What are the advantages and disadvantages of newer oral anti-diabetic (oral hypoglycemic) drugs?

From the Guidelines

Newer oral anti-diabetic drugs, such as SGLT-2 inhibitors and GLP-1 agonists, are recommended as first-line or second-line therapy for type 2 diabetes due to their benefits in reducing all-cause mortality, major adverse cardiovascular events (MACE), and improving renal outcomes, as demonstrated in a systematic review and network meta-analysis 1.

Key Benefits and Drawbacks

The benefits of these newer classes of medications include:

• Cardiovascular and renal protection
• Weight loss effects
• Blood pressure reduction
• Low risk of hypoglycemia
• Once-daily dosing, improving adherence However, they also have some notable drawbacks:
• High cost, limiting accessibility
• Potential for genital mycotic infections, urinary tract infections, and volume depletion with SGLT-2 inhibitors
• Contraindication in patients with eGFR below 30 ml/min for SGLT-2 inhibitors
• Modest glucose-lowering effects and potential association with joint pain and pancreatitis risk for DPP-4 inhibitors
• Specific administration requirements and gastrointestinal side effects for oral semaglutide
• Lack of long-term safety data compared to established medications like metformin and sulfonylureas
• Requirement for dose adjustments in renal impairment

Recommendations

Based on the evidence, SGLT-2 inhibitors and GLP-1 agonists are preferred over DPP-4 inhibitors, insulin, and sulfonylureas due to their superior benefits in reducing all-cause mortality and MACE 1. When considering treatment options, it is essential to weigh the potential benefits against the potential harms and adjust the glycemic target accordingly. In patients with type 2 diabetes, lifestyle intervention and metformin are recommended as first-line therapy, unless contraindicated, and SGLT-2 inhibitors or GLP-1 agonists may be considered as second-line therapy 1. Ultimately, the choice of medication should be individualized based on patient characteristics, preferences, and medical history.

From the FDA Drug Label

The amputation data for CANVAS and CANVAS-R are shown in Tables 3 and 4, respectively [see Adverse Reactions (6. 1)]. Amputations of the toe and midfoot (99 out of 140 patients with amputations receiving INVOKANA in the two trials) were the most frequent; however, amputations involving the leg, below and above the knee, were also observed (41 out of 140 patients with amputations receiving INVOKANA in the two trials). Lower limb infections, gangrene, and diabetic foot ulcers were the most common precipitating medical events leading to the need for an amputation. The risk of amputation was highest in patients with a baseline history of prior amputation, peripheral vascular disease, and neuropathy. INVOKANA can cause intravascular volume contraction which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine [see Adverse Reactions (6. 1)] . There have been post-marketing reports of acute kidney injury which are likely related to volume depletion, some requiring hospitalizations and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including INVOKANA. Patients with impaired renal function (eGFR less than 60 mL/min/1. 73 m 2), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving INVOKANA. Treatment with INVOKANA increases the risk for urinary tract infections Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated [see Adverse Reactions (6)] . Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKANA may increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue [see Adverse Reactions (6. 1)] . The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogues) or insulin. Reports of necrotizing fasciitis of the perineum (Fournier's gangrene), a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including INVOKANA INVOKANA increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections and uncircumcised males were more likely to develop genital mycotic infections [see Adverse Reactions (6.1)] . Hypersensitivity reactions, including angioedema and anaphylaxis, have been reported with INVOKANA. These reactions generally occurred within hours to days after initiating INVOKANA. If hypersensitivity reactions occur, discontinue use of INVOKANA; treat and monitor until signs and symptoms resolve [see Contraindications (4)and Adverse Reactions (6.1,6.2)] . An increased risk of bone fracture, occurring as early as 12 weeks after treatment initiation, was observed in adult patients using INVOKANA in the CANVAS trial [see Clinical Studies (14.3)] . Consider factors that contribute to fracture risk prior to initiating INVOKANA [see Adverse Reactions (6. 1)] .

The demerits of canagliflozin (INVOKANA) include:

• Amputations: increased risk of lower limb amputations, particularly in patients with a history of prior amputation, peripheral vascular disease, and neuropathy.
• Volume depletion: may cause intravascular volume contraction, symptomatic hypotension, or acute transient changes in creatinine.
• Urinary tract infections: increased risk of serious urinary tract infections, including urosepsis and pyelonephritis.
• Hypoglycemia: may increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue.
• Necrotizing fasciitis: rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention.
• Genital mycotic infections: increased risk of genital mycotic infections, particularly in patients with a history of genital mycotic infections and uncircumcised males.
• Hypersensitivity reactions: may cause hypersensitivity reactions, including angioedema and anaphylaxis.
• Bone fracture: increased risk of bone fracture, occurring as early as 12 weeks after treatment initiation.

The merits of canagliflozin (INVOKANA) are not explicitly stated in the provided text, but it is implied that the drug is effective in treating type 2 diabetes mellitus, as it is mentioned that treatment with INVOKANA increases the risk of certain adverse reactions. However, the exact benefits of the drug are not specified in the provided text 2.

From the Research

Merits of Newer Oral Anti-Diabetic Drugs

• The newer oral anti-diabetic drugs, such as sodium-glucose cotransporter-2 (SGLT-2) inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors, have shown promising results in terms of cardiovascular safety and efficacy 3, 4, 5, 6.
• SGLT-2 inhibitors have been found to reduce the risk of heart failure and have a renoprotective effect, making them a preferred choice for patients with high or very high cardiorenal risk 5, 6.
• DPP-4 inhibitors have a neutral or beneficial effect on the kidney and do not increase the risk of cardiovascular disease 6.
• The combination of SGLT-2 inhibitors and DPP-4 inhibitors has been found to be safe and effective, with no significant drug-drug interactions, and can be used as initial combination or in a stepwise approach 7.

Demerits of Newer Oral Anti-Diabetic Drugs

• SGLT-2 inhibitors have been associated with an increased risk of female genital mycotic infections, urinary tract infections, and increased urination 4.
• DPP-4 inhibitors have been linked to a heart failure signal, although the evidence is unclear and differs between agents 6.
• SGLT-2 inhibitors can cause acute kidney injury, particularly in patients with moderate to severe renal impairment 6.
• The use of SGLT-2 inhibitors and DPP-4 inhibitors requires careful patient selection and education on potential side effects 6.