ABSTRACT

While lifestyle changes such as dietary modification and increased physical activity can be very effective in improving glycemic control, over the long-term most individuals with Type 2 diabetes (T2DM) will require medications to achieve and maintain glycemic control. The purpose of this chapter is to provide the healthcare practitioner with an overview of the existing oral and injectable (non-insulin) pharmacological options available for the treatment of patients with T2DM. Currently, there are ten classes of orally available pharmacological agents to treat T2DM: 1) sulfonylureas, 2) meglitinides, 3) metformin (a biguanide), 4) thiazolidinediones (TZDs), 5) alpha glucosidase inhibitors, 6) dipeptidyl peptidase IV (DPP-4) inhibitors, 7) bile acid sequestrants, 8) dopamine agonists, 9) sodium-glucose transport protein 2 (SGLT2) inhibitors and 10) oral glucagon like peptide 1 (GLP-1) receptor agonists. In addition, glucagon like peptide 1 (GLP-1) receptor agonists, dual GLP-1 receptor and GIP receptor agonists, and amylin can be administered by injection. Medications from these distinct classes of pharmaceutical agents may be used as treatment by themselves (monotherapy) or in a combination of 2 or more drugs from multiple classes with different mechanisms of action. A variety of fixed combinations of 2 agents are available in the US and in many other countries. In this chapter we discuss the administration, mechanism of action, effect on glycemic control, other benefits, side effects, and the contraindications of the use of these glucose lowering drugs. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

While lifestyle changes such as dietary modification and increased physical activity can be very effective in improving glycemic control, over the long-term most individuals with Type 2 diabetes (T2DM ) will require medications to achieve and maintain glycemic control (1). The purpose of this chapter is to provide the healthcare practitioner with an overview of the existing oral and injectable (non-insulin) pharmacological options available for the treatment of patients with T2DM. The use of these drugs to treat diabetes during pregnancy, in children and adolescents, and for the prevention of diabetes are discussed in other Endotext chapters (2-4). For information on the management of T2DM and selecting amongst the available pharmacological agents see the chapter by Emily Schroeder in Endotext (5).

Currently, there are ten classes of orally available pharmacological agents to treat T2DM: 1) sulfonylureas, 2) meglitinides, 3) metformin (a biguanide), 4) thiazolidinediones (TZDs), 5) alpha glucosidase inhibitors, 6) dipeptidyl peptidase IV (DPP-4) inhibitors, 7) bile acid sequestrants, 8) dopamine agonists, 9) sodium-glucose transport protein 2 (SGLT2) inhibitors and 10) oral glucagon like peptide 1 (GLP-1) receptor agonists (Table 1) (6-8). In addition, glucagon like peptide 1 (GLP-1) receptor agonists, dual GLP-1 receptor and GIP receptor agonists, and amylin can be administered by injection (Table 2) (6-8).

Medications from these distinct classes of pharmaceutical agents may be used as treatment by themselves (monotherapy) or in a combination of 2 or more drugs from multiple classes with different mechanisms of action (6-8). A variety of fixed combination of 2 agents are available in the US and in many other countries (examples shown in Table 3). There are even combinations that contains 3 drugs (Qternmet XR which contains dapagliflozin, saxagliptin, and metformin and Trijardy XR which contains empagliflozin, linagliptin, and metformin). Additionally, there are combinations of GLP-1 receptor agonists and insulin (Table 3). These combination products may be useful and attractive to the patient, as they provide multiple drugs in a single tablet or injection, offering convenience and increased compliance. In the US, they also enable patients to receive two medications for a single medical insurance co-payment. Most importantly, the addition of a second drug results in an additive improvement in glycemic control. When a patient is on drug A if drug B is added to drug A, there is an improvement in glycemic control. This concept can be extended by the addition of a third drug C, and even a fourth drug D (Figure 1).

Figure 1.

Efficacy When Oral Agents are Used as Add-On Therapy. When a patient is on drug A and they are changed to drug B, C, or D, often no improvement in glucose control will be seen. However, if drug B is added to drug A, there is an improvement. This concept can often be extended by the addition of a third drug (C), or even a fourth drug (D). There is decreasing benefit for each additional drug as the baseline A1c level decreases. Note that there is limited data on the use of 4 drug combinations.

OVERVIEW OF DRUGS

There are a number of different abnormalities that contribute to the hyperglycemia that occurs in patients with T2DM (9). Therefore, the drugs used to treat patients with T2DM can have a number of different mechanisms by which they lower glucose levels. Figure 2 shows the various sites of action of the pharmacological therapies for the treatment of T2DM.

Figure 2.

Sites of Action of Pharmacological Therapies for the Treatment of Type 2 Diabetes.

A broad overview of the most commonly used drugs to treat T2DM is shown in Table 4 and the effect of drugs on blood lipid levels is shown in Table 5.

Bloomgarden et al reported results from a meta-regression analysis of 61 clinical trials evaluating the efficacy of the five major classes of oral anti-hyperglycemic agents (10). The results demonstrated that there is a strong direct correlation between baseline A1c level and the magnitude of the decrease in fasting glucose and A1c induced by these drugs (i.e., significantly greater reductions in both fasting plasma glucose and A1c were observed in groups with higher baseline A1c levels). Thus, expectations for the overall magnitude of effect from a given agent might be modest when treating patients whose baseline A1c is <7.5-8.0% while in patients with elevated A1c levels the effect of drug therapy may be more robust (figure 3). A separate meta-analysis of 59 clinical studies reached similar conclusions (11). These results indicate that comparing efficacies among different anti-diabetic medications is challenging, when the baseline HbA1c is different in the studies being compared.

Additionally, the population of patients studied can impact the efficacy of a particular class of drug. For example, patients with limited beta cell function will have a decreased response to sulfonylurea drugs as these agents work via stimulating insulin secretion by the beta cells while TZDs are most effective in patients with insulin resistance. Another example would be the decrease in efficacy of SGLT2 inhibitors lowering A1c levels in patients with decreased renal function. It is thus very difficult to compare the glucose lowering effects of different hypoglycemic drugs except in direct head-to-head comparison studies.

Figure 3.

Relationship between baseline A1c level and the observed reduction in A1c with oral anti-hyperglycemic medications. Irrespective of drug class, the baseline glycemic control markedly influences the overall magnitude of efficacy. Data from Bloomgarden et al, Table 1 (10).

A recent model-based meta-analysis was used to compare glycemic control between a large number of drugs adjusted for important differences between studies, including duration of treatment, baseline A1c, and drug dosages (12). In this analysis 229 studies with 121,914 patients were utilized. Table 6 shows the estimated decrease in A1c levels for different drugs in patients that are drug naïve with an A1c of 8% and a weight of 90kg after 26 weeks of treatment. If one averages the effect on A1c of the highest doses for each drug in a specific drug class the reductions in A1c for each class of drug are metformin 1.09%, sulfonylureas 1.0%, TZDs 0.95%, DPP-4 inhibitors 0.66%, SGLT2 inhibitors 0.83%, and GLP-1 receptor agonists 1.24%. These data and the individual data for each drug in table 6 provides a rough estimate of the efficacy of various drugs and drug classes in lowering A1c levels. One should note that within a drug class there may be differences in the ability of different drugs to lower A1c levels. This is particularly true with the GLP-1 receptor agonist drugs. For additional information there is a website that provides updated comparisons of various agents to treat patients with T2DM (https://www.comparediabetesdrugs.com/). Figures 4, 5, and 6 show the effect of glucose lowering drugs on A1c levels, change in weight, and hypoglycemia (graphs from https://www.comparediabetesdrugs.com/ June 28, 2020).

Figure 4.

The Effect of Hypoglycemic Drugs on A1c Levels

Figure 5.

Change in Weight Induced by Hypoglycemic Drugs

Figure 6.

Relative Risk of Hypoglycemia versus Placebo

The NIH is carrying out a study, Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study, that is randomizing approximately 5,000 patients on metformin therapy to sulfonylureas, DPP-4 inhibitors, GLP-1 receptor agonists, and insulin (13). The primary outcome is the time to primary failure defined as an A1c ≥ 7% over an anticipated mean observation period of 4.8 years (range 4-7 years). Preliminary results of this study were presented at the American Diabetes Association meeting (June 2021) and the results as expected demonstrated that the GLP-1 receptor agonist liraglutide was more effective than the sulfonylurea glimepiride and the DPP4 inhibitor sitagliptin in maintaining the A1c < 7% (GLP1 receptor agonist better than sulfonylurea better than DPP-4 inhibitor). It should be noted that the SGLT2 inhibitor and TZD drugs were not included in this study.

SULFONYLUREAS

Mechanism of Action

Sulfonylureas are insulin secretagogues and lower blood glucose levels by directly stimulating glucose independent insulin secretion by the pancreatic beta cells (14,16). Through the concerted efforts of GLUT2 (the high Km glucose transporter), glucokinase (the enzyme that phosphorylates glucose), and glucose metabolism, pancreatic beta cells sense blood glucose levels and secrete the appropriate amount of insulin in response (17,18). Glucose metabolism leads to ATP generation and increases the intracellular ratio of ATP/ADP, which results in the closure of the ATP-sensitive potassium channel on the plasma membrane (14,17,19). Closure of this channel depolarizes the membrane and triggers the opening of voltage-sensitive calcium channels, leading to the rapid influx of calcium (14,20). Increased intracellular calcium causes an alteration in the cytoskeleton and stimulates translocation of insulin-containing secretory granules to the plasma membrane and the secretion of insulin (Figure 7) (14).

Figure 7.

Mechanism by which glucose, sulfonylureas, and meglitinides stimulate insulin secretion by the beta cells.

The KATP channel is comprised of two subunits, both of which are required for the channel to be functional (20). One subunit contains the cytoplasmic binding sites for both sulfonylureas and ATP, and is designated as the sulfonylurea receptor type 1 (SUR1). The other subunit is the potassium channel, which acts as the pore-forming subunit (20). Either an increase in the ATP/ADP ratio or ligand binding by sulfonylureas or meglitinides to SUR1 results in the closure of the KATP channel and insulin secretion (15,20). Studies comparing sulfonylureas and non-sulfonylurea insulin secretagogues have identified several distinct binding sites on the SUR1 that cause channel closure. Some sites exhibit high affinity for sulfonylureas, while other sites exhibit high affinity for meglitinides.

In addition to binding to SUR1, sulfonylureas also bind to Epac2, a protein activated by cAMP (14). Sulfonylurea-stimulated insulin secretion was reduced both in vitro and in vivo in mice lacking Epac2, indicating that Epac2 also plays a role in sulfonylurea induced insulin secretion (21).

In addition to inducing insulin secretion sulfonylureas have other effects that could play a role in lowering blood glucose levels (14). Specifically, sulfonylureas have been shown to decrease hepatic insulin clearance, inhibit glucagon secretion from pancreatic alpha-cells (this may be secondary to increasing insulin secretion), and enhance insulin sensitivity in peripheral tissues (this may be partially due to lowering glucose levels and reducing glucotoxicity) (14). The contribution and importance of these additional effects in mediating the glucose lowering effects of sulfonylureas is uncertain.

MEGLINATIDES

METFORMIN

THIAZOLIDINEDIONES (TZDS)

ALPHA-GLUCOSIDASE INHIBITORS

SODIUM-GLUCOSE TRANSPORT PROTEIN 2 (SGLT2) INHIBITORS

Mechanism of Action

SGLT2 is a low-affinity, high-capacity glucose transporter in the proximal tubules of the kidneys, which is responsible for the reabsorption of the majority of the filtered glucose (approximately 90%) entering the tubules (16,128). SGLT1, which is predominantly expressed in the intestines is also expressed in the kidneys, is a high-affinity, low-capacity glucose transporter in the proximal tubules, which makes a minor contribution to the reabsorption of filtered glucose (approximately 10%) (16,128). SGLT 1 and 2 transporters are capable of reabsorbing virtually all the filtered glucose when blood glucose levels are less than approximately 180mg/dL. When blood glucose levels are greater than approximately 180mg/dL, glucose begins to appear in the urine (i.e., glycosuria). The higher the blood glucose level the greater the quantity of glucose in the urine. Patients with T2DM express a greater number of SGLT2 transporters in the proximal tubule than do healthy individuals and hence glucose reabsorption from the glomerular filtrate is increased in patients with diabetes and glycosuria occurs at a higher blood glucose level (typically approximately 220mg/dl (129).

Inhibition of SGLT2 by drugs results in glycosuria and can lead to the excretion of 60–90 grams of glucose in the urine per day (Figure 8) (16). The amount of glucose excreted in the urine can vary considerably depending on renal function and the degree of hyperglycemia (16). Decreased renal function results in a decrease in filtered glucose and less glucose in the urine while high blood glucose levels increase filtered glucose and increases the loss of glucose in the urine (16). The ability of the inhibition of SGLT2 to lower blood glucose levels is not dependent on insulin action and hence is not affected by insulin levels or insulin resistance (16). As will be discussed below many of the non-glucose lowering benefits and side effects of SGLT2 inhibitors can be explained by the increase in glucose excretion in the urine. It should be recognized that glycosuria results in an osmotic diuresis. Additionally, because the SGLT2 transporters also facilitate the reabsorption of sodium from the filtrate there is also the loss of sodium in the urine.

Figure 8.

Effect of SGLT2 Inhibitors on the Kidney

COMBINATION SGLT1 AND SGLT2 INHIBITORS

DOPAMINE AGONIST (CYCLOSET)

OVERVIEW OF THE INCRETIN SYSTEM

The incretin effect refers to a greater insulin stimulatory effect after an oral glucose load than from an intravenous glucose infusion when plasma glucose concentrations are matched (219). Thus, glucose and other nutrients delivered via the gastrointestinal tract potentiates the ability of the beta cells in the pancreas to produce insulin resulting in greater insulin secretion than with IV glucose (220). The increase in insulin levels with IV glucose is only approximately one‐third of that elicited by oral glucose. The majority of the incretin effect is due to two GI hormones, glucose-dependent insulinotropic peptide (GIP) and glucagon like peptide-1 (GLP-1) with GIP having a dominant role (Figure 9) (219). The basal plasma levels of the incretin hormones are low but after eating the levels increase reaching concentrations that augment the insulin secretory responses if glucose levels are high but are ineffective at low glucose concentrations (i.e. glucose dependent effect) (219).

Patients with T2DM have a significant reduction of the incretin effect but GLP-1 and GIP levels in the blood after meals are not reduced in patients with T2DM (219). Rather decreased functional beta cell mass and resistance to the effects of GLP-1 and GIP in patients with T2DM accounts for the decreased incretin effect (219). Infusion of GIP has a minimal response on insulin secretion in patients with T2DM (resistance to effect of GIP) whereas GLP-1 administration is able to stimulate insulin secretion but the response is reduced in patients with T2DM compared to normal individuals likely secondary to decreased functional beta cell mass (219). Achieving near-normoglycemia by intensified insulin regimens improved beta cell responsiveness to exogenous GIP and GLP-1, although the increase in insulin secretion was still much lower than in individuals without diabetes (219). The reduced incretin effect in patients with T2DM occurs after the diagnosis of diabetes is established, suggesting this abnormality is secondary to the diabetic state rather than the cause of diabetes (220).

Glucagon Like Peptide-1 (GLP-1)

GLP-1 is cleaved from the pro-glucagon molecule by pro-hormone convertase enzymes in the intestine (220). GLP-1 is stored in the L-cells of the intestine, predominantly in the ileum and colon, and is released at mealtime in response to neurohormonal signals and the presence of food in the gut (219,220). GLP-1 affects postprandial glucose levels through several mechanisms, including enhancing insulin secretion by the beta cells and inhibiting postprandial glucagon secretion by the alpha cells in a glucose-dependent manner (i.e. GLP-1 does not stimulate insulin secretion or inhibit glucagon secretion unless glucose levels are elevated) (220). This glucose dependent effect accounts for why incretin-based drugs do not cause serious hypoglycemia. Activation of GLP-1 receptors on beta cells increases cAMP levels, which potentiates insulin release in the presence of elevated glucose concentrations. In addition, GLP-1 slows the rate of gastric emptying, which is often paradoxically accelerated in patients with diabetes (220). GLP-1 also acts as a postprandial satiety signal through neurohormonal networks that signal the brain to suppress appetite and food intake, which can lead to weight loss (220). Animal studies suggest that exogenous GLP-1 has the ability to increase islet size, enhance beta-cell proliferation, inhibit beta-cell apoptosis, and regulate islet growth (221). The administration of GLP-1 intravenously increases insulin secretion, reduces glucagon secretion, and decreases glucose levels during fasting and in the post-prandial state (219). GLP-1 is rapidly degraded by dipeptidyl peptidase 4 (DPP-4) into inactive peptides (half-life is minutes) (Figure 9).

Figure 9.

Incretin Hormone Secretion and Effect on Pancreas

DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITORS

INJECTABLE GLUCAGON LIKE PROTEIN-1 (GLP-1) RECEPTOR AGONISTS

Introduction

There are currently six GLP-1 receptor agonists available in the US, three drugs administered daily and three drugs administered weekly (Figure 10). Albiglutide (Tanzeum) was withdrawn from the market for commercial reasons and is no longer available. GLP-1 receptor agonists can be used in combination with multiple oral anti‐diabetic drugs or in combination with insulin (239). The concentrations of GLP-1 receptor agonist activity are much higher than physiological levels of GLP-1 activity (16). The GLP-1 receptor agonists that a similar to exendin-4 (Exenatide and Lixisenatide) are eliminated by the kidneys and therefore in patients with severe renal disease these drugs are contraindicated (16). In contrast, the drugs that are analogues of GLP-1 are degraded by peptidases (16).

Figure 10.

Structure of GLP-1 Receptor Agonists

SHORT ACTING GLP-1 RECEPTOR AGONISTS

Exenatide (Byetta) is a synthetic exendin-4 that is a peptide originally isolated from the saliva of the Gila monster that has a 53% homology with human GLP-1 and is resistant to degradation by DPP-4 (16,239). Lixisenatide (Adylyxin) is an exendin-4 analogue with six Lys residues added at the C terminus to confer resistance to DPP-4 (16,239).

LONG ACTING GLP-1 RECPTOR AGONISTS

Even though liraglutide (Victoza) is administered daily it is considered a long acting GLP-1 receptor agonist because its effects on fasting glucose levels are similar to weekly GLP-1 receptor agonists and its effects on gastric emptying wane as seen with weekly GLP-1 receptor agonists. Liraglutide is an analogue of GLP-1 with the addition of a 16-carbon fatty acid chain that masks the DPP-4 cleavage site preventing degradation (8,179). Once weekly exenatide (Bydureon and Bydueron BCise) is a sustained-release formulation that consists of exenatide embedded within biodegradable polymeric microspheres of poly (DL-lactic-co-glycolic acid) (16). Dulaglutide (Trulicity) has two copies of a GLP-1 analogue covalently linked to an Fc fragment of human IgG4 (16,239). Semaglutide (Ozempic) is an analogue of human GLP‐1 RA and is linked via a hydrophilic spacer and a fatty acid side chain to albumin (239).

ORAL GLUCAGON LIKE PROTEIN-1 (GLP-1) RECEPTOR AGONISTS

DUEL GLP-1 RECEPTOR AND GIP RECEPTOR AGONIST

INSULIN-GLP-1 RECEPTOR AGONIST COMBINATIONS

BILE ACID SEQUESTRANTS

PRAMLINTIDE (SYMLIN)

SUMMARY

A large number of drugs are now available for lowering glucose levels. For information on the management of T2DM and selecting amongst the available pharmacological agents see the chapter by Schroeder (5). For information on the use of these drugs to treat diabetes during pregnancy, in children and adolescents, and for the prevention of diabetes see other Endotext chapters (2-4).

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