Glycemic control and cardiovascular risk factor management are priority considerations when choosing a treatment for type 2 diabetes mellitus (T2DM).¹ The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) emphasize the importance of making significant lifestyle modifications such as eating a healthy diet and exercising for all individuals with T2DM. At the same time, in most cases pharmacotherapy is also recommended early in the diagnosis to effectively control blood glucose levels and reduce the risks of cardiovascular and microvascular complications.^2,3

Generally, pharmacotherapy should be initiated alongside significant lifestyle changes at the time of T2DM diagnosis. However, for patients who are highly motivated and with near-target A1C levels (ie, <7.5%), a period of 3-6 months may be given to assess the effects of intense lifestyle modification on glycemic control before determining whether pharmacotherapy should be initiated.

When choosing the appropriate pharmacological agent(s) for glycemic control, the ADA and EASD recommend a patient-centered approach that considers the following factors:¹

• Comorbidities (eg, atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), and chronic kidney disease (CKD))
• Risk of hypoglycemia
• Effects on body weight
• Adverse effects
• Cost
• Patient preferences

Information and recommendations on the following commonly prescribed oral and injectable medications come from the 2018 ADA/EASD Consensus Report on the management of hyperglycemia in T2DM and the 2019 Consensus Report Update:^1,4

• Metformin
• Sodium glucose co-transporter-2 (SGLT2) inhibitors
• Glucagon-like peptide-1 (GLP-1) receptor agonists
• Dipeptidyl peptidase-4 (DPP-4) inhibitors
• Thiazolidinediones (TZDs)
• Sulfonylureas
• Insulin therapy

Other glucose-lowering medications (eg, meglitinides, a-glucosidase inhibitors, etc.) are less commonly prescribed and are not discussed in this article.

METFORMIN

Metformin is an oral medication that is highly effective in achieving glycemic control with minimal risk of hypoglycemia.¹ It reduces blood glucose levels through multiple complex mechanisms;⁵ notably, metformin inhibits gluconeogenesis (synthesis of new glucose) and reduces circulating glucose levels by acting on both the gut microbiota and hepatocytes (liver cells).

Due to its efficacy, weight loss benefits, low cost, and safety profile, metformin is usually recommended as the first-line treatment for T2DM. A sub-study of the large UK Prospective Diabetes Study (UKPDS) showed that initial monotherapy with metformin resulted in favorable diabetic clinical outcomes with less weight gain and incidences of hypoglycemia when compared to the use of insulin or sulfonylureas.⁶

Metformin should be initiated along with comprehensive lifestyle changes.⁷ Once metformin is used, it should be continued if it is well-tolerated, even as other agents are added to the regimen. A stepwise addition of other glucose-lowering medication is preferred to initial combination therapy.¹

SGLT2 INHIBITORS

SGLT2 inhibitors are oral medications recommended in patients with T2DM with certain comorbidities. In patients with or at high risk of ASCVD, CKD, or HF, SGLT2 inhibitors are preferred when HF or CKD predominates.⁴ Especially in patients with HF with reduced ejection fraction (HFrEF), SGLT2 inhibitors are shown to reduce major adverse cardiovascular events and CVD-related death. SGLT2 inhibitors have also shown to prevent the progression of CKD in patients with CKD and T2DM. In individuals whose concern for ASCVD predominates but GLP-1 receptor agonists are contraindicated or not preferred, SGLT2 inhibitors with CVD benefits are the next recommended agent. Additionally, SGLT2 inhibitors are recommended in patients without established ASCVD or CKD and with a compelling need to promote weight loss or prevent weight gain.

SGLT2 inhibitors achieve glycemic control by facilitating urinary excretion of glucose.¹ SGLT2 inhibitors also promote weight loss and blood pressure reduction with no increased risk of hypoglycemia. However, their effectiveness depends on renal function measured by the estimated glomerular filtration rate (eGFR); thus, initiation and continuation of SGLT2 inhibitors is restricted based on eGFR. An individual on SGLT2 inhibitors also needs continued monitoring of renal function. Currently no SGLT2 inhibitors are approved for use at eGFR below 45 mL/min.

SGLT2 inhibitors include:

• Canagliflozin
• Dapagliflozin
• Empagliflozin
• Ertugliflozin 

GLP-1 RECEPTOR AGONISTS

GLP-1 receptor agonists are injectable agents recommended in patients with T2DM with certain comorbidities. In patients with or at high risk of ASCVD, CKD, or HF, GLP-1 receptor agonists with CVD benefits are preferred when concern for ASCVD predominates.⁴ Evidence suggests that GLP-1 receptor agonists have the greatest benefit in reducing major adverse cardiovascular events especially in individuals with established ASCVD (eg, prior myocardial infarction, ischemic stroke, etc.). In individuals whose concern for HF or CKD predominates but SGLT2 inhibitors are contraindicated or not preferred, GLP-1 receptor agonists are the next recommended agent. Additionally, GLP-1 receptor agonists, along with SGLT2 inhibitors, are recommended in patients without established ASCVD or CKD and with a compelling need to promote weight loss or prevent weight gain.

GLP-1 receptor agonists promote weight loss and improve satiety by stimulating insulin secretion and reducing glucagon secretion.¹ GLP-1 receptor agonists have minimal risk for hypoglycemia when used as a monotherapy. The medication is recommended as the first injectable agent in most cases and comes in short or long-acting forms, administered in different frequencies.

GLP-1 receptor agonists include:

• Short Acting
  • Exenatide
  • Lixisenatide 
• Long Acting
  • Dulaglutide
  • Exenatide extended-release
  • Liraglutide
  • Semaglutide 

DPP-4 INHIBITORS

DPP-4 inhibitors are oral medications that work in a glucose-dependent manner to increase insulin secretion and reduce glucagon secretion.¹ It has a moderate glucose-lowering efficacy, minimal hypoglycemia risk as a monotherapy, neutral effect on weight, and is usually well tolerated. It is generally recommended in patients without established ASCVD or CKD and with a compelling reason to minimize hypoglycemia.

DPP-4 inhibitors include:

• Sitagliptin
• Saxagliptin
• Linagliptin
• Alogliptin 

TZDs

TZDs are oral medications that increase insulin sensitivity. It is known to have a high glycemic durability (able to maintain optimal glycemic control over time) and may increase HDL-cholesterol levels. However, the medication is associated with fluid retention and weight gain. It is usually recommended in patients without established ASCVD or CKD and with a compelling reason to minimize hypoglycemia or when cost is a major concern.

TZDs include:

• Pioglitazone
• Rosiglitazone

SULFONYLUREAS

Sulfonylureas are oral medications that stimulate pancreatic β-cells to secrete insulin. Sulfonylureas are associated with weight gain and a risk for hypoglycemia. However, given their efficacy, availability, safety profiles, and low cost, sulfonylureas are a reasonable choice when cost is an important factor. They should be used with caution among patients at high risk of hypoglycemia (eg, older patients and those with CKD).

Sulfonylureas include:

• Glibenclamide/glyburide
• Glipizide
• Glimepiride 

INSULIN THERAPY

Insulin therapy can be introduced early in the pharmacotherapy regimen if the individual has very high blood glucose or A1C levels, has symptoms of hyperglycemia, or shows signs of weight loss.⁸ However, even with the initiation of insulin therapy, metformin should be continued unless there are contraindications as there are glycemic and metabolic benefits.

Even though various formulations of insulin are available, its effectiveness highly depends on its appropriate use by the patient, among many other factors.¹ Insulin has an advantage over other glucose-lowering medications in that it can lower glucose in a dose-dependent manner over a wide range. However, insulin therapy requires glucose monitoring, frequent titration, injection, and is associated with weight gain and hypoglycemia.