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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 detailed information on 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 (2-5). For information on the management of T2DM and selecting amongst the available pharmacological agents see the chapter by Emily Schroeder in Endotext ().

Currently, there are ten classes of orally available pharmacological agents to treat T2DM: 1) sulfonylureas (SU), 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 pramlintide 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. 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 (GLP-1 RAs) and insulin. 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 ().

There are a number of different abnormalities that contribute to the hyperglycemia that occurs in patients with T2DM (). Therefore, the drugs used to treat patients with T2DM can have a number of different mechanisms by which they lower glucose levels. shows the various sites of action of the pharmacological therapies for the treatment of T2DM. A broad overview of the most commonly used drugs to treat T2DM is shown in and the effect of drugs on blood lipid levels is shown in .

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 (). 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 (). A separate meta-analysis of 59 clinical studies reached similar conclusions (). 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. A recent trial demonstrated that in individuals with a BMI > 30 pioglitazone reduced HbA1c levels better than sitagliptin while in individuals with a BMI < 30 sitagliptin was more effective (). In individuals with an eGFR > 90 canagliflozin lowered HbA1c better than sitagliptin while in individuals with an eGFR between 60-90 sitagliptin was more effective (). These results demonstrate that certain patient characteristics will influence the response to treatment with specific drugs indicating the ability to target drug therapy for the specific patient. Investigators are developing models to predict the efficacy of DPP-4 inhibitors, GLP-1 RAs, SGLT-2 inhibitors, sulfonylureas, and thiazolidinediones to lower HbA1c levels using widely available clinical features (age, duration of diabetes, sex, baseline HbA1c, BMI, estimated glomerular filtration rate, HDL cholesterol, total cholesterol, and alanine aminotransferase) to facilitate therapy (). Additionally, the variation in response of patients makes it difficult to compare the glucose lowering effects of different hypoglycemic drugs except in direct head-to-head comparison studies.

A 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 (). In this analysis 229 studies with 121,914 patients were utilized. 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 RAs 1.24%. These data and the individual data for each drug in 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/ ). This website shows the effect of glucose lowering drugs on A1c levels, change in weight, and hypoglycemia.

The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study randomized approximately 5,000 patients with relatively recent onset of T2DM (4.2 years) on metformin therapy to sulfonylureas, DPP-4 inhibitors, GLP-1 RAs, or insulin (). The primary outcome was the time to primary failure defined as an A1c ≥ 7% over an anticipated mean observation period of 5 years 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% (GLP-1 receptor agonist better than sulfonylurea better than DPP-4 inhibitor) (). Liraglutide and glargine insulin were similarly effective in lowering A1c levels (). Significantly the majority of patients regardless of drug assignment did not have an A1c level less than 7% demonstrating the progressive nature of diabetes and the difficulty in maintaining good glycemic control. It should be noted that the SGLT2 inhibitors and TZD drugs were not included in this study. The incidences of microvascular complications (renal disease and neuropathy) and death were not different among the four treatment groups (). There was a suggestion of a decrease in cardiovascular disease in the liraglutide treated group (,).

Sulfonylureas were developed in the 1950s and have been widely used in the treatment of patients with T2DM (,). First generation sulfonylureas (acetohexamide, chlorpropamide, tolazamide, and tolbutamide) possess a lower binding affinity for the ATP-sensitive potassium channel, their molecular target (vide infra), and thus require higher doses to achieve efficacy (,). These first-generation sulfonylureas are currently rarely used. Subsequently, in the 1980s 2 nd generation sulfonylureas including glyburide (glibenclamide), glipizide, gliclazide, and glimepiride were developed and are now widely used (). The 2 nd generation sulfonylureas are much more potent compounds (~100-fold). Sulfonylureas can be used as monotherapy or in combination with any other class of oral diabetic medications except meglitinides because they lower glucose levels by a similar mechanism of action (,).

Key characteristics of the different sulfonylureas are shown in (). Of clinical importance is the duration of action, which varies with the rate of hepatic metabolism and the hypoglycemic activity of drug metabolites. Drugs with a long duration of action are more likely to cause severe and prolonged hypoglycemia whereas short acting drugs need to be given multiple times per day (). Additionally, drugs that are metabolized to active agents (for example glyburide) are also more likely to cause hypoglycemia (). Most sulfonylureas are metabolized in the liver and are to some extent excreted by the kidney; therefore, hepatic and/or renal impairment increases the risk of hypoglycemia ().

Sulfonylureas should be taken 30 minutes before meals starting with a low dose with an increase in dosage until desired glycemic control has been achieved. In patients with a high risk of severe hypoglycemia a very low dose can be the initial therapy while in patients with very high A1c levels one can initiate therapy at a higher dose. The recommended starting dose of glipizide is 5 mg approximately 30 minutes before breakfast. Geriatric patients or those with liver or renal disease or other risk factors for severe hypoglycemia can be started at 2.5 mg. Patients with very high A1c levels may be started on a higher dose. Based on the glucose response the dose can be increased weekly by 2.5-5 mg. If a once-a-day dose is not satisfactory or the patient requires more than 15 mg per day one can give the drug before breakfast and dinner. The maximum daily dose is 40 mg per day. The usual starting dose of extended-release glipizide is 5 mg per day with breakfast. Those patients who are at high risk of hypoglycemia may be started at a lower dose. The dose can be increased based on glucose or A1c measurements. The maximum dose is 20 mg per day.

The usual starting dose of glyburide is 2.5 to 5 mg daily with breakfast or the first main meal. Patients at high risk for hypoglycemia should be started on 1.25 mg per day. The dose should be increased weekly by 2.5 mg based on the glucose response. The maximum dose per day is 20 mg. The usual starting dose of micronized glyburide is 1.5 to 3 mg daily with breakfast or the first main meal. Patients at high risk for hypoglycemia should be started on 0.75 mg per day. The dose should be increased weekly by 1.5 mg based on the glucose response. The maximum dose per day is 12 mg per day. The recommended starting dose of glimepiride is 1 or 2 mg once daily. Patients at increased risk for hypoglycemia should start on 1 mg once daily. The dose should be increased every 1-2 weeks in increments of 1 or 2 mg based upon the patient’s glycemic response. The maximum dose is 8 mg per day. The recommended starting dose of gliclazide is 40 - 80mg once daily. Patients at increased risk for hypoglycemia should start on 40 mg once daily. The dose should be increased every 1-2 weeks in increments of 40 or 80 mg based upon the patient’s glycemic response. The maximum dose is 160mg twice a day.

Sulfonylureas are insulin secretagogues and lower blood glucose levels by directly stimulating glucose independent insulin secretion by the pancreatic beta cells (,). 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 (,). 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 (,,). Closure of this channel depolarizes the membrane and triggers the opening of voltage-sensitive calcium channels, leading to the rapid influx of calcium (,). 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 () ().

The KATP channel is comprised of two subunits, both of which are required for the channel to be functional (). 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 (). 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 (,). 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 (). 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 ().

In addition to inducing insulin secretion sulfonylureas have other effects that could play a role in lowering blood glucose levels (). 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) (). The contribution and importance of these additional effects in mediating the glucose lowering effects of sulfonylureas is uncertain.

When used at maximally effective doses, results from well-controlled clinical trials have not indicated a marked superiority of one 2 nd generation sulfonylurea over another in improving glycemic control (). Similarly, 2 nd generation sulfonylureas exhibit similar clinical efficacy compared to the 1 st generation agents (). Sulfonylureas do not have a linear dose-response relationship and the majority of the A1C reduction occurs at half maximum dosage. The effect of sulfonylureas as monotherapy or when added to metformin therapy on A1c levels varies but typically results in reductions in A1c of approximately 0.50-1.5% (,,,,). If A1c levels are very high decreases in the range of 1.5- 2.0% may be seen (,,). Patients with a short duration of diabetes with residual beta cell function (high C-peptide levels) are likely to be most responsive to sulfonylurea therapy (). Overtime many patients on sulfonylureas require additional therapies (secondary failure). In the ADOPT study, after 5 years 34% of the patients on glyburide monotherapy had fasting glucose levels > 180 mg/dl (i.e., secondary failure) (). Similarly, in the United Kingdom Prospective Diabetes Study (UKPDS), only 34% of patients attained an A1c <7% at 6 years treated with sulfonylureas (glyburide or chlorpropamide) and this number declined to 24% at 9 years (). This lack of durability of sulfonylurea therapy is likely to be due to beta cell exhaustion. In addition, the weight gain induced by sulfonylurea therapy may also adversely affect glycemic control.

The results of the GRADE study, which compared glargine insulin, glimepiride, liraglutide, and sitagliptin added to metformin, were discussed earlier in the section entitled “OVERVIEW OF DRUGS”.

Based on the University Group Diabetes Project (UGDP) sulfonylureas carry a “black box” warning regarding cardiovascular disease (,). However, the U.K. Prospective Diabetes Study Group (UKPDS) studied a large number of newly diagnosed patients with T2DM at risk for cardiovascular disease. In this study improved glycemic control with sulfonylureas reduced cardiovascular disease by approximately 16%, which just missed being statistically significant (p=0.052) (). In the UKPDS, A1c was reduced by approximately 0.9% and the 16% reduction in cardiovascular disease was in the range predicted based on epidemiological studies. Thus, the reduction in cardiovascular events was likely due to improvements in glycemic control and not a direct benefit of sulfonylurea treatment. In support of this conjecture is that in the UKPDS, insulin treatment resulted in a similar decrease in A1c levels and reduction in cardiovascular events (). Additionally, a large randomized cardiovascular outcome study (Carolina Study) reported that linagliptin, a DPP-4 inhibitor, and glimepiride, a sulfonylurea, had similar effects on cardiovascular events (hazard ratio 0.98) (). Taken together these results suggest that sulfonylureas have a neutral effect on cardiovascular disease.

The major side effect of sulfonylurea treatment is hypoglycemia, which is more likely to occur and is more severe with long- acting sulfonylureas (,). In the UKPDS severe hypoglycemia, defined by need for third-party assistance, occurred each year in 0.4–0.6/100 patients treated with a sulfonylurea while non-severe hypoglycemia was seen in 7.9/100 persons treated with a sulfonylurea (). Other studies have found even higher rates of severe hypoglycemia with 20–40% of patients receiving sulfonylureas having hypoglycemia and severe hypoglycemia (requiring third-party assistance) occurring in 1–7% of patients (,). With continuous glucose monitoring 30% of well controlled patients with T2DM had episodes of hypoglycemia that were often asymptomatic and nocturnal (). Of great concern these hypoglycemic events were associated with EKG changes, particularly QTc prolongation (). Other studies have also observed a very high rate of hypoglycemia in patients with T2DM treated with sulfonylureas when monitored using continuous glucose monitoring ().

Hypoglycemia typically occurs after periods of fasting or exercise. In light of this hypoglycemic risk, initiation of treatment with sulfonylureas should be at the lowest recommended dose and the dose slowly increased in patients with modestly elevated A1c levels. Older patients (> age 65) and patients with hepatic or renal disease are more likely to experience frequent and severe hypoglycemic reactions, particularly if the goals of therapy aim for inappropriately tight glycemic control (). Many clinicians avoid the use of long acting sulfonylureas (glyburide) in these high-risk patients as glyburide has a higher risk of hypoglycemia compared to other sulfonylureas ().

In the UKPDS, sulfonylurea treatment caused a net weight gain of approximately 3 kg, which occurred during the first 3-4 years of treatment and then stabilized (,). Other studies have similarly observed weight gain with sulfonylurea treatment ().

Chlorpropamide can induce hyponatremia and water retention due to inappropriate secretion of antidiuretic hormone (ADH) (). In addition, tolbutamide and chlorpropamide, in certain susceptible individuals, is associated with alcohol-induced flushing (). Because of an increased risk of side effects 1 st generation sulfonylureas are seldom used.

Sulfonylureas are best avoided in patients with a sulfa allergy who experienced prior severe allergic reactions (Package insert). Otherwise, cross-reactivity between antibacterial and nonantibacterial sulfonamide agents is rare. In renal failure, the dose of the sulfonylurea agent will require adjustment based on glucose monitoring to avoid hypoglycemia (). Because it is metabolized primarily in the liver without the formation of active metabolites, glipizide is the preferred sulfonylurea in patients with renal disease (). In the elderly, long acting sulfonylureas, such as glyburide, glimepiride and chlorpropamide are not recommended (). Sulfonylureas can cause hemolytic anemia in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency and therefore should be used with caution in such patients (Package insert). Certain drugs may enhance the glucose-lowering effects of sulfonylureas by inhibition of their hepatic metabolism (antifungals and monoamine oxidase inhibitors), displacing them from binding to plasma proteins (coumarins, NSAIDs, and sulfonamides), or inhibiting their excretion (probenecid) ().

While the ability of sulfonylureas to improve glycemic control is robust, the risk of hypoglycemia and weight gain reduce the desirability of this drug class. Additionally, the shorter durability of effectiveness is also a limiting factor. In patients at high risk for the occurrence of severe hypoglycemic reactions or in patients who are obese, using drugs other than sulfonylureas to treat T2DM is indicated if possible. Similarly, in patients with atherosclerotic cardiovascular disease, heart failure, or at high risk for cardiovascular disease or renal disease other hypoglycemic drugs have important advantages. Nevertheless, because sulfonylureas are generic drugs and very inexpensive, they continue to be used and play a role in the management of patients with T2DM.

The meglitinides are non-sulfonylurea insulin secretagogues characterized by a very rapid onset and abbreviated duration of action (,). Repaglinide (Prandin), a benzoic acid derivative introduced in 1998, was the first member of the meglitinide class. Nateglinide (Starlix) is a derivative of the amino acid D-phenylalanine and was introduced to the market in 2001. Unlike sulfonylureas, repaglinide and nateglinide stimulation of insulin secretion is dependent on the presence of glucose (,). As glucose levels decrease, insulin secretion decreases, which reduces the risk of hypoglycemia compared with sulfonylureas. Meglitinides are rapidly absorbed with maximum serum concentrations generally attained within 1 hour and then quickly metabolized by the liver cytochrome CYP3A4 and CYP2C8 pathways, producing inactive metabolites, resulting in a plasma half-life of around 1 h (). This rapid onset and short duration of action results in the ability of this class of drugs to predominantly reduce postprandial glucose levels (). Because of the rapid onset and short duration of action meglitinides are given 1-30 minutes prior to meals. The drug should not be administered if the patient is going to skip the meal.

The pharmacokinetics of meglitinides differ with nateglinide having a faster onset and shorter duration of action than repaglinide (). Nateglinide stimulates early insulin release faster and to a greater extent than repaglinide with insulin levels returning to baseline levels more rapidly (,).

The recommended starting dose of nateglinide is 120 mg three times per day before meals (1-30 minutes). In patients who are near their glycemic goal when treatment is initiated the recommended starting dose of nateglinide is 60 mg three times per day before meals. The maximum dose of nateglinide is 120 mg three times per day before meals. The recommended starting dose of repaglinide for patients whose A1c is less than 8% is 0.5 mg before each meal (1-30 minutes). For patients whose A1c is 8% or greater the starting dose is 1 or 2 mg orally before each meal. The patient’s dose should be doubled up to 4mg with each meal until satisfactory glycemic control is achieved (should wait one week between increasing dose). The maximum daily dose is 16 mg per day.

Meglitinides bind to a different site on SUR1 in β cells that is separate from the sulfonylurea binding site () (,). The effect of meglitinide binding is similar to the effect of sulfonylureas with binding resulting in the closure of the KATP channel leading to cell depolarization and calcium influx resulting in insulin secretion (,,). However, the relatively rapid onset and short duration of action of meglitinides suits their use as prandial glucose-lowering agents (,).

Studies have shown that A1c reductions are similar to, or slightly less, than those observed with sulfonylurea or metformin treatment when meglitinides are used as monotherapy (,). In studies comparing repaglinide monotherapy with sulfonylurea or metformin therapy the decrease in A1c was similar (,). In contrast, a study comparing nateglinide with metformin demonstrated that metformin was more effective in lowering A1c levels (). In a randomized trial comparing repaglinide and nateglinide in patients with T2DM previously treated with diet and exercise, repaglinide was more effective in lowering A1c levels (1.57% vs. 1.04%) (). While postprandial glucose levels were similar repaglinide was more effective in reducing fasting glucose levels, probably due to its longer duration of action. These clinical findings can be incorporated into clinical decision making. For example, if the main issue for the patient is postprandial hyperglycemia, and fasting glucoses are near normal, an agent, such as nateglinide, that has a limited effect on the fasting glucose would be ideal. However, if one needs reductions in both fasting and postprandial glucose levels a longer acting agent such as repaglinide is a better choice.

The Navigator study was a double-blind, randomized clinical trial in 9,306 individuals with impaired glucose tolerance and either cardiovascular disease or cardiovascular risk factors who received nateglinide (up to 60 mg three times daily) or placebo (). After 5 years, nateglinide administration did not alter the incidence of cardiovascular outcomes suggesting that meglitinides do not have adverse or beneficial cardiovascular effects. The effect of meglitinides on cardiovascular disease has not been studied in patients with T2DM.