Diagnosis and Management of Type 2 Diabetes Mellitus

©Stephen D. Sisson MD/Ambulatory Curriculum

2023

Objectives
At the completion of this module, the majority of housestaff will rate their knowledge as "good" or better on
the following subjects:

1. Diagnostic criteria for type 2 diabetes mellitus.

2. Diagnostic criteria for increased risk of diabetes
3. Issues related to screening for diabetes.
4. The role of diet, weight loss, exercise and pharmacotherapy in the prevention of diabetes.
5. Pharmacologic options for management of type 2 diabetes mellitus.
6. Algorithms for pharmacotherapy of diabetes
7. Role of glycemic control and blood pressure control in microvascular and macrovascular
complications of diabetes.
a. The results from major clinical studies (e.g., DCCT, UKPDS, Steno-2) that guide management
of diabetes.

Section 1: Diagnosing type 2 diabetes

Your first patient in clinic is Fred Banting, a 52-year-old male with hypertension treated with lisinopril. He
complains of fatigue. When you ask further, he states that he is not sleeping well because he wakes up frequently
to urinate. He blames this on drinking a lot of water, but states that if he does not, he is always thirsty. His past
medical history is otherwise unremarkable.

On exam, he is afebrile; blood pressure is 124/76. He weighs 212 pounds (down 12 pounds over the past two
months). BMI is 31kg/m2. There are no orthostatic changes in his pulse or blood pressure, and the remainder of
the physical exam is unremarkable.

Which ONE of the following statements is correct?

A. A fasting plasma glucose > 100 mg/dl would be sufficient to diagnose Mr. Banting with diabetes.
B. A random plasma glucose > 140mg/dl would be sufficient to diagnose Mr. Banting with diabetes.
 C. A random plasma glucose >200mg/dl would be sufficient to diagnose Mr. Banting with diabetes.
D. A hemoglobin A1C of 7.5 or greater is now used to diagnose individuals with diabetes.

Pop Up Answers
A. Incorrect. This cut-off for diagnosing diabetes is too low to use to diagnose an individual with
diabetes. Plasma glucose levels in this range may represent glucose intolerance; fasting glucose
between 100-126mg/dl represents impaired fasting glucose (IFG).
B. Incorrect. This cut-off for random plasma glucose is too low to diagnose him with diabetes.
C. Correct. This patient has symptoms of diabetes and therefore random plasma glucose >200mg/dl
would be sufficient to diagnose him with diabetes.
D. Incorrect. A hemoglobin A1C of 6.5 or greater is used to diagnose diabetes.

Summary Answer
The correct answer is C: A random plasma glucose >200mg/dl would be sufficient to diagnose Mr. Banting with
diabetes.

Introduction
The reason to diagnose a patient with diabetes is to initiate the process of care that will result in improved
glycemic control and the prevention of complications of persistent hyperglycemia. In addition, the diagnosis of
diabetes will affect blood pressure treatment and cholesterol management, and prompt monitoring for
diabetes-specific complications.

The approach to diagnosing a patient with type 2 diabetes depends on appropriate historical details (symptoms
such as polyuria, polydipsia, polyphagia, weight loss) and laboratory evaluation (e.g., hemoglobin A1C testing,
fasting glucose levels and/or glucose tolerance tests). The good news is that patients with T2DM who have
glucose, lipids, blood pressure, tobacco, and albuminuria controlled do not have excess mortality when
compared to the general population. This should be the goal with every patient with diabetes you treat.

This module reviews diagnosis and management of type 2 diabetes (T2DM) according to the American Diabetes
Association (ADA) 2022 guidelines. Unless otherwise noted, use of the term 'diabetes' in this module refers to
'type 2 diabetes'.

Options for evaluating a patient's glucose

The clinician has several options to evaluate a patient's glucose, including fasting plasma glucose, random
glucose, glycosylated hemoglobin levels, oral glucose tolerance testing, or urine dipstick for glucose.
Fasting plasma glucose
Fasting plasma glucose (FPG) is defined as no caloric intake for 8 hours, and is a commonly used test to diagnose
diabetes. The FPG has its advantages; ease of use, acceptability to patients, and lower cost relative to other
tests. A patient with FPG >126mg/dl and symptoms of diabetes can be diagnosed with diabetes. Asymptomatic
patients require additional testing, discussed below.

Random plasma glucose

Random glucose levels are most useful in evaluating the patient with symptoms suggestive of hyperglycemia
(i.e., polyuria; polydipsia). While used to diagnose diabetes, random glucose levels vary according to recent food
intake, and therefore lack reproducibility. A patient with symptoms of diabetes and a random plasma glucose
>200mg/dl can be diagnosed with diabetes. Asymptomatic patients require additional testing, discussed below.

Glycosylated hemoglobin
The A1C represents the pathologic process of persistent hyperglycemia that is associated with the microvascular
complications of diabetes (i.e., protein glycosylation). A1C levels correlate more strongly with retinopathy than
do FPG levels, and avoid the daily fluctuations inherent in a single test such as the FPG. When using the A1C to
diagnose diabetes, a result of 6.5% or greater (either in the presence of unequivocal symptoms of hyperglycemia,
or in conjunction with an elevated FPG or random plasma glucose) is used to diagnose diabetes.

An A1C of 5.7 % to 6.4% defines prediabetes. As with other tests, unless unequivocal signs or symptoms of
hyperglycemia are present, this test should be repeated on a separate occasion to make the diagnosis of
diabetes. Point of care A1C testing is not considered sufficiently accurate to use in diagnosing a patient with
diabetes.

Individuals with hemoglobinopathies (e.g., sickle cell trait and anemia) and with high RBC turnover (e.g.,
hemolytic anemia; blood loss; G6PD deficiency; hemodialysis) should have tests other than the A1C used to
diagnose diabetes. Medical conditions with low RBC production (e.g., iron deficiency anemia) will elevate A1C
levels. HIV also alters A1C results.

Oral glucose tolerance test

With the oral glucose tolerance test, a patient is given a 75g oral load of glucose; if plasma glucose is >200mg/dl
two hours later, those findings are consistent with diabetes. As with other tests used to diagnose diabetes, it
should be repeated when used to diagnose diabetes (unless the person has unequivocal symptoms of diabetes).
While this test is still in use clinically (primarily for the diagnosis of gestational diabetes), it is cumbersome, time-
intensive, and less reproducible than the FPG.

Urine glucose
The urine dipstick test for glucose has no role in the diagnosis of diabetes, due to its low sensitivity and
reproducibility. A urine dipstick obtained for other reasons should prompt further evaluation of the patient if
glycosuria is noted.

Current diagnostic criteria for diabetes

Summarizing the above, FPG, random plasma glucose, A1C, or oral glucose tolerance testing can be used to
diagnose T2DM. A single test result should not be used to diagnose diabetes, unless unequivocal symptoms of
diabetes are present. Two tests, either different tests from the same sample, or on different days, should be
used to diagnose diabetes. The random plasma glucose is less reproducible, so the other options are favored.

Table 1 reviews current diagnostic criteria for type 2 diabetes

Table 1: Diagnostic criteria for type 2 diabetes

When confirming the suspected diagnosis of diabetes, the confirming test may be done from the same or
different samples. If there is discrepancy between the A1C, FPG, or oral glucose tolerance test, the FPG and oral
GTT are considered more accurate.

Prediabetes
Individuals with borderline, but not diagnostic, results of diagnostic tests for diabetes are at increased risk of
developing diabetes. These patients may have impaired fasting glucose, impaired glucose tolerance, or a
borderline A1C result. Although not diagnosed with diabetes, these individuals have increased risk for the
development of diabetes and cardiovascular disease, and warrant lifestyle modification and closer follow up.

Table 2: Categories of increased risk of diabetes/Prediabetes

Note that patients with normal glucose (or even normal A1C) are not free from risk of developing diabetes. A
cohort of young men followed for an average of almost 6 years showed that those with the risk of developing
diabetes increased with increasing glucose, even for those with a normal glucose.

Remission of diabetes
Many patients will be highly motivated to lose weight and engage in lifestyle modification once diagnosed with
T2DM and started on pharmacotherapy. Once glycemic control is consistently outstanding, you may taper and
even discontinue pharmacotherapy. In such cases, T2DM is considered to be in remission when the A1C is < 6.5
three months after discontinuation of pharmacotherapy. Diet and lifestyle should still be monitored, and A1C
should be checked no less than yearly. If weight gain is noted, or lifestyle deteriorates, more frequent A1C
monitoring is indicated.

Diabetes variants
Most diabetic American adults (90%) have type 2 diabetes, characterized by insulin resistance and compensatory
hyperinsulinemia. Even though insulin levels are elevated, they are elevated inadequately relative to the level
of hyperglycemia. Insulin resistance in peripheral tissues is also present.

The next most common category of diabetes (5-7% of individuals with diabetes) is type 1 diabetes, characterized
by islet cell failure, insulinopenia, and ketosis, and is due to autoimmune destruction of beta cells. The peak age
of incidence for type 1 diabetes is the early-teens, but it may occur at older ages as well. All individuals with type
1 diabetes require insulin to remain healthy, but not all individuals on insulin have type 1 diabetes.

Some classify type 1 and type 2 diabetes as "primary" types of diabetes mellitus. There are other disease states
that also may result in diabetes mellitus, which some classify as "secondary" diabetes. Chronic pancreatitis or
pancreatectomy induces diabetes with many clinical features of type 1 diabetes, except for the lack of an
autoimmune component. Corticosteroid use induces diabetes with many clinical features of type 2 diabetes. At
the initial encounter, the physician should consider these and other causes of secondary diabetes mellitus, such
as Cushing syndrome, hemochromatosis, acromegaly, pheochromocytoma, and glucagonoma.

MODY and LADA

MODY is a syndrome in which a relatively young individual presents with hyperglycemia, but is relatively
unlikely to develop ketosis. In other words, this individual is young, presenting at an age in which type 1
diabetes is predominant, but with clinical characteristics of type 2 diabetes. Termed Maturity-Onset Diabetes
of the Young (MODY), it is an autosomal dominant disorder that is the most common monogenic syndrome
associated with diabetes (the defect is on the short arm of chromosome 7 in the glucokinase gene).

LADA (latent autoimmune diabetes of adults) is present in individuals with autoimmune destruction of beta cells
(as seen in type 1 diabetes), but presenting at a later age (i.e., age > 25). Clinical presentation is often slowly
progressive (often leading the clinician to diagnose type 2 diabetes), but anti-islet antibodies (anti-GAD 65
antibodies) will be present, C-peptide levels will be low, and insulin resistance is not seen. These patients will
need treatment with insulin.

Section 2: Screening
Your next patient is Charlene Best, a 48-year-old Native American woman, who comes in for follow up of
hypertension. She is otherwise healthy. Several family members have type 2 diabetes. She does not smoke, she
does not drink, and review of systems is notable only for a sedentary lifestyle. She is entirely without symptoms.

Ms. Best is concerned about diabetes, and asks if she should be screened. She also wants to tell her sister with
diabetes to make sure she gets the best screening for damage from diabetes. Which ONE of the following is
true?

A. Patients with diabetes should have a spot urine albumin to creatinine ratio checked every 3-5 years to
screen for renal damage from diabetes.
B. The American Diabetes Association and US Preventive Services Task Force recommend that all
individuals over the age of 50 should be screened annually for diabetes.
C. Carotid ultrasound should be obtained annually on all individuals with diabetes to screen for
cerebrovascular disease.
D. Predictors associated with an increased risk for developing diabetes include dyslipidemia, hypertension,
 and BMI > 25kg/m2.

Pop Up Answers
A. Incorrect. Spot urine albumin-to-creatinine ratios should be checked annually on all patients with
diabetes. Normal is <30.
B. Incorrect. While the ADA recommends screening the general population age 35 and over every 3 years
for diabetes, only individuals at increased risk of developing diabetes should be screening more
frequently.
C. Incorrect. There is no scientific evidence that screening carotid ultrasound is of benefit in individuals
with diabetes.
D. Correct. Low HDL-cholesterol or elevated triglycerides, hypertension, and overweight are among the
predictors associated with a higher risk of developing diabetes.

Summary answer
The correct answer is D: Predictors associated with an increased risk for developing diabetes include
dyslipidemia, hypertension, and BMI > 25kg/m2.

Screening for diabetes

With criteria for the diagnosis of diabetes in place, the question then becomes whether or not to screen
asymptomatic individuals for diabetes. Unfortunately, there is no evidence that screening for type 2 diabetes
improves mortality. (Type 1 diabetes has an acute onset, and is not included in discussions about screening.)
Issues in the debate over whether or not to screen include defining the population to screen, the frequency of
screening, and which test should be used (fasting vs. non-fasting glucose; urine glucose; oral glucose tolerance
testing; hemoglobin A1C).

Screening for gestational diabetes mellitus and screening of adolescents is beyond the scope of this module.

Two opinions on screening: The American Diabetes Association and the US Preventive Services Task Force
Both the American Diabetes Association (ADA) and US Preventive Services Task Force (USPSTF) note that no
clinical trials have been performed demonstrating the cost effectiveness of screening for type 2 diabetes. In fact,
screening for diabetes does not reduce mortality rates even after 10 years of follow up.

The ADA's expert opinion suggests screening the general population for type 2 diabetes at least every 3 years,
beginning at age 35. They also recommend screening all adults with HIV for T2DM. The ADA also recommends
screening adults at any age if their BMI is greater than 25kg/m2 (or >23kg/m2 in those of Asian descent) and they
have at least one additional risk factor for diabetes, including:

 Physical inactivity
 Hypertension
 First-degree relative with diabetes
 High-risk populations: African-American; Native American; Latino; Asian American; Pacific Islander
 Low HDL-cholesterol (<35mg/dl) or high triglyceride (>250mg/dl) levels
 History of gestational DM
 Polycystic ovary syndrome
 Other evidence of insulin resistance (i.e., acanthosis nigricans; severe obesity)
 History of vascular disease
 A1C>5.7, impaired fasting glucose or impaired glucose tolerance

The USPSTF has more focused recommendations on screening for type 2 diabetes: screen all adults 35 – 70 with
BMI >25kg/m2 for diabetes. The USPSTF suggests screening every 3 years. If a diagnosis of prediabetes or
diabetes is suggested, repeat testing should be used to confirm the diagnosis. The hemoglobin A1C is suggested
as the most convenient test for screening, but fasting plasma glucose and the oral glucose tolerance test are also
accepted. Note they leave out the random plasma glucose as an option.

We summarize recommendations for screening in the table below.

Table 3: Two opinions on screening for type 2 diabetes

Screening for cardiovascular risk and diabetes-related complications

Diabetes is associated with many important complications that significantly affect morbidity and mortality.
These complications may be divided into microvascular complications (i.e., nephropathy, retinopathy, and
neuropathy) and macrovascular complications (i.e., myocardial infarction; stroke; peripheral vascular disease).
These are discussed in detail later in this module. The ADA has established guidelines for screening of
microvascular and macrovascular complications in the patient with diabetes, which are summarized in Table 4.

To ensure glycemic control, hemoglobin A1C testing should be done twice a year in individuals who have stable
glucose control and quarterly on those for whom therapy has changed or who are not at goal.
Table 4: Screening for DM-associated morbidity

Liver enzymes should be checked when T2DM is diagnosed, to screen for fatty liver disease.

The ADA recommends low-dose aspirin for the primary prevention of coronary artery disease in patients with
type 2 diabetes who have increased cardiovascular risk (i.e., 10-year risk of MI of >10%, which includes most
patients with diabetes 50 or older who have at least one additional major cardiovascular risk). US Preventive
Services Task Force guidelines recommend against aspirin for primary prevention of CAD in all individuals 60 and
older.

Section 3: Prevention of diabetes

You have finished examining Ms. Best. Recent blood work showed fasting plasma glucose of 118mg/dl. Other
blood work shows total cholesterol of 212, HDL 67, LDL 125, and triglycerides 100. Reviewing blood work over
the past 18 months reveals several random glucose levels between 130-150mg/dl, and an A1C of 6.1%. Asking
additional questions, she denies polyuria or polydipsia.
Which ONE of the following would be appropriate advice to the patient?

A. Pharmacotherapy is superior to lifestyle modification for the prevention of diabetes in those at risk.
B. The single most important modifiable risk factor to prevent the onset of diabetes is to change to a low-
fiber, low concentrated sweets diet.
C. A patient for whom testing has shown increased risk of diabetes and a positive family history of diabetes
will be unable to delay diabetes.
D. Modest weight reduction (4-5 kg) alone can significantly reduce the risk of developing diabetes.

Pop Up Answers
A. Incorrect. Lifestyle modification is superior to pharmacotherapy for the prevention of diabetes, and
provides cardiovascular benefit.
B. Incorrect. Weight loss is the single most important modifiable risk factor used to prevent diabetes. A
high fiber diet should be recommended to all patients at risk for the development of diabetes.
C. Incorrect. Exercise and weight loss can decrease the risk of developing diabetes by greater than 50%,
even in those with a positive family history of diabetes.
D. Correct. Many overestimate the weight loss needed to prevent the development of diabetes.

Summary answer
The correct answer is D: Modest weight reduction (4-5kg) alone can significantly reduce the risk of developing
diabetes.

Prevention of diabetes
In this section, we review risk factors for progression to type 2 diabetes and studies to prevent progression to
type 2 diabetes. The two areas of study to prevent progression to type 2 diabetes have centered on the role of
lifestyle modification (i.e., diet, exercise, weight reduction) or pharmacotherapy in the prevention of diabetes.

The most important risk factor associated with the development of diabetes is obesity. The risk of diabetes
increases with increasing BMI, even in the normal range. Other factors associated with an increased risk of
developing diabetes are lack of exercise, regardless of BMI, and cigarette smoking. A diet rich in fiber and
polyunsaturated fat that is low in saturated fats and concentrated sweets is associated with a reduced risk of
developing diabetes, as is moderate alcohol intake.

Lifestyle modification and the prevention of diabetes

The impact of improving physical activity and weight loss on the development of diabetes has been prospectively
studied in an interventional trial in Finland. They studied whether intervention in physical activity and weight
lowered the risk of developing diabetes in those at increased risk. They found that losing an average of 4.2kg
and exercising reduced the risk of developing diabetes by 58%. Those that lost weight but did not exercise, and
those that exercised but did not lose weight, also had significant reductions in the development of diabetes. This
study, and others like it, have shown that we can dramatically reduce the risk of developing diabetes in patients
at risk with lifestyle intervention (i.e., weight loss, or exercise, or both).

Pharmacotherapy and the prevention of diabetes

The Diabetes Prevention Program was a major study that looked at pharmacotherapy on the risk of developing
diabetes. In this study, individuals with prediabetes were randomized to treatment with metformin (850mg
twice daily), or lifestyle intervention, or placebo. Compared to placebo, metformin reduced the incidence of
diabetes by 31%. These results tell us that pharmacotherapy with metformin can prevent diabetes, although
critics state metformin is merely treating diabetes rather than preventing it. However, lifestyle intervention was
nearly twice as effective, reducing the incidence of diabetes by 58%.

It is important to remember than while pharmacotherapy may be of use in individuals at risk for diabetes who
cannot participate in lifestyle modification, lifestyle modification will also impact the risk for developing
hypertension and other cardiovascular risk (benefits that may not be seen with pharmacotherapy), and should
be included in those in whom pharmacotherapy is chosen to prevent diabetes.

In sum, and based in part on the trials mentioned above, the ADA makes the following recommendations for
those at greatest risk of developing diabetes:
 Patients at increased risk of developing diabetes should have goal weight loss of 5-10% and increase
physical activity to 150 minutes a week, delivered through a lifestyle counseling program with follow up
visits
 In addition to lifestyle counseling, metformin may be considered in those aged 25-59 with prediabetes,
especially those with BMI > 35kg/m2, A1C > 6.0, or FPG > 110mg/dl.
 The ADA does not recommend use of drugs other than metformin to prevent diabetes, due to expense,
risk of side effects, and lack of long term efficacy
Section 4: Treatment options for type 2 diabetes: diet
A 54-year-old man is diagnosed with T2DM after presenting with polyuria, polydipsia, and weight loss. Past
history is notable for sedentary lifestyle, hypertension, and elevated cholesterol. Medications are lisinopril,
HCTZ, and simvastatin. On physical exam, blood pressure is 122/76. His BMI is 31kg/m 2. He mentions that his
morning he ate an egg, sausage, scrapple, and bacon sandwich, washing it down with fruit punch. Which one of
the following dietary recommendations is true?

A. His breakfast sandwich was full of protein, and thus is acceptable in patients with diabetes.
B. The fruit punch is high in carbohydrates; he should eliminate carbohydrates from his diet.
C. He should be advised to eat more fatty foods such as salmon and almonds.
D. Because of its effects on the glucose metabolism, he should not drink alcoholic beverages.

Pop Up Answers
A. Incorrect! Although his breakfast sandwich does have protein, it is also full of fat and saturated fat.
Saturated fat is not considered part of a healthful diet.
B. Incorrect! Patients with diabetes should avoid simple sugars, replacing them with complex
carbohydrates as in whole grains, vegetables, fruit and legumes.
C. Correct! A diet rich in healthy fats (i.e., omega-3 fatty acids and unsaturated fat), such as seen in salmon
and nuts, should be recommended.
D. Incorrect! Alcohol can result in delayed hypoglycemia (especially in those taking insulin), but otherwise
alcohol is not absolutely contraindicated in patients with diabetes.

Summary answer
The correct answer is C: He should be advised to eat more fatty foods such as salmon and almonds.

Introduction
In this section, we address the essential role of diet in managing type 2 diabetes. Diet (sometimes referred to as
'medical nutrition therapy', or MNT) can reduce A1C levels by as much as 2% in adherent patients. Even a 5%
reduction in weight can significantly improve glycemic control. Counseling by a nutritionist is recommended for
all patients with diabetes. As dietary changes are addressed, physical exercise should also be recommended. The
most recent nutrition guidelines from the ADA are available here.

Dietary recommendations for individuals with type 2 diabetes

Before discussing pharmacotherapy, the role of proper diet, body weight and exercise should all be discussed
with every patient with diabetes at every visit (including after pharmacotherapy has been initiated). The initial
diagnosis of diabetes should ideally prompt a referral to a nutritionist. The patient's weight should be checked
every visit and discussed between you and your patient. Patients with overweight/obesity should use diet,
physical activity, and behavioral therapy to achieve and maintain at least a 5% reduction in weight. Education
should also include discussion of the risk of complications of diabetes. Patients can be referred to the official
web site of the American Diabetes Association (www.diabetes.org), which has patient-friendly information on
diet, exercise and other areas of concern.

Patients with diabetes should be kept up to date on tetanus boosters, influenza vaccination, hepatitis B
vaccination and pneumococcal vaccination.

Simply cutting daily total caloric intake is beneficial in controlling blood sugar. Caloric restriction can drop serum
glucose levels within a few days, even before weight loss has occurred.

When considering macronutrients (i.e., carbohydrates, fats, protein), there is no single best mix of nutrients for
all patients with diabetes. More important than the type of nutrient is weight reduction in those who are
overweight or obese. You should have an individualized discussion of diet with every patient with diabetes based
on recommendations listed in the table below.
Table 5: Basic nutrition recommendations for individuals with diabetes

Exercise
In addition to dietary changes, patients with type 2 diabetes should engage in exercise. One study showed that
those engaging in aerobic and resistance training were able to reduce hemoglobin A1C levels by 0.5% compared
to controls that did not exercise. The ADA recommends at least 150 minutes of moderate-intensity
cardiovascular exercise weekly, spread over 3 days/week, with no more than two consecutive days without
exercise. Resistance training twice weekly should also be encouraged.

Unfortunately, there is some evidence that lifestyle changes (i.e., weight loss and exercise) do not reduce
cardiovascular outcomes in patients with diabetes

Section 5: Glycemic treatment goals

A 54-year-old woman with a 12-year history of type 2 diabetes presents for follow up. Past medical history
includes gout, treated with indomethacin during flares. She is taking metformin and irbesartan. She does not
smoke, does not drink, and lives alone. Review of systems is notable for menopause last year.
On exam, her BMI is 32.6kg/m2. Her blood pressure is 164/98 mmHg; numerous microaneurysms in both fundi
and new vessel growth adjacent to the right optic disc are noted, as well as absent dorsalis pedis pulses
bilaterally. Diminished light touch sensation is noted in both feet. The remainder of the exam is unremarkable.
Laboratory examination reveals A1C 10.2%, and 1+ urine protein on dipstick. Creatinine is 1.5mg/dl.

Which ONE of the following goals of therapy in patients with diabetes is correct?

A. This patient will benefit more from lowering her A1C from 10% to 8%, rather than from 8% to 6%.
B. Patients with long-standing diabetes are more likely to have macrovascular complications reduced by
normalizing A1C levels.
C. Patients with new-onset diabetes should have A1C levels treated to 8%, with more aggressive goals (e.g.,
normalizing A1C levels) after 10 years of treatment.
D. Both microvascular and macrovascular complications are decreased by lowering A1C values to near-
normal levels.

Pop Up Answers
A. Correct! The benefits from bringing poorly controlled diabetes to fair control are greater than in bringing
a fair-controlled diabetic to normal levels. There are benefits to bringing the A1C to levels below 8%, but
the risk of hypoglycemia increases, and the benefits seen are less impressive.
B. Incorrect. Studies suggest that the risk of macrovascular complications (especially MI) is increased when
normalizing A1C levels in patients with long-standing diabetes.
C. Incorrect. If any population is to benefit from tight glycemic control, it is those patients with new-onset
diabetes and the absence of complications.
D. Incorrect. While "tight" glycemic control has been shown to reduce microvascular complications, the
benefits on macrovascular complications is less clear, and the risk of cardiac death (a macrovascular
complication) increases with near-normalization of A1C levels.

Summary answer
The correct answer is A: This patient will benefit more from lowering her A1C from 10% to 8%, rather than
from 8% to 6%.

Introduction
The remainder of this module is going to focus on pharmacologic treatment of type 2 diabetes. The hemoglobin
A1C is used as the target of treatment in diabetes, and has the most evidence of its predictive value on
complications for diabetes. Self-monitoring of blood glucose (SMBG) is useful in adjusting pharmacotherapy in
patients treated with insulin, but evidence of its use in predicting and preventing complications of diabetes is
less extensive than for using A1C values to direct treatment. SMBG has no proven value in patients treated
exclusively with oral hypoglycemics. In the American Board of Internal Medicine's Choosing Wisely campaign,
the American Academy of Family Physicians states:

 Don't routinely recommend daily home glucose monitoring for patients who have Type 2 diabetes
mellitus and are not using insulin.

Treatment of type 2 diabetes

We start here with review of the key issues in choosing targets of glycemic control. In later sections, we review
treatment algorithms in diabetes. As we discuss treatment of diabetes and diabetic complications, the good
news is that over the past two decades complications of diabetes have declined dramatically, offset in part by
the increased prevalence of diabetes seen with the obesity epidemic.

Issue 1: Does "tight" glycemic control reduce microvascular or macrovascular complications?

The first evidence that tight glycemic control in patients with diabetes reduced the complications of diabetes
came from the landmark Diabetes Control and Complications Trial (DCCT). DCCT looked at 1441 patients with
type 1 diabetes, and compared those treated with usual care (usually with one or two insulin injections daily) to
those treated with intensive therapy (frequent monitoring and adjustment of insulin dosing, which was
administered three to four times daily). In the usual care group, the average A1C during the study was 9%; in the
intensive control group, the average A1C was 7%. Compared to the usual care group, those getting intensive
control experienced the following:

 50% reduction of new-onset retinopathy (primary prevention)

 54% reduction in progression of established retinopathy (secondary prevention)
 34% reduction of new-onset microalbuminuria (primary prevention)
 43% reduction of progression of established microalbuminuria (secondary prevention)
 69% reduction of new-onset neuropathy (primary prevention)
 57% reduction of progression of established neuropathy (secondary prevention)

Thus the DCCT showed that in patient with type 1 diabetes, intensive therapy reduced the incidence of (and
progression of) microvascular complications (retinopathy, nephropathy and neuropathy) as compared to usual
care. As patients with hyperlipidemia, hypertension or coronary artery disease were excluded from the DCCT,
the impact on macrovascular complications (MI, CVA) tracked during the study was not clinically significant.
The other landmark study that initially showed that tight glycemic control resulted in fewer diabetic
complications was the United Kingdom Prospective Diabetes Study (UKPDS). Whereas DCCT studied patients
with type 1 diabetes, UKPDS was a study of patients with type 2 diabetes. In UKPDS, 5100 patients with newly-
diagnosed type 2 diabetes between the ages of 25 and 65 were originally treated with diet, and if that failed
(which it did in 95% of individuals), they were randomized to 3 types of therapy head-to-head: a) glyburide, b)
metformin (in overweight individuals only), or c) insulin. Patients were then followed for the development of
diabetes-related complications and mortality. Compared to diet therapy alone, all three drugs produced similarly
impressive reductions in microvascular complications with similarly tolerable side effect profiles. Each 1%
reduction in hemoglobin A1C resulted in a 37% reduction in risk for microvascular complications. During the
study, the impact of tight glycemic control on macrovascular complications did not reach statistical significance.

Issue 2: What level of tight glycemic control is best, and what about macrovascular complications?
DCCT and UKPDS established that tighter glycemic control was superior to usual care in preventing microvascular
complications in patients with type 1 and type 2 diabetes. Further analysis of results from these two studies
showed that the relationship between A1C levels and microvascular complications did not plateau, and that
lowering A1C levels to near normal levels (i.e., from 7% to 6%) was associated with a further reduction in risk of
microvascular complications, albeit the absolute risk reductions were smaller. What was also clear from these
studies was that the risk of hypoglycemia increased as A1C levels were lowered. Overall there is greater benefit
in taking a patient from poor control to fair or good control than in taking a patient from good control to
normoglycemia. Unanswered was the optimal A1C target for treatment, balancing the benefits on microvascular
complications with the risk of severe hypoglycemia. Also unanswered was the impact of tight control on
macrovascular complications.

Three studies (ACCORD, ADVANCE, and VADT) have tried to determine the optimal A1C target for treatment and
the effect on macrovascular complications. These studies looked at patients with either established CAD or
those at increased risk of CAD, and looked at tight glycemic control and macrovascular outcomes. The Action to
Control Cardiovascular Risk in Diabetes (ACCORD) study looked at patients with either a history of cardiovascular
events or significant cardiovascular risk, and compared cardiac outcomes (specifically nonfatal MI, nonfatal CVA,
or cardiovascular death) when treated to usual care (A1C of 7.0-7.9%) or intensive treatment (A1C of <6.0%).
After 3.5 years, the study was prematurely terminated because of higher all-cause and higher cardiovascular
death in the intensive treatment group. Although non-fatal MIs were reduced in the intensive control group,
questions were raised by this study about the benefit of targeting an A1C under 6% in patients with type 2
diabetes and cardiovascular risk. Similar results have been shown in patients with type 1 diabetes; lowering the
A1C below 7% doubles the risk of death.
The other two studies looking at macrovascular outcomes in high-risk patients were ADVANCE and VADT. The
ADVANCE study looked at patients with type 2 diabetes who were at least 55, with a history of microvascular or
macrovascular disease, or at least one risk factor for vascular disease. Patients were randomized to either
intensive control (A1C of <6.5%) or usual care. After 5 years of follow up, patients receiving intensive control had
fewer microvascular complications (specifically, microalbuminuria), but there was no reduction of
macrovascular events in the intensive control group when compared to usual care. Later analysis showed that
patients in ADVANCE who had severe hypoglycemia had increased risk of major macrovascular and
microvascular events, as well as a greater risk of death when compared to those patients who did not have
severe hypoglycemia.

The Veterans Affairs Diabetes Trial (VADT) looked at patients with poorly controlled type 2 diabetes (average
A1C at entry 9.4%), and treated them intensively (goal A1C 6%) or with usual care (goal A1C 1.5% above intensive
control group). The primary endpoint was macrovascular outcomes (specifically, MI, CVA, cardiovascular death,
CHF, surgery for vascular disease, inoperable CAD, or amputation for ischemic gangrene). No early benefit on
these macrovascular outcomes was shown in the intensive therapy group, although after 10 years, there were
fewer major cardiovascular events in those treated with intensive therapy. Despite that benefit, overall survival
was the same in both groups.

Summary conclusions
These studies demonstrated the risk of intensive glycemic control in patients with either long-standing diabetes
or significant risk of CAD. The question then becomes one of possible benefit of tight glycemic control in patients
with shorter duration of diabetes or lower cardiovascular risk. We find the answer to this in long-term follow up
of patients in UKPDS and DCCT, which enrolled patients with either short duration of diabetes or low
cardiovascular risk (or both). In both of these studies, those patients treated with intensive treatment early in
disease (and typically at younger ages) had long-term reductions in cardiovascular outcomes (note the long-term
benefit of intensive initial control was less clear in VADT). This suggests that intensive glycemic control might
be of benefit in patients with a short duration of diabetes or low cardiovascular risk, but in long-standing
diabetes or significant cardiovascular risk, tight glycemic control carries with it significant risk.

These five major studies are reviewed in the table below.

Table 8: Five diabetes control studies and microvascular/macrovascular outcomes

A more recent meta-analysis confirmed the benefit of early tight control on macrovascular outcomes, showing
that those treated to lower target A1C had fewer macrovascular outcomes (specifically non-fatal MIs) when
compared to those treated to a higher target A1C. As a result, ADA guidelines state:

o A reasonable A1C goal for many non-pregnant adults is <7%.

o Providers might reasonably suggest more stringent A1C goals (such as <6.5%) for selected
individual patients if this can be achieved without significant hypoglycemia or other adverse
effects of treatment. Appropriate patients might include those with short duration of diabetes,
type 2 diabetes treated with lifestyle of metformin only, long life expectancy, or no significant
cardiovascular disease.
o Less stringent A1C goals (such as <8%) may be appropriate for patients with a history of severe
hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications,
extensive comorbid conditions, or long-standing diabetes in whom the general goal is difficult
to maintain despite diabetes self-management education, appropriate glucose monitoring, and
effective doses of multiple glucose-lowering agents including insulin.

Finally, a computer model of hypothetical patients aged 60-80 years old with diabetes with different
comorbidities showed that the benefits of intensive glycemic control (i.e., A1C of 7.0%) compared to less
intensive glycemic control (i.e., A1C of 7.9%) diminish as the patient ages and comorbidities increase. Based on
this model, A1C targets can be relaxed as a patient's age or comorbidities increase. This is summarized nicely in
the figure below, reproduced from the 2022 ADA guidelines.

Figure 1: Approach to management of hyperglycemia

In this figure, we target more stringent glycemic control in those who are newly diagnosed, with longer life
expectancy, lower risk of hypoglycemia, fewer comorbidities or vascular complications, and with better attitude,
resources and support.

For patients using continuous glucose monitoring, goal of therapy is to have glucose in the target range at least
70% of the time, with less than 4% of time below range. Preprandial glucose goal is 80 – 130mg/dl and post-
prandial glucose goal is < 180mg/dl.

Section 6: Pharmacotherapy part 1

Your next patient is Eli Lilly, a 46-year-old man with type 2 diabetes and hypertension. He has been doing
relatively well since being diagnosed with diabetes 3 months ago, but he hates the metformin you put him on,
stating it gives him diarrhea. Since you last saw him, he has self-discontinued his metformin. He wants to learn
about other options for treatment.

Which one of the following is true?

A. If Mr. Lilly wants to avoid hypoglycemia, the best drug to take is a sulfonylurea.
B. If Mr. Lilly wants to avoid gastrointestinal side effects, the best drug to take is an alpha-glucosidase
inhibitor, such as acarbose.
C. If Mr. Lilly wants to take an oral hypoglycemic to help lose weight, he should take either a GLP-1 receptor
agonist or an SGLT-2 inhibitor.
D. If Mr. Lilly wants to take the medication that is least likely to cause weight gain, he should take a
thiazolidinedione (TZD).

Pop Up Answers
A. Incorrect. Sulfonylureas (as well as glitinides and insulin) are the most likely to cause hypoglycemia.
B. Incorrect. Alpha-glucosidase inhibitors, metformin, and GLP-1 receptor agonists are all associated with
GI side effects.
C. Correct! GLP-1 receptor agonists and SGLT-2 inhibitors result in weight loss.
D. Incorrect. TZDs, insulin, and sulfonylureas are the most likely agents to cause weight gain.

Summary answer
The correct answer is C: If Mr. Lilly wants to take an oral hypoglycemic to help lose weight, he should take
either a GLP-1 receptor agonist (e.g., liraglutide) or an SGLT-2 inhibitor (e.g., canagliflozin).

Introduction
Pharmacotherapy for T2DM has evolved as new classes of hypoglycemics have been added. Metformin remains
the foundation of most regimens, but insulin (with its risk of weight gain and hypoglycemia) has lost its primary
role in the management of T2DM. In fact, we shall see that glucagon-like peptide 1 receptor agonists (GLP-1 RA)
have become the preferred injectable therapy over insulin for most patients. Factors leading to changes in
diabetes pharmacotherapy include impact on cardiovascular outcomes (both ASCVD events and heart failure),
renal outcomes, risk of hypoglycemia, and weight gain. ADA guidelines recommend that the following be
included when choosing pharmacotherapy to treat T2DM:

 Key comorbidities (ASCVD; heart failure; CKD)

 Hypoglycemia risk
  Effects on body weight
 Side effects
 Cost
 Patient preferences

We start our review with a brief description of each class of hypoglycemic used in the management of T2DM, so
keep the above list in mind as you review each class. Each oral drug class added to initial therapy incrementally
lowers A1C 0.7 – 1%.

Not covered here are colesevelam (the bile acid sequestrant, which has mild hypoglycemic effects) or
bromocriptine (the dopamine receptor agonist, which also has mild hypoglycemic effects). They are very
expensive and have yet to see widespread use in the management of type 2 diabetes.

Metformin
Metformin forms the cornerstone of oral hypoglycemic therapy in most patients with type 2 diabetes, due to its
lower risk of hypoglycemia, less weight gain, low cost, and demonstrated efficacy in reducing the long-term
complications of type 2 diabetes.

Metformin decreases hepatic glucose output by reducing hepatic gluconeogenesis and glycogenolysis, as well as
enhancing peripheral glucose uptake and enhancing insulin sensitivity. Metformin also has a modest effect on
decreasing glucose absorption in the GI tract (hence the common GI side effects), and reduces hemoglobin A1C
levels by 1.5%. Metformin decreases triglyceride levels, lowers LDL-cholesterol, and may increase HDL-
cholesterol. Metformin should be administered with the largest meal of the day, or if in divided doses, it should
be administered with breakfast and dinner. Vitamin B12 deficiency may develop on metformin, so in patients
who develop anemia or neuropathy, B12 levels should be monitored.

The major concern about the use of metformin is the risk of lactic acidosis, which is increased in renal and hepatic
insufficiency, as well as CHF. However, a review of metformin use in patients showed no worsening of clinical
outcomes in patients with mild and moderate renal or liver disease, or mild/moderate CHF. That being said,
patients with a GFR <30ml/min should not be treated with metformin.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors

The newest class of oral hypoglycemics is the SGLT2 inhibitor. Examples include canagliflozin (brand name
Invokana), empagliflozin (brand name Jardiance), dapagliflozin (Farxiga), and ertugliflozin (Steglatro).
SGLT2 inhibitors block renal glucose absorption, resulting in glycosuria. Because of this mechanism,
hypoglycemia is not seen with this class, and due to the caloric loss of glycosuria, weight loss is common. Not
surprisingly, genital fungal infections (and even Fournier’s gangrene) and dehydration may result, and renal dose
adjustment is required in CKD.

SGLT2 inhibitors triple the risk of diabetic ketoacidosis in those who take them. In fact, because of concerns
about ketosis and DKA, these agents should be held 24H prior to scheduled surgeries and anticipated
metabolically stressful activities (i.e., extreme sports or very low carbohydrate meal plans). SGLT2 inhibitors
(specifically canagliflozin) was thought to increase risk of leg amputation, but later studies have not found this.

SGLT2 inhibitors have quickly become valued in management of T2DM because of demonstrated beneficial
effects on ASCVD events, heart failure, and CKD. For example, empagliflozin, used as monotherapy in patients
with type 2 diabetes and cardiovascular disease, has been shown to improve cardiovascular outcomes. SGLT2
inhibitors are therefore favored in those with established atherosclerotic disease, as well as heart failure and
chronic kidney disease. In some patients with, or at high risk for, CAD, CHF, or CKD, SGLT2 inhibitors are
appropriate initial pharmacotherapy for T2DM, even before starting metformin.

GLP-1 receptor agonists

GLP-1 receptor agonists (GLP-1 RAs) are injectable drugs developed to mimic the effects of incretins (which
augment glucose-stimulated pancreatic insulin secretion). These agents delay gastric emptying, improving
satiety (but at risk of nausea), leading to weight loss. They are effective at lowering blood glucose levels, but
with low risk of hypoglycemia. Examples include exenatide (brand name Byetta), liraglutide (Victoza), and
dulaglutide (Trulicity). An oral GLP-1 RA is also available (semaglutide). Gastrointestinal side effects (e.g.,
nausea; bloating; vomiting; diarrhea) are common with these medications, but with the benefit of weight loss.
Some GLP-1 RAs are more effective than others at reducing weight. ADA guidelines rank weight loss
effectiveness as follows: semaglutide>liraglutide>dulaglutide>exenatide>lixenatide.

Tirzepatide is a new weekly injectable hypoglycemic that works both as a GLP-1 RA and a glucose-dependent
insulinotropic polypeptide. In hyperglycemia, this drug stimulates release of insulin, lowers glucagon levels, and
suppresses appetite. There is early evidence that tirzepatide is more effective than semaglutide and reducing
A1C and weight, with similar side effects.

All GLP-1 RAs have a black box warning of increased risk of thyroid C-cell tumors, and may have a slight increased
risk of causing pancreatitis.

In addition to the demonstrated benefit of weight loss and the low risk of hypoglycemia, liraglutide reduces
cardiovascular mortality when added to standard of care, and may reduce progression of CKD. In contrast to
SGLT2 inhibitors, GLP-1 RAs do not have a CHF benefit.

When compared to insulin, efficacy of GLP-1 RAs is similar, but with less risk of hypoglycemia and beneficial
effects on weight. Because of this, GLP-1 RAs are now preferred over insulin for most patients when injectable
therapy is indicated. (As discussed below, insulin remains preferred in patients presenting with severe and/or
symptomatic hyperglycemia). As with SGLT2 inhibitors, in some patients with, or at high risk for, CAD or CKD,
GLP-1 RAs may be used as initial pharmacotherapy, even before using metformin.

DPP-4 inhibitors
Dipeptidyl peptidase 4 (DPP-4) is an enzyme that degrades incretin, so DPP-4 inhibitors will result in increased
incretin (and therefore insulin) levels. Their mechanism of action of DPP-4 inhibitors is similar to GLP-1 receptor
agonists, so these classes of drugs are not used in combination with each other. DPP-4 inhibitors are dosed
orally, but are less effective at lowering blood glucose levels than GLP-1 receptor agonists. Similar to GLP-1
receptor agonists, DPP-4 inhibitors do not cause weight gain. Although unproven in reducing microvascular or
macrovascular complications (and with potential increased risk of heart failure), these drugs have found favor
because of ease of dosing (they are given once daily) and have few side effects (they may rarely cause severe
joint pain, urticaria/angioedema, and may increase the risk of pancreatitis). DPP-4 inhibitors are very expensive
and only modestly effective at lowering A1C levels. The most commonly used DPP-4 inhibitor is sitagliptin (brand
name Januvia).

Thiazolidinediones
Thiazolidinediones (TZDs) sensitize muscle, fat and liver cells to the effects of insulin. TZDs cause reductions in
fasting plasma glucose levels and hemoglobin A1C, and have a low risk of hypoglycemia. Congestive heart failure
or fluid retention is a concern in patients treated with TZDs, particularly when used at higher doses and in
combination with insulin. As a result, TZDs carry a black box warning for increased risk of heart failure, and are
contraindicated for use in patients with NYHA Class III or IV CHF. The most commonly used TZD is pioglitazone
(brand name Actos). Pioglitazone may reduce cardiovascular events when added to existing hypoglycemic
regimens. At this time, the effect of TZDs on microvascular outcomes is unknown.

Insulin secretagogues: Sulfonylureas and glitinides

There are two categories of insulin secretagogues: sulfonylureas and glitinides. As a class, these agents stimulate
beta cells to produce insulin, thus lowering blood glucose levels. This class of drugs has a high risk of
hypoglycemia and weight gain, and has fallen into disfavor.
Sulfonylureas are potent insulin secretagogues, and can lower hemoglobin A1C results by 1.5 percentage points.
They reduce microvascular complications of diabetes. However, when compared head-to-head with metformin
in a retrospective study of veterans, sulfonylureas (specifically glyburide and glipizide) were more likely to be
associated with more cardiovascular events and death. Over time, sulfonylureas become less effective, and the
need to increase dosage is common. Examples of sulfonylureas include glyburide (associated with prolonged
hypoglycemia, and not recommended), glipizide, glimepiride, and gliclazide.

Glitinides are less potent insulin secretagogues. Their chief advantage is a shorter half-life, so they are dosed
with meals and serve a role in those with irregular eating patterns. This class includes nateglinide (brand name
Starlix) and repaglinide (brand name Prandin). Repaglinide can cause severe hypoglycemia when used in
conjunction with gemfibrozil, and the use of these two agents together is contraindicated. Their long-term
impact on microvascular and macrovascular complications of diabetes has not been established for this class of
drug.

Alpha-glucosidase inhibitors
Alpha-glucosidase inhibitors reduce intra-intestinal polysaccharidase activity, preventing breakdown of
carbohydrates into simple sugars, which are then not absorbed. Their effect on lowering hemoglobin A1C levels
is less than other oral agents (0.5-0.8%), chiefly through reductions in post-prandial glucose elevation. These
agents do not result in weight gain. Most side effects are gastrointestinal; flatulence is seen in the majority of
patients (75%), and diarrhea is seen in about one-third. Acarbose (brand name Precose) is administered three
times daily, with meals. The impact of this class of agents on microvascular and macrovascular complications is
unknown and their role in management of diabetes is limited.

Insulin
The best-known drug to treat type 2 diabetes is insulin. Insulin is well studied and very effective at achieving
glycemic control. Insulin is proven to reduce microvascular complications, a major benefit when considering its
use. Insulin remains the most effective at lowering blood glucose levels, and should be the drug of choice in the
following hyperglycemic patients:

 Those with ongoing weight loss (i.e., catabolic state)

 Those with symptoms of hyperglycemia
 Those with A1C>10 or blood glucose levels >300

The major risks of insulin are hypoglycemia and weight gain. As mentioned above, GLP-1 RAs are equivalent in
efficacy to insulin, without risk of hypoglycemia or weight gain, and are thus preferred to insulin for most
patients (other than the three scenarios immediately above). Insulin remains the treatment of choice for women
who are, or who may become pregnant. Monotherapy with insulin tends to become less effective over time, but
increasing the dose of insulin will always improve glycemic control (i.e., there is no ceiling to insulin dosages).

The standard concentration of insulin is 100 units/ml (U100). Concentrated insulins are now available, and have
delayed onset of action and longer half-lives (and lower risk of hypoglycemia) than standard concentrations.
Concentrated insulin may improve patient comfort in those on high doses of insulin. Formulations of
concentrated insulin include U500 regular insulin, U300 glargine, and U200 degludec. Long-acting insulin
formulations are termed "basal" insulin; rapid-acting insulin formulations are often referred to as "prandial"
insulin. Currently available formulations of insulin include the following:

Table 6: Insulin formulations

The cost of insulin has increased, and for patients, insulin is often a very expensive option. There is no proven
clinical benefit of synthetic insulins (e.g., glargine; detemir; degludec) relative to much less expensive insulins
(e.g., regular insulin; NPH insulin).
Medication summary
Before reviewing the classes of medications, it is important to remember that lifestyle modification (i.e., diet;
exercise; weight loss) is a cornerstone of therapy that should be addressed with every visit. Hypertension, lipids,
and tobacco use (if present) should also be addressed with every visit. Note that drugs with potential benefit
with CAD, CHF, and/or CKD are favored in the management of type 2 diabetes.

Table 7: Review of oral diabetes agents used as add-on therapy to metformin

Section 7: Pharmacotherapy Part 2

A 63-year-old man is diagnosed with T2DM. A1C from today is 7.8. He has been seeing nutrition regularly, and
counseled on lifestyle modification. Past medical history includes hypertension, hyperlipidemia, tobacco use,
stage III chronic kidney disease (GFR 40ml/min), and gout. In addition to considering metformin for initial
therapy, which medication should also be considered as initial therapy of T2DM in this person?

A. Empagliflozin
 B. Glimepiride
C. NPH insulin
D. Pioglitazone

Pop up answers
A. Correct. Empagliflozin would be ideal. He has multiple cardiovascular risk factors and CKD, both of which
are benefitted by the addition of empagliflozin.
B. Incorrect. Sulfonylureas are not typically first or second line agents, due to weight gain, risk of
hypoglycemia, and better options.
C. Incorrect. Insulin risks weight gain and hypoglycemia in this individual, and has become second-line add-
on therapy in patients with T2D.
D. Incorrect. Pioglitazone is unproven in reducing ASCVD events or progression of CKD in patients with
T2DM.

Summary answer
The correct answer is A: Empagliflozin.

Introduction
Pharmacotherapy for T2DM has evolved as new classes of oral and injectable therapy have been developed and
clinical trials have demonstrated cardiovascular and renal benefits of some classes of pharmacotherapy.
Choosing pharmacotherapy is now based in large part of weighing the specific risks and benefits relative to each
individual patient. While metformin has typically been considered first-line pharmacotherapy in nearly all
patients, SGLT2 inhibitors and GLP-1 RAs are now considered first line in patients with, or at increased risk for,
CAD and CKD. SGLT2 inhibitors are also potential first line agents in patients with T2DM who have CHF.

In this section, we review the specific risks and benefits of pharmacotherapy for T2DM mentioned in the previous
section, and summarize which classes of agents show benefit or peril for each risk.

ASCVD benefit
In the United States, myocardial infarction and stroke are major causes of death. We start this section by
reviewing those classes and agents of hypoglycemics associated with cardiovascular benefit.

Classes and agents demonstrating ASCVD benefit include:

 Metformin: potential benefit

  SGLT2-inhibitors: specifically canagliflozin and empagliflozin (empagliflozin has an FDA indication for
this benefit)
 GLP-1 receptor agonists: specifically liraglutide (same FDA indication as empagliflozin), but also
semaglutide and exenatide extended release
 Thiazolidinediones (TZDs): potential benefit with pioglitazone

Recall that the ACCORD study demonstrated intensive treatment of T2DM with insulin could increase risk of
myocardial infarction.

Heart failure benefit (and risk)

Heart failure is another cardiac outcome affected by the choice of pharmacotherapy for T2DM. There are fewer
classes of agents that improve heart failure outcomes, and in fact more classes with potential risk or worsening
heart failure.

Medications that improve heart failure outcomes:

 SGLT2-inhibitors: specifically canagliflozin, empagliflozin and dapagliflozin (empagliflozin has an FDA

indication for heart failure)

Medications that may worsen heart failure outcomes:

 DPP-4 inhibitors: specifically saxagliptin and alogliptin

 TZDs: considered a class effect, and includes a black box warning of heart failure risk

CKD and diabetes-related CKD progression benefit

Along with hypertension, diabetes is the most common cause of kidney failure in the United States. One of the
major outcomes that we hope to improve by management of T2DM is the reduction of progression of diabetes-
related CKD. That said, many of these agents are renally cleared, and because of the prevalence of CKD in
patients with T2DM, it is important to be familiar with dosing adjustment of these medications in CKD.

Those agents that have shown CKD benefit include:

 SGLT2-inhibitors: specifically canagliflozin, empagliflozin and dapagliflozin

 GLP-1 receptor agonists: specifically liraglutide
Dosing adjustment of hypoglycemics is as follows:

 Metformin: contraindicated when GFR < 30 ml/min

 SGLT2-inhibitors: requires renal dose adjustment that varies by agent; generally not used when GFR <
30 ml/min
 GLP-1 receptor agonists: may be associated with acute kidney injury. Exenatide and lixisenatide require
renal dose adjustment (exenatide is contraindicated when GFR < 30 ml/min; experience with lixisenatide
in CKD is limited)
 DPP-4 inhibitors: dose adjustment in CKD when GFR < 50 ml/min (except linagliptin, which requires no
dose adjustment)
 TZDs: generally not used in CKD due to risk of fluid retention
 Sulfonylureas: glyburide not recommended in CKD; caution in CKD with other agents
 Insulin: lower doses needed in CKD

Hypoglycemia and weight gain

Two major side effects of hypoglycemics are the risk of symptomatic hypoglycemia and the risk of weight gain.
Agents that risk hypoglycemia include sulfonylureas and insulin. Other classes of agents are associated with no
real risk of hypoglycemia. Agents that risk weight gain include sulfonylureas and insulin, but also TZDs. SGLT2
inhibitors and GLP-1 receptor agonists are associated with weight loss, and metformin has potential for modest
weight loss.

Cost
Cost is an important final consideration in treating patients with T2DM. Most of the newer classes of agents
(e.g., SGLT2 inhibitors; GLP-1 receptor agonists; DPP-4 inhibitors) are very expensive. Synthetic insulins are also
very expensive (recall synthetic insulins have no demonstrated improvement in clinical outcomes relative to
older human insulin formulations). Metformin, sulfonylureas, TZDs, and human insulin are the less expensive
treatment options for those patients in whom cost is paramount.

Summary
When choosing pharmacotherapy for T2DM, we continue to use metformin as a cornerstone of therapy, along
with consistent attention to lifestyle therapy. Should additional pharmacotherapy be indicated, agents are
chosen based on the potential risks and benefits relevant to the patient’s clinical status. SGLT2 inhibitors and
GLP-1 receptor agonists have become favored because of improved cardiovascular and renal outcomes,
especially in those with established cardiovascular disease. SGLT2 inhibitors are also favored in those with CHF.
These agents also have demonstrated benefit of weight reduction. However, these classes of drugs are
expensive, and when cost is a consideration, sulfonylureas, metformin, human insulin and TZDs are favored.

Section 8: Pharmacotherapy part 3

A 44-year-old man presents with frequent nocturia. He denies blurred vision, and weight is unchanged from six
months ago. In evaluation of his nocturia, you test his A1C, which is 8.9%. Which of the following statements on
management is correct?

A. Insulin should be started in all patients who have symptoms of hyperglycemia.

B. Since metformin is the cornerstone of therapy, he should be started on monotherapy with metformin.
C. Because of the level of hyperglycemia, he should be started on metformin plus a second hypoglycemic.
D. It is premature to diagnose diabetes in this patient.

Pop Up answers
A. Incorrect. Insulin should be started in extreme hyperglycemia (i.e., A1C >10%) or symptomatic
hyperglycemia. While he does have nocturia, weight is stable, and he does not have blurred vision. There
is not enough clinical derangement to warrant insulin therapy.
B. Incorrect. When A1C is >1.5% above goal (and for this young individual, goal A1C should be 7% or less),
metformin plus a second agent should be started (i.e., dual therapy).
C. Correct. When A1C is >1.5% above goal, metformin plus a second agent (i.e., dual therapy) should be
initiated.
D. Incorrect. This patient has symptomatic hyperglycemia and an A1C of 8.9%. He should be diagnosed with
T2DM.

Summary answer
The correct answer is C: Because of the level of hyperglycemia, he should be started on metformin plus a
second hypoglycemic.

Introduction
Having learned the risks and benefits of each class of hypoglycemic, we now combine that information with the
patient’s clinical presentation to begin pharmacotherapy. It bears repeating that lifestyle modification
discussions should continue through the initiation and maintenance of pharmacotherapy.

Initiation of pharmacotherapy: Monotherapy, dual therapy, or insulin

We have already learned that metformin is the cornerstone of T2DM treatment for nearly all patients (except
those with GFR < 30 ml/min, or otherwise intolerant of metformin). The next question is to consider if metformin
plus an additional agent (e.g., ‘dual therapy’) should be started, or if insulin should be part of initial therapy.
Based on consensus management guidelines from both the American Diabetes Association and the European
Association for the Study of Diabetes, therapy other than monotherapy should be considered in the following
scenarios:

 Dual therapy: consider when A1C > 1.5% above target

 Insulin therapy: consider when A1C > 10%, glucose > 300mg/dl, or the patient is symptomatic from
hyperglycemia, or catabolic state is present (e.g., weight loss)

Monotherapy with metformin

When starting with monotherapy, metformin is often your first choice of therapy (unless, as we discussed, CAD,
CHF or CKD are present, or the patient is high risk for any of these). While addressing lifestyle modification (at
every visit), the dose of metformin should be escalated rapidly, with the goal of rapid improvement of glycemic
control. Dosing of metformin is as follows:

 Start with metformin 500mg once or twice (with breakfast and dinner) daily, or 850mg once daily
 After 5-7 days, if GI side effects absent, double dose
 Maximal dose is either 850mg twice daily or 1000mg twice daily for most individuals
 If GI side effects occur, lower dose to previous tolerated dose

In some patients, such as those who are obese, you may stick with a lower dose of metformin to allow the
addition of an SGLT2 inhibitor or GLP-1 RA to assist with weight loss. There is some debate about monotherapy
with metformin. Treatment failure (i.e., poor glycemic control) occurs earlier in patients treated with metformin
monotherapy than in those treated with metformin plus a DPP4-inhibitor.

Next steps
Once initial therapy has begun (typically with metformin), we then choose add-on therapy based on patient
factors and cost. Here, we combine the information we know about each class of hypoglycemic specific to
cardiovascular risk, heart failure, CKD, weight loss goals, risk of hypoglycemia, and cost to consider choice of our
next agent.

The figure below shows considerations in add-on treatment of T2DM.

Figure 2: Considerations in add-on treatment of T2DM
A more detailed algorithm is supplied to us in the 2022 ADA guideline.

Figure 3: ADA management algorithm 2021

Section 9: Pharmacotherapy with injectable medications

Which of the following statements about injectable hypoglycemics used in the treatment of type 2 diabetes is
true?

A. A patient who presents initially with an A1C greater than 8.5% should be started on therapy with insulin.
B. A patient who presents initially with an A1C greater than 10% should be started on either a GLP-1
receptor agonist or insulin.
C. Insulin is favored over GLP-1 receptor agonists in patients with type 2 diabetes and microalbuminuria.
D. GLP-1 receptor agonists are favored over insulin as initial injectable treatment, other than in patients
who present with severe hyperglycemia.

Pop Up answers
A. Incorrect. We consider starting patients on insulin as first-line therapy when they present with an
 A1C>10%, or with very symptomatic hyperglycemia.
B. Incorrect. Insulin is recommended in this clinical scenario.
C. Incorrect. GLP-1 RAs (specifically liraglutide) can delay the progression of diabetes-related kidney
disease.
D. Correct. GLP-1 RAs are favored over insulin due to cardiovascular and renal benefit, weight loss, and less
risk of hypoglycemia.

Summary answer
The correct answer is D: GLP-1 receptor agonists are favored over insulin as initial injectable treatment, other
than in patients who present with severe hyperglycemia.

Introduction
We have learned that comorbidities and risk/benefit profiles of different hypoglycemics drive our choices when
treating T2DM. We have also learned that when the presenting A1C is greater than 10%, insulin therapy is
indicated. In this section, we discuss injectable pharmacotherapy for T2DM. While we do not typically use
injectable therapy as initial pharmacotherapy, when diabetes remains uncontrolled on two or three oral agents,
we typically transition to injectable therapy.

Indications for injectable therapy

We typically start patients on oral therapy when diagnosed with T2DM. An exception is when the presenting
A1C is greater than 10%, and/or the patient is symptomatic from hyperglycemia. In these scenarios, we typically
start insulin to get glucose under control, and then consider oral therapy once extreme hyperglycemia is
controlled. But in most patients, we normally start with oral therapy options and add additional agents if A1C is
not at goal. If a patient's glucose is not at goal despite being on two or three classes of oral hypoglycemics, it is
time to consider injectable therapy. In fact, if a patient on two or three oral agents has an A1C > 10%, or the A1C
is 2% above target for that patient, dual injectable therapy with a GLP-1 RA and basal insulin, or basal insulin
plus prandial insulin, is indicated.

Managing glucose with injectable therapy

Our first choice for injectable therapy in many patients is a GLP-1 receptor agonist. GLP-1 receptor agonists are
favored over insulin when choosing injectable therapy because of the demonstrated cardiovascular benefit
(especially liraglutide, semaglutide, and exenatide ER), the improvement in CKD progression (i.e., liraglutide),
low risk of hypoglycemia, and the weight loss associated with these medications. Insulin may be favored when
cost is a factor and when glycemic control is especially poor, but risks hypoglycemia and weight gain, without
the proven benefits seen with GLP-1 receptor agonists.
Because of the gastrointestinal side effects seen with GLP-1 RAs, dosing of these agents is typically ramped up
over time. For example, liraglutide dosing is started 0.6mg subcutaneously once daily for a week, and then
increased to 1.2mg daily. Full dose of liraglutide is 1.8mg daily. Semaglutide is started at 0.25mg weekly for four
weeks, and then increased to 0.5mg weekly. Anticipating gastrointestinal side effects is important to improve
compliance, as these side effects are very common.

We do not typically use fasting plasma glucose to titrate GLP-1 RAs; rather, we use A1C values. When A1C is
above goal despite the maximally tolerated dose of a GLP-1 RA, the addition of insulin therapy is indicated. The
combination of a GLP-1 RA and insulin has been proven effective at improving glycemic control, and premixed
combinations of these two classes of medications are commercially available, but expensive (e.g.; iDegLira;
iGlarLixi).

When choosing insulin, either as initial injectable therapy or as add on therapy to a GLP-1 RA, basal insulin at a
dose of either 10 units/day or 0.1-0.2 units/kg/day is used. Distinct from other medications, we can titrate insulin
frequently based on morning fasting plasma glucose until glycemic control is achieved.

 Starting basal insulin: dose 10 units/day or 0.1-0.2 units/kg/day.

 Titrating basal insulin: increase basal insulin by 2 units every three days until goal morning fasting
plasma glucose is reached (i.e., fasting plasma glucose < 130mg/dl in most patients).

With basal insulin, if fasting plasma glucose is at goal and A1C remains above goal, options are to add oral
therapy, injectable therapy with a GLP-1 RA (discussed above), or prandial insulin. If metformin has not been
used, metformin should be added to improve glycemic control. SGLT-2 inhibitors may also be added in this
scenario, which may improve weight loss and allow the down-titration of basal insulin. TZDs and sulfonylureas
are not typically used as add-on therapy to insulin.

If prandial insulin is chosen, prandial insulin may be added with the largest meal of the day ('basal-bolus
therapy'). Another indication for adding prandial insulin is when basal insulin has been titrated up to a dose
exceeding 0.7 – 1.0 units/kg body weight. Such large doses of basal insulin should prompt the addition of prandial
insulin.

 Starting prandial insulin: start 4 units/day or 10% of basal dose, used with the largest meal of the day
 Titrating prandial insulin: increase dose by 1-2 units or 10-15% twice weekly until morning fasting
plasma glucose controlled
Should goal A1C not be met with the addition of prandial insulin, then prandial insulin is added to a second meal
of the day, following the same dosing as above. Should goal A1C remain elusive on two doses of prandial insulin,
prandial insulin is added to the third meal of the day (known as 'full basal-bolus therapy').

When hypoglycemia occurs, either on basal or basal-bolus therapy, the cause of hypoglycemia should be
explored (e.g., missed meals; compliance). If no contributing factor is found, insulin dosing should be decreased
by 10-20%

Overbasalization
In theory, the ideal basal insulin dose should allow a patient with T2DM to fast for 24H without hypoglycemia.
Basal insulin, however, has a ceiling effect, such that continued increases in basal insulin will increase risk of
hypoglycemia and weight gain, but without improvement in A1C. Termed 'overbasalization', it is likely the result
of physician reluctance to add prandial insulin. Clues to overbasalization include:

 Basal insulin dose > 0.5 units/kg

 Large differential between bedtime and morning glucose
 Large differential between post- and pre-prandial glucose

When suspected, treatment is to lower basal insulin dosing and add prandial insulin.

Oral therapy + injectable therapy

When injectable therapy is added on to a patient's oral regimen, some combinations of oral and injectable
therapy should be avoided. For example, since DPP-4 inhibitors work by the same mechanism as GLP-1 RAs, DPP-
4 inhibitors should be discontinued when a GLP-1 RA is begun.

TZDs and sulfonylureas are discontinued when either insulin is started, or the dose of the oral medication is
reduced by 50%. The combination of insulin plus a sulfonylurea is particularly potent in resulting in
hypoglycemia. If a patient remains on insulin and a (reduced dose) sulfonylurea and prandial insulin is added, at
that point the sulfonylurea should be discontinued.

Injectable therapy is reviewed in Table 8.

Table 8: Injectable therapy

Injection therapy is also reviewed in the figure below.

Figure 4: ADA guideline on injection therapy

Section 10: Pharmacotherapy practice case 1

A 47-year-old man is diagnosed with type 2 diabetes and A1C is 7.4%. On physical exam, blood pressure is
112/76. Other vital signs are normal. He weighs 100kg, and BMI is 30 kg/m 2. You discuss options for
pharmacotherapy, as you complete a referral to the nutritionist and ophthalmology. The patient promises to
lose weight and start to exercise. Appropriate management at this point would be:
 A. Start metformin 500mg daily; increase to 500mg twice daily in 1 week.
B. Start canagliflozin 100mg daily.
C. Start a sulfonylurea once daily; advance dose weekly until hypoglycemia develops.
D. Start exenatide 5mg twice daily to help him lose weight.

Pop Up Answers
A. Correct. Initiation of metformin at the time of diagnosis of diabetes is considered standard of care.
Should he have CAD or CKD (or be at high risk for either), an SGLT2-i or GLP-1 RA could also be used. If
he had CHF, an SGLT2-i could be used.
B. Incorrect. SGLT-2 inhibitors (i.e., canagliflozin; empagliflozin) should be considered as monotherapy only
in the patient who could not tolerate metformin or was at high risk for CAD or CKD, or had symptomatic
CAD, CKD, or CHF.
C. Incorrect. Sulfonylureas are not considered first-line therapy.
D. Incorrect. We do not typically start injectable therapy unless severe hyperglycemia is present or the
patient is uncontrolled on oral therapy. Neither is present in this patient.

Summary answer
The correct answer is A: Start metformin 500mg daily; increase to 500mg twice daily in 1 week.

This case reviews metformin-based therapy in a patient with only a modest elevation in A1C (7.4%) and with no
risk for, or evidence of, CAD, CKD, or CHF. Metformin is considered a cornerstone of therapy in nearly all of these
patients. With metformin-based therapy, metformin is initiated at 500mg daily or twice daily, and then doubled
in 5-7 days. The maximal dose is 1000mg twice daily. If GI side effects occur, the dose is typically lowered to the
maximal dose that did not result in side effects. Once the maximal tolerated dose is achieved, the dose should
be maintained for the next three months, at which time glycemic control is reassessed with A1C testing. In the
meantime, instruction on lifestyle modification, including evaluation by a nutritionist, should be undertaken. If
maximal dosing of metformin does not result in goal glycemic control, an additional agent will be needed.

Section 11: Pharmacotherapy practice case 2

A 53-year-old man presents with three months of urinary frequency and weight loss. Past medical history is
notable for hypertension, obstructive sleep apnea, and degenerative knee arthritis. He is on lisinopril,
chlorthalidone, and acetaminophen. Physical examination is unremarkable, other than weight of 120kg, down
4kg over the past three months. Point of care A1C is 11.2%. Further testing includes a basic metabolic panel,
which is normal. Which of the following is appropriate management for this patient?
 A. Start metformin 500mg twice daily
B. Start metformin 500mg plus empagliflozin 10mg daily
C. Start liraglutide 0.6 mg daily
D. Start glargine 20 units daily

Pop up answers
A. Incorrect. At this level of hyperglycemia, injectable therapy with insulin should be started
B. Incorrect. At this level of hyperglycemia, injectable therapy with insulin should be started
C. Incorrect. Although injectable therapy should be started, insulin should be used when A1C>10%,
especially if symptomatic hyperglycemia (i.e., weight loss) is present. Both are seen in this patient.
D. Correct. Insulin therapy is indicated in the treatment naïve patient when A1C >10%, especially if
catabolic signs (i.e., weight loss) are present. A dose of either 10 units, or 0.1-0.2 units/kg/day should be
used as initial therapy.

Summary answer
The correct answer is D: Start glargine 20 units daily

We have learned that metformin is the cornerstone of therapy for most patients with T2DM. When patients
cannot tolerate metformin, we will typically start with other oral medications before resorting to injectable
therapy. We consider starting a patient with more than just metformin when treating T2DM in two scenarios:

 A1C is greater than 1.5% above goal. We know that each oral medication results in a 0.7 -1% drop in
A1C, so should the A1C be 1.5% above goal, we know that the patient will need two medications to
achieve glycemic control.
 A1C is 10% or greater (with or without symptoms of hyperglycemia). When severe hyperglycemia is
present, we typically begin with basal insulin therapy as insulin is the most effective at improving
glycemic control. When starting basal insulin, dosing is either 10 units/day, or 0.1 – 0.2 units/kg/day.

Section 12. Pharmacotherapy practice case 3

A 53-year-old man with hypertension and T2DM presents for routine follow up. Medications include metformin
1000mg twice daily, empagliflozin 25mg daily, pioglitazone 45mg daily, losartan/HCTZ 50/12.5mg daily, and
atorvastatin 40mg daily. On physical examination, blood pressure is 112/78; weight is 100 kg, with BMI 33kg/m 2.
A1C today is 8.1%. He reports full compliance with medications. In addition to continuing to address diet and
exercise, which of the following is appropriate initial management of this patient?
 A. Add glimepiride 2mg daily
B. Add glargine 10 units daily
C. Add liraglutide 0.6 mg daily
D. Add glargine 10 units and liraglutide 0.6mg daily

Pop up answers
A. Incorrect. This patient is obese, and sulfonylureas are likely to contribute to weight gain
B. Incorrect. This patient is obese, and insulin will contribute to weight gain.
C. Correct. This scenario illustrates the need for injectable therapy (failure to control glucose on two or
three oral medications). Because of his obesity, a GLP-1 RA is preferred over insulin to help with weight
loss.
D. Incorrect. There is not an indication for dual injectable therapy in this patient. Indications for dual
injectable therapy include A1C >10% on two or three oral agents, or A1C >2% above goal. Neither is
present in this patient.

Summary answer
The correct answer is C: Add liraglutide 0.6mg daily

This patient is on maximal oral therapy (three agents from different classes), but with A1C above his goal (which
is likely in the range of 6.5%). Considerations here include his obesity and the difference between his A1C and
his goal A1C. Because of his obesity, GLP-1 RAs are favored over insulin. His A1C of 8.1% is 1.6% above goal.
When A1C is 2% above goal despite maximal oral therapy, we would consider starting dual injection therapy
with a GLP-1 RA plus insulin. That is not present here, so monotherapy with the addition of a GLP-1 RA is
indicated.

Section 13. Practice case 4

A 47-year-old woman with T2DM and hypertension presents for follow up. Her current diabetic regimen is
metformin 1000mg twice daily and glargine 46 units nightly. She has not tolerated GLP-1 receptor agonists due
to gastrointestinal side effects. Morning fasting plasma glucose has averaged 112mg/dl. Physical examination is
normal; BMI is 33kg/m2. Hemoglobin A1C is 8.2%. Which of the following is appropriate management for this
patient?

A. Increase glargine to 50 units nightly

 B. Add empagliflozin 10mg daily
C. Add glimepiride 2mg daily
D. Add insulin lispro 4 units with her largest meal of the day

Pop up answers
A. Incorrect. Since morning fasting plasma glucose is controlled, increasing basal insulin is likely to result in
hypoglycemia.
B. Correct. With her obesity, adding an SGLT-2 inhibitor will improve glycemic control and contribute to
weight loss.
C. Incorrect. Sulfonylureas are not typically started in patients already on insulin, due to risk of
hypoglycemia and weight gain.
D. Incorrect. While the dosing is correct and theoretically an option in this patient, her obesity will be
worsened by additional insulin. A better choice is to add either an SGLT-2 inhibitor or a GLP-1 RA.

Summary answer
The correct answer is B: Add empagliflozin 10mg daily.

When basal insulin therapy is used, the first step is to control morning fasting plasma glucose, with goal
<130mg/dl for most patients. If that goal is reached and A1C remains above goal, increasing basal insulin is likely
to cause hypoglycemia without necessarily improving overall glycemic control. Options at this point are:

 Start prandial insulin with the largest meal of the day. Prandial insulin is started at either 4 units or 10%
of the current basal dose.
 Add an SGLT-2 inhibitor. This may help with weight loss and down-titration of basal insulin.
 Add a GLP-1 RA. This may help with weight loss. Commercial combinations of basal insulin plus a GLP-1
RA exist, but are expensive.
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