Updates to Type 2 Diabetes Treatment Guidelines: The Latest in Pharmacotherapy

Introduction

The treatment landscape for Type 2 Diabetes Mellitus (T2DM) has undergone significant changes over the past five years. Advances in pharmacotherapy have introduced new oral and injectable medications that offer improved efficacy in lowering HbA1c levels, reduced risk of hypoglycemia, and a better side effect profile. This comprehensive review delves into these updates, supported by evidence from peer-reviewed studies, clinical trial data, and meta-analyses, with a focus on official American guidelines.

Advancements in Oral Medications

1. SGLT2 Inhibitors

Sodium-glucose cotransporter-2 (SGLT2) inhibitors have become a cornerstone in the management of T2DM due to their glucose-lowering effects and additional benefits, particularly in cardiovascular health.

• Efficacy in Lowering HbA1c: SGLT2 inhibitors, including empagliflozin, dapagliflozin, and canagliflozin, have shown a substantial reduction in HbA1c levels, typically ranging from 0.5-1.0%. For instance, the EMPA-REG OUTCOME trial demonstrated that empagliflozin significantly reduced HbA1c by 0.7-0.9% over a 24-week period.

• Hypoglycemia Risk: One of the notable advantages of SGLT2 inhibitors is their low risk of hypoglycemia. This is primarily because their mechanism of action is independent of insulin secretion. They promote glucose excretion through the urine, which avoids the potential for hypoglycemia seen with other diabetes medications like sulfonylureas.

• Side Effects: Common side effects of SGLT2 inhibitors include genital mycotic infections, urinary tract infections, and increased urination. Rare but serious side effects include diabetic ketoacidosis (DKA), particularly in patients with reduced insulin doses, and acute kidney injury. The CANVAS program also highlighted an increased risk of lower limb amputations with canagliflozin.

• Cardiovascular and Renal Benefits: SGLT2 inhibitors have demonstrated significant cardiovascular benefits. Empagliflozin, in the EMPA-REG OUTCOME trial, showed a 14% reduction in the primary composite outcome of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. Canagliflozin, in the CANVAS program, reduced major adverse cardiovascular events by 14%. Moreover, these medications have shown renal protective effects, delaying the progression of diabetic nephropathy.

2. GLP-1 Receptor Agonists

Glucagon-like peptide-1 (GLP-1) receptor agonists, such as liraglutide, semaglutide, and dulaglutide, offer potent glucose-lowering effects along with cardiovascular and weight loss benefits.

• Efficacy in Lowering HbA1c: GLP-1 receptor agonists can reduce HbA1c by 1.0-1.5%. For example, the SUSTAIN-6 trial demonstrated that semaglutide reduced HbA1c by up to 1.5%. These agents work by enhancing glucose-dependent insulin secretion, slowing gastric emptying, and promoting satiety.

• Hypoglycemia Risk: The risk of hypoglycemia with GLP-1 receptor agonists is low, especially when not used in combination with insulin or sulfonylureas. Their glucose-dependent mechanism of action helps prevent hypoglycemia.

• Side Effects: Gastrointestinal side effects, such as nausea, vomiting, and diarrhea, are common with GLP-1 receptor agonists. These symptoms are typically transient and can be managed by gradual dose escalation. Other side effects include injection site reactions and, in rare cases, pancreatitis and thyroid C-cell tumors.

• Cardiovascular Benefits: GLP-1 receptor agonists have shown significant cardiovascular benefits. The LEADER trial for liraglutide demonstrated a 13% reduction in major adverse cardiovascular events, while the SUSTAIN-6 trial for semaglutide showed a 26% reduction. These cardiovascular benefits make GLP-1 receptor agonists a preferred choice for patients with T2DM and established cardiovascular disease.

3. DPP-4 Inhibitors

Dipeptidyl peptidase-4 (DPP-4) inhibitors, such as sitagliptin, saxagliptin, and linagliptin, are another class of oral medications used in T2DM management.

• Efficacy in Lowering HbA1c: DPP-4 inhibitors offer modest reductions in HbA1c, typically around 0.5-0.8%. They work by prolonging the action of incretin hormones, which stimulate insulin release and inhibit glucagon secretion.

• Hypoglycemia Risk: DPP-4 inhibitors have a low risk of hypoglycemia, particularly when used as monotherapy or in combination with metformin. This makes them a safer option for patients at risk of hypoglycemia.

• Side Effects: Common side effects include nasopharyngitis, headache, and upper respiratory tract infections. Saxagliptin has been associated with an increased risk of heart failure in some studies, necessitating cautious use in patients with a history of heart failure.

• Cardiovascular Safety: Cardiovascular outcome trials have demonstrated that DPP-4 inhibitors are generally safe in terms of cardiovascular risk. The TECOS trial for sitagliptin showed no increased risk of major adverse cardiovascular events, heart failure, or hospitalization for heart failure.
  

Advancements in Injectable Medications

1. Insulin Analogues

New insulin analogues, including faster-acting insulins and ultra-long-acting insulins, have been introduced to improve glycemic control and patient adherence.

• Faster-Acting Insulins: Faster-acting insulin aspart (Fiasp) is a novel formulation designed to improve postprandial glucose control. Clinical trials have shown that Fiasp offers superior HbA1c reduction compared to conventional insulin aspart, with a similar safety profile.

• Ultra-Long-Acting Insulins: Ultra-long-acting insulin degludec (Tresiba) provides a stable and prolonged action profile, allowing for once-daily dosing with a reduced risk of nocturnal hypoglycemia. Studies have shown that insulin degludec reduces HbA1c effectively, with a lower incidence of hypoglycemia compared to insulin glargine.

• Hypoglycemia Risk: New insulin analogues aim to reduce the risk of hypoglycemia through more predictable pharmacokinetic profiles. Ultra-long-acting insulins like degludec have demonstrated a lower risk of nocturnal hypoglycemia, enhancing patient safety.

• Side Effects: Common side effects of insulin therapy include hypoglycemia, weight gain, and injection site reactions. However, newer formulations are designed to minimize these risks and improve patient adherence.

2. Combination Injectable Therapies

Fixed-ratio combinations of basal insulin and GLP-1 receptor agonists offer enhanced glycemic control with fewer injections, improving patient adherence and outcomes.

• Efficacy in Lowering HbA1c: Combination therapies such as insulin glargine/lixisenatide (Soliqua) and insulin degludec/liraglutide (Xultophy) have demonstrated superior HbA1c reduction compared to their individual components. Clinical trials show reductions of up to 1.6%, making them highly effective options for patients requiring intensive glycemic control.

• Hypoglycemia Risk: Combination therapies maintain a low risk of hypoglycemia due to the balanced pharmacokinetic profiles of the combined agents. The GLP-1 component helps mitigate the risk of hypoglycemia typically associated with basal insulin.

• Side Effects: Side effects are generally consistent with those of the individual components, with gastrointestinal symptoms being the most common. These combination therapies offer the additional benefit of weight reduction, particularly due to the GLP-1 receptor agonist component.

Emerging Therapies and Future Directions

1. Dual GIP/GLP-1 Receptor Agonists

Dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonists represent a promising new class of medications for T2DM. Tirzepatide is the first agent in this class to be approved.

• Efficacy in Lowering HbA1c: Tirzepatide has shown remarkable efficacy in lowering HbA1c, with reductions of up to 2.0% observed in clinical trials. This dual action enhances insulin secretion, inhibits glucagon release, and promotes satiety.

• Hypoglycemia Risk: Tirzepatide has a low risk of hypoglycemia when used as monotherapy or in combination with non-insulin therapies, owing to its glucose-dependent mechanism of action.

• Side Effects: Gastrointestinal side effects, such as nausea and vomiting, are common but tend to decrease over time. Tirzepatide also offers significant weight loss benefits, which is a major advantage for patients with T2DM.

2. Novel Insulin Delivery Systems

Advancements in insulin delivery systems, such as closed-loop insulin pumps and smart insulin pens, aim to improve glycemic control and patient convenience.

• Closed-Loop Insulin Pumps: Closed-loop systems, also known as artificial pancreas systems, automatically adjust insulin delivery based on continuous glucose monitoring. These systems have shown superior HbA1c reduction and reduced hypoglycemia compared to traditional insulin therapy. Also commonly utilized for T1DM. Speak to your MD for details.

• Smart Insulin Pens: The advanced features of smart insulin pens offer several clinical benefits, including improved accuracy in insulin dosing, enhanced adherence to prescribed regimens, and better overall glycemic control. They are quite similar to the currently available insulin pens, but have a variety of tech capabilities, including dose tracking, bluetooth connectivity, alerts, data collection, etc. One example I've seen in practice is the InPen by Companion Medical. Check with your prescription insurance provider for coverage details.

References

1. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22):2117-2128. doi:10.1056/NEJMoa1504720

2. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016;375(4):311-322. doi:10.1056/NEJMoa1603827

3. Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016;375(19):1834-1844. doi:10.1056/NEJMoa1607141

4. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm – 2020 Executive Summary. Endocr Pract. 2020;26(1):107-139. doi:10.4158/CS-2019-0472

5. Davies MJ, D’Alessio DA, Fradkin J, et al. Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018;41(12):2669-2701. doi:10.2337/dci18-0033