Evolution of Glucose-Lowering Drugs for Type 2 Diabetes

C H A P T E R

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Evolution of Glucose-Lowering Drugs for Type 2 Diabetes: A New Era of Cardioprotection Andrew J. Krentz Senior Research Fellow, ProSciento, Chula Vista, CA, United States

O U T L I N E Cardiovascular Safety of DPP-4 Inhibitors 446 Glucagon-Like Peptide-1 Receptor Agonists 446 Cardiovascular Effects of GLP-1 Receptor Agonists448 Sodium-Glucose Cotransporter-2 Inhibitors 449 Cardiovascular Effects of SGLT2 Inhibitors 450

Introduction432 Pre-CVOT Era Drugs for Type 2 Diabetes 433 Biguanides433 Sulfonylureas440 Meglitinide Analogs 440 Alpha-Glucosidase Inhibitors 441 Thiazolidinediones441 Bromocriptine443 Colesevelam443 Amylin Analogs 443 CVOT Era Drugs for Type 2 Diabetes: Benefits and Risks Drugs Acting via the Incretin Axis Dipeptidyl Peptidase-4 Inhibitors

Nutritional and Therapeutic Interventions for Diabetes and Metabolic Syndrome https://doi.org/10.1016/B978-0-12-812019-4.00033-7

Conclusions451 References451

444 444 444

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© 2018 Elsevier Inc. All rights reserved.

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33.  EVOLUTION OF GLUCOSE-LOWERING DRUGS FOR TYPE 2 DIABETES: A NEW ERA OF CARDIOPROTECTION

INTRODUCTION After many years of therapeutic near stagnation in the pharmacotherapy of type 2 diabetes, new glucose-lowering drugs have entered the market during the last decade or so; still more are currently being evaluated in clinical trials. Several classes of novel drugs for type 2 diabetes are currently being positioned within treatment algorithms alongside more established agents as clinical efficacy and safety data continue to accumulate.1 These newer drugs, e.g., dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and sodiumglucose cotransporter-2 (SGLT2) inhibitors, avoid some of the adverse effects and limitations of older drugs such as biguanides and sulfonylureas (see later). In particular, the cardiovascular efficacy and safety profiles of the newer classes have been assessed much more rigorously compared with older agents.2 However, no diabetes drugs are devoid of unwanted effects and unexpected toxicity profiles have been observed with some newer agents. By definition, clinical experience of these newer drugs is limited and their long-term efficacy and safety have yet to be fully quantified. Unanticipated safety issues that emerged after many years of use—most notably with the thiazolidionediones (glitazones)—altered the perceptions of risks and benefits of glucose-­ lowering agents.3,4 The rosiglitazone controversy prompted regulators to insist on more rigorous assessment of cardiovascular safety in patients with type 2 diabetes. This consideration is of enormous importance because the risk of atherothrombotic events (macrovascular disease), primarily ischemic heart disease and stroke, are greatly increased in type 2 diabetes.5,6 The fact that these complications are the leading cause of death among patients with diabetes makes exclusion of adverse cardiovascular effects of new drugs imperative. Separating the intrinsic risk of ischemic events from toxic effects of new drugs can be problematic in the absence of rigorously controlled clinical trials.

On a more positive note, the place of metformin as foundation therapy was cemented by the results of the United Kingdom Prospective Diabetes Study (UKPDS)7 and the subsequent 10-year follow-up.8 Sulfonylureas are still used extensively, although the advantages of newer drugs, notably avoidance of weight gain and freedom from hypoglycemia, are increasingly being considered by physicians as they take a more patient-centric view of prescribing.9 A detailed exposition of the aims and approaches of managing type 2 diabetes is outside the scope of this chapter. However, a few guiding principles are warranted. The management of type 2 diabetes centers on attaining glycemic control to relieve acute osmotic symptoms and preventing, or at least retarding, the development of long-term microvascular and macrovascular complications. More often than not, lifestyle measures have to be supplemented with pharmacological therapy. In general, oral glucose-lowering agents are used first as long as hyperglycemia is not too extreme, with marked osmotic symptoms reflecting severe insulin deficiency. Pharmacotherapy is stepped up with injectable glucose-lowering agents, i.e., GLP-1 receptor agonists and insulin, being held in reserve. Sufficient residual pancreatic β-cell function is necessary for most orally active drugs to exert their maximal glucose-lowering effects. Combinations of drugs from different agents, e.g., insulin sensitizers + insulin secretagogues, are often required as endogenous insulin production wanes. Ultimately, insulin replacement therapy is required by many patients after failure to maintain glycemic control with two to three oral agents. Various options are available when transitioning to insulin and often one, less commonly more than one, oral agents are continued in combination with insulin. Balancing the risk–benefit profile of glucoselowering drugs and setting and maintaining glycemic targets appropriate to the individual patient are major tenets of therapy. Special care must be taken in highly vulnerable groups such as older patients and those with comorbidities

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Pre-CVOT Era Drugs for Type 2 Diabetes

such as renal or hepatic impairment, or a history of cardiovascular disease (see later). Great care is also needed in women of childbearing age because of the risk of pregnancy. Diabetes in pregnancy requires specialist care. Major metabolic decompensation, i.e., diabetic ketoacidosis and hyperosmolar nonketotic state, requires immediate insulin treatment and intensive supportive measures, including rehydration, in an acute hospital setting. Of note, diabetic ketoacidosis has emerged as an unexpected safety issue with SGLT2 inhibitors (see later).10 Glucose-lowering therapy must be complemented by additional measures directed at reducing the risk of atherothrombotic (macrovascular) complications: these are the leading cause of premature mortality in type 2 diabetes.11 Nonglucose-dependent effects of drugs for diabetes, such as improvements in aspects of lipid profiles or reductions in blood pressure, are therefore highly relevant considerations. However, positive effects on these risk factors cannot be assumed to translate into better clinical outcomes in the long term. This lesson was brought home by the aforementioned storm of controversy that led to major regulatory restrictions on the use of rosiglitazone. The rosiglitazone controversy brought cardiovascular safety to the forefront of regulatory considerations. A recent series of cardiovascular outcome trials (CVOTs) that were mandated by the US Food and Drug Administration (FDA) have demonstrated cardioprotective effects of members of the SGLT2 inhibitors and GLP-1 receptor agonist classes.12–14 The results of these trials, which are considered later in the chapter, are now being incorporated into clinical practice.15 In this chapter we briefly review the more established classes of glucose-lowering drugs that are used for type 2 diabetes, noting that some are more popular than others (Table 33.1). We then consider the range of oral and injectable agents acting on the incretin axis. Finally, we briefly review the SGLT2 inhibitor class. The results of recent CVOTs are presented (Tables 33.2 and 33.3). Limitations of space preclude

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in-depth discussion of insulin options for patients with type 2 diabetes. The role of antiobesity drugs in the treatment of type 2 diabetes lies outside the scope of this review.16,17

PRE-CVOT ERA DRUGS FOR TYPE 2 DIABETES Biguanides Metformin (dimethylbiguanide) is now the only member of the biguanide class available in many countries. Phenformin was withdrawn from the United Kingdom and other markets in the l970s because of its association with lactic acidosis.18 Worldwide, metformin is the most extensively used oral agent for type 2 diabetes. The drug, which has been in use since the 1950s, is widely regarded as first-line monotherapy for type 2 diabetes inadequately controlled by lifestyle measures, as recommended by the American Diabetes Association and European Association for the Study of Diabetes.19 In the UKPDS, metformin not only provided protection against microvascular complications of diabetes but also reduced the incidence of atherothrombotic events compared with diet therapy.7 In contrast to sulfonylureas or insulin, metformin also reduced diabetes-related deaths and all-cause mortality in overweight and obese participants who were initially randomized to the drug in UKPDS. Metformin has been credited with vasoprotective effects not shared by other classes of glucose-­lowering agents.20 These include increased rates of fibrinolysis and reduced levels of plasminogen activator inhibitor-1. However, attributing the relative contributions of these actions and the glucose-lowering effects of metformin has been p ­ roblematic.21 An additional issue is that some studies, notably the UKPDS, have suggested that combination therapy using metformin with a sulfonylurea may be detrimental.7,21,22 However, a putative role for metformin as an anticancer agent has emerged.23

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Putative Mechanism of Action

Primary Pharmacologic Effect

• Metformin

Activates AMP kinase (?other actions)

↓ Hepatic glucose production

No dose adjustment if eGFR >45; do not initiate OR assess risk–benefit if currently on metformin if eGFR 30–45; discontinue if eGFR <30

• Glyburide/ glibenclamide • Glipizide • Glimepiride

Closes KATP channels on β-cell plasma membranes

↑ Insulin secretion

• Avoid use in patients with renal impairment • Initiate at 2.5 mg daily to avoid hypoglycemia • Initiate at 1 mg daily to avoid hypoglycemia

Meglitinides (glinides) • Repaglinide • Nateglinide

Closes KATP channels on β-cell plasma membranes

↑ Insulin secretion

• Initiate conservatively at 0.5 mg with meals if eGFR <30 • Initiate conservatively at 60 mg with meals if eGFR <30

Thiazolidinediones

• Pioglitazone • Rosiglitazoneb

Activates nuclear ↑ Insulin sensitivity transcription factor PPAR-γ

• No dose adjustment required • No dose adjustment required

α-Glucosidase inhibitors

• Acarbose • Miglitol

Inhibition of intestinal α-glucosidase

Slows intestinal carbohydrate digestion/ absorption

• Avoid if eGFR <30 • Avoid if eGFR <25

DPP-4 inhibitors

• Sitagliptin • Saxagliptin • Linagliptin • Alogliptin

Inhibits DPP-4 activity, increasing postprandial incretin (GLP-1, GIP) concentrations

↑ Insulin secretion (glucose dependent); ↓ Glucagon secretion (glucose dependent)

100 mg daily if eGFR >50; 50 mg daily if eGFR 30–50; 25 mg daily if eGFR <30

Class

Examples

Biguanides

Sulfonylureas (second generation)

Renal Dosing Recommendationsa

5 mg daily if eGFR >50; 2.5 mg daily if eGFR ≤50 • No dose adjustment required 25 mg daily if eGFR >60; 12.5 mg daily if eGFR 30–60; 6.25 mg daily if eGFR <30

Bile acid sequestrants

• Colesevelam

Binds bile acids in intestinal tract, increasing hepatic bile acid production

? ↓ Hepatic glucose production; ? ↑ Incretin levels

Dopamine-2 agonists

• Bromocriptine (quick release)b

Activate dopaminergic receptors

Modulates hypothalamic • No specific dose adjustment recommended regulation of metabolism; ↑ Insulin sensitivity

• No specific dose adjustment recommended

33.  EVOLUTION OF GLUCOSE-LOWERING DRUGS FOR TYPE 2 DIABETES: A NEW ERA OF CARDIOPROTECTION

TABLE 33.1 Available Glucose-Lowering Agents in the United States for the Treatment of Type 2 Diabetes

SGLT2 inhibitors

• Canagliflozin • Dapagliflozin • Empagliflozin

Inhibits SGLT2 in the proximal nephron

Blocks glucose reabsorption by the kidney, increasing glucosuria

No dose adjustment required if eGFR ≥60; 100 mg daily if eGFR 45–59; avoid use and discontinue in patients with eGFR persistently <45 Avoid initiating if eGFR <60; not recommended with eGFR 30–60; contraindicated with eGFR <30

GLP-1 receptor agonists

• Exenatide • Exenatide extended release • Liraglutide • Albiglutide • Lixisenatide • Dulaglutide

Activates GLP-1 receptors

↑ Insulin secretion (glucose dependent) ↓ Glucagon secretion (glucose dependent); Slow gastric emptying; ↑ Satiety

• Not recommended with eGFR <30 • Not recommended with eGFR <30 • No specific dose adjustment recommended by the manufacturer; limited experience in patients with severe renal impairment • No dose adjustment required for eGFR 15–89 per manufacturer; limited experience in patients with severe renal impairment • No dose adjustment required for eGFR 60–89; no dose adjustment required for eGFR 30–59, but patients should be monitored for adverse effects and changes in kidney function; clinical experience is limited with eGFR 15–29; patients should be monitored for adverse effects and changes in kidney function; avoid if eGFR <15 • No specific dose adjustment recommended by the manufacturer; limited experience in patients with severe renal impairment

Amylin mimetics

• Pramlintideb

Activate amylin receptors

↓ Glucagon secretion; slows gastric emptying; ↑ Satiety

• No specific dose adjustment recommended

PRE-CVOT ERA DRUGS FOR TYPE 2 DIABETES

VI.  PREVENTION AND TREATMENT 2: DRUGS AND PHARMACEUTICALS

• Contraindicated with eGFR <30

a

eGFR is given in mL/min/1.73 m2. Not licensed in Europe for type 2 diabetes. eGFR, estimated glomerular filtration rate; GIP, glucose-dependent insulinotropic peptide; PPAR-γ, peroxisome proliferator-activated receptor gamma; SGLT2, sodiumglucose cotransporter-2. Modified from American Diabetes Association. Diabetes Care 2018;41(Suppl. 1):S73–85. b

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TABLE 33.2 Completed Food and Drug Administration (FDA)-Mandated Diabetes Cardiovascular Outcome Trials (CVOTs) by Class and Drug DPP-4 INHIBITORS Alogliptin Saxagliptin Sitagliptin SGLT2 INHIBITORS Empagliflozin Canagliflozin GLP-1 RECEPTOR AGONISTS Lixisenatide Liraglutide Semaglutide Exenatide DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; SGLT2, sodium-glucose cotransporter-2.

Metformin acts mainly by improving insulin action, i.e., by reducing insulin resistance24; insulin levels are not stimulated and may be reduced along with plasma glucose concentration. Part of the effect of metformin insulin sensitivity, e.g., improved insulin action in muscle, may be secondary to lowered hepatic glucose production. Blood glucose is lowered without any appreciable risk of hypoglycemia at therapeutic dosages. However, hypoglycemia may become an issue when metformin is used in combination with an insulin-releasing agent, e.g., a sulfonylurea, or insulin. The full efficacy of metformin requires the presence of islet β-cell function that is adequate to provide the necessary levels of circulating insulin. At the cellular level, metformin improves insulin signaling, thereby activating the cellular energy-regulating enzyme adenosine 5′-monophosphate-activated protein kinase.25 The predominant action of metformin is to reduce the inappropriately elevated levels of hepatic glucose production that drive

fasting hyperglycemia in type 2 diabetes.26 This is achieved predominantly through decreased gluconeogenesis. Metformin also reduces hepatic glycogenolysis. Insulin-stimulated glucose uptake and glycogen formation in skeletal muscle are also enhanced. Reduced fatty acid oxidation also contributes to improvements in intermediary metabolism. Metformin is the drug of choice for overweight or obese patients because it does not cause weight gain and may aid weight reduction to a modest degree. Metformin can be used in combination with any other class of oral glucose-lowering agent, as well as with insulin. While metformin is cleared unchanged via the kidney, drug levels generally remain within the therapeutic range and lactate concentrations are not substantially increased when used in patients with estimated glomerular filtration rates (eGFRs) of 30–60 mL/min per 1.73 m2.27 The dose of metformin should be reviewed if eGFR falls below 45 mL/min. Renal function should be monitored every 3–6 months. At eGFR rates <30 mL/min, use of metformin should be avoided. This caution reflects concerns about the most feared, if uncommon, adverse event—lactic acidosis, the incidence of which is much lower than phenformin. Nonetheless, use of metformin in patients with cardiac or respiratory insufficiency and during major intercurrent illnesses such as severe infection, dehydration, recent myocardial infarction, or shock that predispose to tissue hypoxia and hyperlactatemia should be avoided. Liver disease, alcohol abuse, and a history of metabolic acidosis are additional contraindications. Metformin may cause resumption in women with polycystic ovary syndrome. Optimally titrated metformin monotherapy can generally be expected to reduce fasting plasma glucose by approximately 2–4 mmol/L and decreases hemoglobin A1c (HbA1c) by 1%–2%. However, as with all drugs for diabetes, responses are variable between patients and depend on factors such as the pretreatment HbA1c and the degree of insulin deficiency in

VI.  PREVENTION AND TREATMENT 2: DRUGS AND PHARMACEUTICALS

TABLE 33.3 Completed Cardiovascular Outcome Trials (CVOTs) of Diabetes Medications

Alogliptin

2013

EXAMINE published 2013

3-point MACE (major adverse cardiovascular events)

N = 5380; established cardiovascular disease

New Drug Application submitted December 2007. In a complete response letter in June 2009, the FDA requested an additional cardiovascular safety trial to satisfy the criteria outlined in the December 2008 Guidance for Industry

FDA (Food and Drug Administration) black box heart failure warning issued in 2015

Saxagliptin

2009

SAVOR-TIMI 53 published 2013

3-point MACE

N = 6.492; established cardiovascular disease or multiple risk factors for vascular disease

SAVOR-TIMI 53 was a cardiovascular outcome trial conducted as a postmarketing requirement in accordance with the FDA’s 2008 Guidance

FDA black box warning added in 2015 in response to 27% increase in the rate of the first event of hospitalization for heart failure and a potential increased risk for all-cause mortality in EXAMINE

Sitagliptin

2006

TECOS (Trial 4-point MACE Evaluating Cardiovascular Outcomes with Sitagliptin) published in 2015

N = 14,671; established cardiovascular disease

TECOS was initiated before the 2008 FDA instituted requirements for cardiovascular outcome trials with diabetes drugs. No heart failure safety signal. Neutral for primary endpoint

In 2017 the FDA declined an application from the manufacturer to include cardiovascular safety data on the labels of sitagliptincontaining drugs

EMPA-REG OUTCOME published 2015

7020; preexisting New Drug Application filed March 2013. cardiovascular FDA marketing approval in 2014 required disease completion of an ongoing cardiovascular outcomes trial as part of postmarketing studies. 14% relative risk reduction for the primary composite outcome in patients receiving empagliflozin compared with those receiving placebo (P < .001 for noninferiority). Risk reduction primarily driven by a 38% relative risk reduction in cardiovascular death (P < 0.001). In addition, 32% relative risk reduction in all-cause mortality (P < 0.001) and a 35% relative risk reduction in the incidence of hospitalization for heart failure (P = .002). An analysis of secondary microvascular outcomes demonstrated that patients on empagliflozin experienced slower progression of kidney disease and a lower risk of progressing to clinical (macro) albuminuria than those on placebo

Empagliflozin 2014

Primary MACE Study Endpoint Population

3-point MACE

Notes

FDA Label Changes Post- CVOT

In December 2016, the FDA approved a new indication for empagliflozin of improving survival in adults with type 2 diabetes and cardiovascular disease

Pre-CVOT Era Drugs for Type 2 Diabetes

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Drug

FDA Approval Date CVOT

437 Continued

Lixisenatide

2016

ELIXA published 4-point MACE 2015

6068; preexisting New Drug Application submitted and cardiovascular accepted in 2013 but withdrawn and disease resubmitted in September 2015. As mandated in the 2008 FDA guidance a cardiovascular outcome trial ELIXA—the first cardiovascular outcome trial to be reported with a GLP-1 receptor agonist— confirmed that lixisenatide did not increase the risk of cardiovascular adverse events

Liraglutide

2010

LEADER published 2016

9340; preexisting cardiovascular disease or high risk of cardiovascular events due to additional risk factors

Primary MACE Study Endpoint Population

3-point MACE

Notes

Application for approval was submitted before issuance of the the FDA 2008 cardiovascular safety guidance; the manufacturer had not designed the recommended cardiovascular safety trials. FDA reviewed the available cardiovascular safety data and determined there was no evidence of excess cardiovascular risk. In April 2009, a majority of the FDA Endocrinologic and Metabolic Drugs Advisory Committee voted that the available data adequately addressed the cardiovascular safety concern to support approval. Nonetheless, the FDA required a postapproval study (LEADER, published in 2016) to specifically evaluate cardiovascular safety in a higher risk population. The hazard ratio for the primary composite outcome in LEADER was lower with liraglutide (P < .001 for noninferiority; P = .001 for superiority). Fewer patients died from cardiovascular causes in the liraglutide group than in the placebo group (P = .007). The death rate from any cause was lower in the liraglutide group than in the placebo group (P = .02). Microvascular benefits of liraglutide, driven by reduced renal events, were also demonstrated

FDA Label Changes Post- CVOT

In August 2017, the FDA approved a new indication for liraglutide for reducing the risk for myocardial infarction, stroke, and cardiovascular death in adults with type 2 diabetes who have established cardiovascular disease

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Drug

FDA Approval Date CVOT

438

TABLE 33.3 Completed Cardiovascular Outcome Trials (CVOTs) of Diabetes Medications—cont’d

Not yet SUSTAIN-6 approved published 2016

3-point MACE

3297; 83% with preexisting cardiovascular disease, the remainder being at high risk of cardiovascular events conferred by additional risk factors

New Drug Application filed December 2016. In SUSTAIN-6 semaglutide once a week was associated with a significant 26% lower risk of the primary composite outcome over 2 years compared with those receiving placebo (P < .001 for noninferiority; P = .02 for superiority although the test for superiority was not a prespecified endpoint). A higher rate of retinopathy complications was observed in patients receiving semaglutide (P = .02)

Canagliflozin

2013

3-point MACE

10,142; approximately two-thirds of participants with preexisting cardiovascular disease and the remainder being at high risk of cardiovascular events

New Drug Application May 2012. FDA required five postmarketing studies, including a cardiovascular outcomes trial. The CANVAS program (CANVAS and CANVAS-R) trials were combined. The rate of the primary composite outcome was lower with canagliflozin than with placebo (P < .001 for noninferiority; P = .02 for superiority). Each component of the 3-point MACE contributed equally to risk reduction. However, CANVAS confirmed a doubling in the risk for amputations, primarily of the toe or metatarsal

Exenatide

2005; EXSCEL exenatide extendedrelease approved 2012

3-point MACE

14,752; with or without additional cardiovascular risk factors or prior cardiovascular events (73.1%)

In this phase IIIb/IV study, exenatide, administered once weekly, was noninferior to placebo with respect to safety (P < .001 for noninferiority) but was not superior to placebo with respect to efficacy (P = .06 for superiority)

CANVAS published 2017

In May 2016, the FDA issued a safety communication based on interim clinical trial results that found an increased risk of leg and foot amputations mostly affecting the toes

Pre-CVOT Era Drugs for Type 2 Diabetes

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Semaglutide

CVOTs are listed in chronological order of publication date. See text for definitions and further details. Modified from Krentz AJ. Rodriguez-Araujo G. Pharm Med 2017;31:399–421

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the individual. As a broad generalization, however, no particular class of oral glucose-­lowering drugs can be regarded as clearly the most efficacious in the majority of patients; that said, clinical trials suggest that some classes may be somewhat more effective at lowering plasma glucose than others. Tolerability issues are well recognized with metformin. These are mainly related to the gastrointestinal tract and include abdominal discomfort and diarrhea. Low doses of the drug may be tolerated but approximately 5%–10%, perhaps more, of patients find that gastrointestinal symptoms preclude long-term therapy. Long-term metformin therapy can reportedly reduce absorption of vitamin B12.28

Sulfonylureas The first generation of sulfonylureas has largely been replaced by potent second-­generation sulfonylureas, including glibenclamide (also known as glyburide in the United States and Canada), gliclazide, glipizide, and glimepiride (Table 33.1).29 The liver metabolizes all sulfonylureas although metabolite activity and routes of elimination vary. It has long been recognized that sulfonylureas with a longer duration of action carry a higher risk of hypoglycemia. Sulfonylureas stimulate insulin secretion from β cells. The drugs bind to the sulfonylurea receptor (SUR), a component of the transmembrane complex that includes the ATP-sensitive Kir 6.2 potassium channels (K-ATP channels). Binding closes the K-ATP channels, leading to intracellular events that culminate in the release of insulin from preformed granules. Cardiac and vascular smooth muscle cells express different isoforms of the SUR.30 Concerns about potential cardiotoxicity of sulfonylureas date back to the 1970s and have not been satisfactorily resolved.31 To this day, package inserts for sulfonylureas carry a warning about possible increased risk of cardiovascular disease mortality. The propensity of sulfonylureas to cause

hypoglycemia and weight gain may be relevant to their putative association with cardiovascular risk.32 Avoidance of asymptomatic or symptomatic hypoglycemia is an important objective in managing diabetes. All sulfonylureas have the capacity to cause hypoglycemia because they stimulate insulin release even at low blood glucose concentrations. Starting doses should always be at the lower end of the dose range to minimize the risk of hypoglycemia. The efficacy of sulfonylureas is broadly similar to that of metformin, although responses may differ between individual patients. Sulfonylureas have traditionally been preferred for patients who are not overweight since they often cause some weight gain. However, such patients may have more marked relative insulin deficiency, which is reflected in the need for additional therapy.33 Irreversible deterioration of glycemic control during sulfonylurea therapy is held to be largely a consequence of progressive β-cell failure in patients with type 2 diabetes.33

Meglitinide Analogs These agents (also known as glinides) release insulin from islet β cells.34 Two agents, the meglitinide derivative repaglinide and the structurally related phenylalanine derivative nateglinide, were introduced in 1998 and 2001, respectively (Table 33.1). Although acting mainly during the prandial and early postprandial period, their effects extend sufficiently to produce some reduction of fasting hyperglycemia, particularly with repaglinide.29 Taken about 15 min before a meal, repaglinide produces a prompt insulin response, which lasts about 3 h, coinciding with the duration of meal digestion. Nateglinide has a slightly faster onset and shorter duration of action. As insulin secretagogues, neither agent has proved to be as popular as the sulfonylureas. As rapid-acting insulin releasers they can be helpful to individuals with irregular lifestyles with unpredictable or missed meals.35 The lower risk of hypoglycemia also provides a useful

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Pre-CVOT Era Drugs for Type 2 Diabetes

option for some elderly patients, particularly if other agents are contraindicated. When a meal is not consumed, the corresponding dose of repaglinide should be omitted. With appropriate caution and monitoring, repaglinide can be given to patients with moderate renal impairment where some sulfonylureas and metformin are contraindicated. Nateglinide can be used as monotherapy in much the same way as repaglinide, although nateglinide tends to be faster and shorter acting and requires caution in patients with hepatic disease. In some countries, such as the United Kingdom, nateglinide is not licensed for use as monotherapy, only for combination therapy. Consistent with their use to boost prandial insulin secretion, repaglinide (0.5–4 mg) or nateglinide (60–180 mg) taken before meals produce dose-dependent increases in insulin concentrations and reduce postprandial hyperglycemia. There is usually a small reduction in fasting hyperglycemia. Reductions in HbA1c are similar to or smaller than with sulfonylureas, as predicted by their shorter duration of action. Hypoglycemic episodes are generally fewer and less severe with prandial insulin releasers than with sulfonylureas.

Alpha-Glucosidase Inhibitors Alpha-glucosidase inhibitors retard carbohydrate digestion via competitive inhibition of the activity of α-glucosidase enzymes located in the brush border of the enterocytes that line the intestinal villi (Table 33.1).36 The α-glucosidase inhibitors bind to these enzymes preventing breakdown of disaccharide and oligosaccharide substrates into absorbable monosaccharides. Glucose absorption is completed over a longer period and postprandial hyperglycemia is reduced. The secretion of glucose-­dependent insulinotropic polypeptide (GIP) may be reduced whereas secretion of GLP-1 is increased. When used as monotherapy in patients complying with dietary advice, an α-glucosidase

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inhibitor can be expected to reduce peak postprandial glucose concentrations by approximately 1–3 mmol/L. Furthermore, there is often a reduction in fasting hyperglycemia of up to 1 mmol/L. The improvement in HbA1c is generally less pronounced than with sulfonylureas or metformin, i.e., ∼0.5%, but sometimes exceeding 1% if a high dose of the drug is tolerated and dietary modifications are maintained. Alpha-glucosidase inhibitors do not cause weight gain. The fermentation of unabsorbed carbohydrates in the large bowel is responsible for the common problems of flatulence, abdominal discomfort, and diarrhea. Acarbose has never been popular in the United Kingdom but is widely used in some countries such as China. Low rates of use of the drug in the United Kingdom mainly reflect the aforementioned poor tolerability of acarbose. Two other α-glucosidase inhibitors, miglitol and voglibose, are available in some countries. The controversial results of a trial of acarbose in subjects with impaired glucose tolerance (IGT)—STOP-NIDDM37—that suggested a reduction in cardiovascular disease have not been confirmed. In the ACE (Acarbose Cardiovascular Evaluation) trial, Chinese patients with coronary heart disease and IGT, acarbose did not reduce the risk of major adverse cardiovascular events.38 However, the incidence of new cases of diabetes was reduced in ACE.38

Thiazolidinediones The thiazolidinediones were introduced into clinical practice at the end of the 20th century (Table 33.1). High hopes surrounded this novel class of glucose-lowering drugs, which seemed to offer a means of countering insulin ­resistance, present in the great majority of patients with type 2 diabetes.39 The drugs improve insulin sensitivity by stimulating a widely distributed nuclear receptor known as the peroxisome proliferator-activated receptor-γ.40 This promotes adipocyte differentiation and lipogenesis mainly in subcutaneous depots. Stimulation of

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lipogenesis reduces circulating nonesterified fatty acids thereby facilitating glucose uptake by muscle and insulin-sensitive adipocytes; hepatic gluconeogenesis is reduced. The first of the thiazolidinediones, troglitazone, was withdrawn because of severe hepatotoxicity. Two others, rosiglitazone and pioglitazone, subsequently became available, neither of which was associated with adverse hepatic effects.41,42 However, rosiglitazone was withdrawn from the European market in 2010 and use of the drug was restricted in the United States. As detailed later, these actions were the culmination of a highly charged debate that revolved around concerns that rosiglitazone might be associated with an increased risk of myocardial ischemic events. Thiazolidinedione monotherapy can reduce fasting plasma glucose by 2–3  mmol/L and HbA1c by approximately 1.5%. All thiazolidinediones have the propensity to cause fluid retention with increased plasma volume, reduced hematocrit, and a decrease in hemoglobin. The drugs should be avoided in patients with heart failure.43 Precise exclusions on the basis of cardiac status have varied between Europe and the United States. Fluid retention accounts for some of the weight gain that is commonly encountered with these drugs. Visceral adipose depots may be reduced while subcutaneous adipose depots increase. Used as monotherapy or in combination with drugs such as metformin, thiazolidinediones do not cause hypoglycemia. Rosiglitazone causes a small rise in total cholesterol levels, accounted for by a rise in both low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol.44 Pioglitazone has little effect on total cholesterol, raises HDL cholesterol, and reduces fasting triglycerides.45 As experience accumulated with the use of these drugs in clinical practice, new safety concerns centered on (1) the impact on cardiovascular outcomes, and (2) adverse effects of bone metabolism. The European Medicines Agency (EMA) approved the use of pioglitazone and rosiglitazone in 2000, but demanded postmarketing

cardiovascular outcome studies, there being no long-term safety and efficacy data at the time.41 This deficiency in the evidence base notwithstanding, the thiazolidinediones enjoyed a growth in use as other drugs, notably sulfonylureas in the UK market, declined. The class attained socalled blockbuster status until worrying data about cardiovascular events associated with rosiglitazone came to light. In 2007, rosiglitazone came under intense scrutiny with the publication of a controversial metaanalysis.46 This suggested a statistically significant 43% increase in the risk of myocardial infarction and a 64% rise in cardiovascular death risk among patients taking rosiglitazone compared with placebo or other classes of glucose-lowering drugs. In 2010, the FDA placed a Risk Evaluation and Mitigation Strategy in place while the drug was withdrawn from the market by the EMA.4 A series of subsequent metaanalyses were unable to confirm or refute the concern that rosiglitazone increased the risk of myocardial infarction.4,47 The results of the Rosiglitazone Evaluated for Cardiovascular Outcomes (RECORD) study were reassuring, although critics pointed to methodological issues that in their opinion may have precluded firm conclusions.48 In 2014, the FDA relaxed its prescribing restrictions on rosiglitazone. Current evidence for pioglitazone suggests protection against atherothrombotic vascular events, albeit at the cost of an increased incidence of heart failure.42,49–51 In the placebo-controlled Insulin Resistance Intervention after Stroke (IRIS) trial, patients without diabetes who had insulin resistance along with a recent history of ischemic stroke or transient ischemic attack had a lower risk of stroke or myocardial infarction when treated with pioglitazone.52 In IRIS, pioglitazone was also associated with a lower risk of diabetes but with higher risks of weight gain, edema, and skeletal fracture.52 Both rosiglitazone and pioglitazone increase the risk of distal bone fractures in women. Thiazolidinediones contribute to bone loss, the effect being most prominent in postmenopausal women.53 This

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safety issue was not anticipated and emerged only after the drugs had been in clinical use for a decade. While macular edema has been reported with thiazolidinediones, no association with eye complications was observed in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) Eye Study.54 In 2011, pioglitazone was withdrawn from the French market in response to concerns about a potential risk of bladder cancer. While aspects of this association remain uncertain,55 current bladder cancer or a history of bladder cancer are contraindications to pioglitazone therapy.

Bromocriptine The dopamine D2 receptor agonist bromocriptine has an indication for use in the treatment of type 2 diabetes in some countries, including the United States (Table 33.1).56,57 Low-dose bromocriptine administered early in the morning soon after waking temporarily increases hypothalamic dopamine. This impacts the circadian periodicity of glucose homeostasis by reducing sympathetic tone and enhancing the neural suppression of hepatic glucose production. Additionally, there is a reduction of adipose tissue lipolysis and an improvement in peripheral glucose disposal without elevation of plasma insulin, indicating improved peripheral insulin sensitivity.91,92 The low-dose formulation of bromocriptine used for blood glucose lowering is rapidly absorbed and highly protein bound, is rapidly removed by the liver (metabolized primarily by CYP3A4), and is eliminated in the bile. Patients with type 2 diabetes receiving low doses of quickly acting bromocriptine early in the morning show HbA1c reductions of about 0.5%–0.7% when taken as monotherapy or in combination with other oral glucose-lowering agents. Fasting and postprandial glucose, fatty acid, and triglyceride concentrations are reduced and plasma insulin is not raised. The risk of hypoglycemia is low with no weight gain.56,57

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Colesevelam As well as being used as a bile acid sequestrant to treat hypercholesterolemia, colesevelam also has an indication as a glucose-lowering drug in some countries (Table 33.1). The glucose-­ lowering mechanism of the drug is unclear. By interrupting the enterohepatic circulation of bile acids, colesevelam appears to reduce the availability of bile acids to activate the bile acid receptor-1 (TGR5) and the farnesoid X receptor (FXR) resulting in increased hepatic glucose metabolism.58 Bile acids carried more distally along the intestine due to their entrapment by colesevelam could enhance the secretion of intestinal GLP-1 (see later). Up to three 625 mg tablets of colesevelam can be taken with each of two main meals daily: the drug is not systemically absorbed. Caution is required in intestinal disorders, especially obstruction. Colesevelam can alter the absorption of other oral medications, including oral glucose-lowering therapies; dose adjustments may be required. Clinical trials with colesevelam in type 2 diabetes subjects have noted modest reductions of HbA1c of about 0.5% when used as an add-on to metformin, sulfonylurea, or insulin. There is no effect on body weight, low risk of hypoglycemia, and consistent with its use in the treatment of hypercholesterolemia there is usually a reduction in LDL cholesterol.58 Colesevelam may increase circulating triglycerides and cause abdominal symptoms, especially constipation.

Amylin Analogs Islet amyloid polypeptide, or amylin, is a peptide hormone cosecreted with insulin from islet β cells. The hormone activates central neural pathways that decrease glucagon release from pancreatic α cells, retard gastric emptying, and promote satiety. Pramlintide is a soluble synthetic amylin analog (Table 33.1).59 In the United States pramlintide is approved for use in patients with type 2

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diabetes as an add-on therapy to certain orally active glucose-lowering agents or insulin. The drug can promote weight loss in addition to improving glycemic control.60 The principal adverse effects of the drug are nausea and hypoglycemia.

CVOT ERA DRUGS FOR TYPE 2 DIABETES: BENEFITS AND RISKS Drugs Acting via the Incretin Axis DPP-4 inhibitors and GLP-1 receptor agonists, recent classes of glucose-lowering drugs to be introduced into clinical practice, reduce plasma glucose levels through effects mediated via the so-called incretin axis. This approach circumvents some of the unwanted effects of the sulfonylureas—principally weight gain and hypoglycemia. These new agents also provide an alternative to thiazolidinediones, thereby avoiding weight gain, fluid retention, heart failure, and increased risk of fractures. The incretin effect is held to account for up to 70% of postprandial insulin secretion in healthy subjects. The most important incretin hormones are GLP-1 and GIP.61 These are secreted by the L cells of the distal ileum and colon, and the K cells of the duodenum and upper jejunum, respectively. Plasma levels of the incretin hormones rise within minutes of eating. GLP-1 and GIP act on β-cell G-protein-coupled receptors to enhance glucose-stimulated insulin secretion. Acute release of insulin is followed by insulin biosynthesis and insulin gene transcription. The acute effect of GLP-1 serves to potentiate glucose-dependent insulin release of preformed insulin; importantly, this only occurs when circulating glucose concentrations are raised. Thus as glucose levels return to normal the incretininduced release of insulin is switched off and insulin levels rapidly decline. GLP-1, but not GIP, slows gastric emptying and suppresses appetite via central effects. The

incretin effect is deficient in patients with type 2 diabetes.62 Thus postprandial GLP-1 secretion from the gut is reduced and the insulinotropic action of GIP is attenuated. The secretion of ­glucagon—a potent stimulus to hepatic glucose production—is reduced by GLP-1. In type 2 diabetes, glucagon levels from the islet α cells are not adequately ­ suppressed by hyperglycemia. This has been a somewhat neglected aspect of the pathophysiology of type 2 diabetes that, in part, reflects the limited scope for therapeutic manipulation. GLP-1 and GIP are rapidly degraded, principally by a widely distributed proteolytic cell surface enzyme, DPP-4. As a consequence, the half-life of GLP-1 in the circulation is less than 2 min. Novel glucose-lowering therapies exploiting the defective incretin effect in type 2 diabetes have been developed, based on the pathophysiology of the incretin hormone axis.39 These include the orally active DPP-4 inhibitors that increase the endogenous levels of the incretin hormones. The injectable GLP mimetics include: (1) derivatives of GLP-1 that have been modified to resist proteolysis, and (2) novel peptides that have metabolic actions similar to GLP-1 and are intrinsically resistant to proteolysis.63

Dipeptidyl Peptidase-4 Inhibitors Members of this class of orally active glucoselowering drugs are also known as gliptins (Table 33.1). The first three DPP-4 inhibitors to be marketed in the United States were sitagliptin and saxagliptin; these have since been joined by alogliptin and linagliptin. Other DPP-4 inhibitors are available in markets including Europe, Japan, and Korea. Clinically relevant differences in metabolism and safety profiles are evident between the three drugs. The FDA deferred approval of vildagliptin because of skin lesions in a primate model and issues of safety in patients with renal impairment. Linagliptin, which is nonrenally eliminated, was approved in 2011. DPP-4

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inhibitors can raise the levels of active incretin hormone concentrations two- to threefold. Sitagliptin is a competitive inhibitor of DPP-4 that has high bioavailability (∼90%) with a plasma half-life of 8–14 h; tmax is 1–4 h. Plasma protein binding is approximately 40%. A small proportion of the drug is metabolized by CYP3A4 and CYP2C6 with about 80% of sitagliptin being eliminated unchanged in the urine through renal tubular secretion. In a single dose, 100 mg sitagliptin achieves near complete inhibition of DPP-4 activity for about 12 h with around 80% inhibition up to 24 h. Saxagliptin provides maximal inhibition of DPP-4 for approximately 2–3 h through reversible covalent complex formation; DPP-4 inhibition extends to approximately 24 h. As for sitagliptin, saxagliptin has greater specificity for DPP-4 than for either cytosolic DPP-8 or DPP-9, members of the same gene family as DPP-4. Saxagliptin is eliminated by renal and hepatic pathways. Kidney metabolism generates a hydroxylated metabolite that has 50% of the activity of the parent compound. There is some evidence of active renal excretion of the parent compound and blood levels of drug and metabolite are increased by renal impairment. In vitro, serum protein binding of saxagliptin is ≤30%. The indications for use of these drugs differ between countries. In theory, they can be used as monotherapy, in combination with metformin, a sulfonylurea, or a thiazolidinedione. Combining a DPP-4 inhibitor with insulin can also be advantageous. Full efficacy of DPP-4 inhibitors requires the presence of adequate β-cell function. While the class is regarded as being weight neutral, some studies have shown modest degrees of weight loss. The latter property contrasts with sulfonylurea or thiazolidinediones making DPP-4 inhibitors an attractive option for overweight and obese patients. Because insulin secretion is closely linked to blood glucose concentration, DPP-4 inhibitors carry a low risk of hypoglycemia. This is the case when they are used as monotherapy, or in conjunction with

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agents such as metformin or thiazolidinediones. If hypoglycemia occurs when a DPP-4 inhibitor is combined with a sulfonylurea, reducing the dose of the sulfonylurea or withdrawal of the DPP-4 inhibitor is recommended. A reduced dose of sitagliptin, i.e., 50 mg once daily, is recommended in moderate renal insufficiency, i.e., creatinine clearance ≥30 to <50 mL/min. With more severe renal insufficiency or end-stage renal disease, a dose of 25 mg once daily should be considered. Sitagliptin can be used in patients with minor to moderate impairment of liver function. Circulating levels of saxagliptin and its metabolite are reduced if liver function is impaired. All DPP-4 inhibitors should be avoided in pregnancy and in women planning or at risk of conception. Linagliptin is of particular interest in the context of diabetic nephropathy as it is the only compound that is not predominantly excreted in the urine.64 No dose reduction is required for linagliptin in patients with renal impairment. In clinical trials, administration of 100 mg/ day sitagliptin as monotherapy or add-on therapy to other agents reduces HbA1c from a baseline of ∼8% by ∼0.7 percentage points after 24–52 weeks. At higher baseline HbA1c levels, reductions in HbA1c >1% have been reported. Fasting blood glucose is reduced by 1.0–1.5  mmol/L. Postprandial glucose levels after a standard mixed meal are reduced by approximately 3 mmol/L. A daily dose of 5 mg saxagliptin either as monotherapy, or in combination with metformin, a sulfonylurea, or a thiazolidinedione produces mean placebo-­ subtracted reductions in HbA1c of 0.60–0.65%. In phase 3 trials, tolerability was generally good for DPP-4 inhibitors with a low frequency of adverse events. Compared with placebo and comparator drugs, a slightly higher incidence of upper respiratory tract infections was reported. Theoretical concerns about interference with innate immunity were raised because DPP-4 also functions as the lymphocyte CD36 protein. However, neither CD26 knockout mice nor the DPP-4 inhibitors used in humans have

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shown any significant untoward effects on immune function. These reassuring observations notwithstanding, minor decreases in blood lymphocyte count have been observed in association with sitagliptin and saxagliptin in human studies. In 2009 the FDA revised the prescribing information for sitagliptin following reports of acute pancreatitis. As a class, DPP-4 inhibitors appear to be associated with a small increased incidence of acute pancreatitis in placebo-controlled trials, although it is considered that most observational studies have been reassuring.65

Cardiovascular Safety of DPP-4 Inhibitors Saxagliptin was the first diabetes drug to receive approval after the issuance of the FDA’s 2008 guidelines requiring CVOTs of new diabetes medications (Tables 33.2 and 33.3). In the Saxaglipitin Assessment of Vascular outcomes Recorded in Patients with Diabetes Mellitus— Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial, noninferiority to placebo in terms of cardiovascular safety among highrisk patients was demonstrated.66 However, more patients in the saxagliptin treatment group than in the placebo group were hospitalized for heart failure (3.5% vs. 2.8%; hazard ratio [HR] 1.27; 95% confidence interval [CI] 1.07 to 1.51; P = .007). Patients with impaired renal function were at increased risk of heart failure hospitalization. In the alogliptin CVOT (Examination of Cardiovascular Outcomes with Alogliptin Versus Standard of Care (EXAMINE)) 3.9% of alogliptin-treated patients were hospitalized for heart failure versus 3.3% in the placebo group (HR 1.19, P = NS).67 In 2015, the FDA Endocrinologic and Metabolic Drugs Advisory Committee recommended a label warning on the risk of heart failure and the need for further heart failure safety monitoring for saxagliptin and alogliptin.68 In contrast, no signal for heart failure was observed for sitagliptin.69

CAROLINA (Cardiovascular Outcome Trial of Linagliptin Versus Glimepiride in Type 2 Diabetes) is an ongoing, randomized trial in subjects with early type 2 diabetes at increased cardiovascular risk comparing linagliptin with the sulfonylurea glimepiride.70

Glucagon-Like Peptide-1 Receptor Agonists GLP-1 mimetics mimic the actions of native GLP-1. Agents in this class, which require subcutaneous administration, are designed to be resistant to the actions of DPP-4.40 Compared with DPP-4 inhibitors, use of GLP-1 agonists is generally associated with greater reductions in blood glucose that is often accompanied by loss of body weight. Islet β-cell function is improved by GLP-receptor agonists, but no evidence has emerged that this is sustained beyond the duration of treatment. Thus, to date, no drugs used for glucose control in type 2 diabetes can be said to satisfy the criteria as being disease modifying. Synthetic exendin-4, or exenatide, was approved for use in the United States in 2005; the drug has been available in the United Kingdom since 2007. Exendin-4 is an agonist for the GLP-1 receptor present in the venom of Heloderma suspectum, a venomous lizard indigenous to the Southwestern United States. The intrinsic resistance of exendin-4 to inactivation by DDP-4 provided the development of exenatide.71 In 2009, liraglutide entered clinical practice. The main attributes of GLP-1 agonists are reduction of hyperglycemia in concert with the potential for simultaneous weight loss and an intrinsically low risk of hypoglycemia. GLP-1 mimetics lower glycated hemoglobin by approximately 1% compared with placebo. Moreover, GLP-1 receptor agonists can produce weight loss of between 1.5 and 4.5–5.0 kg versus placebo and insulin therapy, respectively. This contrasts with the weight gain observed in some oral agents discussed earlier and insulin. Open label extension studies show that reductions in

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glycemic control are sustained, and progressive reductions in body weight may be achieved in some patients. Improvements in vascular risk factors, including blood pressure and lipid profiles, have been reported. Reductions in hepatic transaminase levels have also been observed. Exenatide has approximately 50% sequence homology with human GLP-1. However, the drug has a 20- to 30-fold longer half-life and much greater potency than GLP-1 in its effects on blood glucose. Resistance to DDP-4 is achieved through substitution of Gly2 for Ala2 at the inactivation site of the molecule. Exenatide is rapidly absorbed and is detectable in the circulation within 15 min after subcutaneous injection. Maximum drug concentrations are achieved at 2–3 h. The formation of antibodies to exenatide can reportedly increase the Cmax and may extend the half-life of the drug. Effects on blood glucose are evident for 6–8 h after injection. Thus twice-daily administration is required. Elimination half-life is 3–4 h. Clearance of the drug is reduced in patients with severe renal impairment. The clinical significance of exenatide antibodies, which have been observed in approximately 40% of patients in some studies, is uncertain. There is evidence that the metabolic effects of exenatide may be impaired by high antibody titers in a minority (<5%) of patients. In the United States, exenatide is licensed as an adjunctive therapy for patients with inadequate glycemic control on metformin, a sulfonylurea, a thiazolidinedione, a combination of metformin and a sulfonylurea, or a combination of metformin and a thiazolidinedione. Exenatide is administered using a prefilled pen device in the thigh, abdomen, or upper arm. The starting dose is 5 μg given any time within the 60-min period before the main morning and evening meals, or before the two main meals of the day about 6 h apart or longer. If tolerated, the dose is increased to 10 μg twice daily after 4 weeks if the therapeutic response demands a higher dose. If gastrointestinal side effects pose difficulties, dose escalation can be deferred

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another 4–6 weeks. Because insulin secretion is coupled to blood glucose levels, no reduction in dose is necessary for meal size or physical activity levels. There is a small risk of hypoglycemia when exenatide is used in conjunction with a sulfonylurea and the dose of the latter drug may need to be reduced. If added to metformin, no dose adjustment of either drug is required. In older people, exenatide should be used with caution; dose escalation from 5 to 10 μg should proceed with care in patients >70 years. Clinical experience in patients >75 years is limited. No dosage adjustment is required for patients with mild renal impairment, defined as a creatinine clearance of 50–80 mL/min. If creatinine clearance is 30–50 mL/min, dose escalation should proceed cautiously. Exenatide is not recommended in patients if creatinine clearance is <30 mL/min. No dosage adjustment is necessary if hepatic function is impaired. Nausea is the most common side effect; this is usually relatively mild and tends to dissipate with time but affects 30–50% of recipients.72 Vomiting may be troublesome and preclude long-term therapy. There are no adequate studies of exenatide in pregnancy and the drug should be avoided in lactation. Postmarketing reports of acute pancreatitis in patients taking exenatide have generated some concern. Most of the patients affected had preexisting risk factors for acute pancreatitis such as gallstones, severe hypertriglyceridemia, or excessive alcohol consumption. Nonetheless, the FDA requested a change to the package insert that warns about pancreatitis. Patients should be informed of the symptoms of pancreatitis and the need to seek prompt medical attention should they develop. Exenatide should be discontinued if pancreatitis is suspected. Exenatide LAR was approved for clinical use in 2011. This is a sustained release formulation of injectable microspheres of exenatide and poly(d,l lactic-co-glycolic acid), which is a biodegradable medical polymer. Gradual drug delivery at a controlled rate enables once-weekly injection.

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Liraglutide is a GLP-1 mimetic that is resistant to the actions of DPP-4. The drug has a 97% sequence identity to native GLP-1 that comprises a modified GLP-1 peptide sequence that is attached to a palmitoyl chain.73 This enables noncovalent binding to albumin after subcutaneous injection. Islet β-cell function is improved with enhanced potentiation of meal-associated insulin secretion. Postprandial blood glucagon levels are decreased, in line with the aforementioned actions of GLP-1. Binding to albumin retards renal elimination, giving liraglutide a half-life of approximately 12 h. The slow absorption of liraglutide from subcutaneous tissues produces a maximum blood concentration after 8–12 h, thereby permitting once-daily injection. It is postulated that avoiding peaks of the drug helps to reduce the characteristic gastrointestinal side effects. Liraglutide is formulated as a solution for subcutaneous injection in prefilled pens delivering 0.6, 1.2, or 1.8 mg per dose. The suggested starting dose is 0.6 mg daily, increasing after not less than a week to the maintenance dose of 1.2 mg daily. After at least another week, the dose can be increased to 1.8 mg if required. Use of liraglutide is not recommended in patients with moderate degrees of renal impairment, i.e., where creatinine clearance is 30–60  mL/min. Liraglutide has not been studied in patients with severely impaired renal function, and data in patients with hepatic impairment are limited. In patients with type 2 diabetes, liraglutide can significantly lower HbA1c with concomitant improvements in fasting and postprandial blood glucose levels. Body weight is dose-­ dependently reduced by approximately 1–3 kg. The main adverse events are nausea and diarrhea, although the frequency of gastrointestinal side effects will often decrease over time. Lowering of triglycerides and reductions in blood pressure have also been observed. In preclinical studies C-cell thyroid tumors were observed in rodent models. In clinical use, increased rates of clinical thyroid-related

adverse events, including neoplasms, elevated blood calcitonin levels, and goiter, have been observed in ≤1% of liraglutide-treated patients. Antibody formation has been reported in <10% of patients but their presence does not appear to have a significant impact on the efficacy of the drug. A small number of cases of acute pancreatitis have been reported. However, no evidence of causality has been established. Liraglutide is also licensed as a long-term weight-reducing drug in nondiabetic obesity in a 3.0 mg formulation.74 Other GLP-1 receptor agonists include lixisenatide (a short-acting once-daily GLP-1 receptor agonist) approved by the FDA in 2016 and semaglutide (once weekly) in 2017. Semaglutide is also being developed in an oral formulation. In addition to exenatide LAR, other GLP-1 receptor agonists requiring less frequent administration have been developed. Of these, development of taspoglutide was discontinued during phase 3 in 2010 because of safety and tolerability issues, while albiglutide, which was approved by the FDA in 2014, is to be withdrawn globally in 2018 for commercial reasons. Premixed combinations of GLP-1 agonists and insulin licensed for use in patients with type 2 diabetes include iGlarLixi, a titratable fixedratio combination of insulin glargine 100 U/ mL + lixisenatide,75 and IDegLira, which contained insulin degludec + liraglutide.76

Cardiovascular Effects of GLP-1 Receptor Agonists The relatively short-acting GLP-1 agonist lixisenatide demonstrated noninferiority compared to placebo in an FDA-mandated CVOT known as ELIXA (Evaluation of Lixisenatide in Acute Coronary Syndrome) (Tables 33.2 and 33.3).77 The primary composite endpoint of cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina (4-point MACE [major adverse cardiovascular events]) occurred in 13.4% of the lixisenatide patients

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and 13.2% of the control patients (HR 1.02; P < .001 for noninferiority; P = .81 for superiority).77 Similarly, in EXSCEL (EXenatide Study of Cardiovascular Event Lowering) once-weekly exenatide was noninferior to placebo with respect to safety (P < .001 for noninferiority) but was not superior to placebo with respect to efficacy (P = .06 for superiority).78 Thus cardiovascular safety, as defined by the FDA, was confirmed for these drugs in these studies. In contrast, CVOTs of liraglutide and semaglutide both showed not only noninferiority to placebo but, according to hierarchical statistical testing, superiority, i.e., efficacy was demonstrated in reducing major composite cardiovascular endpoints. The LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Result) study examined the vascular effects of once-daily subcutaneous liraglutide in >9000 patients.79 As with all diabetes CVOTs, the study population comprised patients with type 2 diabetes selected as being at high risk of cardiovascular events. The HR for the primary composite outcome (3-point MACE) was 0.87 (95% CI 0.78–0.97; P < .001 for noninferiority; P = .001 for superiority).79 Deaths from cardiovascular causes were significantly reduced by liraglutide (HR 0.78; 95% CI 0.66 to 0.93; P = .007). The Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN-6) was smaller and shorter than LEADER. The primary composite outcome (3-point MACE) occurred in 6.6% of participants in the semaglutide group and in 8.9% in the placebo group (HR 0.74; 95% CI 0.58 to 0.95; P < .001 for noninferiority; P = .02 for superiority although the test for superiority was not a prespecified endpoint).80 Semaglutide, like liraglutide, provided evidence of renoprotection as well as cardioprotection. However, in SUSTAIN-6, vitreous hemorrhage, blindness, or ocular conditions requiring treatment with an intravitreal agent or photocoagulation were significantly higher among subjects receiving

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semaglutide.80 These adverse eye effects have been attributed to the rapid reduction in HbA1c in SUSTAIN.81 Note, however, that CVOTs of diabetes drugs are not intended to induce a difference in glycemic control between treatment groups. However, differences have tended to become apparent on active treatment even though increases in glucose-lowering medications are permitted in the control subjects to maintain glycemic equipoise. The results of these CVOTs have been interpreted as showing beneficial effects of liraglutide and semaglutide on the progression of atherosclerosis.82 Improvements in traditional cardiovascular risk factors do not account for the observed risk reductions. The mechanisms mediating the cardioprotective (and renoprotective) effects remain to be delineated.83,84

Sodium-Glucose Cotransporter-2 Inhibitors Approximately 160–180 g of glucose is filtered daily via the kidney into the urine in healthy adults. Reabsorption of glucose is proportional to the filtered glucose load until the transport maximum is exceeded. Glucose requires carrier proteins to move across cell membranes. SGLT2 and SGLT1 reabsorb 90% and 10%, respectively, of filtered glucose.85 SGLT2 is expressed almost entirely on proximal renal tubule cell membranes. This low-affinity, high-capacity transporter couples reabsorption of each glucose molecule to a sodium ion. A new class of glucose-lowering agents, the SGLT2 inhibitors, has been introduced into clinical practice in recent years.86,87 These drugs, which include dapagliflozin and canagliflozin, promote renal glucose excretion, thereby reducing blood glucose concentrations.88 The class carries a predictably low risk of hypoglycemia. Urinary calorie loss, which can reach 200–300 kcal/day, promotes weight reduction. An increased frequency of urogenital infections has consistently been reported in clinical trials of SGLT2 inhibitors.

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In May 2015, regulatory agencies issued a warning that SGLT2 inhibitors may cause diabetic ketoacidosis. Certain predisposing patient characteristics have been identified.10,89 Of note, plasma glucose concentrations may not be markedly elevated (although the term “euglycemic ketoacidosis” rarely applies according to strict definitions). Awareness of this risk is required by prescribers.90 While ketoacidosis was not a predicted safety issue the reduction in insulin levels in concert with increases in glucagon levels and changes in substrate metabolism consequent on SGLT2 inhibition appear to be relevant from a pathophysiologic perspective.91,92

Cardiovascular Effects of SGLT2 Inhibitors In what is now regarded as a landmark clinical trial, the placebo-controlled EMPA-REG OUTCOME study not only confirmed cardiovascular safety of empagliflozin (i.e., noninferiority, as defined by the FDA) but demonstrated a significant, 14% reduction for the primary endpoint of 3-point MACE (HR 0.86; 95% CI 0.74, 0.99; P = .04 for superiority) (Tables 33.2 and 33.3).93 Significantly lower rates were observed for death from cardiovascular causes (3.7% vs. 5.9% in the placebo group; 38% relative risk reduction), hospitalization for heart failure (2.7% and 4.1%, respectively; 35% relative risk reduction), and all-cause mortality (5.7% and 8.3%, respectively; 32% relative risk reduction). An early separation of the two treatment groups, which was observed for both heart failure and mortality, raised the possibility of a hemodynamic mechanism of benefit, rather than the putative antiatherosclerotic benefits of the GLP-1 receptor agonists discussed earlier.94–96 The results of EMPA-REG OUTCOME have refocused attention on the increased risk of heart failure in patients with type 2 diabetes.97,98 In 2016, on the basis of the results of the EMPAREG OUTCOME study, empagliflozin became the first diabetes drug to be granted a label claim

for the reduction of the risk of cardiovascular death in adults with type 2 diabetes and established cardiovascular disease. Empagliflozin was also associated with slower progression of kidney disease and lower rates of clinically relevant renal events.99 In the CANVAS (Canagliflozin Cardiovascular Safety Assessment) study the rate of the primary composite outcome (3-point MACE; see Table 33.4) was lower with canagliflozin than with placebo (26.9 vs. 31.5 participants per 1000 patientyears; HR 0.86; 95% CI 0.75 to 0.97; P < .001 for noninferiority; P = .02 for superiority).100 While the CANVAS program trial results have widely been interpreted as supporting a class effect of SGLT2 inhibitors on cardiovascular outcomes in type 2 diabetes, there has been much debate about the disparities between the EMPA-REG OUTCOME and the CANVAS program results. Neither all-cause nor cardiovascular death was significantly reduced in CANVAS as in EMPAREG. While nearly all EMPA-REG subjects had established cardiovascular disease, only around two-thirds of CANVAS patients were at this high level of risk. CANVAS also revealed a doubling in the risk for amputations, primarily of the toe or metatarsal (6.3 vs. 3.4 cases per 1000 patient-years; HR 1.97).100 Patients with a prior amputation or significant peripheral vascular disease were at highest absolute risk for further amputation. Prior to the publication of the TABLE 33.4 MACE Primary Composite Endpoints Applied in Diabetes Cardiovascular Outcome Trials (CVOTs) to Date 3-point MACE

4-point MACE

Cardiovascular (CV) death

CV death

Nonfatal myocardial infarction

Nonfatal myocardial infarction

Nonfatal stroke

Nonfatal stroke Hospitalization for unstable angina

MACE, major adverse cardiovascular events.

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References

full results of CANVAS, the FDA announced a requirement for the addition of a boxed warning for increased risk of leg and foot amputations to the labels for canagliflozin and canagliflozincontaining medications. Evidence of renoprotection was demonstrated in CANVAS.

CONCLUSIONS All drugs for lowering blood glucose in patients with type 2 diabetes have limitations in terms of long-term efficacy and the potential for adverse, potentially fatal in some circumstances, effects. The arrival of drugs with novel modes of action that can be used alongside more established agents is welcome. However, a degree of caution is appropriate until the risk–benefit profiles of these new agents are fully delineated. The lessons from the rosiglitazone controversy have strengthened regulatory requirements for new glucose-lowering drugs. However, the potential for the emergence of unanticipated serious adverse effects after many years of clinical use underlines the need for circumspection and vigilance. The risk of diabetic ketoacidosis with the SGLT2 inhibitor class and the increased risk of amputations with canagliflozin in particular provide highly relevant reminders of the need for rigorous assessment in well-conducted clinical trials. The results of recent CVOTs of novel glucoselowering drugs have opened a new therapeutic era for patients with type 2 diabetes. When considering which agents to use in a particular patient the absence or presence of cardiovascular disease has now become an important consideration that is being incorporated into expert clinical guidelines.101 However, while a personalized approach to glucose-lowering therapy—within a context of evidence-based multifactorial cardiovascular risk reduction—is welcome there is still much to be learned about optimal selection of the most appropriate patients for specific interventions.1

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