Oral hypoglycemic drugs: groups and use

Oral hypoglycemic agents are medications taken in tablet form that lower blood glucose levels in type 2 diabetes. They work in various ways: some increase the secretion of insulin by the pancreas, others reduce glucose production by the liver, increase tissue sensitivity to insulin, or reduce sugar absorption in the intestines. Current guidelines emphasize that drug therapy always complements, and does not replace, lifestyle changes such as diet, physical activity, and weight management. [1]

The primary application of oral medications is the treatment of type 2 diabetes in adults. The focus now is not only on glucose reduction, but also on the impact on cardiovascular risk, weight, kidney function, and quality of life. Several modern classes, primarily sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists, have demonstrated their ability to reduce the risk of heart attack, stroke, heart failure, and progression of chronic kidney disease, changing the approach to therapy selection. [2]

Oral hypoglycemic agents are used in a variety of situations. In some patients, they can maintain target glycated hemoglobin levels for a long time, while in others, they are combined with each other or with insulin. The advent of new medications has expanded the possibilities for personalized treatment: age, body mass index, cardiovascular and renal disease, risk of hypoglycemia, cost, and patient preference are taken into account. [3]

It's important to understand that different classes of oral medications vary in efficacy, safety, and proven impact on outcomes. Metformin remains the standard first-line drug for most people with type 2 diabetes unless contraindicated, while sulfonylureas and thiazolidinediones are increasingly being replaced by safer, more organ-protective agents. [4]

Finally, oral medications are not a fixed regimen, but a dynamic tool. As the course of diabetes changes, complications arise, or kidney or heart function declines, therapy is regularly reviewed. This minimizes the risk of side effects and maximizes the benefits of new medications. [5]

Table 1. The place of oral hypoglycemic agents in the treatment of type 2 diabetes

Element of treatment	The role of oral medications
Lifestyle changes	The basis of treatment, drugs complement these measures
Glucose control	Reduction of glycated hemoglobin and glycemia
Prevention of complications	Some classes protect the heart and kidneys
Delaying the transition to insulin	Often possible with rational combinations
Personalization of therapy	Selection by comorbidity, risk of hypoglycemia and weight

[6]

Main mechanisms of action and classes of oral drugs

Modern pharmacology distinguishes several major classes of oral hypoglycemic agents. These include biguanides (metformin), sulfonylureas, glinides (meglitinides), thiazolidinediones, dipeptidyl peptidase 4 inhibitors, sodium-glucose cotransporter 2 inhibitors, and alpha-glucosidase inhibitors. An oral form of the glucagon-like peptide 1 receptor agonist (semaglutide) is also used to treat type 2 diabetes, although most drugs in this class are administered subcutaneously. [7]

The biguanide metformin reduces hepatic glucose production, increases tissue sensitivity to insulin, and slightly slows intestinal glucose absorption. It causes virtually no hypoglycemia, does not contribute to weight gain, and has proven benefits for cardiovascular and renal outcomes, especially when combined with sodium-glucose cotransporter 2 inhibitors. [8]

Sulfonylureas stimulate pancreatic β-cells to secrete greater amounts of insulin. This powerfully reduces glycemia, but the price of this mechanism is an increased risk of hypoglycemia and a tendency to weight gain. Efficacy may decline after several years of treatment, as the β-cell secretory reserve is depleted. Therefore, this class is gradually becoming less popular, especially in the elderly and patients at high risk of hypoglycemia. [9]

Dipeptidyl peptidase 4 inhibitors (also known as gliptins) block the enzyme that breaks down incretin hormones. This enhances the physiological response to food intake—increasing insulin release and suppressing glucagon secretion under conditions of elevated glycemia. These drugs generally do not cause hypoglycemia and have virtually no effect on body weight, but they also produce a moderate reduction in glycated hemoglobin. Cardiovascular safety has been demonstrated in large studies, although one agent (saxagliptin) has been associated with an increased risk of hospitalization for heart failure. [10]

Sodium-glucose cotransporter 2 inhibitors lower glucose levels by increasing its excretion in urine through the renal tubules. This mechanism is largely independent of insulin, making these drugs useful at various stages of type 2 diabetes. Large studies have shown that they reduce the risk of hospitalization for heart failure, progression of chronic kidney disease, and a number of cardiovascular outcomes, with the benefit persisting even in people without diabetes but with cardiac or renal disease. [11]

Thiazolidinediones (such as pioglitazone) improve tissue sensitivity to insulin by acting through receptors that regulate lipid and carbohydrate metabolism. They effectively reduce glycemia and can have a beneficial effect on cardiovascular outcomes, but they increase the risk of edema, heart failure, and fractures, especially in the elderly. Therefore, these drugs are used selectively, with careful benefit-risk assessment. [12]

Table 2. Main classes of oral hypoglycemic agents and their key mechanisms

Drug class	The main mechanism of action
Metformin (biguanide)	Decreased glucose production by the liver, increased insulin sensitivity
Sulfonylurea derivatives	Stimulation of insulin secretion by β-cells
Glinides (meglitinides)	Short-term stimulation of insulin secretion before meals
Thiazolidinediones	Increased insulin sensitivity in muscle and adipose tissue
Dipeptidyl peptidase 4 inhibitors	Enhancement of glucose-dependent incretin response
Sodium-glucose cotransporter 2 inhibitors	Increased urinary glucose excretion
Alpha-glucosidase inhibitors	Slowing down the breakdown and absorption of carbohydrates in the intestines

[13]

How is oral therapy chosen for type 2 diabetes?

Current guidelines recommend the following as the basic strategy for type 2 diabetes: all patients are advised to implement lifestyle changes, with metformin prescribed as the first drug in the absence of contraindications. This is done taking into account the patient's baseline risk of cardiovascular and renal complications, obesity, hypoglycemia, and preferences. If glycated hemoglobin targets are not achieved, medications from other classes, often with proven organ protection, are added. [14]

In patients with existing atherosclerotic cardiovascular disease or at high risk of developing it, drugs with proven cardiovascular benefit are prioritized. These include glucagon-like peptide 1 receptor agonists and sodium-glucose cotransporter 2 inhibitors, which reduce the risk of heart attack, stroke, and heart failure. In such situations, they can be prescribed early in the course of therapy, in combination with metformin or even before it if glycemia is moderately elevated and the risk of cardiovascular events is high. [15]

With the prevalence of obesity and the need for weight loss, particular attention is being paid to drugs that promote weight loss. These include glucagon-like peptide 1 receptor agonists and sodium-glucose cotransporter 2 inhibitors. These classes not only improve glycemic control but also help reduce body weight and visceral fat, which further reduces cardiovascular risk. [16]

In patients with chronic kidney disease, drug selection is particularly important. Metformin is tolerated up to a certain glomerular filtration rate (GFR), usually no less than 30 ml/min, with the dose adjusted as kidney function declines. Sodium-glucose cotransporter 2 inhibitors are considered a key class for slowing the progression of renal failure and reducing the risk of hospitalizations associated with cardiac and renal disease. [17]

If the main concern is the risk of hypoglycemia (old age, living alone, work requiring high concentration), it is preferable to use drugs with a low risk of a sharp drop in sugar: metformin, dipeptidyl peptidase 4 inhibitors, glucagon-like peptide 1 receptor agonists, sodium-glucose cotransporter 2 inhibitors, and alpha-glucosidase inhibitors. In this situation, sulfonylurea derivatives and glinides are prescribed with particular caution or replaced. [18]

Table 3. Examples of oral therapy choices in typical clinical situations

Clinical situation	Preferred classes
No complications, just type 2 diabetes	Metformin, if necessary, adding any classes taking into account the patient's profile
Atherosclerotic cardiovascular diseases	Glucagon-like peptide 1 receptor agonists, sodium-glucose cotransporter 2 inhibitors
Heart failure	Sodium-glucose cotransporter 2 inhibitors
Chronic kidney disease	Metformin (up to a certain level of renal function), sodium-glucose cotransporter 2 inhibitors
High risk of hypoglycemia	Metformin, dipeptidyl peptidase 4 inhibitors, glucagon-like peptide 1 receptor agonists, sodium-glucose cotransporter 2 inhibitors

[19]

Major classes of oral medications: a brief overview of advantages and limitations

Metformin is the first choice for most patients, as it combines effective reduction of glycated hemoglobin with a low risk of hypoglycemia and potential cardiovascular benefits. Current data show that the risk of lactic acidosis with metformin is extremely low when contraindications are observed, and the benefits in terms of reduced mortality and slowing the progression of chronic kidney disease are significant, especially when combined with sodium-glucose cotransporter 2 inhibitors. [20]

Sulfonylureas remain an effective and relatively inexpensive way to lower blood sugar, but their use increases the risk of severe hypoglycemia and weight gain. They are suitable for patients without high cardiovascular and hypoglycemic risk, especially when access to more modern drugs is limited. However, they have not been shown to provide cardiorenal benefits comparable to those of sodium-glucose cotransporter 2 inhibitors or glucagon-like peptide 1 receptor agonists. [21]

Glinides (repaglinide and analogs) have a short duration of action and are taken before meals, helping to control postprandial hyperglycemia. They are less likely to cause late-night hypoglycemia, but can still cause it, especially if a meal is taken at the wrong time or if a meal is skipped after taking a pill. This class may be useful in patients with irregular eating patterns, but new guidelines place glinides in a secondary position compared to incretin agents and sodium-glucose cotransporter 2 inhibitors. [22]

Thiazolidinediones are effective in severe insulin resistance, but the risk of edema, weight gain, heart failure, and fractures limits their use. In some patients with high cardiometabolic risk, pioglitazone may reduce the incidence of major cardiovascular events and, according to some studies, even the risk of dementia, but these potential benefits must be weighed against the likelihood of adverse events. This balance makes thiazolidinediones a drug for carefully selected patients rather than for general use. [23]

Dipeptidyl peptidase 4 inhibitors and sodium-glucose cotransporter 2 inhibitors are among the most popular modern classes of oral medications due to their good tolerability and low risk of hypoglycemia. The former are often chosen when safety and minimal impact on weight are a priority, while the latter are chosen when reducing cardiovascular and renal risk and achieving moderate weight loss are important. Combining these classes with metformin and, if necessary, a glucagon-like peptide 1 receptor agonist allows for a multi-step, yet physiologically sound and organ-protective, therapy. [24]

Table 4. Comparative characteristics of key classes of oral drugs

Class	Effect on glycated hemoglobin	Risk of hypoglycemia	Effect on body weight
Metformin	Average	Short	Neutral or slightly reduced
Sulfonylureas	High	High	Increase
Glynides	Average (especially after meals)	Average	A slight increase
Thiazolidinediones	Average	Short	Increase
Dipeptidyl peptidase 4 inhibitors	Average	Short	Neutral
Sodium-glucose cotransporter 2 inhibitors	Average	Short	Decrease

[25]

Safety, side effects and drug interactions

Like any medication, oral hypoglycemic agents can cause side effects. The most common gastrointestinal side effects for metformin include nausea, abdominal discomfort, and diarrhea. These side effects are often reduced by slowly titrating the dose and taking the medication with food. Lactic acidosis is a rare but potentially serious complication, the risk of which is minimal if contraindications are followed and renal function is taken into account. [26]

The main risk of sulfonylureas is hypoglycemia, especially in the elderly, when skipping meals, when consuming alcohol excessively, and when combined with other glucose-lowering medications. In severe cases, this condition can manifest as confusion, seizures, and even loss of consciousness, requiring emergency treatment. An additional concern is weight gain, which can worsen blood pressure control, lipid profile, and overall cardiovascular health. [27]

Dipeptidyl peptidase 4 inhibitors are generally well tolerated, cause hypoglycemia less frequently, and do not affect body weight, but may cause uncommon side effects such as upper respiratory tract infections, skin reactions, and, according to some studies, pancreatitis. One member of the class has been shown to increase the risk of hospitalization for heart failure, leading to more cautious use in patients with significant cardiac disease. [28]

Sodium-glucose cotransporter 2 inhibitors have an interesting side effect profile. They can cause increased urination, a mild decrease in blood pressure, an increased risk of genital yeast infections, and, in isolated cases, ketoacidosis in the presence of relatively moderate hyperglycemia. However, the cardiovascular and renal benefits of this class have been so significant in large studies that they are recommended for many patients with heart failure and chronic kidney disease, even with moderately elevated glucose levels. [29]

In terms of drug interactions, the induction of liver enzymes by metformin and some older drugs is particularly important, as is the effect of thiazolidinediones and sulfonylureas on the action of anticoagulants, antihypertensives, and lipid-lowering agents. Any addition of a new drug to a diabetes treatment regimen requires a review of the entire medication load, including over-the-counter medications and dietary supplements, to avoid unexpected interactions and increased side effects. [30]

Table 5. Typical side effects of the main classes of oral drugs

Class	Common side effects	Rare but serious complications
Metformin	Nausea, diarrhea, abdominal discomfort	Lactic acidosis in severe concomitant diseases
Sulfonylureas	Hypoglycemia, weight gain	Severe hypoglycemia, allergic reactions
Dipeptidyl peptidase 4 inhibitors	Mild infections, skin reactions	Pancreatitis, heart failure for certain drugs
Sodium-glucose cotransporter 2 inhibitors	Genital infections, decreased blood pressure	Ketoacidosis, rare severe infections
Thiazolidinediones	Edema, weight gain	Heart failure, fractures

[31]

Special patient groups, combination therapy and practical implications

In elderly patients, those with cognitive impairment, high risk of falls, and polypharmacy, minimizing hypoglycemia and drug interactions is a key goal. For these patients, regimens based on metformin, dipeptidyl peptidase 4 inhibitors, and sodium-glucose cotransporter 2 inhibitors are preferred, while sulfonylureas and glinides are used sparingly or avoided. This approach reduces the risk of hospitalizations associated with falls, confusion, and severe hypoglycemia. [32]

In the combination of type 2 diabetes with obesity, atherosclerosis, and chronic kidney disease, glucagon-like peptide 1 receptor agonists and sodium-glucose cotransporter 2 inhibitors become the primary treatment. Glucagon-like peptide 1 receptor agonists, including oral semaglutide, improve glycemic control, promote significant weight loss, and have been shown to reduce the risk of major cardiovascular events. Sodium-glucose cotransporter 2 inhibitors protect the heart and kidneys, which is especially important for patients with existing complications. [33]

Combination therapy has become standard for many patients, as a single drug is rarely able to provide stable glycemic control at all stages of the disease. Common combinations include metformin with a sodium-glucose cotransporter 2 inhibitor, a dipeptidyl peptidase 4 inhibitor, or a glucagon-like peptide 1 receptor agonist. These strategies consider not only the reduction in glycated hemoglobin but also the impact on weight, blood pressure, lipid profile, renal function, and tolerability. [34]

If target glycated hemoglobin levels are unattainable or severe complications develop despite maximally tolerated oral therapy, insulin therapy becomes necessary. Oral medications are often not discontinued completely: metformin and sodium-glucose cotransporter 2 inhibitors are continued to reduce insulin requirements and protect organs. This stepwise approach allows for smooth adaptation of therapy to disease progression and the patient's needs. [35]

The main practical conclusion for patients: oral hypoglycemic agents are part of a comprehensive strategy that includes lifestyle changes, weight management, blood pressure and lipid management, smoking cessation, and regular medical monitoring. Self-modification of dosages, adding "strong pills," or refusing prescribed treatment due to temporary side effects without consulting a specialist are potentially dangerous. Any questions about medications, their combinations, and their effects on the heart and kidneys should be discussed with a doctor, who is guided by current international recommendations and the individual's condition. [36]

Table 6. Example of stepwise intensification of oral therapy for type 2 diabetes

Stage of therapy	Possible scheme
Stage 1	Lifestyle plus metformin
Stage 2 (insufficient control)	Metformin plus a sodium-glucose cotransporter 2 inhibitor or a glucagon-like peptide 1 receptor agonist
Stage 3	Addition of a third drug (dipeptidyl peptidase 4 inhibitor or other agent) based on the patient's profile
Stage 4	Addition of basal insulin while maintaining metformin and organ-protective drugs
Stage 5	Individual combination regimen of insulin and oral agents under the supervision of a specialist

[37]