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MODULE 3: TREATMENT OF
TYPE 2 DIABETES
___________________________________________________________________________________Table of Contents
TABLE OF CONTENTS
INTRODUCTION.................................................................................................................................................................... 1
CHAPTER 1: STUDIES EVALUATING TREATMENT OF TYPE 2 DIABETES..................................................................... 3
INTRODUCTION............................................................................................................................................................... 3
LEARNING OBJECTIVES................................................................................................................................................. 3
Glucose Control in Diabetes.............................................................................................................................................. 5
Diabetes Control and Complications Trial (DCCT)........................................................................................................ 8
Epidemiology of Diabetes Interventions and Complications (EDIC)............................................................................ 10
Kumamoto Study......................................................................................................................................................... 11
UKPDS........................................................................................................................................................................ 13
Action in Diabetes and Vascular Disease (ADVANCE) Trial....................................................................................... 16
Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial ........................................................................... 17
Veterans Affairs Diabetes Trial (VADT)....................................................................................................................... 18
Landmark Studies Compared With Recent Studies Assessing Intensive Glucose Control......................................... 18
Blood Pressure Control in Diabetes ................................................................................................................................ 19
UKPDS 38................................................................................................................................................................... 20
ACCORD..................................................................................................................................................................... 22
Lipid Control in Diabetes ................................................................................................................................................. 23
Heart Protection Study (HPS) ..................................................................................................................................... 24
Collaborative Atorvastatin Study (CARDS) ................................................................................................................. 24
Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study ................................................................... 25
Multiple Risk Factor Reduction: The STENO-2 Study..................................................................................................... 25
Treatment of Nephropathy in Diabetes ........................................................................................................................... 26
Summary......................................................................................................................................................................... 27
SELF-ASSESSMENT QUESTIONS .................................................................................................................................... 29
Self-Assessment QuestionsAnswers........................................................................................................................... 32
_______________________________________________________________________________________ Introduction
INTRODUCTION
Diabetes is a chronic illness that requires continual medical care and educated patient
participation to help maintain glucose control, blood pressure (BP), and cholesterol, and
thereby reduce the risk of acute and long-term complications. This is often referred to as
treating the ABCs of diabetes:
A = A1C (a measurement of blood glucose levels over a 2- to 3-month period;
generally recommended goal is <7%)
B = Blood pressure (generally recommended goal is <130/80 mm Hg)
C = Cholesterol (generally recommended LDL-C goal is <100 mg/dL)
Data from numerous clinical studies indicate that treating the ABCs of diabetes reduces
the risk for developing many of the long-term complications of diabetes.
Module 3: The Treatment of Type 2 Diabetes will review the results of several of these
clinical studies, which provide the scientific basis for currently recommended diabetes
treatment guidelines. It also will review the current therapeutic options for the treatment
of type 2 diabetes. Specific topics in this module include the following:
Chapter 1 describes some of the landmark clinical trials conducted in patients with
diabetes. Chapter 1 also reviews some more recent trials that compare intensive
glucose-lowering therapy with standard glucose-lowering therapy. It will describe how
the results from recent trials differ from the landmark trials and introduce possible
reasons for these differences. Finally, the results of studies and subgroup analyses
that provide evidence for the treatment of blood pressure and lipid levels in patients
with type 2 diabetes will also be presented.
Chapter 2 discusses the therapeutic options that are available for the treatment of
type 2 diabetes, including recommended nonpharmacologic options and currently
available pharmacologic treatments.
Throughout the text, medical terms are defined in the margin. The module concludes
with a summary, a glossary, and a bibliography.
LEARNING OBJECTIVES
Upon completion of this chapter, you should be able to:
1. Discuss several landmark trials that demonstrate the benefits of lowering blood
glucose levels.
2. Discuss several studies that emphasize the benefits of tight glucose control.
3. Describe the differences in cardiovascular outcomes between landmark trials and
more recent trials.
4. Discuss the possible reasons for the different outcomes seen between landmark and
more recent studies.
5. Discuss the results of studies and subgroup analyses that show benefits associated
with treatment of blood pressure and lipid levels.
The proportion of patients with complications also continued to rise throughout the trial.
These results emphasized the need for new approaches for diabetes treatment.
The primary endpoint was the development and progression of retinopathy, but renal,
neurologic, and cardiovascular complications were also studied. The results of DCCT
are described in the following table.
retinopathy (ret-n-OP-uh-thee):
damage to the retina of the eye;
can lead to blindness
NS = not significant.
nephropathy (nuh-FROP-uh-thee):
kidney damage that can arise
as a complication of chronic
hyperglycemia
microalbuminuria (MAHY-kroh-albyoo-muh-NYOOR-ee-uh): the
leakage of a small amount of albumin
into the urine, defined as 20 mcg/min
to 200 mcg/min
neuropathy (nyoo-ROP-uh-thee):
nerve damage, primarily peripheral
neuropathy (in which the nerves in
the extremities are affected); loss
of sensation may occur, which may
result in serious infection, gangrene,
and the need for amputation
10
More recently, the results from the DCCT/EDIC study were compared with results from a
subset of patients in the Pittsburgh Epidemiology of Diabetes Complications (EDC) study,
a population-based observational study conducted during an overlapping time frame with
the DCCT/EDIC study. The 2 studies used similar methods of data collection and patients
in the EDC cohort had similar patient characteristics as those enrolled in the DCCT.
This analysis of the cumulative incidence of long-term complications was designed to
describe the current-day clinical course of type 1 diabetes based on the study results of
patients who have had the disease for 30 years.
Patients who received conventional treatment in the DCCT and those enrolled in the
EDC had similar incidences of proliferative retinopathy (50% versus 47%, respectively),
nephropathy (25% versus 17%, respectively), and cardiovascular disease (14% for both
cohorts). Patients who received intensive treatment in the DCCT had substantially lower
incidences of proliferative retinopathy, nephropathy, and cardiovascular disease (21%,
9%, and 9%, respectively). The authors concluded that serious complications from
type 1 diabetes are lower than reported historically, particularly in patients who receive
intensive treatment.
Kumamoto Study
This study, which was conducted at Kumamoto University in Japan, was a milestone
study of intensive glucose control conducted in patients with type 2 diabetes. Patients
received insulin therapy, and the goal was to compare the effect of an intensive insulin
regimen with a standard insulin regimen on the development and/or progression of
complications of type 2 diabetes. Intensive insulin therapy, including 3 or more insulin
injections per day, was used to achieve as normal glucose values as possible.
Standard therapy consisted of 1 or 2 injections of intermediate-acting insulin per day.
Similar to the DCCT, this study evaluated 2 groups of patients:
A primary prevention group, consisting of patients with no complications at the
start of the study, randomized to receive intensive therapy (n = 26) or standard
therapy (n = 25)
A secondary intervention group, consisting of patients with simple retinopathy at
the start of the study, randomized to receive intensive therapy (n = 26) or standard
therapy (n = 25)
11
Patients were followed for 6 years. The following table summarizes key results of the
Kumamoto Study.
postprandial
(pohst-PRAN-dee-uhl): after a meal
For the primary prevention group, intensive glucose control significantly reduced:
The risk of development of retinopathy (P = 0.039)
The risk of developing nephropathy (P = 0.032)
For the secondary prevention group, intensive glucose control significantly
reduced:
The risk of progression of retinopathy (P = 0.049)
The risk of progression of nephropathy (P = 0.044)
For the combined group, intensive glucose control significantly reduced the risk
of neuropathy (P < 0.05)
As A1C, FPG, and postprandial blood glucose concentrations increased
(i.e., glucose control worsened), the risk of worsening complications such as
retinopathy and nephropathy also increased
At the end of the Kumamoto Study, patients were informed of the superiority of intensive
therapy and were allowed to choose their own insulin regimen. Two patients elected to switch
to intensive therapy while the remainder chose to continue their current treatment regimen.
After 8 years of treatment, patients in the primary treatment group who received intensive
therapy had significantly lower cumulative incidences of retinopathy and nephropathy
compared with patients receiving standard therapy:
Retinopathy: 15.4% compared with 47.8%; P = 0.022
Nephropathy: 11.5% compared with 43.5%; P = 0.029
After 8 years of treatment, patients in the secondary treatment group who received
intensive therapy had significantly lower cumulative incidences of retinopathy and
nephropathy compared with patients receiving standard therapy:
Retinopathy: 24% compared with 56%; P = 0.023
Nephropathy: 16% compared with 40%; P = 0.043
12
After 8 years, patients in either study cohort who received intensive therapy demonstrated
significant improvement in nerve conduction (P < 0.05), while those who received
standard therapy experienced significant decreases in nerve conduction (P < 0.05).
UKPDS
The United Kingdom Prospective Diabetes Study (UKPDS) is a landmark trial that
has studied the importance of tight glucose control on reducing the development of
complications in patients with newly diagnosed type 2 diabetes. Unlike the Kumamoto
Study, which used intensive insulin therapy, in UKPDS, patients with type 2 diabetes
were treated with a variety of oral antidiabetic agents, insulin, or diet.
This study began in 1977. Physicians from participating hospitals referred newly
diagnosed patients between the ages of 25 and 65 to the study, of which 5102 were
recruited. Patients followed an established diet for 3 months (overweight patients were
advised to reduce calorie intake) and then their FPG was measured. Patients were then
separated into 2 groups (overweight and not overweight) and randomized to various
treatment regimens.
Many articles related to UKPDS have been and continue to be published. Here, we will
review some key UKPDS publications related to glucose control:
UKPDS 33
UKPDS 34
UKPDS 35
UKPDS 33: UKPDS 33 compared the effects of intensive blood glucose control to
conventional treatment with diet on the risk of microvascular and macrovascular
disease. The 2 groups were defined as:
Intensive therapy: treatment with sulfonylureas or insulin, with medication adjusted
in order to achieve normal glucose levels
Conventional treatment: diet
13
Patients were followed for a median of 10 years for endpoint analysis. There were 21
clinical endpoints in the study. Compared with conventional treatment, intensive therapy
resulted in a:
Significant reduction in A1C (P < 0.0001), although A1C increased in both groups
over the length of the trial
Significant 25% reduction in risk of microvascular disease (P = 0.0099)
Significant 12% reduction in risk of any diabetes-related endpoint (P = 0.029)
16% reduction in risk of heart attack (P = NS)
Following completion of the trial, patients were seen annually at UKPDS clinics for 5
years; however, they were not required to maintain their previously assigned therapies.
Annual questionnaires were provided to patients unable to attend the clinic for the
additional 5-year period. All patients were assessed via annual questionnaire from Year 6
to Year 10.
At 10 years, compared with patients who received conventional treatment, patients
treated with a sulfonylurea and/or insulin had a:
Significant 9% reduction in risk for any diabetes-related endpoint (P = 0.04)
Significant 24% reduction in risk for microvascular disease (P = 0.001)
Additionally, during post-trial follow-up, significant reductions in risk were observed for:
Diabetes-related death (RR = 17%, P = 0.01)
Heart attack (RR = 18%, P = 0.01)
Death from any cause (RR = 13%, P = 0.007)
UKPDS 34: UKPDS 34 studied a group of overweight patients and the effect of intensive
treatment on the risk of complications of type 2 diabetes. The primary goal was to compare
411 patients assigned to a conventional treatment of diet with 342 patients assigned to an
intensive treatment with metformin, a drug that reduces glucose production and absorption.
As noted previously, intensive therapy was defined as a treatment program in which the
medication (metformin) was adjusted in order to achieve near-normal glucose levels.
The median follow-up time was 10.7 years.
14
hyperglycemia
(hahy-per-glahy-SEE-mee-uh):
abnormally high blood glucose levels
hypoglycemia
(hahy-poh-glahy-SEE-mee-uh):
abnormally low concentrations of
glucose in the circulating blood
15
16
17
18
It has been hypothesized that ACCORD, ADVANCE, and VADT did not show CVD
benefits from intensive glycemic control that were seen in DCCT/EDIC, UKDPS, and
other studies because:
Patients enrolled in ACCORD, ADVANCE, and VADT received treatment for other
CVD risk factors and the overall rate of CVD was lower than predicted in the standardtreatment arms of all three trials. In patients with type 2 diabetes, the benefits of
glucose lowering on CVD are probably modest and incremental to the treatment of
other risk factors for CVD. Larger and/or longer trials might be needed to demonstrate
additive benefits from intensive glucose control.
Benefits of intensive glycemic control may be greater in patients with a shorter
disease duration, lower A1C, and those without known CVD. ACCORD, ADVANCE,
and VADT evaluated patients with established diabetes who either had known CVD or
multiple CVD risk factors. However, subgroup analyses from these studies suggested
significant CVD benefits in patients who had a more recent diagnosis of diabetes,
a lower A1C at study entry, and/or were not known to have CVD. CVD benefits
demonstrated in long-term results from the DCCT/EDIC trial, which was conducted in
patients with type 1 diabetes who did not have CVD risk factors, and in UKDPS, which
was conducted in patients with newly diagnosed diabetes, support this hypothesis.
Importantly, the results from ACCORD, ADVANCE, and VADT do not indicate a need to
change glycemic control targets. Instead, they confirm the need to individualize treatment
goals based on a patients desires and individual requirements.
19
Additional Therapies
Data from one of the UKPDS trials demonstrate that lowering blood pressure reduces
the risk of endpoints related to diabetes.
UKPDS 38
UKPDS 38 examined whether tight control of blood pressure reduces microvascular and
macrovascular diseases compared to less tight control of blood pressure in patients with
type 2 diabetes and hypertension. Patients allocated to tight control of blood pressure
and patients allocated to less tight control received different antihypertensive regimens.
Less tight control of BP was defined as <180/105 mm Hg, and tight control of blood
pressure was defined as BP <150/85 mm Hg. Please note that the goal BP level for
patients with diabetes is now much lower than when this trial conducted; the BP goal
for patients with diabetes is now <130/80 mm Hg.
Results from UKPDS 38 demonstrated that tight blood pressure control resulted in a:
Significant 24% reduction in any diabetes-related endpoint, such as death, renal
failure, amputation, or stroke (P = 0.0046)
Significant 32% reduction in death from diseases known to be related to diabetes
(MI, sudden death, stroke, peripheral vascular disease, and renal failure) (P = 0.019)
Figure 5 illustrates the results from UKPDS 38.
20
21
As you learned previously, the UKPDS included a long-term follow-up period in which
patients visited a UKPDS clinic annually for 5 years and then continued to be monitored
via questionnaires from Year 6 to Year 10.
Between-group differences in blood pressure were no longer seen within 2 years of the
end of the trial. The significant relative risk reductions that were observed during the trial
(any diabetes-related endpoint, diabetes-related death, microvascular disease, and
stroke) were not maintained during the follow-up period. However, a relative risk reduction
for peripheral vascular disease became significant during the follow-up period (P = 0.02).
There were no relative risk reductions for MI and death from any cause during the study
or during the follow-up period. The authors concluded that good blood pressure control
must be maintained to continue to see the benefits associated with tight control.
ACCORD
A subset of patients in the ACCORD trial were also randomly selected to undergo
intensive versus standard therapy for lowering blood pressure. The blood pressure
goal for the intensive therapy group (n = 2362) was <120 mm Hg, while the goal for
the standard therapy group (n = 2371) was <140 mm Hg. The primary outcome was
the same as for the overall studythe first occurrence of nonfatal MI, nonfatal stroke,
or cardiovascular death. Key results include:
Systolic BP was lower in the intensive therapy group: 119.3 mm Hg versus
133.5 mm Hg in the standard therapy group, with a 14.2 mm Hg difference
(95% CI, 13.7 to 14.7)
Diastolic BP was also reduced in the intensive therapy group: 64.4 mm Hg versus
70.5 mm Hg, with an average difference of 6.1 mm Hg (95% CI, 5.7 to 6.5)
The rate of the primary outcome was not significantly different between the 2 groups,
with a rate of 1.87% in the intensive therapy group and 2.09% in the standard therapy
group (HR = 0.88, 95% CI 0.73 to 1.06, P = 0.20)
hypokalemia
(hahy-poh-key-LEE-mee-uh):
abnormally low level of potassium
ions in the blood
Patients in the intensive therapy group were on more antihypertensive agents than
the standard therapy group (means of 3.4 drugs versus 2.1 drugs) and experienced
significantly more serious adverse events attributable to antihypertensive treatment,
as well as rates of hypokalemia and elevated serum creatinine levels
22
Lifestyle modifications, including the reduction of saturated fat and cholesterol intake,
weight loss, increased physical activity, and smoking cessation, have been shown to
improve the lipid profile in patients with diabetes. Patients who do not achieve lipid goals
with lifestyle modifications require pharmacologic therapy. The following table provides
the recommendations for statin therapy from the ADA.
23
macroalbuminuria
(MAK-roh-al-byoo-muh-NYOOR-eeuh): the leakage of large amounts
of albumin into the urine; defined
as >200 mcg/min
24
25
26
SUMMARY
The following table summarizes the information presented in this chapter on evaluating glucose, blood pressure, and lipid
control in diabetes.
Evaluation of Glucose, Blood Pressure, and Lipid Control in Diabetes
Glucose Control in Diabetes
Glucose control or the reduction of glucose levels to meet certain goals is a major factor in decreasing the morbidity
and mortality associated with this disease
However, glucose control is challenging, for even with commonly used therapies, most patients find it difficult
to reach their A1C goal
Clinical trials have demonstrated that tight glucose control and lowering A1C provides benefits, including:
Reduction of risk for complications of diabetes
Decreased progression of the microvascular and macrovascular diseases associated with diabetes
Reduction of risk for death related to diabetes
Long-term follow-up of the UKPDS has demonstrated that a reduced rate of complications is maintained
even when intensive therapy is discontinued
Landmark studies that emphasize the importance of intensive glucose control include:
Diabetes Control and Complications Trial (DCCT)
Epidemiology of Diabetes Interventions and Complications (EDIC)
Kumamoto Study
United Kingdom Prospective Diabetes Study (UKPDS)
More recent studies evaluating the effects of intensive glucose control, providing mixed results on effects on
cardiovascular events and mortality, include:
Action in Diabetes and Vascular Disease (ADVANCE) trial
Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial
Veterans Affairs Diabetes Trial (VADT)
Landmark studies such as the DCCT/EDIC and UKDPS suggest that intensive glucose control reduces the risk for
cardiovascular disease compared with standard glucose control. More recently, studies such as ADVANCE and
VADT have not demonstrated cardiovascular benefits from intensive glucose control compared with standard
glucose control. In the ACCORD study, patients receiving intensive glucose control had significantly higher rates
of all-cause mortality compared with those randomized to standard glucose control.
It has been hypothesized that:
The benefits of glucose lowering on CVD is likely modest and incremental to the treatment of other risk
factors for CVD; larger and/or longer trials might be required to demonstrate additive benefits from intensive
glucose control
The benefits of intensive glycemic control may be greater in patients with a shorter disease duration, lower
A1C, and those without known CVD
(cont.)
27
Hypertension is common in patients with diabetes, and it is also a risk factor for cardiovascular disease
In UKPDS, blood pressure control significantly reduced the risk of diabetes-associated complications and mortality
Long-term follow-up indicates that the benefits associated with tight blood pressure control are lost if blood
pressure control is not maintained
In ACCORD, intensive blood pressure control did not result in significant reductions in the composite primary endpoint
of nonfatal MI, nonfatal stroke, or cardiovascular death
Lipid Control in Diabetes
Patients with type 2 diabetes have an increased prevalence of lipid abnormalities that contributes to higher rates
of cardiovascular disease
Lifestyle modification has been shown to improve the lipid profile in patients with diabetes; pharmacologic therapy
is recommended for patients who do not meet the LDL goals
ADA recommends LDL-C levels <100 mg/dL in patients without cardiovascular disease and notes that
<70 mg/dL is an optional goal for patients with cardiovascular disease
AACE recommends LDL-C levels <100 mg/dL in patients without cardiovascular disease and <70 mg/dL
for patients with cardiovascular disease
In HPS, the LDL cholesterol reduction from baseline with simvastatin treatment was associated with a reduction
in the relative risk for major coronary artery events and stroke
In CARDS, patients with type 2 diabetes who received atorvastatin had a reduction in the risk of major
cardiovascular events
In FIELD, treatment with fenofibrate significantly reduced the risk of nonfatal MI or coronary revascularization,
but did not significantly reduce the risk for the primary endpoint (first occurrence of nonfatal MI or death from
coronary heart disease)
In Steno-2, intensive therapy addressing multiple risk factors (blood pressure, lipids, glucose levels) in patients with
diabetes resulted in significant reductions in the occurrence of cardiovascular events or need for interventions
Treatment of Nephropathy
28
In patients with diabetes, treatment with ACE inhibitors and ARBs has been shown to delay or prevent the
occurrence of end-stage renal disease, independent of their effects on blood pressure; guidelines recommend
treatment with ACE inhibitors or ARBs in nonpregnant patients with diabetes and micro- or macroalbuminuria
___________________________________________________________________________Self-Assessment Questions
SELF-ASSESSMENT QUESTIONS
There may be more than one correct answer to each question
1. Which of the following statements about the Kumamoto Study is (are) true?
_____ A. Intensive glucose control significantly reduced the risk of developing neuropathy in all patients.
_____ B. Intensive therapy consisted of 3 or more insulin injections per day.
_____ C. The study population included only patients with type 1 diabetes.
_____ D. Only patients who had no complications of diabetes at the outset of the study were included.
2. The effects of tight control of blood pressure on microvascular and macrovascular diseases were studied in:
_____ A. UKPDS 33.
_____ B. UKPDS 35.
_____ C. UKPDS 38.
_____ D. the Kumamoto Study.
3. Match each trial with its description.
A. ACCORD _____
1.
2.
3.
4.
B. ADVANCE _____
C. Steno-2 _____
D. VADT _____
29
4. Subgroup analyses from the ACCORD, ADVANCE, and VADT trials suggest that intensive glucose control may
provide increased cardiovascular benefits in type 2 diabetes patients who:
_____ A. are younger.
_____ B. have pre-existing cardiovascular disease.
_____ C. have lower A1C levels.
_____ D. have had diabetes for a shorter period of time.
5. True or false? Long-term follow-up of the UKPDS has demonstrated that a reduced rate of complications is
maintained even when intensive therapy is discontinued.
_____ A. true
_____ B. false
30
___________________________________________________________________________Self-Assessment Questions
31
SELF-ASSESSMENT QUESTIONSANSWERS
1. A, B
2. C
3. A4; B1; C2; D3
4. C, D
5. True
32
LEARNING OBJECTIVES
Upon completion of this chapter, you should be able to:
1. Describe a patient-centered approach to the treatment of type 2 diabetes.
2. List recommended lifestyle modifications and explain their limitations.
3. List the main available classes of antidiabetic medications and give examples
of each.
4. Describe the role of insulin in the management of type 2 diabetes.
33
34
35
Factors such as a patients life expectancy, attitude and motivation, and comorbidities should be
considered when setting glycemic goals. The ADA recommends an A1C goal of 7%. However,
for patients with the characteristics shown at the left of the scale (e.g., less motivated, short life
expectancy), a less stringent goal (e.g., 7.5% or 8%) might be appropriate. Conversely, for patients
who have characteristics shown at the right of the scale (e.g., newly diagnosed, no comorbidities),
an A1C goal of 6% or 6.5% might be appropriate. Whenever possible, patients should participate
in setting their glycemic goals to ensure the goals are consistent with their needs, values,
and preferences.
Adapted from: Inzucchi SE, Nauck M, Bergenstal RM, et al. Diabetes Care. 2012;35:13641379.
Lets review some of the general treatment recommendations for patients with type 2
diabetes.
36
LIFESTYLE MODIFICATIONS
Guidelines note that changing patterns of eating and physical activity may help reduce
the risk of many of the complications associated with diabetes. This chapter discusses
recommendations for nutrition and exercise. This chapter also features case studies that
illustrate key concepts relating to lifestyle modifications in the treatment of diabetes.
Nutrition
Nutrition therapy is an integral component of diabetes management, and patients
should receive individualized nutrition counseling and planning to achieve treatment
goals. Registered dietitians are important members of the healthcare team for patients
with diabetes.
Nutrition therapy has the following goals for patients with diabetes:
Achieve and maintain blood glucose levels in the normal range
Reduce cardiovascular risk factors, including dyslipidemia and hypertension
Provide a balanced, nutritional diet
Help to promote weight loss (for patients who are overweight or obese)
Prevent or slow the development of the chronic complications of diabetes
Address individual nutrition needs, taking into account personal and cultural
preferences and willingness to change
Maintain the pleasure of eating by not limiting food choices unless indicated
by scientific evidence
In order to achieve these goals, guidelines provide recommendations for consumption
of carbohydrates, protein, dietary fat, micronutrients (vitamin or mineral supplements),
and alcohol. Another recommendation is the plate method, in which the focus is filling
the majority of the plate with nonstarchy vegetables and having smaller portions of
starchy foods and meats. Figure 7 illustrates the ADA plate method.
37
Ongoing nutritional consultation about diet and eating habits needs to be available for
patients with diabetes. The following case study illustrates how nutrition therapy can be
used as part of a patients diabetes treatment plan.
Jake: Nutrition Therapy to Control Diabetes
38
Jake is an obese 60-year-old man who was diagnosed with type 2 diabetes 2 months
ago. At the time of diagnosis, Jakes A1C was 8.3%, his FPG was >140 mg/dL
(>7.8 mmol/L), and his LDL cholesterol level was 138 mg/dL (3.6 mmol/L). When
diagnosed, Jake had a body mass index (BMI) of 32 mg/kg2. Jakes internist,
Dr. Somers, recommended that Jake work with a registered dietitian to modify his
diet. Ms. Riggs, the registered dietitian, specifically advises patients with diabetes
about nutrition therapy and helps her patients to create an individualized diet plan.
Ms. Riggs knows that its often difficult for patients to adapt to a new dietary plan, and
she makes sure to customize her recommendations for Jakes eating patterns and
preferences. Jake is pleased with the plan Ms. Riggs devised (which includes eating
whole grains, fruits, vegetables, and low-fat foods), and after 2 months, Jakes FPG
is measured at <120 mg/dL (<6.7 mmol/L), his A1C is 8.0%, and his LDL cholesterol
level is 110 mg/dL (2.8 mmol/L), which are closer to the recommended goals. He has
also lost some weight and now has a BMI of 30 mg/kg2.
Exercise
Guidelines recommend that patients with diabetes exercise regularly, because regular
exercise can improve blood glucose, reduce cardiovascular risk factors, and contribute
to weight loss. Exercise may help prevent type 2 diabetes in high-risk individuals.
Before beginning any physical activity program, patients should be screened for any
underlying complications that could be exacerbated by certain types of exercise, including
uncontrolled hypertension, severe autonomic or peripheral neuropathy, history of foot
lesions, and unstable proliferative retinopathy.
An exercise program should be individualized to the patient; the guidelines list specific
considerations for activity limitation in patients with diabetes complications or using
insulin. For example, in patients with some forms of retinopathy, the guidelines note
that strenuous activities, like weight lifting or jogging, are not appropriate because
the strain may cause hemorrhage in the eye or retinal detachment.
The following case study illustrates how exercise can play a role in a patients diabetes
management; it also illustrates that patients may find it difficult to follow exercise
recommendations.
Amanda: Exercise in Diabetes Management
Amanda is an overweight 49-year-old woman who was diagnosed with type 2 diabetes
a month ago. At the time of diagnosis, Amandas FPG was >175 mg/dL (>9.1 mmol/L),
her A1C was 9.5%, and her LDL cholesterol was 135 mg/dL (3.5 mmol/L). Her
internist, Dr. Gilbert, recommends an exercise program for Amanda. He tells her to
exercise at a moderate pace (brisk walking, bicycling, swimming, jogging) 3 times a
week for 30 minutes each time. He also recommends a diet plan. Dr. Gilbert tells
Amanda that in 2 months, hell check her glucose levels for improvement. Amanda
returns to Dr. Gilberts office in 2 months, and she has lost 3 pounds. Dr. Gilbert
measures Amandas A1C and finds that it is still 9.5%, her FPG is 160 mg/dL
(8.9 mmol/L), and her LDL cholesterol is unchanged. When he asks Amanda about her
compliance with the exercise and diet regimen he recommended, Amanda tells him
that she followed the diet plan at the beginning then became less strict and started to
sneak treats. The hardest part for her was the exercise plan, she tells Dr. Gilbert.
Because Amanda lives in a cold climate, she finds it difficult to exercise outside.
Dr. Gilbert recommends that Amanda join a gym or get an exercise home video.
He also starts her on oral antidiabetic therapy and tells her to set up another
appointment in 2 months to re-test her glucose and lipid levels.
39
40
Guidelines recommend that all patients with diabetes modify nutrient intake and
lifestyle to reach recommended metabolic outcomes and prevent and treat obesity,
dyslipidemia, cardiovascular disease, hypertension, and nephropathy
Goals of nutrition therapy
Achieve and maintain blood glucose levels in the normal range
Reduce cardiovascular risk factors, including dyslipidemia and hypertension
Provide a balanced, nutritional diet
Lose weight
Prevent or slow the development of the chronic complications of diabetes
Address individual nutrition needs, taking into account personal & cultural
preferences and willingness to change
Maintain the pleasure of eating by not limiting food choices unless indicated
by scientific evidence
Regular exercise can improve blood glucose, reduce cardiovascular risk
factors, contribute to weight loss, and may even help prevent type 2 diabetes
in high-risk individuals
Exercise program should be individualized to the patient
Patients may have difficulty maintaining lifestyle modifications and their
beneficial effects
TREATMENT OPTIONS
While lifestyle modifications are an important component of the treatment of diabetes,
many patients with type 2 diabetes will require pharmacologic treatment. A number of
different oral and injectable pharmacologic options, as well as insulin, are available for
glucose control, and this chapter briefly introduces them. The following modules will
discuss them in greater detail.
Pharmacologic Options
The following table provides an overview of the pharmacologic options for type 2 diabetes
that have been approved by the US Food and Drug Administration.
Mechanism of Action
Sulfonylureas
Biguanides/Metformin
Acts by:
Thiazolidinediones (TZDs)
Incretin mimetics/agonists
Meglitinides
(prandial glucose regulators)
41
Mechanism of Action
Alpha-glucosidase inhibitors
Dipeptidyl peptidase-4
(DPP-4) inhibitors
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SUMMARY
The following table summarizes the information presented in this chapter on treatment options for type 2 diabetes.
Treatment Options
Patient-Centered Care
Patient-centered care is defined as providing care that is respectful of and responsive to individual patient
preferences, needs, and values and ensuring that patient values guide all clinical decisions
In patient-centered care, the patient and healthcare provider work together to determine a therapeutic regimen that
is individualized based upon the patients needs, desires, and tolerances
Lifestyle Modifications
Nutrition therapy is an integral component of diabetes management, and patients should receive individualized
nutrition counseling and planning to achieve treatment goals; registered dietitians are important members of the
healthcare team for patients with diabetes
Nutrition therapy has the following goals for patients with diabetes:
Achieve and maintain blood glucose levels in the normal range
Reduce cardiovascular risk factors, including dyslipidemia and hypertension
Provide a balanced, nutritional diet
Help to promote weight loss (for patients who are overweight or obese)
Prevent or slow the development of the chronic complications of diabetes
Address individual nutrition needs, taking into account personal and cultural preferences and willingness
to change
Maintain the pleasure of eating by not limiting food choices unless indicated by scientific evidence
Guidelines recommend that patients with diabetes exercise regularly as regular exercise can improve blood
glucose, reduce cardiovascular risk factors, and contribute to weight loss; exercise may help prevent type 2
diabetes in high-risk individuals
Before beginning any physical activity program, patients should be screened for any underlying complications
that could be exacerbated by certain types of exercise; for example, in patients with some forms of retinopathy,
strenuous aerobic or weight-training exercise might be contraindicated because of a risk for hemorrhage or
retinal detachment
(cont.)
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Pharmacologic treatments that have been FDA-approved for type 2 diabetes include:
Sulfonylureas
Biguanides/Metformin
TZDs
Incretin mimetics/agonists
Meglitinides
Alpha-glucosidase inhibitors
DPP-4 inhibitors
Bile-acid binding resin
Insulin (basal and prandial)
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SELF-ASSESMENT QUESTIONS
There may be more than one correct answer for each question.
1. A patient-centered approach type 2 diabetes might take into effect factors such as:
_____ A. Patient attitude and expected treatment efforts.
_____ B. Disease duration.
_____ C. Life expectancy.
_____ D. Established vascular complications.
2. Which of the following statements about regular exercise is (are) true?
_____ A. It can improve blood glucose levels.
_____ B. It can reduce cardiovascular risk factors.
_____ C. It can contribute to weight loss.
_____ D. It may help prevent type 2 diabetes in high-risk individuals.
3. The plate method recommends that _______ should fill the majority of a persons plate at a meal.
_____ A. dairy products
_____ B. fish
_____ C. nonstarchy vegetables
_____ D. meat and chicken
4. Sulfonylureas act to reduce blood glucose levels by __________________________.
_____ A. inhibiting the intestinal breakdown of carbohydrates.
_____ B. mimicking the action of amylin.
_____ C. mimicking the actions of the incretin GLP-1.
_____ D. increasing insulin secretion.
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___________________________________________________________________________Self-Assessment Questions
5. Which of the following statements about the use of insulin therapy in type 2 diabetes is (are) true?
_____ A. No patients with type 2 diabetes require insulin therapy.
_____ B. Patients with type 2 diabetes are generally not dependent on insulin therapy for survival.
_____ C. As type 2 diabetes progresses, supplemental insulin may be required.
_____ D. All patients with type 2 diabetes require insulin therapy.
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SELF-ASSESSMENT QUESTIONSANSWERS
1. A, B, C, D
2. A, B, C, D
3. C
4. D
5. B, C
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___________________________________________________________________________________Module Summary
MODULE SUMMARY
1) Glucose control, or the reduction of glucose levels to meet certain goals, is a major
factor in decreasing the morbidity and mortality associated with this disease.
However, glucose control is challenging for most patients even with commonly
used therapies, and most patients find it difficult to reach their A1C goal.
Clinical trials have demonstrated that intensive glucose control and lowering A1C
provides benefits, including:
Kumamoto Study
More recent studies evaluating the effects of intensive glucose control, providing
mixed results on effects on cardiovascular events and mortality, include:
Landmark studies such as the DCCT/EDIC and UKDPS suggest that intensive
glycemic control reduces the risk for cardiovascular disease compared with standard
glucose control; however, recent studies such as ADVANCE and VADT have not
demonstrated cardiovascular benefits from intensive glucose control compared with
standard glucose treatment. In the ACCORD study, patients receiving intensive
glucose control had significantly higher rates of all-cause mortality compared with
those randomized to standard glucose control.
It has been hypothesized that:
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Hypertension is common in patients with diabetes, and it is also a risk factor for
cardiovascular disease. In UKPDS, controlling blood pressure significantly reduced
the risk of diabetes-associated complications and mortality. In ACCORD, no
significant reduction cardiovascular events or death was found with intensive
blood pressure therapy.
Patients with type 2 diabetes have an increased prevalence of lipid abnormalities that
contribute to higher rates of cardiovascular disease. Lifestyle modification has been
shown to improve the lipid profile in patients with diabetes, but pharmacologic therapy
is recommended for patients who do not meet the LDL-C goal. For patients without
CVD, ADA recommends an LDL-C goal of <100 mg/dL. The ADA notes that
achieving an LDC-C <70 mg/dL is an optional goal for very high-risk patients.
In HPS, the LDL-cholesterol reduction from baseline with simvastatin treatment was
associated with a reduction in the risk for major coronary artery events and stroke.
In CARDS, 10 mg daily of atorvastatin, a lipid-lowering drug, was found to reduce
the risk of major cardiovascular events in patients with type 2 diabetes.
In the Steno-2 trial, intensive therapy addressing multiple risk factors (blood pressure,
lipids, glucose levels) in patients with diabetes resulted in significant reductions in the
occurrence of cardiovascular events and interventions.
Research is ongoing to find additional ways to prevent or reduce complications in
patients with diabetes in areas such as using certain types of antihypertensive agents
to help reduce the risk of nephropathy.
2) Guidelines recommend that all patients with diabetes modify nutrient intake and
lifestyle to reach recommended metabolic outcomes and prevent and treat obesity,
dyslipidemia, cardiovascular disease, hypertension, and nephropathy.
Goals of nutrition therapy include:
50
Help to promote weight loss (for patients who are overweight or obese)
Address individual nutrition needs, taking into account personal and cultural
preferences and willingness to change
Maintain the pleasure of eating by not limiting food choices unless indicated
by scientific evidence
___________________________________________________________________________________Module Summary
Regular exercise can improve blood glucose, reduce cardiovascular risk factors,
contribute to weight loss, and may even help prevent type 2 diabetes in high-risk
individuals. An exercise program should be individualized to the patient. Patients
may have difficulty maintaining lifestyle modifications and their beneficial effects.
While lifestyle modifications are an important component of the treatment of
diabetes, many patients with type 2 diabetes will require pharmacologic treatment.
Pharmacologic treatment options include use of one or more of the following
classes of agents:
Sulfonylureas
Biguanides/Metformin
Thiazolidinediones
Incretin mimetics/agonists
Alpha-glucosidase inhibitors
DPP-4 inhibitors
Basal insulin: These long-acting insulin analogs are slowly released into the
circulation up to 24 hours after an injection and are designed to supply the basal
level of insulin required by the body
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52
__________________________________________________________________________________________Glossary
GLOSSARY
body mass index (BMI): calculated value used to describe an individuals weight relative to height; calculated using
the following formula: BMI = kg/m2
creatinine: a waste product filtered from the blood and excreted in the urine
end-stage renal disease (ESRD): kidney failure
fasting plasma glucose (FPG): test of blood glucose levels; measured when the patient has not eaten for at least 8 hours
glucagon-like peptide 1 (GLP-1): a hormone in the gut that is released in response to food ingestion; during hyperglycemia,
GLP-1 stimulates insulin secretion, suppresses glucagon secretion, and decreases the rate of gastric emptying
glycosylated hemoglobin (A1C): the amount of hemoglobin within red blood cells with glucose attached; provides an
estimate of blood sugar control for the previous 2 to 3 months
high-density lipoprotein (HDL) cholesterol: good cholesterol; transports excess cholesterol to the liver for elimination
hyperglycemia: abnormally high blood glucose levels
hypertension: elevated blood pressure
hypoglycemia: abnormally low concentrations of glucose in the circulating blood
hypokalemia: abnormally low level of potassium ions in the blood
incretin: class of insulinotropic substances that are released in the gastrointestinal tract in response to food ingestion
insulin: hormone secreted by the beta-cells of the pancreas that is the key regulator of the metabolism of glucose
and processes necessary for metabolism of fats, carbohydrates, and proteins; opposes the action of glucagon
lipid: fat; found almost exclusively in foods of animal origin and continuously synthesized in the body
low-density lipoprotein (LDL) cholesterol: bad cholesterol; transports most cholesterol in the blood; when present
in high amounts, deposits cholesterol in the walls of arteries, forming lipid plaques
macroalbuminuria: the leakage of large amounts of albumin into the urine; defined as >200 mcg/min
microalbuminuria: the leakage of a small amount of albumin into the urine, defined as 20 mcg/min to 200 mcg/min
53
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________________________________________________________________________________________References
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