A1C, glycosylated hemoglobin; FPG, fasting plasma glucose; OGTT, oral glucose tolerance test.
Individuals with A1C, FPG, or OGTT values that are intermediate between normal
and those considered diagnostic of diabetes are considered to have prediabetes. The
terms IFG and IGT should not be used interchangeably because each results from
somewhat different physiologic processes. It is important to interpret the categories
listed in Table 53-3 as a continuum of increased risk for diabetes, rather than focus
on the absolute cutoff points for prediabetes or diabetes.
Many factors can impair glucose tolerance or increase plasma glucose. These must
be excluded before a definitive diagnosis is made. For example, an individual who
has not fasted for a minimum of 8 hours may have an elevated FPG. Patients who are
tested for glucose tolerance during, or very soon after, an acute illness (e.g., a
myocardial infarction [MI]) or who are on corticosteroids (e.g., prednisone,
dexamethasone) may be misdiagnosed because of the presence of high concentrations
of counter-regulatory hormones that increase glucose concentrations. Glucose
tolerance often returns to normal in these individuals.
diabetic population. Complications are typically designated as microvascular or
macrovascular in nature. Glucose toxicity contributes most to the development and
progression of microvascular complications (retinopathy, nephropathy, and
neuropathy) owing to the particular susceptibility of these cell systems to elevated
leading cause of new cases of adult blindness and kidney failure in the United States.
About 60% to 70% of people with diabetes also have some manifestation of
peripheral or autonomic neuropathy. Severe peripheral neuropathy coupled with
1,23 Finally, poor glucose control
promotes development of dental and oral complications and increases the risk of
complications during pregnancy for both mother and fetus.
complications are multifactorial in their etiology and less dependent on
hyperglycemia. Diabetes mellitus itself is a well-known risk factor for
macrovascular disease (peripheral vascular disease, CVD, stroke). Patients with
diabetes have a threefold-to-fourfold elevated risk for MI and cardiovascular death
compared with nondiabetic subjects.
Insulin resistance and the resultant
hyperinsulinemia in Type 2 diabetes mellitus contribute to the development of
hypertension, dyslipidemia, and platelet hypersensitivity, all of which then contribute
to the increased CVD risk in patients with diabetes.
27 Thus, although tight glycemic
control (A1C <7.0%) will dramatically reduce the risk for microvascular disease, its
relationship to macrovascular disease is still under intense debate.
RELATIONSHIP OF GLYCEMIC CONTROL TO
MICROVASCULAR AND MACROVASCULAR
Although epidemiologic studies have shown a general relationship between glucose
control and cardiovascular events, recent randomized trials have failed to confirm a
benefit of tight glucose control compared with standard control, which highlights the
multifactorial nature of macrovascular disease.
28 However, the clear relationship
between microvascular events and glycemic control is well established from
randomized, clinical trials. The Diabetes Control and Complications Trial (DCCT),
and the open-label follow-up trial, DCCT-EDIC (Epidemiology of Diabetes
Interventions and Complications), established the benefits of intensive glycemic
control on microvascular end points.
In the DCCT, intensive treatment (A1C
7.1% vs. 9.0%) reduced the risk of clinically meaningful retinopathy, nephropathy,
treatment group were shown to have a persistently lower incidence of microvascular
complications even after the glucose control reached parity between the two study
groups after the end of the randomized portion of the trial.
showed a significant reduction in cardiovascular complications among patients
previously assigned to the intensive therapy DCCT arm.
glycemic goals of intensive insulin therapy (herein called physiologic or basal-bolus
therapy). This persistence of the microvascular benefits of glycemic control has also
been demonstrated in patients with Type 2 diabetes in the United Kingdom
Prospective Diabetes Study (UKPDS) (see Case 53-11, Question 2).
The relationship between glycemic control and macrovascular disease has always
been less clear. Evidence of early atherosclerosis in patients with Type 1 diabetes in
whom dyslipidemia and hypertension are typically absent argues strongly for a role
of hyperglycemia itself in the development or progression of macrovascular
34 The UKPDS trial was the first to report the benefit of tight BG control on
cardiovascular complications in Type 2 diabetes.
benefits were clear, the 21% relative risk reduction for fatal and nonfatal MI and
sudden cardiac death failed to reach statistical significance (p = 0.052). However, in
a planned 10-year follow-up of patients enrolled in the trial, a significant 15%
reduction was seen in the risk of MI (p = 0.01).
33 A similar finding for macrovascular
benefit was reported in a 17-year follow-up of the DCCT-EDIC study.
although glycemic control benefited macrovascular disease, it took more than a
decade to see the benefit. Reducing macrovascular risk in patients with diabetes thus
takes a more comprehensive approach than just glycemic control. In a trial of
multiple risk factor control in Type 2 diabetes, the STENO-2 trial found a significant
53% reduction in macrovascular events with modest control of hypertension,
dyslipidemia, and glycemia simultaneously.
36 Control of all major CVD risk factors
is highlighted by the ADA for its importance in reducing macrovascular disease
37 See Table 53-5 for the metabolic goals for adults with diabetes.
Goals of Physiologic (Basal-Bolus) Insulin Therapy
Premeals 80–130 90–130 90–130 60–99
Absent to rare Absent to rare Rare
therapeutic program of diabetes management and requires a team approach.
Complications Trial (DCCT)-based assay.
microvascular or macrovascular complications, or other complicating features (Table 53-10).
dDoes not apply to type 2 diabetes patients.
Three trials published in 2008 and 2009 have raised new questions about tight
glycemic control in patients with Type 2 diabetes. In the Action to Control
Cardiovascular Risk in Diabetes (ACCORD) trial, a higher rate of mortality was
seen in the intensive treatment arm, which achieved an A1C of 6.4% compared with
the standard arm, which achieved 7.5%.
40 The ACCORD study was a National Heart,
Lung, and Blood Institute study of more than 10,000 patients with Type 2 diabetes
with known heart disease or multiple cardiovascular risk factors. The intensively
treated group had an excess of 3 deaths per 1,000 participants per year compared
with the standard group during an average of 4 years on treatment (257 vs. 203
deaths). The higher mortality rate was not attributable to a specific drug therapy or to
41 A second trial, the Action in Diabetes and Vascular Disease
a Controlled Evaluation (ADVANCE), was an even larger study of more than 11,000
patients, which had different findings from ACCORD. In ADVANCE, there was an
insignificant trend for reduced cardiovascular mortality and reduced overall
mortality with tight glycemic control (A1C of 6.3% compared with 7.0%).
in the smaller Veterans Affairs Diabetes Trial (VADT), nearly 2,000 patients were
studied and found to have an insignificant 12% relative risk reduction in
macrovascular end points but a 7% relative increase in overall mortality (95 vs. 102
deaths). Neither finding was statistically significant.
43 After approximately 10-year
follow-up to the VADT trial, the study found 1 fewer cardiovascular event/116
person-years without a reduction in mortality. The intensive arm of this study had a
In the face of these new data, the ADA, along with the American Heart Association
(AHA) and the American College of Cardiology (ACC), issued a position statement
45 Although acknowledging the findings of the ACCORD trial, the persistent
trend for reductions in macrovascular events in all three trials was found to be
reassuring. The position of the committee (which continues to be the official position
of the ADA in the 2015 guidelines) is that although intensive glycemic control did not
improve macrovascular outcomes, a goal of less than 7% is still reasonable based on
microvascular benefits and a clear lack of harm across the trials of intensive versus
38 However, the ADA does acknowledge that there is room
to individualize the A1C goal and that achieving an A1C of less than 7% has limited
macrovascular benefit compared with A1C values of 7% to 8%. Patients with Type 2
diabetes and CVD or multiple risk factors for CVD should discuss their treatment
goals with their providers. In these patients, a less intensive goal may be appropriate,
particularly for patients who have difficulty achieving the goal of less than 7%.
American Diabetes Association Metabolic Goals for Adults with Diabetes
Preprandial plasma glucose 80–130 mg/dL (3.9–7.2 mmol/L)
Postprandial plasma glucose <180 mg/dL (<10.0 mmol/L)
Blood pressure <140/90 mm Hg (Refer to Essential Hypertension
Lipids Refer to Lipid Chapter 8
Questions 1–4, for broader discussion.
Endocrinologists/American College of Endocrinology recommends A1C goal of ≤6.5%.
PREVENTION OF TYPE 1 AND TYPE 2 DIABETES
Because the clinical symptoms of Type 1 diabetes mellitus are the overt expression
of an insidious pathogenic process that begins years earlier, investigators are
focusing attention on strategies that alter the natural history of the disease (Fig. 53-1).
First-degree relatives of individuals with Type 1 diabetes mellitus have an increased
risk for developing the diabetes and can be identified by the presence of immune
markers that may herald the disease by many years.
11 This has led to attempts at
immune intervention at the prediabetes stage (primary prevention) or after the
development of islet antibodies (secondary prevention). Most immunotherapy trials
are tertiary prevention after diagnosis of Type 1 diabetes. Results have not been
extraordinary, but will areas of future study. For primary prevention, vaccines, and
secondary prevention, immunomodulatory agents will continue to be an area of
46 The Diabetes Prevention Program Research Group studied a diverse
group of 3,234 individuals at high risk for developing diabetes to determine whether
lifestyle interventions or metformin (850 mg by mouth [PO] twice a day [BID])
would prevent or delay the onset of Type 2 diabetes.
47 After 3 years, the incidence of
diabetes was reduced by 58% and 31% in the intensive lifestyle and metformin
groups, respectively, compared with the control group. Diabetes incidence during 10
years of follow-up was persistently lower in the groups originally treated with
lifestyle (34% reduction) and metformin (18% reduction) interventions compared
48 Other studies have confirmed the value of lifestyle
intervention and other drugs (acarbose, orlistat, and various thiazolidinediones
(TZDs)) in the prevention of Type 2 diabetes, but the strongest evidence is with
49 Lifelong medication therapy, however, is not without its own risks and
complications. Current recommendations regarding the treatment for individuals with
prediabetes include lifestyle modification (5%–10% weight loss and 150
minutes/week of moderately intense physical activity).
effective than lifestyle changes, can be considered for very high-risk individuals.
QUESTION 1: R.P. is a 43-year-old African-American woman visiting a primary-care clinic to obtain a
) and blood pressure (BP) 145/85 mm Hg. R.P. denies any symptoms of polyphagia,
with an increased risk of developing Type 2 diabetes?
The features of R.P.’s history that are consistent with an increased risk of
developing Type 2 diabetes include her age, ethnicity, weight, family history of
diabetes, history of GDM, and a documented IFG. In addition, Type 2 diabetes is
also often associated with other disorders such as hypertension. The fact that R.P. has
hypertension that is not well controlled and has a family history of hypertension and
CVD may indicate that she is predisposed to insulin resistance, further putting her at
risk for developing Type 2 diabetes.
CASE 53-1, QUESTION 2: The physician orders an A1C for R.P., which comes back at 6.1%. How should
Both the A1C and FPG values are in the prediabetes range. R.P. should be
educated about her risk for developing Type 2 diabetes. Working with her healthcare
providers, R.P. should be encouraged and educated on how to institute lifestyle
modifications (MNT, physical activity) that will help her to lose weight, improve her
cardiovascular health, and decrease her risk for developing Type 2 diabetes. A
weight-loss goal of 5% to 10% during the next 6 to 12 months should be
recommended, and she should increase her level of moderate physical activity to at
least 150 minutes/week. Her hypertension should be managed. At this time, the use of
pharmacologic agents (i.e., metformin) to prevent the development of Type 2
There are three major components to the treatment of diabetes: diet, drugs (insulin
and antidiabetic agents [oral and injectable]), and exercise. Each of these
components interacts with the others to the extent that no assessment and modification
of one can be made without knowledge of the other two.
MNT plays a crucial role in the therapy of all individuals with diabetes.
Unfortunately, patient acceptance and adherence to diet and meal planning are often
poor, but revised evidence-based recommendations that are more flexible than
previous approaches offer new opportunities to increase the effectiveness of nutrition
Nutrition therapy is designed to help patients achieve appropriate metabolic and
physiologic goals (e.g., glucose, lipids, BP, proteinuria, weight), select healthy
foods, and take into consideration personal and cultural preferences. Appropriate
levels and types of physical activity to achieve a healthier status are incorporated
NUTRITION THERAPY AND TYPE 1 DIABETES MELLITUS
For patients with Type 1 diabetes taking fixed doses of insulin, a meal plan is
designed to provide adequate carbohydrates timed to match the peak action of
exogenously administered mealtime insulin. Regularly scheduled meals and snacks
should contain consistent carbohydrate amounts, which are required to prevent
hypoglycemic reactions. Fortunately, newer insulins and insulin regimens provide
much more flexibility in the amount and timing of food intake. Patients who are taught
to count carbohydrates can inject rapid- or short-acting insulin doses designed to
match their anticipated intake. Integration of food intake, physical activity, and
insulin dose is critical and discussed extensively in the cases that follow.
NUTRITION THERAPY AND TYPE 2 DIABETES MELLITUS
For patients with Type 2 diabetes, meal plans emphasize normalizing plasma glucose
and lipid levels as well as maintaining a normal BP to prevent or mitigate
cardiovascular morbidity. Although weight loss reduces insulin resistance and
improves glycemic control, traditional dietary strategies incorporating hypocaloric
diets have not been effective in achieving long-term weight loss. A sustainable
weight loss can be achieved within structured programs that emphasize lifestyle
changes, physical activity, and food intake that modestly reduces caloric and fat
MNT is an integral and critical component of diabetes care. For a more extensive
discussion of the principles underlying nutrition therapy, the reader is directed to
51–53 A few key principles are briefly noted below because they are
common sources of misunderstanding.
Carbohydrates and Artificial Sweeteners
Carbohydrates include sugar (sucrose), starch, and fiber and are liberally
incorporated into the diet of a person with diabetes. In fact, the amount of dietary
carbohydrate is the main determinant of insulin demand and is commonly used to
determine the premeal insulin dose. Furthermore, patients using fixed doses of insulin
or antihyperglycemic medications (e.g., sulfonylureas) must eat meals containing
consistent amounts of carbohydrate to avoid hypoglycemia. Because isocaloric
amounts of sucrose and starch produce the same degree of glycemia, sucrose can be
substituted for a portion of the total carbohydrate intake and should be incorporated
into an otherwise healthful diet.
Whole grains, fruits, and vegetables high in fiber are recommended for people
with diabetes, because they are for the general population. There is no evidence that
larger amounts produce a differential metabolic benefit with regard to plasma
glucose and lipid levels. Nonnutritive sweeteners (saccharin, aspartame, neotame,
acesulfame potassium, sucralose) and sugar alcohols have been rigorously tested by
the US Food and Drug Administration (FDA) for safety in people with diabetes and
are safe at approved daily intakes. Fructose and the reduced-calorie sweeteners
called sugar alcohols produce lower postprandial glucose responses than sucrose,
glucose, and starch. When sugar alcohols (e.g., sorbitol, mannitol, lactitol, xylitol,
and maltitol) are consumed, it is recommended to subtract half of their grams from
the total carbohydrate amount because their effect on BG is less. Patients should be
advised that when these sweeteners are used in foods labeled “dietetic” or “sugar
free,” they still add to the carbohydrate content and provide substantial calories (2
cal/g). Furthermore, excessive intake of sorbitol-sweetened foods (e.g., 30–50 g/day)
can induce an osmotic diarrhea, and excessive amounts of fructose can increase total
When patients are taught to estimate the grams of carbohydrate in a meal, they are
given the following guideline: One carbohydrate serving = 1 starch or 1 fruit or 1 cup
milk = 15 g carbohydrate. Patients vary with regard to their insulin-to-carbohydrate
ratio throughout time and throughout the day; however, a typical starting point is 1
CVD is a major cause of morbidity and mortality in patients with diabetes.
Therefore, saturated fats should be limited to less than 7% of calories. The intake of
trans fat should also be minimized. The recommended cholesterol intake is less than
200 mg/day for patients with diabetes. Two or more servings/week of fish to provide
n-3 polyunsaturated fatty acids and omega-3 fatty acids are advised.
Data are insufficient to support special dietary protein recommendations for persons
with diabetes if kidney function is normal. Generally, 15% to 20% of the daily
caloric intake comes from animal and vegetable protein sources in the US diet. This
amount may be liberalized in pregnant and lactating women or in elderly people.
With the onset of nephropathy, a lower protein intake of 0.8 to 1.0 g/kg/day is
considered sufficiently restrictive. For patients in later stages of nephropathy,
reduction of protein intake to 0.8 g/kg/day is recommended. High-protein diets are
not recommended as a long-term method for weight loss, because the effects on
kidney function are not known.
The ADA recommends a reduced sodium intake of less than 2,300 mg/day in
normotensive and hypertensive individuals. For patients with diabetes and
symptomatic heart failure (HF), sodium should be further restricted to less than 2,000
mg/day to help reduce symptoms. For all other patients, the ADA has no particular
restrictions on sodium intake, but recommends individualizing amounts based on the
patient’s sensitivity to salt and concurrent conditions such as hypertension or
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