Although insulin can be added as an initial step in the hyperglycemic patient with type-2 diabetes, patients and physicians are usually reluctant to or fearful of starting injectable medications. Most commonly, insulin treatment is initiated after a combination of two or three oral medications have failed to achieve adequate glycemic control [2]. However, insulin should be recommended as initial therapy in patients with type-2 diabetes if they are symptomatic with polyuria and polydipsia and particularly if they are glucotoxic (blood glucose levels >300 mg/dL) or if they present in a catabolic state (i.e., ketosis).

In addition to lifestyle modification, metformin (the only medication of the biguanide class) is usually the first therapeutic intervention recommended to patients with type-2 diabetes [3]. Metformin is an insulin sensitizer that reduces fasting hyperglycemia by decreasing hepatic glucose production. Its HbA1c lowering effect is between 1 and 1.5 % when given as monotherapy. It can also promote mild weight loss in some patients. Furthermore, metformin has been shown to have cardioprotective effects, independent of glycemic improvement. This drug may cause gastrointestinal symptoms (in up to 50 % of patients), including bloating and diarrhea, but these are usually transient and less than 10 % of patients discontinue the medication due to side effects. Metformin is contraindicated in patients with advanced renal dysfunction and decompensated heart failure due to the potential yet rare life-threatening side effect of lactic acidosis [4]. The patient in this case was able to tolerate metformin, and her glycemic control improved. Unfortunately, however, her glycemic control deteriorated with time.

If glycemic endpoints have not been reached with metformin alone, sulfonylureas can be added [3]. The risk of hypoglycemia increases with this combination therapy, as observed in this case. Longer acting sulfonylureas (i.e., glyburide) are more likely to cause hypoglycemia, especially in the elderly and in patients with renal dysfunction [5]. Glipizide is mainly metabolized by the liver and is therefore a safer drug to use in patients with impaired renal function. Weight gain may also occur in patients taking sulfonylureas. Secondary failure with this class of medication is common. This patient was unable to tolerate the lowest dose available of glimepiride and the medication needed to be discontinued.

Meglitinides (i.e., repaglinide) enhance insulin secretion by a similar mechanism to sulfonylureas, but have a shorter half-life and lesser incidence of hypoglycemia [6]. Given with meals, they are useful for addressing postprandial hyperglycemia. However, the lowering effect on fasting glucose levels is minimal. Because our patient had fasting hyperglycemia, this class of medication would not have been helpful.

Thiazolidinediones (TZDs) are agonists for the peroxisome proliferator-activated receptor (PPAR) gamma and increase insulin action in liver and skeletal muscle [7]. Pioglitazone and rosiglitazone belong to this class of drugs, but rosiglitazone is currently only available through a special program, owing to its increase cardiovascular risk. TZDs lower HbA1c levels by 1.5–2 %. They are associated with weight gain and edema and may exacerbate congestive heart failure. Additionally, increased rates of fractures have been reported with TZDs. The patient in this case was trying to lose weight and has risk factors for osteoporosis; therefore, this class of medication would not have been an ideal choice for this patient.

DPP-4 inhibitors are a newer class of oral antihyperglycemic agents [8, 9]. There are four available drugs on this class: sitagliptin, saxagliptin, linagliptin, and the recently FDA-approved alogliptin. Medications in this group increase incretin (glucagon-like peptide-1) action by inhibiting the dipeptidylpeptidase-4 (DPP-4) enzyme, resulting in enhanced insulin secretion suppression of glucagon production. Medications in this class are considered weight neutral and are unlikely to cause hypoglycemia when used as monotherapy. They primarily address postprandial hyperglycemia (via increase of glucose-stimulated insulin release); a mild improvement of fasting hyperglycemia is also mediated by glucagon suppression. The HbA1c decrease obtained with DPP-4 inhibitors ranges from 0.6 % to 1 %. Of note, upper respiratory infections, nasopharyngitis and headaches are reported side effects. Acute pancreatitis has been associated with this class of medications. Our patient experienced headaches, which resolved with discontinuation of the medication.

GLP-1 receptor agonists also target the incretin system. Available medications in this class include exenatide (dosed twice daily), liraglutide, (dosed once daily), and the newer once weekly extended-release exenatide [10]. These are injectable medications that bind to the GLP-1 receptor and stimulate insulin release in a glucose-dependent manner. They also decrease glucagon secretion and gastric emptying. Their HbA1c lowering effect is between 0.5 and 1.5 %. GLP-1 receptor agonist is associated with significant weight loss. They can sometimes cause minor hypoglycemia as monotherapy. Commonly, they can initially cause nausea and vomiting. They may be associated with pancreatitis and should be used with caution in patients with renal dysfunction [11]. The patient in the case was already successfully losing weight through lifestyle change. She struggled with postprandial hypoglycemia when taking sulfonlyureas. Thus, this medication class was not recommended.