Pharmacotherapy of Type 2 Diabetes Mellitus

Abstract

This book chapter provides a comprehensive and comparative overview of available pharmacotherapy options for the management of type 2 diabetes mellitus (T2DM). With the increasing prevalence of T2DM worldwide, it is important to understand the effectiveness of all available options for adequate glycemic control and prevention of long-term complications. The chapter begins with a comprehensive overview on different aspects of T2DM, with special attention to details on different pharmacotherapeutic options available for its management. The role of newer antidiabetic medications such as sodium-glucose transporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonist, bile acid sequestrant, and dual GIP/GLP-1 receptor agonist is also emphasized. Additionally, formulations and usage of insulin and non-insulin injectables have been compared. Moreover, the current trends in management of T2DM and drugs in pipeline have also been discussed briefly. In conclusion, this book chapter provides a complete overview along with comparison of oral as well as injectable antidiabetic agents used for the management of T2DM. The healthcare professional will be equipped with the knowledge needed to optimize treatment strategies and improve outcomes for individuals living with T2DM.

1. Introduction

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by persistent hyperglycemia either due to insulin deficiency or resistance or both. Persistent hyperglycemia can lead to long-term microvascular complications such as blindness, end-stage renal disease, and lower limb amputation. It can also lead to macrovascular complications such as coronary artery disease, peripheral vascular disease, and stroke.

2. Epidemiology

Earlier diabetes was once considered a disease of affluent people now afflicting the even middle and poor population. The 10th edition of International Diabetes Federation (IDF) confirms that diabetes is one of the fastest growing global health emergencies of the twenty-first century. Diabetes is a major health issue that has reached alarming levels. Today, more than half a billion (537 million) people are living with diabetes worldwide [1]. As per 2023 ICMR-INDIAB-17 study, 101 million people are suffering from T2DM and at least 136 million people (15.3% of the population) have prediabetes in India [2]. About 39.4 million (53.1%) adults in India are underdiagnosed and 1 out of 7 diabetic patient in the world is Indian.

One of the contributing factors for future increase in diabetic population in lower- and medium-income countries will be aging population.

3. Etiology

The progression of T2DM is usually slow and following factors increase the risk of development of T2DM [3].

1. Family history of DM

2. Habitual physical inactivity

3. Race or ethnicity

4. Previously identified impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or HbA1c between 5.7% (39 mmol/mol) and 6.4% (46 mmol/mol)

5. Hypertension (blood pressure ≥ 140/90 mmHg or on therapy for hypertension)

6. High-density lipoprotein (HDL) cholesterol <35 mg/dL (0.91 mmol/L) and/or triglyceride level > 250 mg/dL (2.82 mmol/L)

7. History of gestational diabetes mellitus

8. History of cardiovascular disease

9. History of polycystic ovarian syndrome

10. Other conditions associated with insulin resistance (acanthosis nigricans).

4. Pathophysiology

The core pathophysiologic defects in T2DM are beta cell failure and insulin resistance in muscle and liver. In addition to the muscle, liver, and beta cell, other defects are accelerated lipolysis in the fat cell, incretin deficiency or resistance in gastrointestinal tract, hyperglucagonemia due to increased release of glucagon from alpha cells, increased glucose reabsorption in kidney and insulin resistance in brain. All these eight distinct pathophysiological abnormalities play important roles in the development of persistent hyperglycemia in type 2 diabetic individuals [4].

These factors are already well established early in the natural history of T2DM. The activation of inflammatory pathways and impaired insulin-mediated vasodilation contributing to muscle insulin resistance are two additional pathophysiologic defects [5]. Figure 1 depicts all pathophysiological abnormalities contributing to persistent hyperglycemia.

Figure 1.

Pathophysiological mechanisms leading to hyperglycemia in T2DM.

5. Treatment

5.1 Goals of therapy

Major goals of T2DM therapy are:

1. Effective glucose control

2. To prevent, reduce, and manage acute and long-term complications

3. To preserve beta cell function

4. To minimize hypoglycemia

5. To maintain overall quality of life

The primary objective in management of diabetes is to achieve near-normal blood glucose level. The Diabetes Control and Complications Trial (DCCT) [6] and the United Kingdom Prospective Diabetes Study (UKPDS) [7] showed that the risk of developing chronic complications is decreased by lowering blood glucose level. With appropriate public education, lifestyle modification, and medications, near-normal blood glucose level can be achieved.

5.2 Pharmacologic therapy

Lifestyle modification along with physical activity and meal planning is the first step in management of individuals with T2DM. However, in individuals who are unable to achieve glycemic control through it, oral and injectable antidiabetic agents are used. Oral agents are summarized in Table 1 [8, 9].

Drug class	Drugs	Site of action	Impact on blood glucose	Dosing strategy (all agents taken orally)	e-GFR 30–50 mL/min	eGFR 30 mL/min	Adjustment of hepatic impairment	Common adverse events
Alpha glucosidase inhibitors	Acarbose, Miglitol	Brush border of small intestine	Postprandial	25 mg t.i.d daily with first bite of each main meal Advance at 4–8 week intervals to maximum of 100 mg t.i.d daily	SCr > 2 mg/dL. Not recommended	SCr > 2 mg/dL. Not recommended	No specific dose adjustment recommended, contraindicated in cirrhosis	GI (flatulence, diarrhea)
	Voglibose	Brush border of small intestine	Postprandial	0.2 mg t.i.d just before each meal Can be increased to 0.3 mg under close observation of the course of disease	Not available	Not available	Not available	GI (flatulence, diarrhea) Abdominal pain
Meglitinides (should not be used in combination with other insulin secretagogues)	Repaglinide	Pancreas	Postprandial	0.5 mg 15–30 min before each meal. Double preprandial dose every 7 days to maximum of 4 mg/dose or 16 mg/day (to be taken only if eating)	20–40 mL/min initial dose: 0.5 mg with careful titration	<20 mL/min. Not studied	Use conservative initial and maintenance doses and use longer intervals between dose adjustments	Hypoglycemia (although less risk than with sulfonylureas)
	Nateglinide	Pancreas	Postprandial	120 mg t.i.d daily before meals (to be taken only if eating)	No specific dose adjustment recommended	Use with caution in severe dysfunction	No dose adjustment needed in mild impairment; use with caution in moderate to severe dysfunction	Hypoglycemia (although less risk than with sulfonylureas)
Second generation sulfonylureas	Glyburide micronized	Pancreas	Fasting and postpradial	1.5–3 mg/day with breakfast. Increase by 1.5 mg weekly to maximum of 12 mg/day	Not recommended	Not recommended	Use conservative dosing and avoid in severe disease	Hypoglycemia and weight gain
	Glyburide	Pancreas	Fasting and postpradial	2.5–5 mg/day with breakfast. Increase by 2.5 mg weekly to maximum of 20 mg/day	Not recommended	Not recommended	Use conservative dosing and avoid in severe disease	Hypoglycemia and weight gain
	Glipizide	Pancreas	Fasting and postpradial	2.5 mg/day 30 min before a meal increase by 2.5–5 mg weekly to maximum of 40 mg/day;divide dose if >15 mg/day	No specific dose adjustment recommended	No specific dose adjustment recommended	Initial dose 2.5 mg/day	Hypoglycemia, weight gain
	Glipizide ER	Pancreas	Fasting and postpradial	2.5–5 mg once daily before a meal increase by 5–10 mg weekly to maximum of 20 mg/day	No specific dose adjustment recommended	No specific dose adjustment recommended	No specific dose adjustment recommended	Hypoglycemia, weight gain
	Glimepiride	Pancreas	Fasting and postpradial	1–2 mg with breakfast increase by 2 mg every 1–2 weeks to maximum of 8 mg/day	No specific dose adjustment recommended	Initial starting dose should be 1 mg < 15 mL/min consider alternative	No specific dose adjustment recommended	Hypoglycemia, weight gain
Biguanides	Metformin; Metformin ER	Liver	Fasting and postprandial	500 mg/day to twice daily with meals Advance weekly to maximum of 2000–2500 mg/day	Do not start or, if already taking, continue cautiously if eGFR 30–45 mL/min/1.73 m^2. Consider 50% of maximum doses and monitoring of renal function every 3 months	Contraindicated	Avoid or use cautiously in patients at risk for lactic acidosis (renal impairment or alcohol abuse)	GI (diarrhea, abdominal pain)
Thiazolidinediones	Pioglitazone	Peripheral tissue	Fasting and postprandial	15–30 mg/day increase after 12 weeks to maximum of 45 mg/day	No adjustment necessary	No adjustment necessary	Clearance lower in Child-Pugh grade B/C; do not start if transaminsases >2.5 X ULN and discontinue if ALT rises to and remains at more than three times ULN	Weight Gain
Dipeptidyl peptidase-4 inhibitors	Sitagliptin	GI tract (increases GLP-1)	Fasting and postprandial	100 mg/day	50 mg once daily	25 mg once daily	Child Pugh No class A and B: No dosage adjustment necessary; Child-Pugh class C: Not studied	Upper respiratory, diarrhea
	Saxagliptin	GI tract (increases GLP-1)	Fasting and postprandial	2.5 or 5 mg/daily	2.5 mg once daily	2.5 mg once daily	No dose adjustment necessary	UTI, Headache
	Linagliptin	GI tract (increases GLP-1)	Fasting and postprandial	5 mg/day	No dose adjustment necessary	No adjustment necessary	No adjustment necessary	Headache, arthralgia, nasopharyngitis
	Alogliptin	GI tract (increases GLP-1)	Fasting and postprandial	25 mg/day	>30 mL/min but <60 mL/min 12.5 mg/day	>15 mL/min but <30 mL/min 6.25 mg/day; <15 mL/min 6.25 mg/day	No dose adjustment necessary; Child Pugh class C: not studied	Headache, increased ALT greater than three times ULN, nasopharyngitis, upper respiratory tract infections
Selective sodium dependent glucose cotransporter-2 inhibitor	Canagliflozin	Kidney	Fasting and postprandial	100 mg/day in morning, may increase to 300 mg/day	>45 mL/min/1.73 m^2 but <60 mL/min/1.73 m^2:100 mg/day; 30 ml/min/1.73 m^2 with urinary albumin excretion >300 mg/day: 100 mg/day	<30 ml/min/1.73 m^2, contraindicated	Mild to moderate (Child Pugh class A and B) no adjustment necessary severe (Child Pugh class C) not recommended	Hyperkalemia, genitourinary infection, hypovolemia, renal insufficiency, hypotension
	Dapagliflozin	Kidney	Fasting and postprandial	5 mg/day in the morning may increase to 10 mg/day	<45 mL/min/1.73 m^2 not recommended for glycemic control >25 mL/min/1.73 m^2 but <45 mL/min/1.73 m^2 with heart failure or chronic kidney disease: 10 mg/day	<25 ml/min/1.73 m^2 contraindicated	Mild to moderate. No adjustment necessary. Severe not studied	Genitourinary infection, hypovolemia/hypotension, dysuria, polyuria, dyslipidemia, mild hypoglycemia, nasopharyngitis
	Empagliflozin	Kidney	Fasting and postprandial	10 mg/day in the morning; may increase to 25 mg/day	No dosage adjustment	<30 mL/min/1.73 m^2; contraindicated	No dose adjustment necessary	Genitourinary infection, hypovolemia/hypotension, dysuria, polyuria, dyslipidemia, mild hypoglycemia,
	Ertugliflozin	Kidney	Fasting and postprandial	5 mg/day in the morning; may increase to 15 mg/day	<60 mL/min not recommended	<30 mL/min contraindicated		Genitourinary infection, hypovolemia, mild hypoglycemia, polyuria, increased LDL cholesterol, renal insufficiency
GLP1-1 receptor agonist	Semaglutide	GI tract and Pancreas	Fasting and postprandial	3 mg/day in the morning with water 30 min before first food, beverage, or other oral medications for 30 days, increase to 7 mg/day increase to 14 mg/day after 30 days if additional glycemic control needed	No dose adjustment necessary	No dose adjustment necessary	No dose adjustment necessary	GI effects (nausea, diarrhea, flatulence, abdominal pain), risk of pancreatitis, increased heart rate
Dopamine receptor agonist	Bromocriptine mesylate	Hypothalamus	Postprandial	0.8 mg once daily within 2 h of waking, may increase in weekly intervals to 4.8 mg once daily	No dose adjustment necessary	No dose adjustment necessary	No specific dose adjustment recommended, although adjustment may be necessary because of extensive hepatic metabolism	Nausea, headache
Bile acid sequestrant	Colesevelam	Intestinal lumen	Fasting	1.875 g twice daily or 3.75 mg once daily	No dose adjustment necessary	No dose adjustment necessary	No dose adjustment necessary	Constipation

Table 1.

Oral agents for T2DM.

ALT, alanine aminotransferase; eGFR, estimated glomerular filtration rate; ER, extended release; GI, gastrointestinal; GLP-1, glucagon like peptide-1; LDL, low density lipoprotein, SCr, serum creatinine; ULN, upper limit of normal; UTI, urinary tract infection.

With the availability of number of glucose-lowering medication, the management of hyperglycemia has become complex. Consistent efforts to improve diet and exercise and individual-centered decision-making and support remain the foundation of all glycemic management. The recommendation of initial use of metformin followed by addition of glucose-lowering medications is based on individual concerns and comorbidities [10].

Non-insulin drug class with site of action and mechanism of action is listed in Table 2 [8, 10, 11, 12] and the expected HbA1c reduction for each non-insulin antiglycemic drug class is listed in Table 3 [8, 10, 11, 12]. The target and mechanism of action of various class of blood glucose-lowering agents is different. Each of these classes may be used individually or in combination with other medications targeting different organs for synergistic effects.

Site of action	Drug class	Mechanism of action
Pancreas	Sulfonylureas	Enhances insulin secretion
	Nonsulfonylurea secretagogues	Enhances insulin secretion
	GLP-1 agonists	Enhances insulin secretion and suppresses glucagon secretion
	Pramlintide	Suppresses glucagon secretion
Liver	Biguanide	Decreases hepatic glucose production and increases insulin sensitivity
	Thiazolidinedione	Increases insulin sensitivity
Muscle	Biguanide	Increases insulin sensitivity
	Thiazolidinedione	Increases insulin sensitivity
Adipose tissue	Thiazolidinedione	Increases insulin sensitivity
Intestines	GLP-1 agonists	Increases satiety and regulates gastric emptying
	Pramlintide	Increases satiety and regulates gastric emptying
	Dipeptidyl peptidase-4 inhibitors	Increases endogenous GLP-1
	α-Glucosidase inhibitors	Delays absorption of carbohydrates
Kidney	SGLT2 inhibitors	Inhibits glucose reabsorption in the kidney’s proximal tubule

Table 2.

Site and mechanism of non insulin agents.

GLP-1, glucagon-like peptide-1; SGLT2, sodium-dependent glucose cotransporter-2.

Expected A1c reduction for noninsulin antiglycemic drug classes
Drug class	Efficacy	A1c reduction(%)	HbA1 reduction(mmol/mol)
Biguanides	High	1.5–2	17–22
Sulfonylureas	High	1.5–2	17–22
GLP-1 Agonists	High	0.78–1.9	8.8–20
Thiazolidinediones	High	up to 1.5	17
Dipeptidyl peptidase-4 inhibitors	Intermediate	0.7–1	8–11
SGLT2 inhibitors	Intermediate	0.5–1	5–11
Nonsulfonylurea secretagogues	Intermediate	0.3–1	3–11
α-Glucosidase inhibitors	Intermediate	0.3–1	3–11
Central-acting dopamine agonists	Low	0.3–0.6	3–7
Pramlintide	Low	0.4–0.5	4–5
Bile acid sequestrants	Low	0.40	4

Table 3.

Expected A1c reduction of noninsulin antiglycemic agents.

HbA1c, hemoglobin A1c; GLP-1, glucagon like peptide-1; SGLT2, sodium-dependent glucose cotransporter-2.

Treatment algorithm for T2DM by American Diabetes Association (ADA) [12] and American Association of Clinical Endocrinology (AACE) [9] prioritizes treatment options based on treatment benefits and patient-specific factors, especially in patients with cardiovascular disease, heart failure, or chronic kidney disease. Figure 2 shows pharmacologic approaches for glycemic management.

Figure 2.

Type 2 diabetes pharmacotherapy—Updated ADA 2023 treatment algorithm.

Here are the key points of ADA and AACE Guidelines (Table 4).

	ADA	AACE
Starting a patient on two medications	HbA1c ≥ 8.5% (69 mmol/mol)	HbA1c ≥ 7.5% (58 mmol/mol)
First-line therapy	Metformin	Six other non-insulin initial therapy options as possibilities.; In patients with established or high atherosclerotic cardiovascular disease (ASCVD) risk, heart failure with reduced ejection fraction (HFrEF), and/or CKD: the preferred options are SGLT2i or GLP-1RAs

Table 4.

Key differences in ADA and AACE approach of T2DM management.

As T2DM is a progressive disease, many individuals eventually require insulin. ADA favors use of GLP-1RA as an alternative to mealtime insulin in those already maximally titrated with basal regimens. In this scenario, AACE guidelines also suggest DPP-4i or SGLT2i as an option.

5.2.1 Sulfonylureas

There are many antidiabetic drugs available for treatment of T2DM. Despite availability of several treatment options, for nearly 50 years, sulfonylureas have been used extensively and even today widely used for T2DM management [13].

There are two generations of sulfonylureas namely first and second generation. Most commonly prescribed agents are second-generation sulfonylureas include glyburide (also known as glibenclamide), gliclazide, glipizide, and glimepiride. The ATP-sensitive potassium channels in the cell membrane of pancreatic beta cells are blocked by sulfonylureas, which lead to membrane depolarization. This allows an influx of calcium causing translocation of insulin secretory granules to the cell surface. Insulin secretion is enhanced in a non-glucose-dependent manner. Both fasting and postprandial blood glucose levels are lowered. Monotherapy produces a 1.5 (17 mmol/mol) to 2% (22 mmol/mol) decline in HbA1c and a 60–70 mg/dL (3.33–3.885 mmol/l) reduction in fasting blood glucose levels.

Maturity-onset diabetes of the young (MODY) is a type of diabetes with specific features diagnosed usually before the age of 25 years. The mutations mainly in three genes (HNF1A, HNF4A, and GCK) contribute to 95% of all individuals with MODY. Oral hypoglycemic drugs generally sulphonylureas are preferred for individuals with mutations in the HNF4A and HNFA genes. In person with mutations in GCK gene, treatment is usually not necessary [14].

Drug interactions are more likely to be associated with first-generation sulfonylureas. Cytochrome P450 2C9 pathway metabolizes most sulfonylureas. Except tolbutamide, all sulfonylureas require dosage adjustment in renal impairment [15]. Lower starting dose is necessary in elderly or individuals with compromised renal or hepatic function. Hypoglycemia and weight gain are common adverse effects. Increased risk of hemolytic anemia has been found in individuals with glucose-6 phosphate dehydrogenase deficiency [16].

5.2.2 Non-sulfonylureas secretagogues

Nateglinide and repaglinide are the two commonly used meglitinides. Meglitinides have a rapid and short duration of action. Hence, they should be taken 15–30 min before a meal three times a day. They bind to a receptor adjacent to those which sulfonylureas bind. Like sulfonylureas, they block ATP-sensitive potassium channels on the beta cells. They reduce post-meal glucose levels. A reduction of 0.3 (3 mmol/mol)–1% (11 mmol/mol) in HbA1c levels has been demonstrated [15]. Meglitinides are short-acting and associated with lower hypoglycemia risks, weight gain, and chronic hyperinsulinemia than sulfonylurea drugs [17].

Nateglinide has also been studied in individuals with maturity-onset diabetes of the young type 3(MODY3) and it has been found that a low dose of nateglinide prevents rise in acute postprandial glucose more efficiently than glibenclamide with less hypoglycemic symptoms [18]. In individuals with MODY3, improved prandial glucose control with lower risk of hypoglycemia was observed with nateglinide than glibenclamide.

5.2.3 Biguanides

In T2DM treatment, metformin is considered as a foundational therapy along with lifestyle modification. It is often used in combination with other anti-hyperglycemic agents for synergistic effects [12]. Metformin decreases hepatic glucose production and increases insulin sensitivity in both hepatic and peripheral muscle tissues. When used as monotherapy, it reduces HbA1c levels by 1.5 (17 mmol/mol)–2% (22 mmol/mol) and FPG by 60–80 mg/dL (3.33–4.44 mmol/l) [15]. The incidences of hypoglycemia are uncommon as it does not affect insulin release. The most common reported adverse effects are decreased appetite, nausea, and diarrhea. These adverse effects are often subsiding within two weeks. These adverse effects can be also minimized through use of extended release formulation and slow titration of the dose. Long-term treatment with metformin has been associated to cause vitamin B12 deficiency. Hence, periodic testing of vitamin B12 status should be done especially in individuals with macrocytic anemia or peripheral neuropathy. Lactic acidosis is one of the rare side effects reported and individuals who are at risk of lactic acidosis include those with renal impairment or elderly [16].

5.2.4 Thiazolidinedione (TZDs)

The thiazolidinediones are also known as glitazones. Pioglitazone is a TZD, which has been shown to be effective in glycemic control by lowering insulin resistance. TZDs stimulate peroxisome proliferator-activated receptor gamma which increases insulin sensitivity and decreases plasma fatty acids. As monotherapy, a decline in HbA1c is up to 1.5% (17 mmol/mol) and a reduction in FPG levels by around 60–70 mg/dL (3.33–3.885 mmol/l) [15]. Fluid retention, weight gain, and limb fractures are known to occur with TZD therapy. An increased risk of bladder cancer has been found with pioglitazone therapy especially among men and smokers. It is contraindicated in New York Heart Association Class III and IV heart failure.

5.2.5 Alpha glucosidase inhibitors (AGIs)

Examples of AGIs are acarbose, voglibose, and miglitol. The enzymes glucoamylase, sucrase, maltase, and isomaltase that convert complex non-absorbable carbohydrates into simple absorbable carbohydrates are inhibited by AGIs. The reduction in postprandial glucose concentrations is due to delayed absorption of carbohydrates and it is up to 40–50 mg/dL (2.22–2.77 mmol/l). However only 0.3 (3 mmol/mol)–1% (11 mmol/mol) decline in HbA1c has been noted [15]. Because of high incidence of GI side effects, their use has been limited. Compared to sulfonylureas, glycemic control is inferior with AGIs [19].

5.2.6 Dipeptidyl Petidase-4 inhibitors (DPP-4i)

Sitagliptin, saxagliptin, linagliptin, and alogliptin are DPP-4 inhibitors. These drugs act through incretin hormones, which are gut hormones responsible for glucose homeostasis after oral food intake. They inhibit DPP-4, enzyme which degrades endogenous GLP-1 and hence DPP4i increases the amount of GLP-1. They lower postprandial blood glucose levels. They are approved as adjunct to diet and exercise to improve glycemic control in adults with T2DM. Typical HbA1c reductions are 0.7 (8 mmol/mol)–1% (11 mmol/mol) [15]. DPP-4 inhibitors do not seem to confer any significant cardiovascular benefit for individuals with T2DM, while they do not seem to be associated with a significant risk for any major cardiac arrhythmias [20]. Headache and nasopharyngitis are common adverse effects. Acute pancreatitis has been reported in individuals who are taking gliptins. Hence, it is contraindicated in individuals with a history of pancreatitis.

5.2.7 Sodium-dependent glucose cotransporter-2 inhibitors (SGLT2i)

Canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin are SGLT2 inhibitors. They inhibit SGLT2 in the proximal tubules and lower the renal threshold for glucose reabsorption. This results in increased urinary excretion of glucose, and thus lowers plasma blood glucose concentrations. The glucose-lowering effects of SGLT2i are independent of insulin secretion or action. Typical HbA1c reductions are 0.5 (5 mmol/mol)–1% (11 mmol/mol) [15]. They may be used as monotherapy or add-on. The renal function test should be performed at baseline to guide the initial dosing and during the treatment to assess suitability of continuation of SGLT2i. Recent clinical trials have shown that SGLT2i has dramatic beneficial cardiovascular and renal outcomes, including reduced rehospitalization in subjects with heart failure, regardless of the presence of diabetes [21, 22]. In subjects with atherosclerotic cardiovascular disease or heart failure, SGLT2i is found to be effective in decreasing overall morbidity and mortality [23]. Increased incidence of urinary tract infections, genital mycotic infections are common adverse effects. Other notable adverse effects are symptomatic hypotension, euglycemic ketoacidosis, increased risk of bone fracture, newly diagnosed bladder cancer.

5.2.8 Glucagon-like peptide 1 receptor agonists (GLP-1 RA)

Exenatide, liraglutide, dulaglutide, semaglutide, and lixisenatide are glucagon-like peptide 1 receptor agonists (GLP-1 RA). They are called incretin mimetics, or GLP-1 analogs (Table 5) [11, 24, 25]. Blood glucose-lowering effect of GLP-1 RAs is mediated by (a) glucose-dependent insulin secretion; (b) reducing post-meal glucagon secretion; (c) increasing satiety which decreases food intake; (d) regulation of gastric emptying, which allows smooth absorption of nutrients into the circulation. These agents have been shown to reduce HbA1c (by ∼0.8–1.6%), body mass (by ∼1–3 kg), blood pressure, and lipids. Cardiovascular outcome trials have demonstrated that GLP1RA reduces the rates of major adverse cardiovascular events in patients with T2DM [26]. This class of drugs is associated with a low risk of hypoglycemia, and the most common adverse effects are gastrointestinal such as nausea, vomiting, and diarrhea [27]. They are contraindicated in individuals with acute pancreatitis.

Generic name	Dosage strengths	Starting dosage	Dosage interval	Titration interval	Maximum dose	Time to effect (min)	Comments and cautions
Pramlintide	2.7 mL for 60, 120 mcg doses	60 mcg	Three times a day with meals	3–7 days	120 mcg	20	Side effects: hypoglycemia, nausea, vomiting, Available in SymliPen 60 and 120
Exenatide	Immediate release 5 mcg, 10 mcg	Immediate release 5 mcg	Immediate release twice daily	Immediate release 1 month	Immediate release 10 mcg twice daily	Immediate release 15–30	Inject immediate release formulation 15–20 min before two meals of the day with 6 h separating the meals; prefilled disposable pen; may delay absorption of oral drugs; separate doses by 1 h; Side effects: nausea, vomiting, diarrhea, increased hypoglycemia with sulfonylureas
	Extended release 2 mg	Extended release 2 mg	Extended release once weekly	Extended release NA	Extended release 2 mg	NA	Extended release formulation can be administered regardless of meals
Lixisenatide	10 mcg and 20 mcg pen-injector starter kit; 20 mcg pen-injector	10 mcg	Once daily	14 days	20 mcg	N/A	If missed dose, administer within 1 h of next meal
Liraglutide	18 mg/3 mL pen	0.6 mg	Once daily	1 week	1.8 mg	N/A	Can be dosed at any time of day regardless of meals; may delay absorption of oral drugs; separate doses by 1 h; Side effects: nausea, vomiting, increased hypoglycemia with sulfonylureas
Dulaglutide	0.75 mg single dose pen; 1.5-mg single dose pen, 3.0 mg single dose pen; 4.5 mg single dose pen	0.75 mg	Once weekly	4–8 weeks	4.5 mg	N/A	If missed dose occurs within 3 days of regularly scheduled dose, dose should be administered at that time. If missed dose occurs more than 3 days past scheduled dose, wait until next regularly scheduled dose to administer next dose; Side effects: nausea, diarrhea, vomiting, abdominal pain, decreased appetite,dyspepsia, fatigue
Semaglutide	2 mg/1.5 mL pen injector for 0.25 or 0.5 mg/dose pen; 4 mg/3 mL pen-injector for 1 mg/dose pen	0.25 mg	Once weekly	4 weeks	1 mg	N/A	If missed dose occurs within 5 days, administer the dose as soon as possible. If >5 days, do not administer until the next scheduled weekly dose; Side effects: nausea, vomiting, diarrhea, abdominal pain, risk of hypoglycemia, tachycardia

Table 5.

Injectable noninsulin agents for diabetes.

5.2.9 Dual GIP/GLP-1 receptor agonists

Tirzepatide, the most advanced unimolecular dual glucose-dependent insulinotropic polypeptides (GIP/GLP-1) agonist has been recently approved. It is administered as once weekly through subcutaneous route. It stimulates release of insulin from the pancreas leading to reduction of hyperglycemia. The level of adinopectin is also increased. In comparison to GLP-1 RA, the dual agonistic action leads to a significant reduction in hyperglycemia along with reduced appetite, energy intake, and body mass. In the phase III studies, it decreased HbA1c levels upto −2.58% along with loss in body mass by −12.9 kg because of the complementarity of action of the two incretins. The cardiovascular protective effect is also being studied. It is prescribed as a second-line medications in management of T2DM. Except for higher incidence of diarrhea, gastrointestinal tolerance is comparable to that of GLP-1 analogs [28, 29]. The clinical trial evidences suggest that tirzepatide offers a new treatment option for the effective lowering of blood glucose and body mass in adults with T2DM [30].

5.2.10 Central-acting dopamine agonist

Bromocriptine is a central-acting dopamine agonist. A quick release formulation is approved for treatment of T2DM. The mechanism of action of bromocriptine is unknown. The data indicate that it improved insulin sensitivity, likely a result of its effect on dopamine oscillations [15]. It should be considered a last-line option due to the modest effect on blood sugar levels and HbA1c [8]. Rhinitis, dizziness, asthenia, headache, sinusitis, constipation, and nausea are the main side effects. It is contraindicated in syncopal migraine and women who are nursing [16].

It is an attractive treatment option for the treatment of T2DM because of its novel mechanism of action, acceptable side effect profile, and its effects to reduce cardiovascular event rates [31].

5.2.11 Bile acid sequestrants

Colesevelam is bile acid sequestrant. It is approved as adjunctive therapy to improve glycemic control in conjunction with diet, exercise, and insulin or oral agents for treatment of T2DM. It showed significant effects on glycemic control when added on to antidiabetic agents. There is insufficient data on long-term effects particularly in cardiovascular risk management and reduction of micro- and macrovascular complications. It is rarely used [32].

5.2.12 Amylin mimetic

Pramlintide acetate is a synthetic analog of human amylin. Amylin secretion is lower than normal in individuals with T2DM who require insulin. Pramlintide is given subcutaneously before meals to lower postprandial blood glucose elevations. Hypoglycemia, nausea, and vomiting are the most common side effects. Pramlintide slows gastric emptying, suppresses glucagon secretion, and increases satiety. By slowing gastric emptying, the normal initial post-meal spike in blood glucose is reduced [16].

5.2.13 Insulin

In 1921, Banting and Best discovered insulin. They prepared an extract of pancreas after degeneration of the exocrine part and demonstrated its hypoglycemic action. The molecular weight of insulin is 6000 and it has two polypeptide chains having 51 amino acids. The A and B chain has 21 and 30 amino acids respectively. Insulin is synthesized as a single polypeptide chain containing 110 aminoacid called preproinsulin. This is processed to proinsulin and then to insulin and C-peptide. The disposal of meal-derived glucose, amino acids, fatty acids is the overall effect of insulin and promotes fuel storage. Because of its anabolic action, it promotes synthesis of glycogen, lipids, and protein [33, 34, 35].

The mainstay for treatment of virtually all type 1 and type 2 diabetes is insulin. There is no specific maximum dose of insulin and can be titrated as per the need of individual. It can be administered subcutaneously, intramuscularly, or through intravenous route. Currently, the recombinant DNA technology is being used to prepare all insulin formulations. One international unit of insulin is equal to 34.7 mcg of crystalline insulin [33]. The preparations of insulin consist of the amino acid sequence of human insulin and their variations (insulin analogs).

In addition to the combination of insulin plus insulin, insulin plus GLP1RA combinations have also been approved. Furthermore, basal insulin therapy combinations with other drugs or adjunctive therapies are also prescribed [17].

The properties of available insulins are summarized in Table 6 [11, 16, 36]. The time of onset of action, peak effect, and duration of action of insulin greatly varies among individuals and even in the same individual with repeated doses. This depends on the dose size, the injection site, the exercise, and the desire of circulating anti-insulin antibodies.

Generic name (insulin)	Strength	Onset	Peak (h)	Duration (h)	Administration options
Ultra rapid acting insulin
Aspart with niacinamide	U-100	15–20 min	1.5–2	5–7	CSII, IV, SC; 10-mL vial; 3-mL cartridge and Flex Touch Disposable Pen
Recombinant human insulin regular	Not applicable	12–15 min	1	1.5–3	Ihh; Technosphere insulin particles for oral inhalation; 4,8, and 12 U as cartridges
Rapid acting insulin
Lispro	U-100, U-200	15–30 min	0.5–1.5	3–4	CSII, IV, SC; 3-mL and 10 mL vial, 3-mL cartridge, KwikPen disposable pen
	U-100				CSII, IV, SC; 3-mL and 10-mL vial; 3-mL SoloStar disposable pen
Lispro aabc	U-100, U-200	15–30 min	0.5–1.5	4–7	IV, SC; 10-mL vial; 3-mL cartridge and Kwik disposable pen
Aspart	U-100	15–30 min	0.5–1.5	3–5	CSII, IV, SC; 10-mL vial; 3-mL cartridge, FlexPen disposable pen
Glulisine	U-100	15–30 min	1–2	3–4	CSII, IV, SC; 10-mL vial; 3-mL SoloStar disposable pen
Short acting insulin
Regular	U-100, U-500	30–60 min	2–4	5–8	CSII, IV, SC; U-100 10-mL vial; U-500 20-mL vial and 3-mL KwikPen disposable pen
	U-100				CSII, IV, SC; 10-mL vial, 3-mL cartridge, 3-mL Innolet
Intermediate-acting insulin
Neutral protamine Hagedorn	U-100	2–4 h	4–10	10–24	SC; 10-mL vial, 3-mL cartridge
	U-100				SC; 10-mL vial, 3-mL cartridge, 3-mL InnoLet
Long-acting insulin
Glargine	U-100	2–4 h	Flat	20–24	SC; 10-mL vial, 3-mL SoloSTAR disposable pen
	U-300	6 h	Flat	36	SC;1.5-mL SoloStar disposable pen
	U-300				SC; 3-mL SoloStar disposable pen
	U-100	2–4 h	Flat	20–24	SC; 3-mL KwikPen disposable pen
	U-100	1–3 h	Flat	≥ 24	SC; 10-mLvial, 3-mL disposable pen
Detemir	U-100	1.5–4 h	6–14	16–20	SC; 10-mL vial, 3-mL FlexTouch disposable pen
Degludec	U-100, U-200	1 h	Flat	42	SC; 3-mL disposable FlexTouch pen
Combination insulin products
Neutral protamine Hagedorn and regular	U-100	30–60 min	1.5–16	10–16	SC: 10-mL vial, 3-mL KwikPen disposable pen
	U-100	30–60 min	2–12	10–16	SC; 10-mL vial, 3-mL FlexPen disposable pen
Neutral protamine lispro and lispro	U-100	15–30 min	1–6.5	15–18	SC; 10-mL vial, 3-mL KwikPen disposable pen
	U-100				SC; 10-mL vial, 3-mL KwikPen disposable pen
Neutral protamine aspart and aspart	U-100	15–30 min	1–4	Up to 24	SC; 10-mL vial, 3-mL cartridge, 3-mL FlexPen disposable pen
Combination insulin GLP-1 agonist products
Degludec and liraglutide	U-100 degludec/3.6 mg/mL liraglutide	N/A	N/A	N/A	SC; 3-mL pen-injector
Glargine and lixisenatide	U-100 glargine/33 mcg/mL liraglutide	N/A	N/A	N/A	SC; 3-mL pen-injector

Table 6.

Insulin agents for diabetes.

CSII, continuous subcutaneous insulin infusion; GLP-1, glucagon like peptide; Inh, inhalation; IV, intravenous; N/A, not applicable; SC, subcutaneous.

The potential benefits of complementary pre-prandial short-acting insulin therapy in T2DM have also been studied. Insulin treatment led to improvement in Hb1Ac, mean blood glucose, body mass, and self-reported quality of life. The improved blood glucose control was evident from fourth day of treatment. Furthermore, complimentary insulin therapy was more beneficial to individuals in whom insulin was newly introduced compared to individually previously treated with insulin [37].

6. Choice of glucose-lowering therapy

The choice of pharmacologic therapy is guided by treatment goals and person-centered treatment factors including comorbidities. A person-centered approach such as the effects on cardiovascular and renal comorbidities, efficacy, hypoglycemia risk, impact on weight, cost, and access, risk for side effects and individual preferences are considered for appropriate selection of pharmacologic agents. To reduce cardiorenal risk is the ultimate goal of treatment in adults with type 2 diabetes and established/high risk of atherosclerotic cardiovascular disease, heart failure, and/or chronic kidney disease. The usual pharmacologic approaches to achieve and maintain treatment goals are treatment with metformin and other agents including combination therapy. In T2DM management, the approaches that support weight management goals are preferred. A SGLT2i and/or GLP1RA is recommended as part of glucose-lowering regimen in individuals with type 2 diabetes who have established cardiovascular disease or indicators of high cardiovascular risk, established kidney disease or heart failure. Every 3–6 months, medication regimen and medication taking behavior should be evaluated and if needed, treatment should be adjusted to incorporate specific factors that impact choice of treatment. Table 7 summarizes choice of glucose-lowering therapy in T2DM [3, 38].

Drugs/class		Efficacy	Hypoglycemia	Impact on body weight	CV effects		Renal effects		Oral/SC	Clinical considerations
					Effect on MACE	HF	Progression of DKD	Dosing/use considerations*
Metformin		High	No	Neutral (potential for moderate loss)	Potential benefit	Neutral	Neutral	Contraindicated with eGFR <30 mL/min/1.73 m^2	Oral	GI side effects common: to mitigate GI side effects, consider slow dose titration, extended release formulations, and administration with food
SGLT2-Inhibitors		Intermediate to high	No	Loss (Intermediate)	Benefit: canagliflozin, empagliflozin	Benefit: canagliflozin, dapagliflozin, empagliflozin, ertugliflozin	Benefit: canagliflozin, dapagliflozin, empagliflozin	See labels for renal dose considerations of individual agents Glucose-lowering effect is lower for SGLT2 inhibitors at lower eGFR	Oral	DKA risk, rare in T2DM: discontinue, evaluate, and treat promptly if suspected; be aware of predisposing risk factors and clinical presentation (including euglycemic DKA); discontinue before scheduled surgery (e.g., 3–4 days), during critical illness or during prolonged fasting mitigate potential risk; Increased risk of genitourinary tract infections; Necrotizing fasciitis of perineum (Fournier gangrene), rare reports; prompt treatment recommended if suspected; Attention to volume status, blood pressure, adjust other volume-contracting agents as applicable
GLP1-RAs		High to very high	No	Loss (intermediate to very high)	Benefit: dulaglutide, liraglutide, semaglutide (SQ) neutral: exenatide once weekly, lixisenatide	Neutral	Benefit for renal endpoints in CVOTs, driven by albuminuria outcomes: dulaglutide, liraglutide, semaglutide (SQ)	See labels for renal dose considerations of individual agents No dose adjustment for dulaglutide, liraglutide, semaglutide Monitor renal function when initiating or escalating doses in patients with renal impairment reporting severe adverse GI reactions	SC; oral (semaglutide)	Risk of thyroid C-cell tumors in rodents: human relevance not determined (liraglutide, dulaglutide, exenatide extended release, semaglutide); Counsel patients on potential for GI side effects and their typically natural guidance on dietary modifications to mitigate GI side effects (reduction in meal size, eating practices (stop eating once full), decreasing intake of high-fat or spicy food) consider slower dose titration for patients experiencing GI challenges; Pancreatitis has been reported but causality has not been established. Discontinue if pancreatitis is suspected; Evaluate for gall bladder disease if cholelithiasis or cholecystitis is suspected
GIP and GLP-1RA		Very high	No	Loss (very high)	Under investigation	Under investigation	Under investigation	See labels for renal dose considerations of individual agents; No dose adjustment; Monitor renal function when initiating or escalating doses in patients with renal impairment reporting severe adverse GI reactions	SC	Risk of thyroid C-cell tumors in rodents: human relevance not determined Counsel patients on potential for GI side effects and their typically temporary nature; provide guidance on dietary modifications to mitigate GI side effects (reduction in meal size, eating practices (stop eating once full), decreasing intake of high-fat or spicy food) consider slower dose titration for patients experiencing GI challenges
DPP-4 inhibitors		Intermediate	No	Neutral	Neutral	Neutral (potential risk, saxagliptin)	Neutral	Renal dose adjustment required (sitagliptin, saxagliptin, alogliptin); can be used in renal impairment; No dose adjustment required for linagliptin	Oral	Pancreatitis has been reported in clinical trials but causality has not been established, Discontinue if pancreatitis is suspected; Joint pain; Bullous pemphigoid (post-marketing): discontinue if suspected
Thiazolidinediones		High	No	Gain	Potential benefit: Pioglitazone	Increased risk	Neutral	No dose adjustment required; Generally not recommended in renal impairment due to potential for fluid retention	Oral	Congestive HF (pioglitazone, rosiglitazone); Fluid retention (edema; heart failure); Benefit in NASH; Risk of bone fractures; Weight gain: consider lower doses to mitigate weight gain and edema
Sulfonylureas		High	Yes	Gain	Neutral	Neutral	Neutral	Glyburide: generally not recommended in chronic kidney disease; Glipizide and glimepiride: initiate conservatively to avoid hypoglycemia	Oral	FDA special warning on increased risk of CV mortality based on studies of an older sulfonylurea (tolbutamide); glimepiride shown to be safe; Use with caution in persons at risk for hypoglycemia
Insulin	Human	High to very high	Yes	Gain	Neutral	Neutral	Neutral	Lower insulin doses required with a decrease in eGFR; titrate per clinical response	Human: SC; inhaled	Injection site reactions; Higher risk of hypoglycemia with human insulin (NPH or premixed formulations) vs. analogs.
	Analogs								Analogs: SC

Table 7.

Choice of glucose-lowering therapy.

CV, cardiovascular; CVOT, cardiovascular outcomes trial; DKA, diabetic ketoacidosis; DKD, diabetic kidney disease; DPP-4, dipeptidyl peptidase 4; eGFR, estimated glomerular filtration rate; FDA, U.S. Food and Drug Administration; GI, gastrointestinal; GIP, gastric inhibitory polypeptide; GLP-1 RA, glucagon-like peptide 1 receptor agonist; HF, heart failure; NASH, non-alcoholic steatohepatitis; MACE, major adverse cardiovascular events; SGLT2, sodium–glucose cotransporter 2; SC, subcutaneous; T2DM, type 2 diabetes mellitus. *For agent-specific dosing recommendations, please refer to manufacturers’ prescribing information.

7. Trends and newer developments in T2DM management

7.1 Trends in T2DM management

There has been substantial progress in T2DM management with promising results using various treatment regimens. The therapeutic options to treat T2DM are increasing and now there are nearly 60 FDA-approved drugs available. There is an increase in preference for newer drugs such as DPP4i and SGLT2i as per available prescription data [17, 39].

In clinical trials, nearly 100 additional antidiabetic agents are being currently studied. This list includes 19 more GLP1-RA, 10 DPP4i, and 12 SGLT2i. More drugs from these newer classes will be available soon in the pharmaceutical market. They are highly effective but due to their high cost, they are more commonly prescribed to patients in economically developed countries. Metformin is the most preferred first-line drug prescribed in both China and India [40, 41]. The increased use of metformin has influenced a decrease in the prescription trends of SUs and TZDs in economically developed countries [42]. Similar trends have been observed in developing countries [43]. In India, after metformin, DPP4 inhibitors and SUs are being used as second-line treatment and SGLT2 inhibitors are being used as third- or fourth-line antidiabetic agents.

7.2 Newer developments—drugs in the pipeline

7.2.1 LY3502970

Orforglipron is an oral non-peptide GLP-1RA. It is highly potent and selective against other B G-protein-coupled receptors. It has favorable pharmacokinetic profile for oral administration. It is a partial agonist, biased toward G-protein activation over beta-arrestin recruitment at the GLP-1 receptor. The results of Phase II trial have been published and have shown −2.1% HbA1c reduction at 26 weeks and weight loss upto −14.7% at 36 weeks. Currently it is in Phase III and is being developed by Eli Lilly [44, 45, 46].

7.2.2 SCO-094

A drug candidate which has a dual target of the receptors on GIP and GLP-1 has been identified by SCOHIA Company [47].

7.2.3 PF-06882961

Pfizer is developing a small-molecule GLP 1 receptor agonist called danuglipron. The oral formulation of this molecule is being investigated for diabetes mellitus. At 16 weeks, −1.16% HbA1c reduction along with −4.17 kg weight loss has been reported in Phase II trial. To confirm this results, Phase III trial is being conducted. The Phase II trial in obese non-diabetic patient is ongoing and is expected to complete by the end of year 2023. It is a twice a day formulation, work is being done to modify this formulation to once a day formulation [48, 49].

7.2.4 CagriSema

Semaglutide 2.4 mg co-administered with the long-acting amylin analog cagrilintide is known together as CagriSema. This investigational medicine is being developed by Novo Nordisk. It is given subcutaneously once in a week. At the end of 32 weeks, −2.2% HbA1c reduction along with −15.6% weight loss has been reported in Phase II trial. This gut hormone analog has potential to treat obesity and prevent diabesity [50, 51].

7.2.5 Multi-receptor drugs

Dr. Matthias Tschöp, the recipient of 2023 Banting Medal for the scientific achievement from American Diabetes Association (ADA) suggests that discovery of novel classes of dual and triple gut hormone drugs will continue to transform the fight against diabetes and obesity [52].

7.2.6 LY3437943

Retatrutide also known as GGG tri-agonist is a GIP, GLP-1, and glucagon receptor agonist. Eli Lilly is developing it for management of T2DM and obesity. It is administered subcutaneously once in a week. At 24 weeks, upto −2.02% HbA1c reduction along with −16.94% weight loss has been reported in T2DM phase II trial. In obesity phase II trial, weight loss upto −24.2% has been observed. One of the reasons for greater weight reduction with retatrutide may be combining glucagon receptor agonist with GIP and GLP-1 receptor agonism. It is as safe as incretin-based therapies [53, 54, 55].

8. Conclusions

The availability of newer class of drugs in recent years has changed the pharmacotherapeutic approach of management of T2DM. Understanding of underlying pathophysiology of T2DM, treatment strategies can be individualized to address the specific mechanisms contributing to the disease. The effectiveness of medications such as metformin, sulfonylureas, thiazolidinediones, DPP-4 inhibitors, SGLT2 inhibitors, GLP-1 receptor agonists has been extensively studied and proven to enhance glycemic control. The results of completed trials conducted on newer molecules having distinct mechanism of action are promising. These newer potential treatment options will change the management approach of T2DM in future. This chapter has provided a comparative overview of all options available for the management of T2DM highlighting key concepts and current practices.