View the Table: GLP-1 and GIP/GLP-1 Receptor Agonists for Type 2 Diabetes

Glucagon-like peptide-1 (GLP-1) receptor agonists and the dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist tirzepatide (Mounjaro) are widely prescribed for treatment of type 2 diabetes and weight management (see Table 1), but they delay gastric emptying and commonly cause nausea and vomiting. Gastroparesis and bowel obstruction (ileus) have also been reported with their use.

Bexagliflozin (Brenzavvy – TheracosBio), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has been approved by the FDA to improve glycemic control in adults with type 2 diabetes. It is the fifth SGLT2 inhibitor to be approved in the US for this indication (see Table 4).

The sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin has been available for years alone (Jardiance – Boehringer Ingelheim) and in combination with metformin (Synjardy) to improve glycemic control in adults with type 2 diabetes. Both products have now been approved for use in children ≥10 years old. Empagliflozin is the second oral drug to become available in the US for treatment of type 2 diabetes in children; metformin has been available since 2000 for this indication. The injectable glucagon-like peptide-1 (GLP-1) receptor agonists liraglutide (Victoza) and extended-release exenatide (Bydureon BCise) are also approved for use in children ≥10 years old.

Recently published guidelines from the American Diabetes Association (ADA) and the Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group recommend addition of the oral nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone (Kerendia) to standard treatment in patients with type 2 diabetes and chronic kidney disease (CKD).

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.

The FDA has approved tirzepatide (Mounjaro – Lilly), a peptide hormone with activity at both glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, to improve glycemic control in adults with type 2 diabetes. Tirzepatide, which is injected subcutaneously once weekly, is the first dual GIP/GLP-1 receptor agonist to become available in the US. Selective GIP receptor agonists are not available in the US; GLP-1 receptor agonists have been available for years.

Adults with a body mass index (BMI) between 25 and 29.9 kg/m² are considered overweight. Those with a BMI ≥30 are considered obese. The initial recommendation for any weight loss effort is to achieve a 5-10% reduction in weight, which has been associated with a reduction in the risk of developing type 2 diabetes, hypertension, and dyslipidemia. Diet, exercise, and behavior modification are the preferred methods for losing weight, but long-term weight maintenance can be difficult. Several drugs and devices are FDA-approved for weight reduction and maintenance of weight loss.

The FDA has approved a higher-dose injectable formulation of the long-acting glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide (Ozempic) for treatment of type 2 diabetes in adults. A single SC injection of the new 8 mg/3 mL formulation delivers 2 mg of semaglutide.

The sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance – Boehringer Ingelheim) was approved by the FDA in 2021 to reduce the risk of hospitalization for heart failure (HF) and cardiovascular death in patients with heart failure with reduced ejection fraction (HFrEF; LVEF ≤40%), regardless of whether or not they have type 2 diabetes. The indication has now been expanded to include patients with HF with any ejection fraction. Empagliflozin is the first SGLT2 inhibitor to be approved in the US for this indication.

The FDA has approved an expansion of the peripheral artery disease (PAD) indication for the oral direct factor Xa inhibitor rivaroxaban (Xarelto – Janssen) to include patients who have recently undergone a lower extremity revascularization procedure for symptomatic PAD (see Table 1). Rivaroxaban is the first direct oral anticoagulant (DOAC) to be approved for use in patients with PAD.

Finerenone (Kerendia – Bayer), an oral nonsteroidal mineralocorticoid receptor antagonist (MRA), has been approved by the FDA to reduce the risk of sustained eGFR decline, end-stage renal disease, nonfatal MI, hospitalization for heart failure (HF), and cardiovascular death in adults with chronic kidney disease (CKD) associated with type 2 diabetes. It is the first nonsteroidal MRA to be approved in the US.

The FDA has approved dasiglucagon (Zegalogue – Zealand) for subcutaneous (SC) treatment of severe hypoglycemia in patients ≥6 years old with diabetes. Dasiglucagon is the third glucagon product to be marketed in the US that does not require reconstitution before administration; Gvoke, a SC formulation approved for use in patients ≥2 years old, and Baqsimi, an intranasal powder approved for use in patients ≥4 years old, have been available since 2019. Injectable glucagon emergency kits (GlucaGen HypoKit, and generics) have been available for years, but they require reconstitution of the lyophilized powder immediately before administration.

The injectable glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide, previously approved by the FDA as Ozempic to treat type 2 diabetes and to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes and established cardiovascular disease, has now been approved in a higher dose as Wegovy (Novo Nordisk) for chronic weight management in adults with or without type 2 diabetes who have a body mass index (BMI) ≥30 kg/m² or a BMI ≥27 kg/m² and ≥1 weight-related comorbidity (e.g., hypertension, dyslipidemia). An oral formulation of semaglutide (Rybelsus) has been available since 2019 for treatment of type 2 diabetes, but it is not approved for weight management. Liraglutide (Saxenda), another subcutaneously injected GLP-1 receptor agonist, was approved for chronic weight management in 2015.

In recently published clinical trials, once-weekly subcutaneous injection of the glucagon-like peptide 1 (GLP-1) receptor agonist semaglutide (Ozempic – Novo Nordisk), which is FDA-approved for treatment of type 2 diabetes and to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes and established cardiovascular disease, has reduced body weight significantly in patients with and without type 2 diabetes when given in addition to lifestyle intervention. Liraglutide (Saxenda), another GLP-1 receptor agonist, has been FDA-approved for chronic weight management since 2015.

The FDA has approved Semglee (Mylan), an insulin glargine product similar to Lantus, for treatment of type 1 diabetes in children and adults and type 2 diabetes in adults. Semglee is the second "follow-on" insulin glargine product to become available in the US; Basaglar, which is also similar to Lantus, was the first. Lantus is a recombinant analog of human insulin that forms microprecipitates in subcutaneous tissue, prolonging its duration of action to a mean of about 24 hours with no pronounced peak effect.

In a randomized, placebo-controlled trial, the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance – Boehringer Ingelheim/Lilly) reduced the composite risk of cardiovascular death or hospitalization for worsening heart failure (HF) in patients with heart failure with reduced ejection fraction (HFrEF), whether or not they had type 2 diabetes. To date, empagliflozin has not been approved by the FDA for such use. The SGLT2 inhibitor dapagliflozin (Farxiga) was approved by the FDA for this indication earlier this year.

The FDA has approved insulin lispro-aabc (Lyumjev – Lilly), a faster-acting formulation of insulin lispro (Humalog), for treatment of type 1 and type 2 diabetes in adults. Fiasp, a faster-acting formulation of insulin aspart (Novolog), was approved in 2017.

The FDA has approved two additional doses (3 mg and 4.5 mg) of the glucagon-like peptide-1 (GLP-1) receptor agonist dulaglutide (Trulicity – Lilly) for treatment of type 2 diabetes in adults. Dulaglutide has been available in 0.75- and 1.5-mg doses for years.

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.

The sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin (Farxiga), which was initially approved by the FDA for treatment of type 2 diabetes and then to reduce the risk of hospitalization for HF in adults who have type 2 diabetes and established cardiovascular disease (CVD) or multiple cardiovascular risk factors, has now been approved for a third indication: to reduce the risk of cardiovascular death and hospitalization for heart failure (HF) in patients with heart failure with reduced ejection fraction (with or without type 2 diabetes). It is the first SGLT2 inhibitor to be approved in the US for this indication.

The FDA has approved Trijardy XR (Boehringer Ingelheim/Lilly), a fixed-dose combination of the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin, the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin, and extended-release metformin, for oral treatment of type 2 diabetes in adults. Empagliflozin and linagliptin have been available in a fixed-dose combination as Glyxambi since 2015, and both have been available in 2-drug combinations with extended-release metformin for years (see Table 1).

The FDA has approved a new formulation of glucagon (Gvoke – Xeris) for subcutaneous treatment of severe hypoglycemia in patients ≥2 years old with diabetes. Conscious patients with symptoms of hypoglycemia can take oral glucose. Glucagon is usually administered by a caregiver to an unresponsive patient. The new formulation is available in a single-use prefilled syringe (Gvoke PFS) and is expected to become available in a single-use auto-injector (Gvoke HypoPen) in 2020. Unlike previously available injectable glucagon products (Glucagon Emergency Kit, and others), Gvoke does not require reconstitution before administration. A glucagon nasal powder (Baqsimi) that does not require coordination with inhalation was recently approved for use in patients ≥4 years old.

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.

An oral formulation of the glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide (Rybelsus – Novo Nordisk) has been approved by the FDA for once-daily treatment of type 2 diabetes in adults. Semaglutide, which has been available in a subcutaneously-injected formulation (Ozempic) since 2017, is the first GLP-1 receptor agonist to become available for oral administration; the 4 other GLP-1 receptor agonists currently available in the US are administered by subcutaneous (SC) injection.

The FDA has approved glucagon nasal powder (Baqsimi – Lilly) for treatment of severe hypoglycemia in patients ≥4 years old with diabetes. Baqsimi is the first noninjectable glucagon formulation to become available in the US. Injectable glucagon emergency kits (GlucaGen Hypokit, and generic) have been available for years, but they require reconstitution of the lyophilized powder by the caregiver immediately before injection. An injectable glucagon formulation that does not require reconstitution was recently approved by the FDA (Gvoke) and is expected to become available later in 2019; it will be reviewed in a future issue.

The goal of drug therapy for type 2 diabetes is to achieve and maintain a near-normal glycated hemoglobin (A1C) concentration without inducing hypoglycemia; for most patients, the target A1C is <7%. Metformin is the preferred first-line treatment, but most patients with type 2 diabetes eventually require multidrug therapy and/or insulin to achieve glycemic control.

View the Expanded Table: Some Available Insulins

Since 2008, because of safety concerns, the FDA has mandated that long-term cardiovascular outcomes trials be conducted for all new drugs for type 2 diabetes. Reductions in the incidence of macrovascular complications in these trials with some sodium-glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists in patients at risk for cardiovascular disease (see Table 1) have led to new recommendations.

The FDA has approved Admelog (Sanofi-Aventis), an insulin lispro product similar to Humalog (Lilly), which went off patent in 2013.

Approval of Admelog was based on efficacy data with Humalog and on two 6-month, open-label, randomized, noninferiority trials. In SORELLA 11 in 507 patients with type 1 diabetes and SORELLA 22 in 505 patients with type 2 diabetes, Admelog was noninferior to Humalog in lowering A1C, fasting plasma glucose levels, and self-monitored plasma glucose levels. The incidence of adverse effects, including hypoglycemia, was similar.

Even though Admelog is very similar to Humalog in composition, strength, and structural and biological properties, and appears to produce the same glucose-lowering effects, it was not designated as a biosimilar or an interchangeable biologic product by the FDA because of a regulatory technicality: insulin is classified as a chemical, not a biological, entity, so there is no biologic reference product for insulin lispro. Pharmacists cannot substitute Admelog for Humalog without the permission of the prescriber.  

Admelog is available in 10-mL vials and in packages of five multi-dose SoloStar pens, each prefilled with 3 mL of insulin lispro 100 units/mL. A pen can deliver 1 to 80 units per injection. It should be primed with 2 units of insulin lispro before each injection. Admelog should be injected subcutaneously within 15 minutes before a meal, or immediately after a meal.

Admelog is similar to Humalog in efficacy and safety. Patients could use either one.

1. SK Garg et al. Efficacy and safety of biosimilar SAR342434 insulin lispro in adults with type 1 diabetes also using insulin glargine – SORELLA 1 study. Diabetes Technol Ther 2017; 19:516.
2. KM Derwahl et al. Efficacy and safety of biosimilar SAR342434 insulin lispro in adults with type 2 diabetes, also using insulin glargine: SORELLA 2 study. Diabetes Technol Ther 2018; 20:49.

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Adults with a body mass index (BMI) between 25 and 29.9 kg/m2 are considered overweight. Those with a BMI ≥30 are considered obese. The initial recommendation for any weight loss effort is to achieve a 5-10% reduction in weight, which has been associated with a reduction in the risk of developing type 2 diabetes, hypertension, and dyslipidemia. Diet, exercise, and behavior modification are the preferred methods for losing weight, but long-term weight maintenance can be difficult. Several drugs are FDA-approved for weight reduction and maintenance (see Table 1), and procedures such as endoscopic placement of dilated balloons have produced beneficial short-term results (see Table 2), but bariatric surgery has been the most effective intervention for sustainable long-term weight loss and reduction of obesity-related comorbidities.

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).

The FDA has approved Qtern (AstraZeneca), a fixed-dose combination of the sodium-glucose co-transporter 2 (SGLT2) inhibitor dapagliflozin (Farxiga) and the dipeptidyl peptidase-4 (DPP-4) inhibitor saxagliptin (Onglyza), for oral treatment of adults with type 2 diabetes. Dapagliflozin and saxagliptin have each been available for years alone and in combination with extended-release metformin (Xigduo XR; Kombiglyze XR). Three SGLT2/DPP-4 inhibitor combinations are now available in the US (see Table 2).

The FDA has approved semaglutide (Ozempic – Novo Nordisk), a long-acting injectable GLP-1 (glucagon-like peptide-1) receptor agonist, for once-weekly treatment of adults with type 2 diabetes. It is the sixth GLP-1 receptor agonist to be approved in the US.

The FDA has approved Fiasp (Novo Nordisk), a new formulation of insulin aspart, to improve glycemic control in adults with diabetes. Fiasp is described by the manufacturer as faster-acting than conventional insulin aspart (Novolog).

The FDA has approved Xultophy 100/3.6 (Novo Nordisk), a fixed-ratio combination of insulin degludec and the GLP-1 (glucagon-like peptide-1) receptor agonist liraglutide, for once-daily treatment of adults with type 2 diabetes inadequately controlled on basal insulin (<50 units daily) or liraglutide (≤1.8 mg daily).

For many years, the goal of drug therapy for most patients with type 2 diabetes has been to achieve and maintain an A1C of <7%. Achieving that goal can prevent microvascular complications (diabetic retinopathy, nephropathy, neuropathy), but whether it prevents macrovascular complications (myocardial infarction [MI], stroke) has been less clear. The FDA now requires that cardiovascular safety studies be performed for all new drugs for type 2 diabetes.1 Recent findings that some of the newer second-line drugs for type 2 diabetes have cardiovascular benefits have led to new interest in the cardiovascular efficacy and safety of all antidiabetic drugs.

The FDA has approved lixisenatide (Sanofi), a short-acting injectable GLP-1 (glucagon-like peptide-1) receptor agonist, for once-daily treatment of adults with type 2 diabetes, both alone (Adlyxin) and in a fixed-ratio combination with insulin glargine (Soliqua 100/33). Lixisenatide has been available since 2013 in many other countries as Lyxumia. It is the fifth GLP-1 receptor agonist to be approved in the US.

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 Basaglar (Lilly/Boehringer Ingelheim), a "follow-on" 100 units/mL insulin glargine product similar to Lantus (Sanofi), which recently went off patent. A 300 units/mL formulation of insulin glargine (Toujeo) was approved in 2015.

The oral biguanide metformin (Glucophage, and others) is generally the drug of choice for initial treatment of type 2 diabetes. It has also been used to prevent or at least delay the onset of diabetes in patients considered to be at high risk for the disease. Recent guidelines recommend considering use of metformin in patients with prediabetes (fasting plasma glucose 100-125 mg/dL, 2-hr post-load glucose 140-199 mg/dL, or A1C 5.7-6.4%), especially in those who are <60 years old, have a BMI >35 kg/m², or have a history of gestational diabetes. Metformin has not been approved for such use by the FDA.

The FDA has approved Jentadueto XR (Boehringer Ingelheim/Lilly), a once-daily extended-release formulation of the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin and the biguanide metformin, for oral treatment of type 2 diabetes. Linagliptin and metformin have been available for years in a twice-daily immediate-release combination (Jentadueto). Once-daily extended-release formulations combining metformin with the DPP-4 inhibitors saxagliptin (Kombiglyze XR) and sitagliptin (Janumet XR) are also available.

At the same time that the FDA announced it was strengthening existing warnings about the risk of acute kidney injury in patients with type 2 diabetes treated with the sodium-glucose co-transporter 2 (SGLT2) inhibitors canagliflozin (Invokana, and others) and dapagliflozin (Farxiga, and others), a study was published showing that the third SGLT2 inhibitor, empagliflozin (Jardiance, and others), slowed the progression of renal dysfunction in patients with type 2 diabetes.

The FDA has required labeling changes that replace serum creatinine (SCr) with estimated glomerular filtration rate (eGFR) as the parameter used to determine the appropriateness of treatment with the biguanide metformin (Glucophage, and others) in patients with renal impairment. These changes will allow more patients with mild to moderate renal impairment to receive metformin, which is generally the first drug prescribed for treatment of type 2 diabetes.

Metformin was previously contraindicated in women with a SCr level ≥1.4 mg/dL and in men with a SCr level ≥1.5 mg/dL, but use of SCr as a surrogate indicator tends to underestimate renal function in certain populations (e.g., younger patients, men, black patients, patients with greater muscle mass). The calculation of eGFR takes into account age, race, and sex, as well as SCr level, providing a more accurate assessment of kidney function. A literature review summarized in an FDA Drug Safety Communication concluded that, based on eGFR, metformin is safe to use in patients with mild renal impairment and in some patients with moderate renal impairment.1

The eGFR should be calculated before patients begin treatment with metformin and at least annually thereafter. Metformin is now contraindicated in patients with an eGFR <30 mL/min/1.73 m², and starting treatment with the drug in patients with an eGFR between 30 and 45 mL/min/1.73 m² is not recommended. If the eGFR falls below 45 mL/min/1.73 m² in a patient already taking metformin, the benefits and risks of continuing treatment should be assessed. Metformin should be not be administered for 48 hours after an iodinated contrast imaging procedure in patients with an eGFR <60 mL/min/1.73 m² or a history of liver disease, alcoholism, or heart failure, or in those receiving intra-arterial contrast, and the eGFR should be re-evaluated before treatment is restarted.

1. FDA Drug Safety Communication: FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function. Available at: www.fda.gov. Accessed April 14, 2016.

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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 approved insulin degludec (Tresiba – Novo Nordisk) for treatment of adults with type 1 or type 2 diabetes. Insulin degludec is the third long-acting human insulin analog to be approved by the FDA; insulin detemir (Levemir) and insulin glargine (Lantus, Toujeo) were approved earlier.

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 Toujeo (Sanofi), a more concentrated form of insulin glargine containing 300 IU/mL compared to the 100 IU/mL in Lantus (Sanofi). Lantus is nearing the end of its patent protection in the US, and biosimilars are expected to become available.

The FDA has approved Glyxambi (Boehringer Ingelheim/Lilly), a fixed-dose combination of empagliflozin (Jardiance) and linagliptin (Tradjenta), for oral treatment of type 2 diabetes in adults. It is the first combination of a sodium-glucose co-transporter 2 (SGLT2) inhibitor and a dipeptidyl peptidase-4 (DPP-4) inhibitor to be approved in the US.

The FDA has approved an inhaled, rapid-acting, dry-powder formulation of recombinant human insulin (Afrezza – Mannkind/Sanofi) for treatment of adults with type 1 or type 2 diabetes. In patients with type 1 diabetes, the drug must be used in combination with long-acting insulin. Another inhaled, rapid-acting insulin (Exubera) was approved in 2006 for the same indication, but was withdrawn from the market the following year.

Adults with a body mass index (BMI) between 25 and 29.9 kg/m² are considered overweight. Those with a BMI ≥30 are considered obese. Losing even a small amount of weight and increasing physical activity can prevent some of the complications of obesity, particularly type 2 diabetes. Diet and exercise are the preferred methods for losing weight, but long-term failure rates are high. Several drugs have been approved by the FDA for weight reduction, but adherence is poor, adverse effects are common, and patients usually regain the lost weight when the drug is stopped. Bariatric surgery can produce substantial weight loss and significantly reduce obesity-related comorbidities; long-term data on its safety are encouraging, but still limited. Guidelines for the management of overweight or obese adults have recently been published.

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.

Two new injectable GLP-1 (glucagon-like peptide-1) receptor agonists, dulaglutide (Trulicity [trū li si tee] – Lilly) and albiglutide (Tanzeum [tan' zee um] – GSK), have been approved by the FDA for once-weekly treatment of type 2 diabetes. Other available GLP-1 receptor agonists include exenatide, which is approved for injection twice daily (Byetta) or once weekly (Bydureon), and liraglutide (Victoza), which is injected once daily.

Empagliflozin (Jardiance – Boehringer Ingelheim/Lilly), an SGLT2 inhibitor, has been approved by the FDA for oral treatment of type 2 diabetes. It is the third SGLT2 inhibitor to be approved for this indication.

Dapagliflozin (dap" a gli fl oe' zin; Farxiga – Bristol-Myers Squibb/AstraZeneca), an SGLT2 (sodium-glucose co-transporter 2) inhibitor, has been approved by the FDA for oral treatment of type 2 diabetes. Dapagliflozin is the second SGLT2 inhibitor to be approved for this indication; canagliflozin (Invokana) was the first .

HMG-CoA reductase inhibitors (statins) inhibit the enzyme that catalyzes the rate-limiting step in cholesterol synthesis. The subsequent reduction in hepatic cholesterol leads to increased expression of LDL receptors, which in turn increases uptake and clearance of LDL-C from the blood. Statins also lower very low-density lipoprotein cholesterol (VLDL-C) and triglycerides. Most statins increase high-density lipoprotein cholesterol (HDL-C), but only modestly.

The FDA has approved the dipeptidyl peptidase-4 (DPP-4) inhibitor alogliptin (Nesina – Takeda) for treatment of type 2 diabetes. In addition to the single-ingredient product, the FDA also approved fixed-dose combinations of alogliptin/metformin (Kazano) and alogliptin/pioglitazone (Oseni) for the same indication. Alogliptin is the fourth DPP-4 inhibitor to become available in the US. The other three – saxagliptin (Onglyza), sitagliptin (Januvia), and linagliptin (Tradjenta) – are also available in fixed-dose combinations with metformin.

Canagliflozin (kan" a gli floe' zin; Invokana – Janssen), a sodium-glucose co-transporter 2 (SGLT2) inhibitor, has been approved by the FDA for oral treatment of type 2 diabetes.

Several readers have raised questions about the statement in our recent article (Med Lett Drugs Ther 2012; 54:58) that long-acting insulins, like metformin and sulfonylureas, have been shown to decrease long-term cardiovascular risk. Our statement was based on the extension of the UKPDS (RR Holman et al, N Engl J Med 2008; 359:1577), which is the longest prospective trial of drug therapy in patients with type 2 diabetes. Shorter studies in older patients with long-standing diabetes did not find a reduction in cardiovascular risk with these and other drugs (The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008; 358:2545; The ADVANCE Collaborative Group. N Engl J Med 2008; 358:2560; W Duckworth et al. N Engl J Med 2009; 360:129).

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Linagliptin (Tradjenta) and metformin (Glucophage, and others) are now available as a fixed-dose combination (Jentadueto – Boehringer Ingelheim/Lilly) for oral treatment of type 2 diabetes in adults. Metformin is generally the preferred first-line agent for treatment of type 2 diabetes, but most patients eventually require treatment with multiple drugs. Linagliptin is a dipeptidyl peptidase-4 (DDP-4) inhibitor like sitagliptin (Januvia) and saxagliptin (Onglyza). Both sitagliptin and saxagliptin are also available in fixed-dose combinations with metformin.

The FDA has approved a once-weekly extendedrelease formulation of exenatide (Bydureon – Amylin), an injectable glucagon-like peptide-1 (GLP-1) receptor agonist, for treatment of type 2 diabetes.

Citing some recent reports, the FDA has announced changes in the safety labeling of all HMG-CoA reductase inhibitors (statins).

The FDA has approved Juvisync (Merck), a fixed-dose combination of the antihyperglycemic DPP-4 inhibitor sitagliptin (Januvia) and the HMG-CoA reductase inhibitor simvastatin (Zocor, and others).

The development of hyperglycemia in type 2 diabetes results from a combination of metabolic abnormalities that includes insulin resistance, diminished insulin secretion and excess hepatic glucose production. Diet, exercise and weight loss are helpful in improving glucose control, but most patients ultimately require drug therapy.

Linagliptin (Tradjenta – Boehringer Ingelheim/Lilly), a third oral dipeptidyl peptidase-4 (DPP-4) enzyme inhibitor, was recently approved by the FDA for treatment of type 2 diabetes, either alone or in combination with metformin, a sulfonylurea or pioglitazone

Metformin (Glucophage, and others) is generally preferred as the first-line agent for treatment of type 2 diabetes, but most patients subsequently require treatment with more than one drug. Many combination products have been marketed; the latest of these combines saxagliptin with extended-release (ER) metformin as Kombiglyze XR.

The FDA has approved a new tablet formulation of bromocriptine mesylate (Cycloset – VeroScience) for treatment of type 2 diabetes in adults. Bromocriptine (Parlodel, and others) is an ergot-derived dopamine agonist that has been used for more than 20 years to treat hyperprolactinemia, acromegaly, Parkinson’s disease and restless leg syndrome.

The cardiovascular safety of the thiazolidinedione rosiglitazone (Avandia – GlaxoSmithKline) is in the news again, with some authorities calling for its removal from the market (New York Times, February 19, 2010).

Several large European observational studies published on-line this summer have raised questions about whether use of insulin glargine increases the risk of cancer.

A new fixed-dose tablet (PrandiMet - Novo Nordisk) combining metformin (Glucophage, and others) and repaglinide (Prandin) has been approved by the FDA for treatment of type 2 diabetes in patients already taking both metformin and repaglinide, or for patients not adequately controlled on either drug alone.

The development of hyperglycemia in type 2 diabetes results from a combination of metabolic abnormalities including insulin resistance, diminished insulin secretion and excess hepatic glucose production. Diet, exercise and weight loss are helpful in improving glucose control, but most patients ultimately require drug therapy.

The goal for drug therapy of type 2 diabetes is achieving and maintaining a near-normal glycated hemoglobin (HbA_1C) concentration without inducing hypoglycemia; the target has generally been an HbA_1C of 6.5-7.0% or lower. Whether treating to this level prevents macrovascular (cardiovascular) events has been unclear. Now, 2 large randomized, double-blind trials in patients with long-standing diabetes and at high risk for cardiovascular disease have found no decrease in macrovascular events with intensive glucose control.

The ACCORD trial in about 10,000 patients found that patients intensively treated with anti-hyperglycemic drugs, including frequent use of thiazolidinediones, mostly rosiglitazone (Avandia), and insulin, with an HbA_1C target of 6.0% (actual median HbA_1C 6.4%) did not obtain a significant reduction in major cardiovascular events (the primary endpoint) over a period of 3.5 years. The trial was stopped early because of an unexpected increase in all-cause mortality (257 deaths vs. 203) in intensively treated patients compared to patients with an HbA_1C target of 7.0-7.9% (actual median HbA_1C 7.5%). The etiology of the higher mortality is unclear.1

The ADVANCE trial in about 11,000 similar patients treated to an HbA_1C target of 6.5% with a sulfonylurea-based regimen, and infrequent use of thiazolidinediones, also found no decrease in macrovascular events, but no increase in all-cause mortality.2

Whether intensive glycemic control would reduce macrovascular events in patients at lower risk has not been established.

1. The ACCORD Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358:2545.
2. The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008; 358:2560.

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Colesevelam (Welchol - Daiichi Sankyo - Med Lett Drugs Ther 2000; 42:102), a bile-acid sequestrant used to lower LDL cholesterol, has been approved by the FDA as an adjunct to diet and exercise in the treatment of type 2 diabetes. In unpublished studies summarized in the package insert, patients with type 2 diabetes taking metformin (Glucophage, and others), a sulfonylurea or insulin (each as either monotherapy or in combination with other anti-diabetic agents) were given colesevelam 3800 mg per day or placebo; colesevelam significantly reduced glycosylated hemoglobin (A1c) by about 0.5% more than placebo in all three trials. The mechanism is unclear.

Colesevelam can cause constipation, nausea and dyspepsia, increase serum triglyceride concentrations, and interfere with absorption of other oral drugs. One month's treatment with Welchol obtained from drugstore.com would cost about $200. Medical Letter consultants are not enthusiastic about prescribing it for this indication.

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The thiazolidinediones rosiglitazone (Avandia) and pioglitazone (Actos) are peripheral insulin sensitizing agents used to treat hyperglycemia in patients with type 2 diabetes; one or the other is often used as a second or third agent with metformin (Glucophage, and others) and/or a sulfonylurea such as glimepiride (Amaryl, and others). A recent report suggested that rosiglitazone may increase the incidence of myocardial infarction (MI) and cardiovascular mortality.

Sitagliptin (Januvia) and metformin (Glucophage, and others) are now available in a single tablet (Janumet - Merck) for treatment of type 2 diabetes. The combination is approved by the FDA for use in patients not adequately controlled by sitagliptin or meformin alone or in those already taking both drugs. Metformin is also available in combination with the thiazolidinediones pioglitazone and rosiglitazone and with the sulfonylureas glipizide and glyburide.

Sitagliptin phosphate (Januvia - Merck) is the first dipeptidyl-peptidase-4 (DPP-4) inhibitor to be marketed for treatment of type 2 diabetes. It has been approved by the FDA for oral use as monotherapy or in combination with metformin (Glucophage, and others), pioglitazone (Actos) or rosiglitazone (Avandia).

An inhaled, dry-powder formulation of rapid-acting human insulin (Exubera - Pfizer) has been approved by the FDA for treatment of adults with type 1 or type 2 diabetes.

Omega-3 (n-3) polyunsaturated fatty acids (PUFAs), mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are essential human nutrients. The main dietary source of PUFAs is fatty fish such as salmon, but small amounts may be converted from α-linolenic acid in nuts, seeds, and plant oils such as canola or flaxseed oil. An increased intake of these fatty acids has been shown to modify membrane function, inhibit thrombus formation, decrease inflammation, lower plasma triglycerides, and alter the electrical activity of the myocardium.

Insulin detemir (Levemir - Novo Nordisk) is the second long-acting basal insulin analog to be marketed in the US for treatment of both type 1 and type 2 diabetes. Detemir differs from human insulin by the elimination of the amino acid threonine in position B30 and the addition of a 14-carbon fatty acid chain at position B29. Insulin glargine (Lantus), the first long-acting insulin analog, has been available since 2001 and is usually given once daily.1 NPH insulin is an intermediate-acting basal insulin given twice daily. Basal insulins are usually combined with prandial doses of a rapid-acting insulin.

Insulin glulisine (Apidra - Sanofi Aventis) is the third rapid-acting insulin analog to be marketed in the US, following insulin lispro (Humalog) and insulin aspart (Novolog). All three have a more rapid onset and shorter duration of action than regular human insulin. Rapid-acting insulin analogs are generally taken immediately before meals and are usually combined with a long-acting basal insulin.

Avandaryl, a new fixed-dose tablet combining the thiazolidinedione rosiglitazone (Avandia) and the sulfonylurea glimepiride (Amaryl, and others), was recently approved by the FDA for treatment of type 2 diabetes. It is approved for patients already taking a combination of rosiglitazone and a sulfonylurea or those not adequately controlled on rosiglitazone or sulfonylurea monotherapy. Rosiglitazone is also available in a fixed-dose combination with metformin (Avandamet). Most patients with type 2 diabetes eventually require 2 drugs with different mechanisms to control hyperglycemia.

Coenzyme Q10, a fat-soluble antioxidant also known as ubidecarenone, ubiquinone and CoQ10, is marketed as a dietary supplement in the US, both as a single ingredient and in various combination products.

For patients with diabetes poorly controlled with a single oral drug, addition of a second drug with a different mechanism can be helpful. A fixed-dose combination (Actoplus met - Takeda) of two widely used antihyperglycemic drugs, the thiazolidinedione pioglitazone (Actos) and the biguanide metformin (Glucophage, and others), has been approved by the FDA for management of type 2 diabetes. It is indicated for patients already being treated with both pioglitazone and metformin or as second-line therapy for those not adequately controlled with either metformin or pioglitazone alone. Rosiglitazone, another thiazolidinedione, is also available in a fixed-dose combination with metformin (Avandamet).

Chromium is marketed as a dietary supplement, usually containing 20-500 mcg of a chromium salt. It has been promoted for weight loss, muscle building, and for prevention and treatment of diabetes, among other claims. As a dietary supplement, chromium can be sold without proof of efficacy or safety.

The FDA recently approved the use of atorvastatin (Lipitor) to reduce the risk of heart attack and stroke in patients without heart disease who have type 2 diabetes plus other risk factors, with or without hypercholesterolemia. The agency also approved the drug's use to reduce the risk of stroke in high-risk nondiabetic patients without heart disease, whether or not they have hypercholesterolemia. Similar indications were previously approved for simvastatin (Zocor).