daily injection of “pre-mixed” insulin
Intensive insulin – basal/bolus (THE ONLY RECOMMENDED OPTION FOR DM TYPE 1)
40% basal/20% mealtime with each meal

70. Case 1 Breakfast Lunch Dinner Bedtime 9.5 7.5 7.1 7.0
55 year old, 84 kg, BMI 29, T2DM 5 yrs, A1C = 8.5%
On metformin, glyburide,
Breakfast Lunch Dinner Bedtime
Is this patient well controlled?
Does this patient require insulin?
EDUCATIONAL TIP: To gain group comfort with making and expressing decisions, reinforce that there are no wrong answers. Split group evenly into 2-4 groups. Give each a flipchart paper sectioned for each of 4 cases. Each group has 5 minutes to answer the above 5 questions and then present back recording answer in first section.
If a group(s) say that this patient does NOT require insulin, address their reasons, be prepared to address the situation and offer guidance. Encourage the participants who said the patient DOES require insulin to play a role in those discussions. After the discussion, explain the cause of the high fasting blood glucose (gluconeogenesis from the liver).
NOTE: Use of a TZD with insulin is not an approved indication and would be off label for use in Canada.

71. Case 1 - Bedtime Insulin Breakfast Lunch Dinner Bedtime
55 year old, 84 kg, BMI 29, T2DM 5 yrs, A1C = 8.5%
On metformin, glyburide,
Breakfast Lunch Dinner Bedtime
NPH, Glargine or
Detemir - 10 units
Start with 10 units1, or use units/kg and titrate2
Ex. 84 kg X 0.1 = 8 units OR 84 kg X 0.2 = 17 units
Continue metformin, glyburide. Continuing TZD would be off-label in Canada
Educational Tip: Please note that use of a TZD with insulin is not an approved indication and would be off label for use in Canada. Bedtime insulin targets the high fasting blood sugar appropriately.
1 Riddle et.al., Diabetes Care, 2003, 26(11):
2 CDA 2003 CPG, Can J Diabetes 27(Suppl 2):S135

72. Hypoglycemia – Recognition
Hypoglycemia = development of symptoms or a plasma glucose <4.0 mmol/L.
Symptoms of hypoglycemia
Autonomic
Neuroglycopenic
Trembling
Palpitations
Sweating
Anxiety
Hunger
Nausea
Tingling
Difficulty concentrating
Vision changes
Difficulty speaking
Headache
Dizziness
Confusion
Weakness
Drowsiness
Tiredness
Severity of hypoglycemia
Mild: Autonomic symptoms are present. The individual is able to self-treat.
Moderate: Autonomic and neuroglycopenic symptoms are present. The individual is able to self-treat.
Severe: Individual requires assistance of another person. Unconsciousness may occur. Plasma glucose is typically <2.8 mmol/L.
CDA 2003 CPG, Can J Diabetes 27(Suppl 2):S43

73. Diabetic ketoacidosis

74. Diagnostic criteria Hyperglycemia
Glucose >11.1 mmol/l; usually > 15 mmol/l
Metabolic acidosis (increased anion gap)
pH < 7.35
decreased bicarbonate <15 (best estimation with venous)
Positive serum ketones
Urine ketones: may be absent in early stages

75. Insulin deficiency Decreased peripheral glucose utilization
increased glucose production
liver - gluconeogenesis (from aminoacids, glycerol), glycogenolysis
increased ketogenesis
increased lipolysis in adipocytes - provides free fatty acids for ketones and glycerol for gluconeogenesis

76. LEC: Acute and Chronic Complications of Diabetes (revised)

77. LEC: Acute and Chronic Complications of Diabetes (revised)1

78. Clinical features
Hyperglycemia: thirst, polyuria, circulatory collapse
Ketosis: “acetone breath’
Acidosis/ compensatory respiratory alkalosis: tachypnea

79. LEC: Acute and Chronic Complications of Diabetes (revised)

80. Consequences of DKA Hyperglycemia acidosis osmotic diuresis
dehydration
loss of K, Na, HCO3 in urine
hyperosmolar state
increase free water into blood hyponatremia, cerebral dehydration  decreased level of consciousness
acidosis
compensatory respiratory alkalosis
K shifts (hyperkalemia)

81. Laboratory Calculations for diagnosis and treatment
Serum osmolality
2(Na + K) + glucose +BUN
serum Na
for each 3-4 mmol/l increase in glucose, Na should decrease by 1
anion gap
Na -(Cl+HCO3)
compensation for metabolic acidosis
If suspect other causes for acidosis; meausre serum lactate and salicylate

82. Treatment GOAL: replace volume loss (with normal saline)
stop ketone production (with insulin)
replace K loss (K initially high but falls rapidly with treatment)
lower serum glucose
*Need to correct INSULIN DEFICIENCY
*Look for precipitating cause and treat

83. bicarbonate generally avoided potassium
Fluid
NS 1L per hour first 2 hours, then 1L over 4 hrs
NS until glucose < 15
then D5/NS or D5 depending if still replacing volume
insulin
intravenous
50 units regular in 500 normal saline (0.1U/ml)
Bolus 0.1 unit per kg body weight (IM/IV)
Infusion 0.1 unit/kg/hour
Glucoscans q1h, adjust IV rate and IV D5
* Do not stop insulin infusion until acidosis/ AG corrected
bicarbonate generally avoided
potassium
start when K , 20 mmol/L (hold insulin if K is <3.3 and give 40 meq/h

84. Hyperosmolar non-ketotic state
Severe hyperglycemia generally in DM type 2
dehydration
serum hyperosmolality
lack of significant ketosis (still some circulating insulin)
* takes less insulin to prevent ketosis than to stop hyperglycemia

85. Stressor - increased insulin resistance relative insulin deficiency
increased glucose production, decreased utilization
reduced renal excretion of glucose
secondary to renal disease, aging kidneys

86. LEC: Acute and Chronic Complications of Diabetes (revised)

87. Treatment of HONK Correct increased serum osmolality
Blood glucose will fall in response to fluid repletion
If Na>155 mmol/L, start 0.45% NS as initial fluid
Insulin infusion only if persistent hyperglycemia after fluid replete

88. Screening and prevention of complications

89. Who Should Receive Statins?
2013
≥40 yrs old or
Macrovascular disease or
Microvascular disease or
DM >15 yrs duration and age >30 years or
Warrants therapy based on the 2012 Canadian Cardiovascular Society lipid
Among women with childbearing potential, statins should only be used in the presence of proper preconception counseling & reliable contraception. Stop statins prior to conception.

90. Who Should Receive ACEi or ARB Therapy?
2013
≥55 years of age or
Macrovascular disease or
Microvascular disease
At doses that have shown vascular protection [perindopril 8 mg daily (EUROPA), ramipril 10 mg daily (HOPE), telmisartan 80 mg daily (ONTARGET)]
ACE inhiibitor or ARB therapy should be offered to people with diabetes age ≥55 years, or in the presence of macrovasular disease or microvascular disease. This recommendation is regardless of blood pressure. It is important that the ACEi or ARB be titrated to the doses that have been shown to provide vascular protection since low dose ACE-inhibitor or ARB may not result in any benefit (DIABHYCAR study). These vascular protection benefits have been shown to be present irrespective of baseline blood pressure. Since it is not proven that low dose ACEi or ARB confers the same vascular protection, it is recommended that the ACEi or ARB dose be increased to the vascular protective doses (peripdopril 8mg, ramipril 10 mg, telmisartan 80 mg daily). Given that not all ACEi or ARB have conducted “vascular protection” type of studies and of those that have, not all have been positive, it is justified to titrate to doses shown to have vascular protection.
Among women with childbearing potential, ACEi or ARB should only be used in the presence of proper preconception counseling & reliable contraception. Stop ACEi or ARB either prior to conception or immediately upon detection of pregnancy
EUROPA Investigators, Lancet 2003;362(9386):
HOPE study investigators. Lancet. 2000;355:
ONTARGET study investigators. NEJM. 2008:358: