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A drawback to immediate-release metformin is that it requires multiple daily

dosing and its dose also must be titrated to minimize GI effects. After the dose is

established, it is possible to use a long-acting product that can be dosed once daily.

Alternatively, extended-release metformin may be initiated at a dose of 500 mg daily

and titrated upward as tolerated. Renal function tests should be evaluated before the

drug is initiated. L.H. does not have any contraindications (renal or hepatic

dysfunction, cardiorespiratory disease, binge alcohol use) to the use of metformin

that could predispose her to its most significant side effect, lactic acidosis (see Case

53-16, Question 2). Because L.H. exhibits the typical features of insulin resistance

syndrome and has no contraindications for its use, she should be started on

metformin. Her A1C goal of less than 7% will require an additional 1.3% lowering

in her A1C, which can be achieved with metformin. However, any changes in her

lifestyle will further help lower her A1C. L.H. should take metformin 500 mg twice

daily with food.

Titrating Metformin Doses

CASE 53-11, QUESTION 4: L.H. is started on metformin 500 mg BID with food and instructed to increase

her dosage to 500 mg every morning and 1,000 mg every evening after 1 week. Three days after starting

metformin, she phones the clinic complaining of nausea and diarrhea. She admits to taking her doses on an

empty stomach. How should L.H.’s symptoms be addressed?

GI disturbances such as diarrhea, bloating, anorexia, abdominal discomfort,

nausea, and metallic taste often dissipate with time and can be minimized by

initiating metformin in a single 500- or 850-mg dose at breakfast or with the patient’s

largest meal of the day. Consistently taking metformin with food significantly

minimizes the GI side effects. The dosage should be slowly increased (e.g., 500

mg/day every 2 weeks) until the appropriate clinical effect is achieved or the patient

is taking the maximal dose (1,000 mg BID or 850 mg TID). Therefore, L.H.’s

metformin dose should be reduced to 500 mg daily with her largest meal, and she

should be titrated more slowly during a period of several weeks. Metformin is

typically dosed 2 to 3 times daily (the long-acting formulation is dosed once daily

with dinner). Twice-daily dosing for adherence purposes is preferred if a patient can

tolerate a 1,000-mg dose or once daily with the extended-release formulation. If she

continues to experience GI symptoms, an alternative approach is to use the extendedrelease formulation; small studies have demonstrated improved tolerability with the

extended-release tablets versus the immediate-release dosage form.

249 A drawback to

these tablets is their very large size. Also, patients may complain that metformin has

a fishy odor,

250 which seems to be more apparent with certain generic formulations. If

this is significant enough to cause a patient to stop taking it, the extended-release

formulation can be tried, which may be more tolerable.

Monitoring Metformin Therapy

CASE 53-11, QUESTION 5: How should metformin therapy be monitored in L.H.?

As is standard with other agents, L.H. should be encouraged to perform SMBG

(see Case 53-11, Question 6) and have an A1C test performed quarterly until she

achieves consistent values less than 7%. Additional evidence of the therapeutic

benefits of metformin may include an improved lipid profile and some weight loss.

Initially, it is important to monitor GI problems, and although lactic acidosis is

unlikely, L.H. should be warned to bring to the attention of her physician any sudden

symptoms of shortness of breath, weakness, and malaise. A baseline SCr, LFTs, and

complete blood count should be obtained for L.H. and repeated yearly. Metformin

can reduce vitamin B12 absorption, and it is associated with reductions in vitamin B12

levels (19% after 4 years of use in one study) and actual deficiency.

251 Therefore,

monitoring of vitamin B12

levels every 2 to 3 years should be considered with longterm use.

SELF-MONITORING OF BLOOD GLUCOSE IN TYPE 2 DIABETES

CASE 53-11, QUESTION 6: L.H. is interested in learning how to perform BG testing. What are the

advantages and disadvantages of SMBG tests? When and how often should L.H. be instructed to test her BG

concentrations?

SMBG is an important self-management tool for patients such as L.H. to assess the

efficacy of therapy and guide adjustments in nutrition, exercise, and medications.

Disadvantages include cost of testing, inadequate understanding by both healthcare

providers and patients regarding the benefits and proper use of SMBG results, patient

psychological and minor physical discomfort associated with obtaining a blood

sample, and the inconvenience of testing. However, with the current advances in

meter technology and proper patient education, most of these potential barriers can

be overcome.

The ADA states that SMBG may be a useful guide for patients with Type 2

diabetes treated with MNT or noninsulin therapies, although there is insufficient

evidence to determine optimal frequency of testing and demonstrate costeffectiveness for these patients. Although one meta-analysis of SMBG effects in

patients with Type 2 diabetes not on insulin concluded the overall effect on A1C was

a 0.4% reduction, others failed to show a benefit.

252,253 SMBG studies in patients with

Type 2 diabetes are often limited in that multiple interventions, such as education,

diet, and medication adjustments, were used. However, a primary reason studies fail

to show a benefit is that patients are not taught what to do with their BG numbers

(i.e., how to respond to a low BG reading); the BG values are solely used by the

providers to make adjustments to their therapy.

253

SMBG should be considered for most patients with Type 2 diabetes, particularly

those who are learning to adjust their carbohydrate intake and portion sizes and want

to measure how well medications and lifestyle changes are working to improve their

glucose control. Although not always cost-effective, testing 4 times daily before

meals and at bedtime for 1 week is useful, so that the patient can observe his/her

glucose profiles. Later, once the desired A1C has been achieved, BG can be tested

less frequently. Testing times should vary throughout the day so that fasting as well as

postprandial and bedtime values can be assessed. As emphasized by the ADA,

intensive patient education regarding testing technique and interpretation are vital to

the cost-effective use of this monitoring tool. The patient must learn how to respond

to his/her glucose profile and institute lifestyle changes that can have a favorable

effect.

Clinical Use of Antidiabetic Agents

CASE 53-11, QUESTION 7: L.H. was quite motivated to improve her glucose control because her

grandmother “lost a leg” to diabetes and her aunt is undergoing dialysis because “her kidneys have failed.” She

is taking metformin 1,000 mg PO BID and tolerating it reasonably well (she occasionally gets some stomach

discomfort, but states she is fine with it). She is proud that she remembers to

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take the metformin every day as instructed. She met with a dietitian who suggested an 1,800-calorie diet and

45-minute walks 3 times weekly. After 3 months, L.H. lost 6 pounds. L.H. stopped drinking regular sodas and

juices, but eats either breads or two large tortillas at each meal. She admits to eating only small amounts of

“greens” and vegetables. She has not been able to implement her walks 3 times weekly; more often she only

walks once a week. Although her FPG fell to 130 mg/dL, a majority of her postprandial BG levels were more

than 180 mg/dL. Her A1C is 7.4%, and fasting triglyceride levels are now 260 mg/dL. How should her therapy

be adjusted? What factors should be considered when deciding on the next steps for pharmacologic therapy?

L.H.’s A1C has improved by 0.9%. However, she has not fully instituted lifestyle

interventions. Although she has cut out juices and regular sodas, she can still further

improve her diet and lower her postprandial BG (to <180 mg/dL) by reducing her

carbohydrate intake, switching to whole-grain breads, and increasing her vegetable

intake. She also can increase her physical activity to at least 3 times weekly.

Although the A1C is not less than 7%, a reasonable approach would be to continue

metformin at 1,000 mg PO BID and reinforce lifestyle changes at this point before

modifying her pharmacologic therapy.

The amount of A1C lowering in response to adding an antidiabetic agent appears

to depend on the baseline glycemic level. A meta-regression analysis of 61 clinical

trials evaluated the efficacy of the five classes of oral agents (sulfonylureas, glinides,

metformin, TZDs, and α-glucosidase inhibitors).

254 Significant correlations were

found between the baseline A1C and FPG, and their mean decreases as a result of

these agents. Greater reductions in A1C and FPG were observed in groups with

higher baseline levels. In addition, a meta-analysis of oral agents found that every

1% higher baseline A1C level predicted a 0.5% greater reduction in the A1C after 6

months of therapy.

255 Overall, on initiation of noninsulin monotherapy, the A1C will

typically lower by approximately 1% to 1.25%.

255

If L.H. is not able to reach an A1C of less than 7% with lifestyle interventions, the

next step for her would be to add a second antidiabetic agent. Selecting an

antidiabetic agent to treat Type 2 diabetes has become more complex because new

agents with unique mechanisms of action have been introduced into the market.

Several considerations should be taken into account when choosing initial oral

therapy for patients with Type 2 diabetes. As with all therapeutic decisions,

clinicians should also blend their knowledge of the drug (e.g., its efficacy, safety,

hypoglycemic risk, weight gain, other side effects, route of administration, and

cost/hospital formulary) with the unique characteristics of the patient (e.g., level of

glycemic control, organ function, other concurrent diseases and medications, ability

to adhere to complex medication regimens, health insurance coverage) when making

a choice of drug products.

256 The current A1C level and reduction required to reach

the A1C goal is a key consideration. It is also important to remember that studies

report the glucose-lowering effects of antidiabetic agents by their means; some

patients respond more and some respond less than the mean.

Table 53-25 compares and contrasts the efficacy, advantages, and disadvantages

of antidiabetic agents used to treat patients with Type 2 diabetes and can be used to

help select drugs for a specific patient.

The AACE guidelines recommend consideration of initiating insulin therapy (most

often basal insulin) if the A1C is more than 9% with symptoms of hyperglycemia.

39

The ADA guidelines recommend choosing based on patient’s level of glycemia and if

they are symptomatic.

7

It is an option for dual therapy in all patients, especially if

A1C > 9%, but should be strongly considered with an A1C > 10%.

7 Practitioners

should attempt to avoid unnecessarily complex therapy that may confuse the patient,

increase drug costs, and complicate the clinician’s ability to assess each

medication’s contribution to the overall therapeutic outcome.

The ADA recommends initial therapy with lifestyle changes and metformin

monotherapy. If the patient cannot tolerate metformin, any other agent approved for

monotherapy may be used. These agents include sulfonylureas, TZDs, DPP-4

inhibitors, SGLT2 inhibitors, GLP-1 receptor agonists, and insulin. Selection of

appropriate agents will be discussed later in this chapter. If after 3 months of

monotherapy the patient has not achieved their glycemic targets, a second agent may

be added. If the patient still has not achieved their glycemic targets after 3 months of

dual therapy, a third agent may be added. If glycemic targets still have not been

reached after 3 months of triple therapy, different drug classes should be tried and a

basal-bolus insulin approach may be considered.

7

SELECTING AN ALTERNATIVE TO METFORMIN AS MONOTHERAPY

CASE 53-11, QUESTION 8: Which other antidiabetic agents could be considered for L.H. as monotherapy

if she cannot tolerate metformin therapy?

Although the ADA recommends the use of metformin, in combination with lifestyle

modification, as first-line therapy, other antidiabetic agents are approved for use as

monotherapy as well. L.H. is a typical overweight Type 2 diabetes patient with early

evidence of CVD (hypertension), but with no evidence of microvascular

complications. Her liver, renal, and GI functions are normal. Patients like L.H. have

varying degrees of β-cell dysfunction and tissue resistance to insulin. In these

individuals, pulsatile insulin secretion and first-phase insulin release are absent, and

the pancreas is “blind” or unresponsive to high glucose concentrations

(glucotoxicity). Because target tissues are less responsive to insulin, hepatic glucose

output typically is increased and higher concentrations of insulin may be needed for

peripheral glucose utilization. Insulin causes more weight gain and hypoglycemia

than the other antidiabetic agents and is usually reserved for combination therapy

unless the initial A1C at diagnosis is very elevated (>10%) or ketonuria is present.

7

Often, acarbose is eliminated from consideration because slow titration is

required to minimize GI effects; anecdotally, however, people of Mexican American

origin, such as L.H., seem less susceptible to flatulence and diarrhea. Also, because

acarbose has less dramatic effects on the FPG (20–30 mg/dL decrease) and A1C

(0.5%–1.0% decrease) than the other agents, biochemical goals are less likely to be

achieved in patients whose A1C is 8.5% or higher.

Pioglitazone also can be used as monotherapy, and, like metformin, will not cause

hypoglycemia, but weight gain and edema are likely. On the positive side, the TZDs

have been shown to have better “glycemic durability” compared with metformin and

the sulfonylureas. In a double-blind, randomized, controlled trial of 4,360 patients

with Type 2 diabetes, time to monotherapy failure, defined as FPG greater than 180

mg/dL, was assessed for rosiglitazone, metformin, and glyburide (A Diabetes

Outcome Progression Trial [ADOPT]).

257 Patients were treated for a median of 4

years. The Kaplan–Meier analysis showed that the cumulative incidence of failure at

5 years was 15% for rosiglitazone, 21% for metformin, and 34% for glyburide (p <

0.0001). The suggested explanation for the favorable rosiglitazone results was that it

slowed the rate of β-cell function decline. On the negative side, TZDs are associated

with many adverse effects

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