Test your medicine knowledge with the MKSAP challenge, in partnership with the American College of Physicians.

A 38-year-old woman is evaluated after laboratory study results show an HbA1c value of 9.1%. Her HbA1c goal is less than 7% because she has high function, long life expectancy, few comorbidities, good support, health literacy, and access to care. Medical history is significant for morbid obesity, obstructive sleep apnea, hypertension, and hyperlipidemia. Family history is notable for her mother, sister, and brother with type 2 diabetes, obesity, hypertension, and hyperlipidemia. Medications are insulin glargine 110 units subcutaneous injection at bedtime (split into two injection depots), metformin (1000 mg twice daily), atenolol (100 mg daily), lisinopril (20 mg daily), hydrochlorothiazide (25 mg daily), and rosuvastatin (20 mg daily).

On physical examination she is afebrile, blood pressure is 148/79, pulse rate is 68/min, and respiration rate is 14/min. BMI is 42.1.

Laboratory studies show plasma glucose 229 mg/dL (12.7 mmol/L), HDL cholesterol 32 mg/dL (0.83 mmol/L), LDL cholesterol 92 mg/dL (2.4 mmol/L), triglycerides 247 mg/dL (2.8 mmol/L), and estimated glomerular filtration rate (eGFR) 40 mL/min/1.73 m². Results of other laboratory studies, including electrolytes levels and liver chemistry tests, are within normal limits.

Which of the following is the most appropriate treatment for this patient?

A. Increase insulin glargine
B. Initiate fenofibrate
C. Initiate glipizide
D. Initiate liraglutide

MKSAP Answer and Critique

Correct answer: D. Initiate liraglutide.

The most appropriate treatment for this patient is to initiate liraglutide. Liraglutide is a synthetic glucagon-like peptide-1 receptor agonist (GLP-1 agonist) that stimulates glucose-dependent insulin release from the pancreatic islets. It has been shown to decrease HbA1c by up to 1.5% as monotherapy, with relatively low risk of hypoglycemia. A recent study published in Diabetes, Obesity and Metabolism investigated the efficacy and safety of liraglutide versus placebo added to basal insulin analogues (with or without metformin) in patients with type 2 diabetes mellitus. This randomized, double-blind parallel group study showed that in overweight and obese adults from more than 75 sites in North and South America, Europe, and Asia, the addition of liraglutide to a basal insulin regimen that also included metformin in some participants resulted in a significant decrease in HbA1c levels compared with placebo. The authors also showed that body weight and systolic blood pressure significantly decreased in the liraglutide-treated participants (−3 kg and −5 mm Hg, respectively). All three of these outcomes are relevant to this patient who is morbidly obese with an HbA1c level above goal and blood pressure above goal. In the aforementioned study, insulin doses were decreased by 20% at randomization to decrease the risk of hypoglycemia; no severe hypoglycemia (defined in this study as a glucose <56 mg/dL [3.1 mmol/L]) was reported, but there was an increase in minor hypoglycemia in the liraglutide group. When initiating liraglutide in patients already taking insulin, a decrease in insulin dosing should be considered. A thorough neck examination should also be performed to screen for thyroid nodules, as liraglutide has been associated with C-cell tumors of the thyroid, including medullary thyroid cancer; in patients with a personal or family history of medullary thyroid cancer, its use is contraindicated.

The insulin glargine dose should not be increased because the patient’s dose is 110 units, which is more than 1 U/kg/d. If more insulin is required, prandial insulin is safer and more effective. Typically, total daily insulin doses are 50% basal insulin and 50% prandial insulin (split between meals). Increasing her basal insulin dose will increase her risk of hypoglycemia if she misses or is late eating a meal, or if she sleeps late.

Fenofibrate should not be initiated because her triglyceride level of 247 mg/dL (2.8 mmol/L), while elevated, is not high enough to incur a risk of pancreatitis, and the most pressing clinical concern in this patient is getting her HbA1c level to goal to lower her risks of macro- and microvascular complications of diabetes.

Glipizide should not be initiated because in a patient already on high dose insulin with an HbA1c level above 9%, a secretagogue will not offer additional glucose lowering. Her endogenous production of insulin is at its maximum rate, given her estimated average glucose of 215 mg/dL (11.9 mmol/L) (correlates to an HbA1c level of 9.1%).

Key Point

• In a recent clinical trial, liraglutide, in addition to a basal insulin analogue with or without metformin, significantly improved glycemic control, body weight, and systolic blood pressure compared with placebo.

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