by UGT1A9 and UGT2B4 to two inactive metabolites. Approximately 7% is

metabolized by CYP3A4. Approximately 33% of a dose is excreted in the urine as

metabolites and <1% is excreted as unchanged canagliflozin in the urine. The

terminal half-life is 10.6 hours for a 100-mg dose and 13.1 hours for a 300-mg dose.

Dapagliflozin has a bioavailability of 78% after the administration of a 10-mg

dose.

233 The maximal serum concentration (Cmax

) occurs at approximately 2 hours

under fasting state. Taking dapagliflozin with a high-fat meal decreases the Cmax by

up to 50%; however, this change is not clinically significant. Therefore, it may be

administered with or without food. Dapagliflozin is approximately 91% protein

bound and is metabolized primarily by the UGT1A9 pathway and to a small extent by

CYP 3A4 to yield inactive metabolites. This agent and the inactive metabolites are

excreted 75% in the urine and 21% in the feces, with 15% being excreted as

unchanged drug. The terminal half-life is approximately 12.9 hours following a

single-dose administration.

Empagliflozin reached peak plasma concentrations at 1.5 hours postoral

administration.

234 Plasma concentrations then declined in a biphasic manner with a

rapid distribution phase and a slower terminal phase. The Cmax decreased by 37%

after administration with a high-fat meal; however, this was determined to be

clinically insignificant. Therefore, empagliflozin may be administered with or

without food. Empagliflozin is 86.2% bound to plasma proteins, and the agent is

primarily metabolized by glucuronidation by UGT3B7, UGT1A3, UGT1A8, and

UGT1A9. No major metabolites were detected in plasma. Approximately 41.2% of

the drug was eliminated in feces (unchanged parent drug), whereas 54.4% was

eliminated in urine (half is unchanged parent drug). The terminal half-life is

approximately 12.4 hours.

ADVERSE EFFECTS

Canagliflozin commonly reported adverse effects include female genital mycotic

infections, increased urination, and urinary tract infections.

232 The most common

adverse effects associated with dapagliflozin include nasopharyngitis, urinary tract

infections, and female genital mycotic infections.

233 The most common adverse

effects associated with empagliflozin include female genital mycotic infections and

urinary tract infections.

234

CONTRAINDICATIONS AND PRECAUTIONS

All SGLT2 agents are contraindicated in patients with hypersensitivity reactions to

the agents and in patients with severe renal impairment, ESRD, and dialysis.

233–234

Based on the mechanism of action of these agents, they would be ineffective in

patients with severe renal impairment and would place these patients at increased

risk for renal adverse effects. Renal function should be assessed prior to the

initiation of these agents and periodically during treatment. Blood pressure should be

assessed in patients prior to initiation with these agents and hypovolemia should be

corrected due to the potential of these agents to lower blood pressure, especially in

patients already taking antihypertensive medications. Hypoglycemia may occur when

SGLT2 agents are used in combination with insulin and secretagogues; therefore, the

doses of the concomitant agents may need to be decreased. Renal function may be

impaired with use of these agents; therefore, renal function monitoring should occur

during therapy. Serum concentrations of LDL may be increased with SGLT2 therapy,

which may require medication therapy, and serum LDL concentrations should be

monitored. In clinical trials, dapagliflozin has shown an increase in bladder cancer

cases as compared to placebo; therefore, patients with previous history of bladder

cancer should not take dapagliflozin.

235

In May 2015, the FDA released a Drug Safety Communication warning that SGLT2

agents may cause ketoacidosis and patients should be warned to seek medical

attention if they experience signs and symptoms of ketoacidosis including confusion,

fatigue, difficulty breathing, abdominal pain, nausea, or vomiting.

236 The cases were

not typical of DKA cases, because blood sugars were not highly elevated. In some of

the cases, DKA may have been triggered by major illness. The FDA will monitor the

safety of these agents and determine whether prescribing information changes are

warranted.

DRUG INTERACTIONS

Canagliflozin weakly inhibits CYP2B6, CYP2C8, CYP2C9, and CYP3A4, is a weak

inhibitor of P-gp, and is a substrate of drug transporters P-gp and MRP2.

232 Rifampin

decreases the efficacy of canagliflozin; therefore, the dose of canagliflozin may need

to be increased. When administered concomitantly with digoxin, there was an

increase in the AUC (20%) and Cmax

(36%) of digoxin; therefore, digoxin should be

monitored appropriately.

Dapagliflozin does not inhibit CYP enzymes and is a weak substrate of the Pglycoprotein (P-gp) active transporter. The dapagliflozin metabolite is a substrate for

the OAT3 active transporter; however, it did not inhibit P-gp, OCT2, OAT1, or

OAT3 active transporters with any clinical significance. Therefore, dapagliflozin is

unlikely to affect the pharmacokinetics of concurrently administered medications that

are substrates of these enzymes. Coadministration of dapagliflozin with rifampin, a

nonselective inducer of UGT1A9, may cause a decrease in dapagliflozin serum

concentrations, which may lead to a decrease in dapagliflozin efficacy.

233

Empagliflozin does not induce or inhibit CYP450 enzymes or UGT1A1; therefore,

it is not expected to have interactions with concomitantly administered medications

that are substrates of the CYP450 pathway or UGT1A1.

234

EFFICACY

Canagliflozin monotherapy versus placebo decreased A1C by 0.77% to 1.03%,

decreased FPG by 27 to 35 mg/dL, and decreased body weight by 2.8% to 3.9%.

232

In a clinical trial comparing dapagliflozin monotherapy to placebo, A1C was

decreased by 0.8% to 0.9% and FPG was decreased by 24.1 to 28.8 mg/dL.

233

Empagliflozin monotherapy, in a clinical trial compared to placebo, decreased A1C

by 0.7% to 0.8%, decreased FPG by 19 to 25 mg/dL, and decreased body weight by

2.8 to 3.2%.

234

DOSAGE AND CLINICAL USE

The SGLT2 agents are indicated for use in patients with Type 2 DM as an adjunct to

diet and exercise as monotherapy or concomitantly with other antidiabetic agents.

The initial dose of canagliflozin is 100 mg once daily taken before the first meal of

the day and can be increased to 300 mg once daily in patients who need additional

glycemic control and have an eGFR > 60ml/min/1.73 m2

.

237

In patients with an eGFR

of 45 to 60 mL/minute/1.73 m2

, the dose is limited to 100 mg once daily and should

be discontinued in patients with an eGFR <45 mL/minute/1.73 m2

.

232 Dapagliflozin

should be initiated at a dose of 5 mg once daily in the morning, with or without food,

and the dose may be increased in patients who need additional glycemic control.

233

Monitor renal function prior to initiation and do not use in patients with an eGFR <60

mL/minute/1.73 m2

. Empagliflozin should be initiated at a dose of 10 mg once daily

in the morning, with or without food, and may be increased to 25 mg once daily.

238

Do not initiate empagliflozin therapy in patients with an eGFR <45 mL/minute/1.73

m2 and discontinue therapy if eGFR persistently falls below 45 mL/minute/1.73 m2

.

234

Other Agents

COLESEVELAM

In January 2008, the FDA approved a new indication for colesevelam (Welchol), a

bile acid sequestrant, to be used as add-on therapy in Type 2 diabetes as an adjunct

to diet and exercise.

239

p. 1130

p. 1131

The mechanism by which colesevelam reduces glucose is not known. It is a

hydrophilic, water-insoluble polymer that is not absorbed. Therefore, its distribution

is limited to the GI tract.

239–242 The primary side effects of colesevelam are GI

(constipation, nausea, and dyspepsia). The following are contraindications for use of

colesevelam:

Patients with triglyceride levels of more than 500 mg/dL

Patients with a history of bowel obstruction

Patients with a history of pancreatitis caused by hypertriglyceridemia

Patients with of Type 1 diabetes or for the treatment of DKA

Because of its constipating effects, it should not be used in patients with

gastroparesis, other GI motility disorders, or in those who have had major GI tract

surgery and may be at risk for bowel obstruction. The tablets are large and can cause

dysphagia or esophageal obstruction; therefore, it should be used with caution in

patients with dysphagia or swallowing disorders. It should be used with caution in

patients with triglycerides in excess of 300 mg/dL because bile acid sequestrants can

cause concentrations of serum triglycerides to increase.

240–242

Drug interactions are an important consideration for colesevelam because it

reduces GI absorption of some drugs. Drugs with a known interaction with

colesevelam (e.g., phenytoin, warfarin, levothyroxine, oral contraceptives) should be

administered at least 4 hours before colesevelam. The bioavailability of glimepiride,

glyburide, and glipizide may be affected by concomitant administration of

colesevelam; therefore, these medications should be administered 4 hours prior to

colesevelam.

239

A1C reductions associated with colesevelam are 0.3% to 0.4% compared with

baseline (0.5% vs. placebo). Colesevelam also reduces LDL-C by 12% to 16%

when used in combination with metformin or a sulfonylurea respectively.

243 Bile acid

sequestrants can increase triglycerides by 5% to 22% in patients with Type 2

diabetes, depending on which antidiabetic medications are given concomitantly.

239–242

Colesevelam is approved for use as combination therapy with metformin, a

sulfonylurea, and insulin.

239

It has not been studied as monotherapy or in combination

with DPP-4 inhibitors. It can provide an added benefit in patients with dyslipidemia.

The dose is six (625 mg) tablets once daily or three tablets twice daily taken with a

meal and liquid. Alternatively, a 3.75-g packet (powder for oral suspension) once

daily or 1.875-g packet twice daily may be used by dissolving each dose in 4 to 8

ounces of water, fruit juice, or diet soda, and administering with a meal. Since its

approval, its use for treatment of Type 2 diabetes remains quite limited.

BROMOCRIPTINE

Bromocriptine mesylate, an ergot derivative, is a dopamine-2 receptor agonist that is

a quick-release formulation.

244

It was FDA-approved in May 2009 for use in Type 2

diabetes. Bromocriptine has been available since 1978 and was once widely used

for Parkinson disease. The mechanism by which bromocriptine improves glycemic

control is not known. A normal circadian peak in the central dopaminergic tone

occurs in the early morning and has been linked to induction of normal insulin

sensitivity and glucose metabolism.

237

It is theorized that taking bromocriptine in the

morning will increase central dopaminergic tone and reset the normal circadian

rhythm to that of leaner people. The recommended dose of bromocriptine in diabetes

is initiation with 0.8 mg daily, increasing by one tablet weekly until the maximum

tolerated dose of 1.6 to 4.8 mg is reached. Bromocriptine is administered once daily

within 2 hours after waking in the morning.

244

It should be taken with food to help

reduce GI side effects such as nausea. Its effect on A1C lowering is very mild: As

monotherapy, A1C is lowered by 0.1% compared with baseline (0.4% vs. placebo),

and as add-on therapy to a sulfonylurea or metformin, A1C is reduced by 0.5%.

Common side effects include hypotension, dizziness, syncope, nausea, somnolence,

headache, and exacerbation of psychotic disorders. Bromocriptine is contraindicated

in patients with known hypersensitivity to ergot-related drugs, patients with syncopal

migraine, and women who are nursing.

244 Bromocriptine is highly protein bound, and

when given concomitantly with other drugs that are highly protein bound, such as

sulfonamides, salicylates, and probenecid, the unbound fraction of these other drugs

may increase, altering their risk of adverse effects or their effectiveness.

Bromocriptine is metabolized by CYP3A4; therefore, caution should be used when

administering concomitant drugs that are CYP3A4 substrates, inducers or inhibitors.

Neuroleptic agents with dopamine receptor agonist properties, such as olanzapine,

clozapine, and ziprasidone, may reduce the effectiveness of both bromocriptine and

the other drugs; therefore, concomitant use is not recommended. Given the minor

A1C lowering, bromocriptine quick release has a very limited role as a therapeutic

agent.

244

TREATMENT OF PATIENTS WITH TYPE 2

DIABETES

Clinical Presentation

CASE 53-11

QUESTION 1: L.H. is a 45-year-old, overweight, Mexican American woman with central obesity (height, 5

feet 5 inches; weight, 165 lb; BMI, 27.5 kg/m

2

). Three months ago, she was referred to the diabetes clinic

when her gynecologist, who had been treating her for recurrent monilial infections, noted glucosuria on routine

urinalysis. Subsequently, on two separate occasions, she was found to have an FPG of 150 and 167 mg/dL; an

A1C was also checked and it was 8.2%. L.H. denies any symptoms of polyphagia or polyuria, although lately

she has been more thirsty than usual. She does complain of lethargy and takes afternoon naps when she can.

L.H.’s other medical problems include hypertension, which is well controlled on lisinopril 20 mg/day, and

recurrent monilial infections, which are treated with fluconazole. She has given birth to four children (birth

weights, 7, 8.5, 10, and 11 lb) and was told during her last pregnancy that she had “borderline diabetes.” She

currently works as a loan officer in a local bank and spends her weekends “catching up on her sleep” and

reading. L.H. has been smoking one pack of cigarettes per day for 20 years and drinks an occasional glass of

wine. She drinks at least two regular sodas daily and has a “large” glass of orange juice every morning. Her

physical activity consists of routine walking during the day (e.g., to her car). Her family history is significant for

a sister, aunt, and grandmother with Type 2 diabetes; all have “weight problems.” L.H.’s mother is alive and

well at age 77; her father died of a heart attack at age 47.

On presentation, fasting laboratory assessment reveals glucose of 147 mg/dL, triglycerides of 400 mg/dL, and

an A1C of 8.3% (normal, 4%–6%). All other values (including the complete blood count, electrolytes, LFTs,

and renal function tests) are within normal limits. L.H. is given the diagnosis of Type 2 diabetes. What features

in L.H.’s history and physical examination are consistent with this diagnosis?

The features of L.H.’s history that are consistent with Type 2 diabetes include an

FPG concentration of 126 mg/dL or higher on more than one occasion, a A1C of

6.5% or more, high BMI with central obesity, age older than 40, physical inactivity,

family history of diabetes, and Mexican American descent. L.H. also has delivered

large babies, which suggests that she may have had undiagnosed gestational diabetes,

a condition that places women

p. 1131

p. 1132

at high risk for subsequently developing Type 2 diabetes. Diagnosis on routine

examination and mild signs and symptoms of hyperglycemia (including increased

thirst and lethargy), recurrent monilial infections, hypertriglyceridemia, and

indications of CVD (hypertension) also are typical in patients with Type 2 diabetes

(see Type 2 Diabetes section and Table 53-1).

Treatment Goals

CASE 53-11, QUESTION 2: What should the goals of therapy be for L.H. and other patients with Type 2

diabetes? Which biochemical indices should be monitored?

The beginning of this chapter discussed general goals of therapy for all people

with diabetes, which include eliminating acute symptoms of hyperglycemia, avoiding

hypoglycemia, reducing cardiovascular risk factors, and preventing or slowing the

progression of both microvascular and macrovascular diabetic complications. The

ADA recommends that otherwise healthy patients with Type 2 diabetes strive to

achieve the same biochemical goals as those recommended for people with Type 1

diabetes (Tables 53-4 and 53-5).

7 When determining treatment goals for L.H. and

others with Type 2 diabetes, the same individual characteristics should be

considered as for Type 1 diabetes, such as the patient’s capacity to understand and

carry out the treatment regimen and the patient’s risk for severe hypoglycemia. Given

the data from the ACCORD, ADVANCE, and VADT trials, patients with Type 2

diabetes and CVD or multiple CVD risk factors should be carefully assessed when

determining their glycemic goals. For example, less aggressive A1C goals should be

considered for patients with advanced age (and short life expectancy), longer

duration of diabetes (more than 10 years), advanced microvascular complications, or

comorbid conditions such as significant cerebrovascular or coronary artery disease

because of the serious consequences related to hypoglycemia. Therefore, glycemic

goals for patients with Type 2 diabetes must be individualized. Emphasis should be

placed on assessment of all cardiovascular risk factors, including hypertension,

tobacco use, dyslipidemia, and family history.

As presented earlier in the Relationship of Glycemic Control to Microvascular

and Macrovascular Disease section, the UKPDS was a landmark study in patients

with Type 2 diabetes that conclusively demonstrated that improved BG control

reduces the risk of developing retinopathy, nephropathy, and, potentially,

neuropathy.

35,44,238 The 10-year follow-up study demonstrated that these outcomes

persist even though the conventional group achieved similar glycemic control with

time; an overall relative risk reduction in microvascular complications (24%) in the

sulfonylurea- or insulin-treated group compared with patients who initially received

conventional therapy was seen.

33 The exciting finding was that reductions in

macrovascular complications emerged with time, with significant reductions in MI

(15%) and death of any cause (13%) in patients initially intensively treated with

sulfonylurea or insulin. Metformin appeared to be of particular benefit, with even

greater reductions in MI and death of any cause (33% and 27%, respectively).

An additional finding of the UKPDS was that aggressive control of BP also

significantly reduced microvascular complications, strokes, diabetes-related deaths,

HF, and vision loss; during the 10-year follow-up study, these benefits diminished

with time as the BP difference between the two groups was lost (i.e., BP increased in

the tight control group and decreased in the conventional group).

245–247 These findings

stress the importance of maintaining good BP control to reduce the risk of long-term

complications.

Because L.H. is relatively young and has no symptoms of microvascular disease or

neuropathy, every effort should be made to normalize her glucose concentrations to

prevent these complications. Furthermore, a lipid panel should be ordered, and steps

should be taken to achieve normal LDL-C, HDL-C, and triglyceride levels. Often,

triglyceride levels improve as BG concentrations decline and the metabolic response

to insulin improves. (Management of dyslipidemia is addressed more fully later in

this chapter.)

Biochemical indices that should be followed to monitor L.H.’s response to therapy

include fasting, postprandial, and preprandial BG concentrations, A1C values, and

fasting triglyceride levels, as well as LDL-C and HDL-C concentrations. Based on

ADA guidelines initial metabolic goals for L.H. should be an A1C value of less than

7%, an FPG of 80 to 130 mg/dL and postprandial glucose concentrations less than

180 mg/dL.

7

Treatment

LIFESTYLE INTERVENTIONS AND INITIAL THERAPY WITH

METFORMIN

CASE 53-11, QUESTION 3: How should L.H. be managed initially?

Initial therapy of Type 2 diabetes is aimed at lifestyle changes that will minimize

insulin resistance and risk for CVD. In L.H.’s case and in the case of other

overweight (BMI, 25.0–29.9 kg/m2

) or obese (BMI ≥30.0 kg/m2

) Type 2 diabetes

individuals, this includes a lower-calorie, low-fat, low-cholesterol diet; regular

exercise; smoking cessation (see Chapter 91, Tobacco Use and Dependence); and

aggressive management of dyslipidemia and hypertension. Because central obesity is

associated with increased insulin resistance, L.H. should be strongly encouraged to

decrease her caloric intake, start exercising, and lose weight. Simple changes in her

diet (such as cutting out juice and regular soda) and physical activity level can have a

large impact on her glucose control. SMBG monitoring should be encouraged, and

education that addresses the serious nature of diabetes mellitus and its long-term

consequences also should begin. This is discussed in the previous sections, Medical

Nutrition Therapy and Physical Activity, under Treatment (See also Table 53-14).

Initial Pharmacologic Therapy with Metformin

The ADA recommends that most patients diagnosed with Type 2 diabetes begin

therapy with lifestyle modifications, including those mentioned above. In addition,

most patients should begin monotherapy with metformin upon diagnosis. If metformin

is contraindicated or poorly tolerated, agent approved for monotherapy may be used.

7

The selection of alternative agents will be discussed later in this chapter.

Although the UKPDS demonstrated that intensive therapy with sulfonylureas,

metformin, and insulin reduces glucose with equal effectiveness (TZDs were not

studied), metformin is favored as a first-choice agent in Type 2 diabetes, particularly

in overweight patients. This is because metformin lowers BG by decreasing hepatic

glucose output and insulin resistance (indirectly) without causing weight gain or

hypoglycemia. Metformin also has beneficial effects on plasma lipid concentrations

as well due to a reduction in LDL as well as fatty acids.

238

Another reason for metformin being a first choice for initial therapy is not only its

proven benefit to reduce risk of microvascular complications, but also

macrovascular disease and mortality.

33 Furthermore, in an observational study of

patients with Type 2 diabetes, and established coronary artery disease,

cerebrovascular disease, or peripheral arterial disease, metformin use was

associated with a significant reduction in all-cause mortality (22%) after only 2 years

of follow-up.

243 Metformin is also emerging as a therapy that may reduce cancer risk,

possibly attributable to its activation

p. 1132

p. 1133

of AMPK, which can suppress tumor formation. Data so far have been in animal

models and observational studies in humans.

248