1,2,4,5,6Bharati Vidyapeeth (Deemed to be University) Poona College of Pharmacy, Erandwane, Pune, Maharashtra
3Vishwakarma University, University in Pune, Maharashtra
Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic disorder characterized by insulin resistance, impaired insulin secretion, and elevated blood glucose levels. Effective management of T2DM is critical to reducing its associated complications, including cardiovascular disease, nephropathy, neuropathy, and retinopathy. This review examines the pharmacological agents currently available for T2DM management, including their mechanisms of action, efficacy, safety profiles, and potential implications for clinical practice. Classes of antidiabetic drugs discussed include insulin, sulfonylureas, meglitinides, biguanides (e.g., metformin), thiazolidinediones, alpha-glucosidase inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sodium-glucose co-transporter-2 (SGLT2) inhibitors. Emerging therapies and combination regimens are also highlighted, with a focus on personalized treatment strategies that consider patient-specific factors such as age, comorbidities, and risk of adverse effects. By providing an updated understanding of antidiabetic agents, this review aims to guide healthcare professionals in optimizing T2DM management and improving patient outcomes.
Diabetes mellitus (DM) is a complex chronic illness associated with a state of high blood glucose level, or hyperglycemia, occurring from deficiencies in insulin secretion, action, or both. The chronic metabolic imbalance associated with this disease puts patients at high risk for long-term macro- and microvascular complications, which if not provided with high quality care, lead to frequent hospitalization and complications, including elevated risk for cardiovascular diseases (CVDs). The clinical diagnosis of diabetes is reliant on either one of the four plasma glucose (PG) criteria: elevated (i) fasting plasma glucose (FPG) (>126 mg/dL), (ii) 2 h PG during a 75-g oral glucose tolerance test (OGTT) (>200 mg/dL), (iii) random PG (>200 mg/dL) with classic signs and symptoms of hyperglycemia, or (iv) hemoglobin A1C level >6.5%. Recent American Diabetes Association (ADA) guidelines have advocated that no one test may be preferred over another for diagnosis. The recommendation is to test all adults beginning at age 45 years, regardless of body weight, and to test asymptomatic adults of any age who are overweight or obese, present with a diagnostic symptom, and have at least an additional risk factor for development of diabetes. Furthermore, a condition called prediabetes or impaired fasting glucose (IFG), in which the fasting blood glucose is raised more than normal but does not reach the threshold to be considered diabetes (110–126 mg/dL), predisposes patients to diabetes, insulin resistance, and higher risk of cardiovascular (CV) and neurological pathologies . Type 2 diabetes mellitus (T2DM) can co-occur with other medical conditions, such as gestational diabetes occurring during the second or third trimester of pregnancy or pancreatic disease associated with cystic fibrosis. T2DM may also be iatrogenically induced, e.g., by use of glucocorticoids in the inpatient setting or use of highly active antiretroviral agents like protease inhibitors and nucleoside reverse transcription inhibitors in HIV-positive individuals. Chemical diabetes or impaired glucose tolerance (IGT) may also develop with the use of thiazide diuretics, atypical antipsychotic agents, and statins. Type 2 diabetes mellitus is a common and increasingly prevalent disease and is thus a major public health concern worldwide. The International Diabetes Federation estimates that there are approximately 387 million people diagnosed with diabetes across the globe. According to Centers for Disease Control and Prevention, in 2012, 29.1 million adults, or 9.3% of the population, were identified with diabetes in the United States (US). Also in the same year, 86 million people had prediabetes condition and 15–30% of them developed into full-blown diabetes . In general, 1.4 million newly diagnosed cases in the US are being reported every year. If this trend continues, it is projected that in 2050 one in three Americans will have diabetes. Patients with diabetes have increased risk of serious health complications including myocardial infarction, stroke, kidney failure, vision loss, and premature death. Diabetes, with its associated side effects, remains the seventh leading cause of mortality in the US. The World Health Organization estimates that by 2030, mortality related to diabetes will double in number if not given deliberate attention. In addition, epidemiological studies report that diabetes causes more deaths in Americans every year compared to breast cancer and acquired immunodeficiency syndrome (AIDS) combined . The increasing trend in the incidence and prevalence of diabetes is worrisome and poses a great burden on medical costs and in our current healthcare system. The ADA has released a range of recommendations called Standards of Medical Care in Diabetes to improve diabetes out comes. The recommendations include cost-effective screening, diagnostic and therapeutic strategies to prevent, delay, or effectively manage T2DM and its life-threatening complications . Per recommendations of ADA and other organizations, modern approaches to diabetes care should involve a multidisciplinary team of health professionals working in tandem with the patient and the family. The primary aim of these approaches is to obtain optimal glycemic control through dietary and lifestyle modifications and appropriate medications along with regular blood glucose level monitoring. The burden of diabetes can be potentially reduced if the standard of care is implemented as well as patients’ compliance and participation is clinically implemented. The traditional presentations of T2DM occurring only in adults and type 1 diabetes mellitus (T1DM) only in children are not entirely correctly representative, as both diseases occur in both age groups. Occasionally, patients with T2DM may develop the morbid complication of diabetic ketoacidosis (DKA) . Children with T1DM typically present with polyuria and polydipsia and approximately one-third of them present with DKA, which may also be the first presenting feature . The onset of T1DM may be variable in adults, and they may not present with the classic symptoms that are seen in children. The true diagnosis may become apparent with disease progression. The heterogeneity of the presentations should be kept in mind while caring for the patient with T2DM. The scope of this review encompasses current clinical guide lines on the pharmacological management of T2DM.
Clinical diagnosis of type 2 diabetes
The clinical diagnosis of Type 2 Diabetes Mellitus (T2DM) is based on specific criteria established by organizations like the American Diabetes Association (ADA) and the World Health Organization (WHO). Diagnostic tests include the following, with specific cut-off values:
1. Fasting Plasma Glucose (FPG) Test
2. Oral Glucose Tolerance Test (OGTT)
3. Hemoglobin A1c (HbA1c)
4. Random Plasma Glucose (RPG) Test
Clinical management of Type 2 Diabetes
Comprehensive care for a patient with diabetes requires an initial evaluation of the patient’s risk factors, the presence or absence of diabetes complications, and initial review of previous treatments . This will enable the healthcare providers to optimally manage patients with either prediabetes or diabetes. The cornerstones of diabetes management include lifestyle intervention along with pharmacological therapy and routine blood glucose monitoring.
Lifestyle Measures
Clinical trials have shown that lifestyle modifications are cost effective in preventing or delaying the onset of diabetes, with approximately 58% reduction in risk in 3 years . It is highly recommended by the ADA that patients with IGT, IFG or HbA1C level of 5.7–6.4% be counseled on lifestyle changes such as diet and exercise. On the other hand, for patients who are already diagnosed with diabetes, nutrition advice provided by a registered dietitian is recommended. A goal of moderate weight loss (≈7% of body weight) is an important component in the prevention and treatment of diabetes, as it can improve blood glucose levels, and can also positively impact blood pressure and cholesterol levels. Weight loss can be achieved through a healthy balanced diet, with control of total calories and free carbohydrates. However, for patients with diabetes adhering to a low carbohydrate diet, they should be informed on possible side effects such as hypo glycemia, headache and constipation . Other studies have suggested consumption of complex dietary fiber and whole grains to improve glycemic control . Studies show that exercise can improve glycemic control (lower HbA1C level by 0.66%), with or without significant decrease in body weight, and improve the total well-being of patients. It is considered an integral part in the prevention and management of both prediabetes and diabetes. According to the U.S. Department of Health and Human Services, adults ≥18 years of age should do a minimum of 150 min/week of moderate intensity exercise (e.g., walking at a 15- to 20-min mile pace) or 75 min/week of vigorous physical activity (e.g., running, aerobics) spread over at least 3 days/week with no more than two consecutive days without exercise to achieve maximum benefits . For patients ≤18 years old, 60 min of physical activity every day is adequate. Other lifestyle measures that need to be considered in the treatment plan for patients with diabetes are moderate alcohol consumption (≤1 drink for women, ≤2 drinks/men) and reduction in sodium intake especially in patients with comorbidities such as hypertension, habitual tobacco use, and lacking immunizations (influenza, diphtheria, pertussis, tetanus, pneumococcal, and hepatitis B). Consumption of alcohol, especially in a fasted state, can precipitate life-threatening hypoglycemia and coma and should be explicitly counseled to patients during their visits . Moreover, patient education, counseling, and psychosocial support are very important to successfully combat the deleterious effects of diabetes.
Pharmacological Management
An “ominous octet” that leads to hyperglycemia, which occur in isolation or in combination, has been proposed for eight pathophysiological mechanisms underlying T2DM . These include (i) reduced insulin secretion from pancreatic β-cells, (ii) elevated glucagon secretion from pancreatic α cells, (iii) increased production of glucose in liver, (iv) neurotransmitter dysfunction and insulin resistance in the brain, (v) enhanced lipolysis, (vi) increased renal glucose reabsorption, (vii) reduced incretin effect in the small intestine, and (viii) impaired or diminished glucose uptake in peripheral tissues such as skeletal muscle, liver, and adipose tissue. Currently available glucose-lowering therapies target one or more of these key pathways. Good glycemic control remains the main foundation of managing T2DM. Such approaches play a vital role in preventing or delaying the onset and progression of diabetic complications. It is important that a patient-centered approach should be used to guide the choice of pharmacological agents. The factors to be considered include efficacy, cost, potential side effects, weight gain, comorbidities, hypoglycemia risk, and patient preferences. Pharmacological treatment of T2DM should be initiated when glycemic control is not achieved or if HbA1C rises to 6.5% after 2–3 months of lifestyle intervention. Not delaying treatment and motivating patients to initiate pharmacotherapy can considerably prevent the risk of the irreversible microvascular complications such as retinopathy and glomerular damage . Monotherapy with an oral medication should be started concomitantly with intensive lifestyle management. The major classes of oral antidiabetic medications include biguanides, sulfonylureas, meglitinide, thiazolidinedione (TZD), dipeptidyl peptidase 4 (DPP-4) inhibitors, sodium-glucose cotransporter (SGLT2) inhibitors, and α-glucosidase inhibitors. If the HbA1C level rises to 7.5% while on medication or if the initial HbA1C is ≥9%, combination therapy with two oral agents, or with insulin, may be considered .Though these medications may be used in all patients irrespective of their body weight, some medications like liraglutide may have distinct advantages in obese patients in comparison to lean diabetics . A schematic of currently approved medications for T2DM is summarized in Table 1
Biguanide
The discovery of biguanide and its derivatives for the management of diabetes started in the middle ages. Galega officinalis, a herbaceous plant, was found to contain guanidine, galegine, and biguanide, which decreased blood glucose levels. Metformin is a biguanide that is the main first-line oral drug of choice in the management of T2DM across all age groups. Metformin activates adenosine monophosphate-activated protein kinase in the liver, causing hepatic uptake of glucose and inhibiting gluconeogenesis through complex effects on the mitochondrial enzymes. Metformin is highly tolerated and has only mild side effects, low risk of hypoglycemia and low chances of weight gain. Metformin is shown to delay the progression of T2DM, reduce the risk of complications, and reduce mortality rates in patients by decreasing hepatic glucose synthesis (gluconeogenesis) and sensitizing peripheral tissues to insulin. Furthermore, it improves insulin sensitivity by activating insulin receptor expression and enhancing tyrosine kinase activity. Recent evidence also suggest that metformin lowers plasma lipid levels through a peroxisome proliferator-activated receptor (PPAR)-α pathway, which pre vents CVDs . Reduction of food intake possibly occurs by glucagon-like peptide-1 (GLP-1)-mediated incretin-like actions. Metformin may thus induce modest weight loss in overweight and obese individuals at risk for diabetes. Once ingested, metformin (with a half-life of approximately 5 h) is absorbed by organic cation transporters and remains unmetabolized in the body and is widely distributed into different tissues such as intestine, liver, and kidney. The primary route of elimination is via kidney. Metformin is contraindicated in patients with advanced stages of renal insufficiency, indicated by a glomerular filtration rate (GFR) <30 mL/min/1.73 m² . If metformin is used when GFR is significantly diminished, the dose should be reduced and patients should be advised to discontinue the medication if nausea, vomiting, and dehydration arises from any other cause (to prevent ketoacidosis). It is important to assess renal function prior to starting this medication. Metformin has an excellent safety profile, though may cause gastrointestinal disturbances including diarrhea, nausea, and dyspepsia in almost 30% of subjects after initiation. Introduction of metformin at low doses often improve tolerance. Extended release preparations seldom cause any gastrointestinal issues. Very rarely, metformin may cause lactic acidosis, mainly in subjects with severe renal insufficiency. Another potential problem arising from the use of metformin is the reduction in the drug's efficiency as diabetes progresses. Metformin is highly efficient when there is enough insulin production; however, when diabetes reaches the state of failure of ?-cells and resulting in a type 1 phenotype, metformin loses its efficacy. Metformin can cause vitamin B12 and folic acid deficiency .This needs to be monitored, especially in elderly patients. Though very rare, in patients with metformin intolerance or contraindications, an initial drug from other oral classes may be used. Although trials have compared dual therapy with metformin alone, few directly compare drugs as add-on therapy. A comparative effectiveness meta-analysis suggests that overall each new class of non-insulin medications introduced in addition to the initial therapy lowers AIC around 0.9-1.1%. An ongoing Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) has compared the effect of four major drug classes (sulfonylurea, DPP-4 inhibitor, GLP-1 analog, and basal insulin) over 4 years on glycemic control and other psychosocial, medical, and health economic outcomes . Though it will be a welcome development for introduction of oral agents for metformin for gestational diabetes, current FDA regulations do not support it.
Incretin Mimetics
Incretin effect is the difference in insulin secretory response from an oral glucose load in comparison to glucose administered intravenously. The incretin effect is responsible for 50–70% of total insulin secretion after oral glucose intake. The two naturally occurring incretin hormones that play important roles in the maintenance of glycemic control: glucose-dependent insulinotropic polypeptide (GIP, or incretin) and glucagon-like peptide (GLP-1); these peptides have a short half-life, as these are rapidly hydrolyzed by DPP-4 inhibitors within 1½ min. In patients with T2DM, the incretin effect is reduced or absent. In particular, the insulinotropic action of GIP is lost in patients with T2DM. Incretins decrease gastric emptying and causes weight loss. Because of impact on weight loss, these medications may find increasing use in diabesity. Targeting the incretin system has become an important therapeutic approach for treating T2DM. These two drug classes Incretin effect is the difference in insulin secretory response from an oral glucose load in comparison to glucose administered intravenously. The incretin effect is responsible for 50–70% of total insulin secretion after oral glucose intake.The two naturally occurring incretin hormones that play important roles in the maintenance of glycemic control: glucose-dependent insulinotropic polypeptide (GIP, or incretin) and glucagon-like peptide (GLP-1); these peptides have a short half-life, as these are rapidly hydrolyzed by DPP-4 inhibitors within 1½ min. In patients with T2DM, the incretin effect is reduced or absent. In particular, the insulinotropic action of GIP is lost in patients with T2DM. Incretins decrease gastric emptying and causes weight loss. Because of impact on weight loss, these medications may find increasing use in diabesity. Targeting the incretin system has become an important therapeutic approach for treating T2DM. These two drug classes include GLP-1 receptor agonists and DPP-4 inhibitors. Clinical data have revealed that these therapies improve glycemic control while reducing body weight (specifically, GLP-1 receptor ago nists) and systolic blood pressure in patients with T2DM .Furthermore, hypoglycemia is low (except when used in combi nation with a sulfonylurea) because of their glucose-dependent mechanism of action
Table no 1 Pharmacological agents for glycemic control.
Class of antidiabetic medication (route of administration) |
Representative agents |
Mechanism of action |
T1/2 and metabolism |
HbA1C reduction (%) |
Risk of hypoglycemia |
effect on body weight |
Metabolic alterations |
Cardiovascular (Cv) benefit and risk |
Other adverse effects/ additional comments |
Biguanide (o) |
Metformin |
Insulin sensitizer Numerous effects on inhibition of hepatic glucose production |
5 h; unmetabolized, renal excretion |
1–2 |
None |
Mild weight loss due to anorectic effect |
Lactic acidosis (very rare) May cause nausea/vomiting or diarrhea after introduction, which may result in electrolyte or pH alterations |
Reduce MI by 39% and coronary deaths by 50% (UKPDS) |
Vitamin B12 deficiency, which may cause anemia and neuropathy (risk in elderly) Very safe drug, but stop metformin if creatinine >1.5 mg/dL in males and >1.4 mg/dL in females |
Dipeptidyl peptidase 4 (DPP-IV) inhibitor (o) |
Sitagliptin Saxagliptin Upper RTI infection Vidagliptin Linagliptin Alogliptin |
Inhibition of degradation of GLP |
Excreted by kidneys (except linagliptin) (needs dose reduction in renal failure) |
0.5–0.8 |
Low |
|
|
Long-term trials to assess CV risk; decreases postprandial lipemia, however, may cause CHF by degradation of BNP |
Pancreatitis Saxagliptin Upper RTI infection |
Sodium-glucose cotransporter (SGLT2) inhibitor (o) |
Canagliflozin Dapagliflozin Empagliflozin |
Glucosuria due to blocking (90%) of glucose reabsorption in renal PCT; insulin independent mechanism of action |
|
|
Low |
|
|
Positive CV effect due to reduction of sodium and uric acid absorption and reduction of BP |
Ketoacidosis (rare) Genital mycosis May increase LDLc Bone fractures |
Insulin (p) |
Short-acting Regular (R) (Humulin R, Novolin R) Intermediate NPH (N) Long-acting Insulin glargine (Lantus) Insulin detemir (Levemir) Insulin degludec (Tresiba) Rapid-acting Humalog (Lispro) |
Activation of insulin receptors and downstream signaling in multiple sensitive tissues |
30 min-1 r (onset of action) Peak 2–5 h Duration of action 8 h 1.5–4 h (onset of action) Peak 4–12 h Duration of action 24 h 0.8–4 h (onset of action) Peak minimal Duration of action 24 h 10–30 min (onset of action) |
1–2.5 |
Prominent |
Weight gain |
|
HF if used in combination with thiazolidinediones (TZD) |
Lipoatrophy and lipohypertrophy at sites of injection Allergy to injection components Levemir Food and Drug Administration -approved for gestational diabetes mellitus |
|
Novolog (Aspart) Glulisine (Apidra) Pre-mixed 75% insulin lispro protamine/25% insulin lispro (Humalog Mix 75/25) 50% insulin lispro protamine/50% insulin lispro (Humalog Mix 50/50) 70% insulin lispro protamine/30% insulin aspart (Novolog 70/30) 70% NPH insulin/30% regular |
|
Peak 30 min–3 h Duration of action 3–5 h 5–15 min (onset of action) Peak dual Duration of action 10–16 h 30–60 min (onset of action) Peak dual Duration of action 10–16 h |
|
|
|
|
|
|
GLP-1 agonists (p) |
Liraglutide Exenatide Dulaglutide |
Activate GLP1 receptor Increased insulin secretion, decreased glucagon, delayed gastric emptying, increased satiety |
24 h 4–6 h (short acting) 7 days (long acting, extended release) 7 days |
0.5–1.5 |
No [risk if used in combination with sulfonylureas (SU)] |
Weight loss |
|
Reduce CV risk |
Nausea, vomiting, pancreatitis, C cell tumor of thyroid (contraindicated in MEN type 2)
|
SU (o) |
Glimepiride Glipizide Glyburide |
Insulin secretion |
|
1–2 |
Prominent (severe in renal failure) |
Weight gain |
|
Increased cardiovascular disease risk, mainly due to hypoglycemia |
Use beta-blockers with caution |
TZD (o) |
Rosiglitazone Pioglitazone |
True insulin sensitizer |
|
0.5–1.4 |
|
Weight gain |
|
Cardiac failure, pedal edema |
Bladder cancer; fractures |
GLP-1 Receptor Agonists
The currently GLP-1 receptor agonists available are exenatide and liraglutide. These drugs exhibit increased resistance to enzymatic degradation by DPP4. In young patients with recent diagnosis of T2DM, central obesity, and abnormal metabolic profile, one should consider treatment with GLP-1 analogs that would have a beneficial effect on weight loss and improve the metabolic dysfunction. GLP-1 analogs are contraindicated in renal failure.
Exenatide. Exenatide, an exendin-4 mimetic with 53% sequence homology to native GLP-1, is currently approved for T2DM treatment as a single drug in the US and in combination with met formin ± sulfonylurea. Because of its half-life of 2.4 h, exenatide is advised for twice-daily dosing. Treatment with 10 µg exenatide, as an add-on to metformin, resulted in significant weight loss (−2.8 kg) in comparison to patients previously treated with met formin alone. Exenatide is generally well tolerated, with mild-to moderate gastrointestinal effects being the most common adverse effect. Liraglutide. Liraglutide is a GLP-1 analog that shares 97% sequence identity to native GLP-1. Liraglutide has a long duration of action (24 h). Liraglutide causes 1.5% decrease in A1C in individuals with type 2 diabetes, when used as monotherapy or in combination with one or more selected oral antidiabetic drugs. Liraglutide decreases body weight; the greatest weight
Liraglutide. Liraglutide is a GLP-1 analog that shares 97% sequence identity to native GLP-1. Liraglutide has a long duration of action (24 h). Liraglutide causes 1.5% decrease in A1C in individuals with type 2 diabetes, when used as monotherapy or in combination with one or more selected oral antidiabetic drugs. Liraglutide decreases body weight; the greatest weight
loss resulted from treatment with liraglutide in combination with combined metformin/sulfonylurea (−3.24 kg with 1.8 mg liraglutide). Liraglutide also diminishes systolic pressure (mean decrease −2.1 to −6.7 mmHg) (37). Liraglutide is well tolerated, with only nausea and minor hypoglycemia (risk increased with use of sulfonylureas). Serum antibody formation was very low in patients treated with once-weekly GLP-1 receptor agonists. The formation of these antibodies did not decrease efficacy of their actions on blood glucose lowering.
DPP-4 Inhibitors
Dipeptidyl peptidase 4 inhibitors include sitagliptin, saxagliptin, vidagliptin, linagliptin, and alogliptin. These medications may be used as single therapy, or in addition with metformin, sulfonylurea, or TZD. This treatment is similar to the other oral antidiabetic drugs. The gliptins have not been reported to cause higher incidence of hypoglycemic events compared with controls. Dipeptidyl peptidase 4 inhibitors impact postprandial lipid levels. Treatment with vidagliptin for 4 weeks decreases post prandial plasma triglyceride and apolipoprotein B-48-containing triglyceride-rich lipoprotein particle metabolism after a fat-rich meal in T2DM patients who have previously not been exposed to these medications. In diabetic patients with coronary heart disease, it was demonstrated that treatment with sitagliptin improved cardiac function and coronary artery perfusion. T he three most commonly reported adverse reactions in clinical trials with gliptins were nasopharyngitis, upper respiratory tract infection, and headache. Acute pancreatitis was reported in a fraction of subjects taking sitagliptin or metformin and sitagliptin. An increased incidence of hypoglycemia was observed in the sulfonylurea treatment group. In the elderly, DPP-4 inhibitors lower blood glucose but have minimal effect on caloric intake and therefore less catabolic effect on muscle and total body protein mass. In decreased doses, DPP-4 inhibitors are considered safe in patients with moderate to severe renal failure.
SGLT2 Inhibitors
Sodium-glucose cotransporter inhibitors are new classes of glucosuric agents: canagliflozin, dapagliflozin, and empagliflozin. SGLT2 inhibitors provide insulin-independent glucose lowering by blocking glucose reabsorption in the proximal renal tubule by inhibiting SGLT2. Because of glucose-independent mechanism of action, these drugs may be effective in advanced stages of T2DM when pan creatic β-cell reserves are permanently lost. These drugs provide modest weight loss and blood pressure reduction. Urinary tract infections leading to urosepsis and pyelonephritis, as well as genital mycosis, may occur with SGLT2 inhibitors. SGLT2 inhibitors may rarely cause ketoacidosis. Patients should stop taking their SGLT2 inhibitor and seek medical attention immediately if they have symptoms of ketoacidosis (frank nausea or vomiting, or even non-specific features like tiredness or abdominal discomfort).
Insulin
Insulin is a peptide hormone produced by the beta cells of the pancreas. It plays a crucial role in regulating blood glucose levels by facilitating glucose uptake into cells, particularly in muscle, liver, and adipose tissues. Insulin also promotes anabolic processes like glycogenesis and lipogenesis while inhibiting catabolic processes such as glycogenolysis and gluconeogenesis.
Mechanism of Action
Types of Insulin
Insulin formulations are categorized based on onset, peak, and duration of action:
Clinical Uses
Adverse Effects
Sulfonylureas
Sulfonylureas lower blood glucose level by increasing insulin secretion in the pancreas by blocking the KATP channels. They also limit gluconeogenesis in the liver. Sulfonylureas decrease breakdown of lipids to fatty acids and reduce clearance of insulin in the liver
Mechanism of Action:
Sulfonylureas are oral hypoglycemic agents that stimulate insulin secretion from pancreatic beta cells. They act by binding to the sulfonylurea receptor (SUR1) on ATP-sensitive potassium channels in beta-cell membranes. This binding leads to closure of these channels, depolarization of the cell membrane, and subsequent opening of voltage-dependent calcium channels. The influx of calcium triggers the release of insulin.
Clinical Uses:
Common Sulfonylureas:
Advantages:
Limitations and Adverse Effects:
Prescribing Considerations:
Meglitinide
Meglitinides (repaglinide and nateglinide) are non-sulfonylurea secretagogues, which was approved as treatment for T2DM in 1997.
Meglitinides are a class of oral antidiabetic medications used in the management of Type 2 Diabetes Mellitus (T2DM). They act by stimulating insulin secretion from the pancreatic beta cells, specifically targeting the early phase of insulin release. Their effects are glucose-dependent, meaning they primarily act when blood glucose levels are elevated, which helps reduce the risk of severe hypoglycemia compared to some other agents.
Mechanism of Action
Clinical Uses
Administration
Benefits
Adverse Effects
Limitations and Considerations
Efficacy
Thiazolidinedione
Mechanism of Action:
Thiazolidinediones, also known as "glitazones," are oral antidiabetic agents that enhance insulin sensitivity. They primarily act as agonists of the peroxisome proliferator-activated receptor-gamma (PPAR-γ), a nuclear receptor involved in regulating gene expression related to glucose and lipid metabolism. This activation improves insulin sensitivity in adipose tissue, skeletal muscle, and the liver, reducing insulin resistance a core abnormality in Type 2 Diabetes Mellitus (T2DM). TZDs also promote the differentiation of smaller, more insulin-sensitive adipocytes, decrease free fatty acid levels, and reduce inflammation linked to insulin resistance.
Examples of TZDs:
Clinical Uses:
Advantages:
Limitations and Side Effects:
Current Role in Therapy: While TZDs are not first-line treatments due to safety concerns, pioglitazone remains a viable option for patients with significant insulin resistance, especially those who might benefit from its cardiovascular or lipid-modulating effects. Their use is often considered in combination with metformin or other antidiabetic agents.
Other Glucose-Lowering Pharmacologic Agents
Pramlintide, an amylin analog, is an agent that delays gastric emptying, blunts pancreatic secretion of glucagon, and enhances satiety. It is a Food and Drug Administration (FDA)-approved therapy for use in adults with T1DM. Pramlintide induces weight loss and lowers insulin dose. Concurrent reduction of prandial insulin dosing is required to reduce the risk of severe hypoglycemia. Other medications that may lower blood sugar include bromocriptine, alpha-glucosidase inhibitors like voglibose and acarbose, and bile acid sequestrants like colesevelam. It may be noted that metformin sequesters bile acids in intestinal lumen and thus has a lipid-lowering effect, also the same mechanism may contribute to gas production and gastrointestinal disturbances.
Pharmacologic Management of Diabetes Complications
Important components of the Standards of Medical Care in Diabetes involves taking care of complications of diabetes and comorbidities including hypertension, atherosclerotic cardio vascular disease (ASCVD), dyslipidemia, hypercoagulopathy, endothelial cell dysfunction, nephropathy, and retinopathy. CVD is the most important cause of morbidity and mortality in patients with diabetes. The currently recommended goal blood pressure is ≤140/80 for patients with diabetes and hypertension. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are the preferred antihypertensive medication . Optimal blood pressure and blood glucose control can effectively delay the progression of nephropathy and retin opathy in these patients. Patients with existing CVD should be continuously managed with aspirin, including providing primary prevention in subjects less than 50 years old. Patients with diabetes are also recommended to undergo annual lipid profile measurement, and those diagnosed with hyperlipidemia should be treated with statins with a low-density lipoprotein goal of <70 mg/dL. Moreover, it should be noted that an important aspect in the success of pharmacotherapy is patient's adherence and compliance to medications; therefore, close and regular patient follow-up, monitoring, and education are necessary.
Glucose Monitoring
Glucose monitoring is a crucial part of diabetes management, offering real-time insights into how glucose levels fluctuate. Traditionally, this has been done through fingerstick testing using blood glucose meters. However, more advanced methods, such as Continuous Glucose Monitoring (CGM), are becoming increasingly popular due to their ability to track glucose levels continuously, providing more detailed data.
Continuous Glucose Monitoring (CGM):
CGM devices use a small sensor inserted under the skin to measure glucose in the interstitial fluid. These systems transmit data to a receiver, smartphone, or insulin pump, offering real-time glucose readings every few minutes. CGMs help detect fluctuations in glucose levels that might not be captured by intermittent fingerstick testing. This technology can significantly improve diabetes management by allowing users to make timely adjustments to their treatment plan, potentially reducing both hyperglycemia and hypoglycemia.
CGMs offer several benefits:
SUMMARY /CONCLUSION
The article "Clinical Review of Antidiabetic Drugs: Implications for Type 2 Diabetes Mellitus Management" outlines current pharmacological strategies for managing type 2 diabetes mellitus (T2DM), emphasizing the chronic nature of the condition. T2DM is marked by insulin resistance and eventual beta-cell dysfunction, leading to progressive hyperglycemia. The review covers the various classes of drugs used to manage elevated blood glucose levels in T2DM, focusing on their mechanisms, benefits, and limitations.
The management approach incorporates lifestyle modifications such as dietary changes and physical activity, which significantly reduce the risk of developing T2DM in high-risk individuals. Pharmacological treatment includes drugs like metformin, sulfonylureas, SGLT2 inhibitors, GLP-1 receptor agonists, and others, each targeting different aspects of the disease's pathophysiology. The review emphasizes the need for individualized treatment based on patient-specific factors such as comorbid conditions and the risk of complications.
Moreover, the paper stresses the importance of early diagnosis and continuous monitoring to optimize long-term outcomes. Regular blood glucose monitoring and HbA1c testing remain key tools in assessing treatment efficacy and preventing complications.
REFERENCES
Sahil Nivangune*, Shradha Singhi, Shravani Kulkarni, Abhijeet Satpute, Vedanti Walzade, Prathmesh Kadam, Clinical Review of Antidiabetic Drugs: implications for Type 2 Diabetes Mellitus Management, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 3, 520-537. https://doi.org/10.5281/zenodo.14993126