Non-sulfonylureas

I. Introduction

Non-sulfonylureas represent a diverse group of oral and injectable antihyperglycemic agents used in the management of Type 2 Diabetes Mellitus (T2DM) that do not belong to the sulfonylurea class. Unlike sulfonylureas, which stimulate insulin release by binding to sulfonylurea receptors on pancreatic β-cells, non-sulfonylurea antidiabetics include agents that work through varied mechanisms such as enhancing insulin sensitivity, suppressing hepatic glucose production, modulating incretin activity, reducing glucose reabsorption in the kidneys, and delaying carbohydrate absorption in the gut.

These agents are frequently used as monotherapy or in combination with other antidiabetic drugs (including sulfonylureas, insulin, or other non-sulfonylurea agents) to achieve optimal glycemic control and minimize complications.

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II. Classification of Non-Sulfonylurea Antidiabetic Drugs

Non-sulfonylureas can be categorized based on mechanism of action and site of effect. Below is a classification schema with major drug classes:

A. Biguanides

• Example: Metformin

B. Thiazolidinediones (TZDs)

• Examples: Pioglitazone, Rosiglitazone

C. Meglitinides (Glinides) – Not Sulfonylureas, but Secretagogues

• Examples: Repaglinide, Nateglinide

D. Dipeptidyl Peptidase-4 (DPP-4) Inhibitors

• Examples: Sitagliptin, Saxagliptin, Linagliptin, Alogliptin, Vildagliptin

E. Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists

• Examples: Exenatide, Liraglutide, Semaglutide, Dulaglutide, Lixisenatide

F. Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors

• Examples: Dapagliflozin, Empagliflozin, Canagliflozin, Ertugliflozin

G. Alpha-Glucosidase Inhibitors

• Examples: Acarbose, Miglitol

H. Amylin Analogs

• Example: Pramlintide

I. Others (Investigational or niche agents)

• Bromocriptine (D2 agonist)

• Colesevelam (Bile acid sequestrant)

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III. Mechanisms of Action

Each class of non-sulfonylurea drugs utilizes distinct mechanisms for lowering blood glucose:

Class	Mechanism
Biguanides	Decrease hepatic gluconeogenesis, improve insulin sensitivity
TZDs	Activate PPAR-γ to increase peripheral glucose uptake
Meglitinides	Stimulate insulin release via non-sulfonylurea site on β-cells
DPP-4 Inhibitors	Prolong endogenous incretin action (GLP-1 and GIP)
GLP-1 Receptor Agonists	Mimic GLP-1, enhancing insulin, suppressing glucagon, slowing gastric emptying
SGLT2 Inhibitors	Promote urinary glucose excretion via proximal renal tubules
Alpha-glucosidase Inhibitors	Delay carbohydrate absorption in the small intestine
Amylin analogs	Suppress postprandial glucagon, slow gastric emptying

IV. Individual Class Overviews

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A. Biguanides

Metformin

• First-line oral agent for T2DM

• Mechanism: Activates AMP-activated protein kinase (AMPK), reducing hepatic glucose output and increasing insulin sensitivity

• Benefits: No weight gain, low risk of hypoglycemia, possible cardiovascular benefit

• Adverse Effects: GI discomfort, metallic taste, lactic acidosis (rare)

• Contraindications: eGFR < 30 mL/min/1.73 m², hepatic impairment, alcohol abuse

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B. Thiazolidinediones (TZDs)

Pioglitazone and Rosiglitazone

• Mechanism: PPAR-γ agonists enhance peripheral insulin sensitivity

• Onset: Delayed (weeks)

• Benefits: Durable glycemic control, improvement in lipid profile (pioglitazone)

• Risks: Weight gain, fluid retention, heart failure exacerbation, bone fractures, bladder cancer (pioglitazone)

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C. Meglitinides

Repaglinide, Nateglinide

• Mechanism: Stimulate insulin secretion by binding to non-sulfonylurea receptor on β-cells

• Short-acting, targeted at postprandial glucose

• Dosing: With meals; omitted if meal is skipped

• Adverse Effects: Hypoglycemia (less than sulfonylureas), weight gain

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D. DPP-4 Inhibitors (Gliptins)

Sitagliptin, Linagliptin, Saxagliptin, Alogliptin

• Mechanism: Inhibit DPP-4 enzyme, increasing levels of GLP-1 and GIP

• Effect: Glucose-dependent insulin release, decreased glucagon

• Benefits: Oral, weight neutral, low risk of hypoglycemia

• Cautions: Pancreatitis, joint pain, possible heart failure (saxagliptin)

• Renal adjustment: Required for most except linagliptin

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E. GLP-1 Receptor Agonists (Incretin Mimetics)

Exenatide, Liraglutide, Semaglutide, Dulaglutide

• Mechanism: GLP-1 analogs that enhance insulin release, suppress glucagon, delay gastric emptying

• Form: Subcutaneous injection (oral semaglutide now available)

• Advantages:

  • Weight loss

  • Cardiovascular benefit (liraglutide, semaglutide)

• Side Effects: Nausea, vomiting, pancreatitis, gallstones

• Boxed Warning: Thyroid C-cell tumors (in rodents)

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F. SGLT2 Inhibitors (Gliflozins)

Empagliflozin, Dapagliflozin, Canagliflozin, Ertugliflozin

• Mechanism: Inhibit sodium-glucose transporter-2 in renal proximal tubule, increasing urinary glucose excretion

• Benefits:

  • Weight loss

  • Blood pressure reduction

  • Heart failure and CKD benefit (empagliflozin, dapagliflozin)

• Risks:

  • Genital infections, euglycemic ketoacidosis, volume depletion

  • Canagliflozin: bone fractures, amputation risk

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G. Alpha-Glucosidase Inhibitors

Acarbose, Miglitol

• Mechanism: Inhibit alpha-glucosidase enzymes in the intestinal brush border, delaying carbohydrate digestion

• Target: Postprandial hyperglycemia

• Side Effects: Flatulence, diarrhea, abdominal bloating

• Contraindications: IBD, intestinal obstruction

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H. Amylin Analog

Pramlintide

• Synthetic analog of amylin, a hormone co-secreted with insulin

• Use: Type 1 and Type 2 DM (adjunct to insulin)

• Mechanism: Delays gastric emptying, suppresses glucagon, enhances satiety

• Admin: Subcutaneous pre-meal injection

• Side Effects: Nausea, risk of hypoglycemia when used with insulin

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I. Other Non-Sulfonylurea Antidiabetics

1. Bromocriptine-QR (D2 receptor agonist)

   • Alters hypothalamic dopamine activity to improve insulin sensitivity

   • Minimal glucose-lowering efficacy

2. Colesevelam

   • Bile acid sequestrant; mechanism in glycemic control unclear

   • Used as an adjunct in T2DM with hyperlipidemia

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V. Comparison with Sulfonylureas

Feature	Non-Sulfonylureas	Sulfonylureas
Insulin secretion	Mostly indirect or none	Direct stimulation
Hypoglycemia risk	Lower (except meglitinides, pramlintide)	Higher
Weight impact	Weight-neutral or loss in many classes	Weight gain
CV benefit	Shown in GLP-1 RAs, SGLT2i, metformin	Not established
Durability	Varies by class; TZDs and metformin durable	Diminishing over time
Use in CKD	Caution with dose adjustment (varies)	Some contraindicated
Cancer risk	None confirmed (some debated in TZDs)	Possible link in older studies

VI. Treatment Guidelines and Positioning

According to ADA (American Diabetes Association) and EASD (European Association for the Study of Diabetes) consensus reports, non-sulfonylurea agents are favored in many situations due to:

• Better safety profile

• Cardiorenal benefits

• Weight neutrality or reduction

• Lower risk of hypoglycemia

Recommended treatment sequence in T2DM (after metformin):

1. GLP-1 receptor agonist or SGLT2 inhibitor if ASCVD, HF, or CKD

2. DPP-4 inhibitor, TZD, or basal insulin if cost is a barrier

3. Avoid sulfonylureas where hypoglycemia risk is critical

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VII. Special Considerations in Non-Sulfonylurea Therapy

• Renal dosing: Metformin, SGLT2i, and DPP-4i (except linagliptin) require adjustment

• Liver disease: Use metformin with caution; TZDs can be hepatotoxic

• Elderly: Favor agents with low hypoglycemia risk (e.g., DPP-4i)

• Obesity: Prefer GLP-1 RAs or SGLT2 inhibitors

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VIII. Common Non-Sulfonylurea Fixed-Dose Combinations

1. Metformin + DPP-4i

   • Janumet® (sitagliptin/metformin)

   • Kombiglyze XR® (saxagliptin/metformin)

2. Metformin + SGLT2i

   • Xigduo® (dapagliflozin/metformin)

   • Synjardy® (empagliflozin/metformin)

3. Metformin + GLP-1 RA

   • Not common as fixed-dose; co-administered separately

4. DPP-4i + SGLT2i

   • Glyxambi® (empagliflozin/linagliptin)

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IX. Conclusion of Facts

Non-sulfonylurea antidiabetic agents provide diverse mechanisms of action, addressing multiple pathophysiological defects in Type 2 Diabetes. They offer superior safety, weight advantages, and in many cases, cardiorenal protection compared to sulfonylureas. Their individualized selection based on comorbidities, risk of hypoglycemia, cost, and patient preferences has become the cornerstone of modern diabetes management.