Diet, exercise, and weight loss can improve glycemic control, but almost all patients with type 2 diabetes require antihyperglycemic drug therapy. Treating to a target A1C of <7% while minimizing hypoglycemia is recommended to prevent microvascular complications of diabetes (retinopathy, nephropathy, and neuropathy). An A1C target of <8% may be appropriate for some older patients.

View the Comparison Chart: SGLT2 Inhibitors

The FDA has removed a boxed warning from the labeling of products containing the sodium-glucose co-transporter 2 (SGLT2) inhibitor canagliflozin (Invokana, Invokamet, Invokamet XR) that described an increased risk of lower limb amputation associated with use of the drug. Package inserts for canagliflozin products still contain a standard warning about a risk of lower limb amputation.

Diet, exercise, and weight loss can improve glycemic control, but almost all patients with type 2 diabetes eventually require drug therapy. Treating to a glycated hemoglobin (A1C) concentration of <7% can prevent microvascular complications (retinopathy, nephropathy, and neuropathy), but whether it prevents macrovascular complications and death is unclear. An A1C target of <8% may be appropriate for older patients and those with underlying cardiovascular disease (CVD), a history of severe hypoglycemia, diabetes-related complications, a limited life expectancy, or a long duration of disease.

The FDA has approved the sodium-glucose co-transporter 2 (SGLT2) inhibitor ertugliflozin (Merck) for treatment of adults with type 2 diabetes, both alone (Steglatro) and in fixed-dose combinations with metformin (Segluromet) and sitagliptin (Steglujan). Ertugliflozin is the fourth SGLT2 inhibitor to be approved in the US. All four are available in combination with metformin and three are available in combination with a dipeptidyl peptidase-4 (DPP-4) inhibitor (see Table 3).

View the Comparison Table: SGLT2 Inhibitors

The goal of drug therapy for type 2 diabetes is to achieve and maintain a near-normal glycated hemoglobin (A1C) concentration without inducing hypoglycemia; the target is generally an A1C of ≤7%. Treating to this target has been shown to prevent microvascular complications (retinopathy, nephropathy, and neuropathy), but whether it prevents macrovascular outcomes is unclear. An A1C target of <8% may be appropriate for older patients and those with underlying cardiovascular disease, a history of severe hypoglycemia, diabetes-related complications or comorbidities, or a long duration of disease.

The FDA has approved Synjardy (Boehringer Ingelheim/Lilly), a fixed-dose combination of the sodium-glucose co-transporter 2 (SGLT2) inhibitor empagliflozin (Jardiance) and metformin (Glucophage, and others), for treatment of patients with type 2 diabetes not adequately controlled on either of these drugs alone or already being treated with both empagliflozin and metformin. It is the third SGLT2 inhibitor/metformin combination to be approved in the US.

The FDA has warned that use of an SGLT2 (sodium-glucose co-transporter 2) inhibitor for treatment of type 2 diabetes may lead to ketoacidosis.1 Three SGLT2 inhibitors, canagliflozin (Invokana, Invokamet), dapagliflozin (Farxiga, Xigduo XR), and empagliflozin (Jardiance, Glyxambi), are approved for treatment of type 2 diabetes in the US. Between March 2013 and June 2014, 20 cases of ketoacidosis requiring emergency room visits or hospitalization were reported in patients who had recently started taking an SGLT2 inhibitor; the median time to onset of symptoms after initiation of therapy was 2 weeks (range 1-175 days). SGLT2 inhibitors decrease renal glucose reabsorption and increase urinary glucose excretion, resulting in a reduction in blood glucose levels. The mechanism by which these drugs could cause ketoacidosis has not been established.

Diabetic ketoacidosis (DKA) occurs primarily in patients with type 1 diabetes; it is characterized by elevated blood glucose levels (usually ≥250 mg/dL), a high anion gap, glucosuria, and ketonuria.2 Unlike typical cases of DKA, most ketoacidosis cases associated with SGLT2 inhibitors have occurred in patients with type 2 diabetes, and in some patients glucose levels were <200 mg/dL. Only half of the 20 cases were associated with a recognizable DKA-precipitating factor, such as infection, reduced caloric intake, or reduced insulin dose. Other factors that may contribute to the development of high anion gap metabolic acidosis, such as hypovolemia, hypoxemia, reduced oral intake, acute renal impairment, and a history of alcohol use, were identified in some patients.1

1. FDA drug safety communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood. Available at: www.fda.gov. Accessed June 11, 2015.
2. AE Kitabchi et al. Hyperglycemic crises in adult patients with diabetes. Diabetes Care 2009; 32:1335.

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The FDA has approved fixed-dose combinations of metformin with either canagliflozin (Invokamet) or dapagliflozin (Xigduo XR) for treatment of patients with type 2 diabetes not adequately controlled with any one of these drugs, or in those already being treated with both metformin and either canagliflozin or dapagliflozin.