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DIABETES LEARNING SYSTEM

MODULE 3: TREATMENT OF
TYPE 2 DIABETES

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___________________________________________________________________________________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

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CHAPTER 2: TREATMENT OPTIONS ................................................................................................................................33


Introduction ......................................................................................................................................................................33
Learning Objectives .........................................................................................................................................................33
A Patient-Centered Approach to the Treatment of Type 2 Diabetes................................................................................35
Lifestyle Modifications......................................................................................................................................................37
Nutrition .......................................................................................................................................................................37
Exercise .......................................................................................................................................................................39
Sustainability of Lifestyle Modifications........................................................................................................................40
Summary of Lifestyle Modifications .............................................................................................................................40
Treatment Options ...........................................................................................................................................................41
Pharmacologic Options................................................................................................................................................41
Insulin Therapy in Type 2 Diabetes Management .......................................................................................................42
Summary of Treatment Options...................................................................................................................................43
Summary .........................................................................................................................................................................44
SELF-ASSESMENT QUESTIONS .......................................................................................................................................46
Self-Assessment QuestionsAnswers ...........................................................................................................................48
MODULE SUMMARY...........................................................................................................................................................49
GLOSSARY..........................................................................................................................................................................53
REFERENCES .....................................................................................................................................................................55

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_______________________________________________________________________________________ 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.

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________________________________________________ Chapter 1: Studies Evaluating Treatment of Type 2 Diabetes

CHAPTER 1: STUDIES EVALUATING TREATMENT


OF TYPE 2 DIABETES
INTRODUCTION
In this chapter we will briefly discuss several landmark studies that emphasize the
importance of tight glucose control. We also will look at several more recent trials that
compare intensive glucose-lowering therapy with standard glucose-lowering therapy.
Differences between landmark study results and more recent study results will be
examined and possible reasons for the differences will be presented. Finally, this chapter
will present some of the studies and subgroup analyses that support the treatment of
hypertension and dyslipidemia in patients with type 2 diabetes.

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.

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GLUCOSE CONTROL IN DIABETES


Chronically high blood glucose levels are an important cause of the long-term
complications associated with diabetes. Several key clinical trials have demonstrated
the benefits of lowering blood glucose levels and provide data that support the current
recommended management of type 2 diabetes. These studies have shown that lowering
blood glucose levels is associated with:
Reduction of risk for complications of diabetes
Decrease in progression of complications of diabetes
Reduction of risk of death related to diabetes
The following paragraphs discuss several landmark studies that emphasize the
importance of tight glucose control:
Diabetes Control and Complications Trial (DCCT)
Epidemiology of Diabetes Interventions and Complications (EDIC)
Kumamoto study
United Kingdom Prospective Diabetes Study (UKPDS)
This chapter also discusses several more recent trials that compared intensive
glucose-lowering therapy with standard glucose-lowering therapy:
Action in Diabetes and Vascular Disease (ADVANCE) trial
Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial
Veterans Affairs Diabetes Trial (VADT)
It is important to note that despite the data provided by these trials and the availability
of multiple medication options, patients still have a very difficult time achieving and
maintaining their glycosylated hemoglobin (A1C) goal. For example, as shown in
Figure 1, in the UKPDS, A1C continued to deteriorate (that is, increase) in all 3 treatment
groups over 6 years, even with intensive insulin or oral antidiabetic medication therapy.

glycosylated hemoglobin (A1C):


(glahy-KOS-uhl-ahyt-ed HEE-muhgloh-bin) 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
insulin (IN-suh-lin): 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

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Figure 1. A1C Levels Deteriorated Over 6 Years of the UKPDS

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________________________________________________ Chapter 1: Studies Evaluating Treatment of Type 2 Diabetes

The proportion of patients with complications also continued to rise throughout the trial.
These results emphasized the need for new approaches for diabetes treatment.

Figure 2. Proportion of Patients Developing Long-Term Complication Over


6 Years in the UKDPS

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Diabetes Control and Complications Trial (DCCT)


The first study that highlighted the role of intensive glucose control in reducing the
development of diabetes complications was the Diabetes Control and Complications
Trial (DCCT). This landmark trial was conducted in 1441 patients with type 1 diabetes
over a mean of 6.5 years.
The goal of the DCCT was to determine whether diabetes management with a more
intensive insulin regimen compared to a standard insulin regimen could prevent or delay
the progression of complications in patients. The intensive insulin regimen was designed
to achieve as near normal glucose levels as possible by using 3 or more insulin injections
per day or treatment with an insulin pump. The standard regimen consisted of 1 or 2
insulin injections per day. A more intensive insulin regimen would likely result in better
glucose controlthus, the DCCT was designed to evaluate whether lowering glucose
would prevent or delay complications. The trial 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 = 348) or standard therapy
(n = 378)
A secondary intervention group, consisting of patients with mild to moderate
retinopathy at the start of the study, randomized to receive intensive therapy (n = 363)
or standard therapy (n = 352)

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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

Table 1. Results From the DCCT


Glucose Control in Type 1 Diabetes

For the primary prevention group, intensive glucose control significantly


reduced the:
Risk of retinopathy by 76% (P < 0.001), as shown in Figure 3
Risk of nephropathy (microalbuminuria) by 34% (P = 0.04)
The appearance of neuropathy at 5 years by 69% (P = 0.006)
For the secondary intervention group, intensive glucose control significantly
reduced the:
Risk of progression of retinopathy by 54% (P < 0.001), as shown in Figure 3
Risk of nephropathy (microalbuminuria) by 43% (P = 0.001)
The appearance of neuropathy at 5 years by 57% (P < 0.001)
For the 2 groups combined, intensive glucose control reduced the risk of
cardiovascular and peripheral vascular disease by 41% (P = NS)

NS = not significant.

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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

Module 3: Treatment of Type 2 Diabetes _________________________________________________________________

Figure 3. Reduced Risk of Retinopathy in the DCCT

Epidemiology of Diabetes Interventions and Complications (EDIC)


The EDIC (Epidemiology of Diabetes Interventions and Complications) study was a longterm follow-up of the DCCT. Of the original 1441 patients in the DCCT, 97% continued
in EDIC for a mean follow-up of 17 years. At the end of the DCCT, all patients in the
conventional-treatment group were offered intensive treatment and all participants returned
to their own healthcare providers for treatment of their diabetes. As a result, differences
in treatment dissipated and the between-group differences in mean (standard deviation
[SD]) A1C narrowed during the follow-up period.
The primary endpoint in EDIC was the time to the first cardiovascular event, including any
of the following: nonfatal myocardial infarction (MI) or stroke, death due to cardiovascular
disease, subclinical MI, angina, or the need for coronary artery revascularization. The
results of the study showed that the intensive therapy group had a 42% reduction in the
relative risk of any cardiovascular event (P = 0.02) and a 57% risk reduction for nonfatal
MI, stroke, or death from cardiovascular disease (P = 0.02). Since patients in the intensive
and conventional treatment groups received similar treatment during the EDIC study,
these results indicated that approximately 6.5 years of intensive diabetes therapy had
a long-term effect on the risk for developing diabetes complications.

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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)

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Patients were followed for 6 years. The following table summarizes key results of the
Kumamoto Study.

Table 2. Results of the Kumamoto Study


Glucose Control in Type 2 Diabetes

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

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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

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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.

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UKPDS 34 reported that compared to conventional treatment, intensive glucose control


resulted in a:
Significant 32% reduction in risk of any diabetes-related endpoint (death from
hyperglycemia and hypoglycemia, myocardial infarction, angina, heart failure,
renal failure, stroke, amputation, retinopathy) (P = 0.002)
Significant 42% reduction in risk of diabetes-related death (P = 0.017)
Significant 39% reduction in risk of heart attack (P = 0.010)

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

Significant 36% reduction in risk of death due to all causes (P = 0.011)


10 years post-trial follow-up, compared with overweight patients who received
conventional treatment, patients treated with metformin had a:
Significant 21% reduction in risk for any diabetes-related endpoint (P = 0.01)
Significant 30% reduction in risk of diabetes-related death (P = 0.01)
Significant 33% reduction in risk of myocardial infarction (P = 0.005)
Significant 27% reduction in risk of death due to all causes (P = 0.002)
UKPDS 35: UKPDS 35 was designed to determine the relationship between exposure
to high blood glucose levels over time and the risk of macrovascular or microvascular
complications. This study involved 3867 patients randomized to receive conventional
treatment, primarily with diet, or intensive therapy with insulin or a sulfonylurea. As noted
previously, intensive therapy is defined as aiming to achieve near-normal FPG levels.
The rates of macrovascular and microvascular complications were compared to correlated
blood glucose levels as indicated by A1C concentrations.
The results of UKPDS 35 included that for every 1% reduction in A1C, there was a:
Significant 37% decrease in the risk for microvascular endpoints (P < 0.0001)
Significant 14% decrease in the risk for fatal or nonfatal heart attack (P < 0.0001)

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Module 3: Treatment of Type 2 Diabetes _________________________________________________________________

Figure 4 illustrates results from UKPDS 35.

Figure 4. UKPDS 35: Incidence of Microvascular Events Correlated


With Increase in A1C

Action in Diabetes and Vascular Disease (ADVANCE) Trial


The ADVANCE trial assessed the effects of intensive glucose control in reducing vascular
disease in patients with type 2 diabetes. A total of 11,140 patients were randomized
to either intensive glucose control (n = 5571) or standard glucose control (n = 5569).
Patients had a mean age of 66 years, had diabetes for 8 years, had a mean baseline
A1C of 7.5%, and about one-third had previous macrovascular disease. At the end
of the 5-year follow-up period:
A1C was a mean of 6.5% in the intensive therapy group and 7.3% in the standard
therapy group
There was no significant difference in the incidence of macrovascular events
There was a significant reduction in major microvascular events in the intensive
therapy group: (P = 0.01)
There were no significant differences in mortality between the 2 groups

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Action to Control Cardiovascular Risk in Diabetes


(ACCORD) Trial
The ACCORD trial was designed to evaluate whether intensive glucose-lowering
(targeting an A1C of <6.0%) in middle-aged and elderly patients with type 2 diabetes
would reduce the rate of cardiovascular events. A total of 10,251 patients were
randomized to either intensive therapy (targeting an A1C of <6.0%) or standard therapy
(targeting an A1C of 7.0% to 7.9%). Patients in the trial had diabetes for a median of 10
years, a mean age of 62 years, mean A1C levels of 8.3%, and a high cardiovascular risk.
In December 2007, after a mean treatment period of 3.5 years, it was decided to
discontinue the intensive treatment regimen of the glycemia trial due to an increased
rate of all-cause mortality in the intensive therapy group: 5.0% versus 4.0%; (HR 1.22;
95% CI, 1.01 to 1.04, P = 0.04). Other findings included:
Stable median A1C levels were 6.4% in the intensive therapy group and 7.5% in the
standard group
The rate of the primary outcome (nonfatal MI, nonfatal stroke, or death from
cardiovascular causes) was not significantly different in the 2 groups (2.11%/year
for intensive therapy and 2.29%/year for standard therapy)
In February 2008, patients were informed of the decision to discontinue the intensive
treatment arm. Since patients had been assigned to receive treatment for either control
blood pressure or lipid levels, they were switched to standard therapy and continued to
be monitored through the end of the study.
After 5-years of follow-up (at study end), compared with patients who received standard
glycemic therapy, patients randomized to 3.7 years of intensive glycemic control:

lipid (LIP-id): fat; found almost


exclusively in foods of animal
origin and continuously synthesized
in the body

Experienced a decreased incidence of nonfatal MI (1.18 versus 1.42; hazard ratio,


0.82; 95% CI, 0.70 to 0.96; P = 0.01)
Experienced an increased rate of death from cardiovascular causes (0.74 versus 0.57;
hazard ratio, 1.29; 95% CI, 1.04 to 1.60; P = 0.02)
Were 19% more likely to experience death from any cause (1.53 versus 1.27; 95% CI,
1.03 to 1.38; P = 0.02)

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Veterans Affairs Diabetes Trial (VADT)


The VADT study compared the effects of intensive and standard glucose control on
cardiovascular events in veterans with poorly controlled type 2 diabetes. A total of 1791
patients were randomized to receive either intensive treatment (n = 892) or standard
treatment (n = 899). Patients had a mean age of 60 years, had diabetes for a mean of
11.5 years, and 40% had already had a cardiovascular event. The mean A1C level at
baseline was 9.4%. By 6 months of treatment, A1C levels had stabilized at 6.9% in the
intensive therapy group and at 8.4% in the standard therapy group. Patients were
followed for up to 7.5 years, with a median follow-up of 5.6 years.
No significant difference in time to first occurrence of a cardiovascular eventthe primary
outcomewas observed between the 2 groups. There was no significant difference
in time to death from cardiovascular causes or in rate of death from these causes.

Landmark Studies Compared With Recent Studies Assessing


Intensive Glucose Control
Landmark studies such as DCCT/EDIC and UKDPS provide clear evidence that intensive
treatment reduces the risk of developing the microvascular complications (i.e., retinopathy,
neuropathy, and nephropathy) associated with diabetes. These studies also suggest, but
do not provide clear evidence, that the risk of cardiovascular disease is reduced with
intensive glycemic control.
Studies such as ACCORD, ADVANCE, and VADT were designed to further clarify the
effects of intensive glycemic control versus standard glycemic control on cardiovascular
outcomes in patients with type 2 diabetes. As reviewed earlier, neither the ADVANCE
study nor VADT showed significant reduction in cardiovascular events in patients who
received intensive glycemic treatment compared with those who received standard
treatment. In the ACCORD study, intensive glycemic control significantly increased
all-cause mortality and CVD-related deaths. Although a cause could not be identified for
the increase in mortality in the ACCORD trial, it has been theorized that hypoglycemia,
weight gain, unmeasured drug effects or interactions, or the intensity of treatment used to
achieve intensive glycemic control (as opposed to the target A1C) could be responsible.

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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.

BLOOD PRESSURE CONTROL IN DIABETES


Hypertension is a common comorbidity of diabetes, and it is also a major risk factor
for cardiovascular disease and microvascular disease. Several studies have evaluated
whether maintaining blood pressure control decreases the risk for complications
from diabetes.
Recall that both the ADA and AACE recommend a blood pressure goal of
<130/80 mm Hg for most patients with diabetes. Higher or lower blood pressure
targets may be appropriate for some patients. A number of pharmacologic treatments
are available to help patients achieve these blood pressure goals (see Table 3).

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Module 3: Treatment of Type 2 Diabetes _________________________________________________________________

Table 3. Suggested Priority of Initiating Blood Pressure-Lowering Agents


Evidence-Based Therapies

Renin-angiotensin-aldosterone system blockers


Angiotensin-converting enzyme inhibitors
Angiotensin II receptor blockers
Calcium channel blockers
Thiazide diuretic
Beta-adrenergic blockers

Additional Therapies

Aldosterone receptor blockers


Direct renin inhibitor
Selective alpha1-adrenergic blockers
Central alpha2 agonists
Direct vasodilators

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

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________________________________________________ Chapter 1: Studies Evaluating Treatment of Type 2 Diabetes

Figure 5. UKPDS 38: Improved Blood Pressure Control Reduced


Risk of Diabetes-Related Endpoints and Mortality

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Module 3: Treatment of Type 2 Diabetes _________________________________________________________________

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

creatinine (kree-AT-n-in): a waste


product filtered from the blood and
excreted in the urine

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________________________________________________ Chapter 1: Studies Evaluating Treatment of Type 2 Diabetes

LIPID CONTROL IN DIABETES


In addition to glucose and blood pressure control, lipid levels must also be regulated
in patients with diabetes. Patients with type 2 diabetes have an increased prevalence
of lipid abnormalities that contributes to higher rates of cardiovascular disease. Lipid
management that lowers low-density lipoprotein cholesterol LDL-C) and triglycerides
and raises high-density lipoprotein cholesterol (HDL-C) has been shown to reduce
macrovascular disease and mortality in patients with type 2 diabetes, particularly those
who have high baseline cardiovascular disease risk. The following table reviews the LDL
cholesterol goals from the ADA that were presented in Module 2.

Table 4. LDL Cholesterol Goals From the ADA


ADA Recommended LDL Cholesterol Goals

Individuals without overt CVD: <100 mg/dL (<2.6 mmol/L)


Optional goal for individuals with overt CVD: <70 mg/dL (<1.8 mmol/L)

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.

low-density lipoprotein cholesterol


(LDL-C) (lip-oh-PROH-teen
kuh-LES-tuh-rohl): bad
cholesterol; transports most
cholesterol in the blood; when
present in high amounts, deposits
cholesterol in the walls of arteries,
forming lipid plaques
triglycerides (trahy-GLIS-uhrahydz): lipid molecules containing
3 fatty acids bound to glycerol; the
primary fat in the diet and the primary
molecule used for fuel storage
high-density lipoprotein
cholesterol (HDL-C) (lip-oh-PROHteen kuh-LES-tuh-rohl): good
cholesterol; transports excess
cholesterol to the liver for elimination
mortality (mawr-TAL-i-tee):
death rate

Table 5. Recommended Use of Statins in Patients With Diabetes


ADA Recommendations for Statin Use in Patients With Diabetes

Statin therapy should be added to lifestyle therapy, regardless of baseline lipid


levels, for patients with diabetes:
with overt cardiovascular disease
without cardiovascular disease who are over the age of 40 years and who
have at least one cardiovascular disease risk factor
In patients at lower risk (no overt cardiovascular disease and <40 years), statin
therapy should be considered if LDL cholesterol remains >100 mg/dL or those
with multiple cardiovascular risk factors

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Module 3: Treatment of Type 2 Diabetes _________________________________________________________________

Heart Protection Study (HPS)


The Heart Protection Study (HPS) examined the effect of cholesterol lowering in
20,536 patients with cardiovascular disease, of which 3982 had diabetes. The HPS
compared patients receiving simvastatin (a lipid-lowering agent) with patients receiving
placebo. This study demonstrated that LDL cholesterol reduction of approximately 30%
from baseline with simvastatin was associated with:
A significant 27% reduction in the relative risk for major coronary artery events
(nonfatal myocardial infarction or coronary death) (P < 0.0001)
A significant 25% reduction in the relative risk for fatal or nonfatal stroke (P < 0.0001)

Collaborative Atorvastatin Study (CARDS)

macroalbuminuria
(MAK-roh-al-byoo-muh-NYOOR-eeuh): the leakage of large amounts
of albumin into the urine; defined
as >200 mcg/min

24

The Collaborative Atorvastatin Study (CARDS) investigated the effectiveness of 10 mg


daily atorvastatin, a lipid-lowering drug, versus placebo in the primary prevention of
cardiovascular disease in 2819 patients with type 2 diabetes. CARDS was performed in
132 clinical centers in the United Kingdom and Ireland, and included men and women aged
40 to 75 who had been diagnosed with type 2 diabetes at least 6 months before study
entry. In addition, patients had to have one of the following: a history of hypertension,
retinopathy, microalbuminuria or macroalbuminuria, or currently smoking. The duration
of follow-up was 4.0 years for the atorvastatin group and 3.9 years for the placebo group.
The trial was stopped 2 years earlier than planned because of significant benefit at the
second interim analysis. Patients receiving atorvastatin had a significant 37% reduction
in the risk of major cardiovascular events (P < 0.001).

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________________________________________________ Chapter 1: Studies Evaluating Treatment of Type 2 Diabetes

Fenofibrate Intervention and Event Lowering in Diabetes


(FIELD) Study
The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study assessed
whether treatment with fenofibrate would decrease the incidence of cardiovascular events
in patients with type 2 diabetes. The study randomized 9795 individuals between 50 and
75 years of age, who were not taking statin therapy at study entry, to receive either
fenofibrate 200 mg daily or placebo. The primary outcome was first occurrence of either
nonfatal MI or death from coronary heart disease. Compared with placebo, fenofibrate
was associated with a nonsignificant 11% relative reduction in risk for first occurrence of
nonfatal MI or death from coronary heart disease. However, compared with placebo,
fenofibrate treatment resulted in reduced relative risk for nonfatal MI (24% RR reduction)
and coronary revascularizations (21% RR reduction), resulting in a significant 11%
relative reduction in the risk for total cardiovascular disease events (cardiovascular
disease death, MI, stroke, coronary and carotid revascularization; a secondary endpoint of
the study).

MULTIPLE RISK FACTOR REDUCTION: THE STENO-2 STUDY


The Steno-2 study, which was conducted at the Steno Diabetes Center in Denmark, was
designed to evaluate the effect on cardiovascular disease of an intensified, multifactorial
intervention compared to conventional therapy in patients with type 2 diabetes and
microalbuminuria. The 160 patients were randomized to receive:
Intensive therapy (n = 80), which consisted of behavior modification and a stepwise
pharmacologic approach overseen by a team of a physician, a nurse, and a dietitian,
with strict treatment goals for blood pressure, A1C, total cholesterol, and triglycerides
Conventional therapy (n = 80), which had less intense risk factor goals; patients
were seen by their general practitioner with the possibility of referral to a specialist
The primary endpoint was a composite of death from cardiovascular causes, nonfatal MI,
coronary artery bypass grafting, percutaneous coronary intervention, nonfatal stroke,
amputation as a result of ischemia, or vascular surgery for peripheral arterial disease.
After a mean follow-up of 7.8 years, the primary endpoint was significantly reduced in
the intensive therapy group compared with the conventional therapy group: HR 0.47
(95% CI 0.24 to 0.73) (P = 0.008).

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Module 3: Treatment of Type 2 Diabetes _________________________________________________________________

TREATMENT OF NEPHROPATHY IN DIABETES

end-stage renal disease (ESRD):


kidney failure

The treatment of nephropathy is very important for diabetes management because


nephropathy occurs in many patients with diabetes and is among the leading causes
of end-stage renal disease (ESRD).
You have learned that tight control of blood pressure with antihypertensive drugs can
reduce the development of complications of diabetes. In addition, the use of 2 classes
of antihypertensive agents, independent of their effects on blood pressure control,
has shown beneficial effects on delaying or preventing ESRD; these agents are:
ACE inhibitors (angiotensin-converting enzyme inhibitors)
ARBs (angiotensin II receptor blockers)
Guidelines recommend the use of ACE inhibitors or ARBs in nonpregnant patients with
diabetes and microalbuminuria or macroalbuminuria.

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________________________________________________ Chapter 1: Studies Evaluating Treatment of Type 2 Diabetes

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.)

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Module 3: Treatment of Type 2 Diabetes _________________________________________________________________

Evaluation of Glucose, Blood Pressure, and Lipid Control in Diabetes (cont.)


Blood Pressure Control in Diabetes

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)

Multiple Risk Factor Reduction

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

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___________________________________________________________________________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.

Intensive glucose control produced no significant reduction


in macrovascular events or mortality, but did significantly
reduce microvascular events.

2.

Targeting multiple risk factors significantly decreased


cardiovascular events and interventions.

3.

Intensive glucose control in veterans with diabetes did not


significantly reduce cardiovascular events or death.

4.

Higher mortality occurred with intensive glucose control,

B. ADVANCE _____
C. Steno-2 _____
D. VADT _____

which resulted in early discontinuation of the glycemia trial.

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Module 3: Treatment of Type 2 Diabetes _________________________________________________________________

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

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___________________________________________________________________________Self-Assessment Questions

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Module 3: Treatment of Type 2 Diabetes _________________________________________________________________

SELF-ASSESSMENT QUESTIONSANSWERS
1. A, B
2. C
3. A4; B1; C2; D3
4. C, D
5. True

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_________________________________________________________________________ Chapter 2: Treatment Options

CHAPTER 2: TREATMENT OPTIONS


INTRODUCTION
Diabetes is a complex condition that requires ongoing treatment to prevent and
manage its complications. This chapter provides an overview of nonpharmacologic
and pharmacologic treatment options for type 2 diabetes.

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.

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Module 3: Treatment of Type 2 Diabetes _________________________________________________________________

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_________________________________________________________________________ Chapter 2: Treatment Options

A PATIENT-CENTERED APPROACH TO THE TREATMENT


OF TYPE 2 DIABETES
In mid-2012, the ADA and the European Association for the Study of Diabetes (EASD)
released a joint position statement regarding patient-centered care. The guideline
defines patient-centered care 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 consistent with the patients desired level of involvement.
The guidelines note that multifactorial risk reduction is likely to provide greater benefits
for the patient, but recommendations contained within the guidelines need to be
individualized based upon the patients needs, desires, and tolerances (see Figure 6).
Evidence supports that engaging patients in health care decisions is effective and
may increase adherence to therapy.

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Module 3: Treatment of Type 2 Diabetes _________________________________________________________________

Figure 6. Approach to the Management of Hyperglycemia

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.

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_________________________________________________________________________ Chapter 2: Treatment Options

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.

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Module 3: Treatment of Type 2 Diabetes _________________________________________________________________

Figure 7. Nutritional Recommendations for Patients With Diabetes

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

body mass index (BMI): calculated


value used to describe an individuals
weight relative to height; calculated
using the following formula:
BMI = kg/m2

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.

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_________________________________________________________________________ Chapter 2: Treatment Options

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.

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Module 3: Treatment of Type 2 Diabetes _________________________________________________________________

Sustainability of Lifestyle Modifications


One factor that must be considered when implementing nutrition and exercise programs is
the effectiveness of these programs. As noted in Amandas case study, patients may have
difficulty maintaining lifestyle modifications and their beneficial effects. Furthermore, even
if lifestyle modification programs are maintained, diet and exercise may not be enough to
control glucose levels. For example, in UKPDS 33, patients were randomized to treatment
with pharmacologic therapy or diet therapy. If patients were unable to control their glucose
levels through diet alone, they received pharmacologic therapy. By the end of the trial,
approximately 62% of patients required pharmacologic therapy.

Summary of Lifestyle Modifications


The following table summarizes the information on lifestyle modifications.

Table 6. Recommended Lifestyle Modifications


Lifestyle Modifications

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

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_________________________________________________________________________ Chapter 2: Treatment Options

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.

Table 7. Pharmacologic Treatment Options for Type 2 Diabetes


Class

Mechanism of Action

Sulfonylureas

Insulin secretagogues: act mainly by stimulating


insulin release from pancreatic beta-cells

Biguanides/Metformin

Acts by:

Reducing hepatic glucose production


Increasing insulin sensitivity (liver >, muscle, fat)
Reducing intestinal glucose absorption

Thiazolidinediones (TZDs)

Thiazolidinediones improve glycemic control by


increasing sensitivity of fat >, muscle, and liver
to insulin

Incretin mimetics/agonists

Mimics the actions of glucagon-like peptide 1


(GLP-1) by binding to and activating the GLP-1
receptor; enhances glucose-dependent insulin
synthesis and secretion and moderates glucosedependent glucagon secretion; slows gastric
emptying; increases satiety

Meglitinides
(prandial glucose regulators)

incretin (in-KREE-tin): class of


insulinotropic substances that are
released in the gastrointestinal tract
in response to food ingestion
glucagon-like peptide 1 (GLP-1)
(GLOO-kuh-gon): 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

Short-acting insulin secretagogue: stimulates


the release of insulin from pancreatic beta-cells
(cont.)

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Module 3: Treatment of Type 2 Diabetes _________________________________________________________________

Table 7. Pharmacologic Treatment Options for Type 2 Diabetes (cont.)


Class

Mechanism of Action

Alpha-glucosidase inhibitors

Inhibit intestinal enzymes from breaking down


carbohydrates, which delays carbohydrate
digestion and delays glucose uptake into
the blood, decreasing postprandial glucose

Dipeptidyl peptidase-4
(DPP-4) inhibitors

Inhibit DPP-4, the enzyme responsible for the


degradation of incretins; the incretins, glucosedependent insulinotropic peptide (GIP) and
GLP-1, increase insulin secretion and decrease
glucagon secretion

Bile-acid binding resin

The mechanism by which bile acid binding and


removal from enterohepatic circulation lowers
blood glucose has not been established

Combination therapy: Because of the nature of the disease, it is frequently


necessary for a patient with type 2 diabetes to eventually receive more than one
agent. Usually agents with different mechanisms of action are used in combination.
Some patients receive 2 separate agents, but there are also a few products that combine
2 agents in one formulation.

Insulin Therapy in Type 2 Diabetes Management


Patients with type 1 diabetes require insulin therapy, because they produce little or no
insulin and must depend on exogenous insulin for survival. Patients with type 2 diabetes
generally are not dependent on insulin therapy for survival, but a substantial number
of patients with type 2 diabetes will eventually require insulin. For example, as type 2
diabetes progresses, insulin production decreases over time and supplemental insulin
may be required, especially during times of stress and illness. Insulin can be used either
alone or in combination with oral agents for type 2 diabetes.

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_________________________________________________________________________ Chapter 2: Treatment Options

Different types of replacement insulin are available:


Prandial insulins: These rapid-acting insulin analogues are designed to target prandial
glucose levels and are thus injected shortly before a meal
Basal insulins: These long-acting insulin analogues 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
Patients with type 2 diabetes usually initiate treatment with a basal, or long-acting,
insulin analogue. Basal insulins reduce blood glucose levels by suppressing hepatic
insulin production between meals and while the individual sleeps. While most patients
with type 2 diabetes can be adequately treated with basal insulin alone, some individuals
will require treatment with prandial, or rapid-acting, insulin analogues. Prandial insulins
are administered just before the patient eats to improve postprandial glucose control.

Summary of Treatment Options


The following case study illustrates how the concepts presented in this chapter relate
to a physicians choice of antidiabetic therapy for her patient, Luis.
Luis: Factors Influencing Choice of Antidiabetic Agent
Luis is a 65-year-old Hispanic man who was diagnosed with type 2 diabetes 2 years
ago. His physician, Dr. Gupta, prescribed a biguanide to control Luiss glucose levels,
and it worked well in the past. However, the past 2 times that Dr. Gupta measured
Luiss A1C, it has been 8.7%, which is above goal. Dr. Gupta discusses the
consequences of hyperglycemia with Luis, and he agrees that he should try another
oral antidiabetic agent. Dr. Gupta decides to prescribe combination therapy with a
sulfonylurea and a biguanide for Luis. If this doesnt control Luiss glucose levels,
she may need to prescribe insulin as well.

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Module 3: Treatment of Type 2 Diabetes _________________________________________________________________

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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_________________________________________________________________________ Chapter 2: Treatment Options

Treatment Options (cont.)/


Pharmacologic Options

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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Module 3: Treatment of Type 2 Diabetes _________________________________________________________________

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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Module 3: Treatment of Type 2 Diabetes _________________________________________________________________

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:

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

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
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:

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

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Module 3: Treatment of Type 2 Diabetes _________________________________________________________________

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

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

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___________________________________________________________________________________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

Meglitinides (prandial glucose regulators)

Alpha-glucosidase inhibitors

DPP-4 inhibitors

Bile-acid binding resins

Fixed-dose combinations of some oral agents are available. Furthermore, many


patients with type 2 diabetes eventually require insulin, either alone or in combination
with oral agents, to help manage blood glucose levels.
Patients with type 1 diabetes require insulin therapy, because they produce little or
no insulin and must depend on exogenous insulin for survival. Patients with type 2
diabetes are generally not dependent on insulin therapy for survival, but a substantial
number of patients with type 2 diabetes will require insulin.
Different types of replacement insulin are available:

Prandial insulin: These rapid-acting insulin analogs are designed to target


prandial glucose levels and are thus injected shortly before a meal

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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Module 3: Treatment of Type 2 Diabetes _________________________________________________________________

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__________________________________________________________________________________________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

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Module 3: Treatment of Type 2 Diabetes _________________________________________________________________

mortality: death rate


nephropathy: kidney damage that can arise as a complication of chronic hyperglycemia
neuropathy: nerve damage, primarily peripheral neuropathy (in which the peripheral nerves in the extremities are
affected); can result in loss of sensation, which may result in serious infection, gangrene, and the need for amputation
postprandial: after a meal
retinopathy: damage to the retina of the eye; can lead to blindness
triglycerides: lipid molecules containing 3 fatty acids bound to glycerol; the primary fat in the diet and the primary
molecule used for fuel storage

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________________________________________________________________________________________References

REFERENCES
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