Emerging therapies for treating type 2 diabetes

November 8, 2013
Ying Yin Chen, PharmD
Ying Yin Chen, PharmD

,
Daryn K. Norwood, PharmD, BCPS, CGP, FASCP
Daryn K. Norwood, PharmD, BCPS, CGP, FASCP

Type 2 diabetes mellitus presents multiple treatment dilemmas for prescribers and healthcare clinicians. The number of oral agents for treating diabetes has increased over the past decade, and the best treatment regimen for each patient often varies based on comorbid conditions and treatment goals. Hence, understanding the risks and benefits of each agent is vital. While the number of agents for treating type 2 diabetes mellitus continues to increase, prescribers and clinicians may struggle with the need to individualize care as a means to improve treatment outcomes.

ABSTRACT

Type 2 diabetes mellitus presents multiple treatment dilemmas for prescribers and healthcare clinicians. The number of oral agents for treating diabetes has increased over the past decade, and the best treatment regimen for each patient often varies based on comorbid conditions and treatment goals. Hence, understanding the risks and benefits of each agent is vital. While the number of agents for treating type 2 diabetes mellitus continues to increase, prescribers and clinicians may struggle with the need to individualize care as a means to improve treatment outcomes.

Oral agents for type 2 diabetes mellitus (T2DM) have long been an effective means for glycemic control. However, over the past decade the available oral agents for treating T2DM has gone through considerable transition.1,2 Metformin remains the first-line agent for oral therapy and is also the only biguanide approved for use in the United States. Multiple trials have illustrated metformin’s benefit in patients with T2DM.1,2 But, for all of metformin’s benefit in improving glycemic control and hemoglobin A1c (HbA1c) levels, it is not available for use in all patients given the risk for lactic acidosis.1,2 Metformin is not recommended for use in patients with a serum creatinine greater than 1.5 in males or greater than 1.4 in females.1,2

These prohibitions leave a reasonable number of diabetic patients outside of the required parameters to receive the first-line therapy recommended by the American Diabetes Association.1,2 Another class, the sulfonylureas, also comes with notable risks in patients with compromised renal function or advanced age, given the increased risk for hypoglycemia. The negative outcomes of hypoglycemia have been well documented in recent years as data from various trials have become available.1,2 While the sulfonylureas lack the definitive use parameters compared to metformin, precaution is still necessary for those patients most at risk (the elderly or renally insufficient).1,2

The thiazolidinediones (TZDs) are another class of oral agents for diabetes. Initially this class drew concerns over causing fluid retention, which could lead to worse outcomes in stages 3 or 4 heart failure patients.2,3 However, over the last decade, new data have drawn concern over additional negative cardiac outcomes. Whether these negative cardiac outcomes comprise a class effect for both agents (pioglitazone and rosiglitazone) or are a product of just 1 agent (rosiglitazone), the class is now associated with considerable risks.3,4 Fortunately, new agents have emerged, but their actual role in therapy is still open to debate. Many of these newer agents have been approved for use with other agents such as metformin or the sulfonylureas.5

NEW TREATMENT OPTIONS

Sodium glucose cotransporter-2 inhibitor: Canagliflozin

A recent recognition of the kidneys’ role in glucose homeostasis led to an increased focus on drug development for diabetes management.6 Canagliflozin is a new oral agent for the treatment of T2DM that belongs to a novel class called sodium glucose cotransporter-2 (SGLT-2) inhibitors.7 FDA approved canagliflozin in 2013 as an adjunct to diet and exercise to improve glycemic control in adults with T2DM. It is not recommended for treatment of type 1 diabetes mellitus or diabetic ketoacidosis.8

The kidneys and liver work together to maintain glucose homeostasis (along with proper insulin secretion) to ensure proper energy supply for organs by producing and reabsorbing glucose. In normal healthy adults, the kidney filters approximately 180 g of glucose per day that are essentially reabsorbed, with less than 1% excreted in the urine.6,9 Sodium-dependent glucose transporters (SGLT) are responsible for the transport of glucose across plasma membranes. SGLT-2, mainly expressed in the kidneys, is responsible for 90% of glucose reuptake from the glomerular filtrate. SGLT-1, mainly expressed in the intestines, is responsible for only 10% of glucose reuptake. The kidneys reabsorb glucose via the SGLT and primarily the SGLT-2, which is found in the proximal tubules of the kidney. Inhibition of SGLT-2 protein prevents reabsorption of glucose and promotes glucosouria. The SGLT-2 inhibitor, canagliflozin, has a unique mechanism of action as it is the only agent that allows glucose excretion independent of insulin secretion.7

The recommended starting dose for canagliflozin is 100 mg once daily, taken before the first meal of the day. For patients who require additional glycemic control and who have an estimated glomerular filtration rate (eGFR) of 60 mL/min/1.73 m2 or greater, the dosage can be increased to 300 mg once daily. Canagliflozin is not recommended for eGFR of 45 mL/min/1.73 m2 or less.8 The pharmacokinetic properties of canagliflozin in patients with T2DM is similar to that in healthy subjects and does not appear to be affected by age, body weight, sex, race, food, mild to moderate hepatic dysfunction, or mild renal impairment. It is mainly metabolized through the O-glucuronidation elimination pathway to 2 inactive metabolites, with minimal metabolism via the CYP-3A4 oxidative pathway. Treatment with doses of canagliflozin higher than 300 mg prior to a meal has been shown to delay glucose absorption and reduce postprandial glucose, which can be attributed to its effects on SGLT-1 inhibition in the instestines.7,8

In clinical trials, canagliflozin has been studied in adults aged 55 to 80 years with baseline HbA1c from 7.79% to 8.82% and in those with moderate renal impairment. It has been studied both as monotherapy and in combination with other antihyperglycemic agents.8 In a 26-week, double blind, placebo-controlled study, canagliflozin monotherapy 100 mg daily and 300 mg daily significantly reduced HbA1c 0.77% and 1.03%, respectively (compared with an increase in 0.14% with placebo), with a significantly greater proportion of patients achieving a HbA1c of less than 7% compared to placebo. The study also resulted in significant reduction in fasting plasma glucose, improved postprandial glucose, and reduction in body weight.8,10 Canagliflozin has also been studied in combination with metformin, a sulfonylurea, metformin and a sulfonylurea, metformin and a TZD, as well as with insulin (with or without other antihyperglycemic agents). In these trials, the addition of canagliflozin led to a further reduction in HbA1c ranging from 0.63% to 0.89% for canagliflozin 100 mg daily and 0.72% to 1.06% for canagliflozin 300 mg daily dosing. Some potential advantages of canagliflozin include beneficial effects on blood pressure and weight. In clinical studies, canagliflozin demonstrated an average reduction of systolic blood pressure of approximately 2 mm Hg to 8 mm Hg and weight loss of about 2% to 4% after 6 months of treatment with 300 mg once daily. 8

The most common adverse events in clinical studies were the increased rate of genital fungal infections and urinary tract infections, increased urination and thirst, constipation, and nausea. Canagliflozin results in an osmotic diuresis, which is associated with dose-dependent increase in the incidence of hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration. Factors more prominently associated with these volume depletion-related reactions include the use of loop diuretics, moderate renal impairment (eGFR, 30 to <60 mL/min/1.73 m2), and aged ≥75 years. When used as monotherapy, it does not appear to cause hypoglycemia. Additionally, patients with impaired renal function and those predisposed to hyperkalemia should have their potassium levels monitored.8

One SGLT-2 inhibitor, dapagliflozin, was previously denied FDA approval in 2012 due to concerns about breast and bladder cancer risk.11 Similar concerns were not raised for canagliflozin during clinical studies. There is currently a lack of long-term efficacy and safety data with regard to microvascular and macrovascular events for canagliflozin. As a condition for approval, FDA has required that the pharmaceutical company conduct 5 postmarketing studies to evaluate risk for adverse cardiovascular outcomes, malignancies, pancreatitis, effects on bone, and other serious adverse events.12

Although canagliflozin does not target the major pathophysiologic processes such as insulin resistance and impaired insulin secretion, this drug class represents an alternate treatment pathway for patients with T2DM.9 There may be other SGLT-2 options available in the future.7

Glucagon-like peptide-1 receptor agonist

Glucagon-like peptide-1 (GLP-1) receptor agonists are subcutaneous injectables indicated for adjunctive treatment in adult patients with T2DM. GLP-1 is an incretin hormone that stimulates insulin secretion in response to high blood glucose, reduces postprandial glucagon release, and slows gastric emptying. A twice-daily formulation of exenatide was the first GLP-1 receptor agonist to be approved in the United States in 2005.13 In 2010, FDA approved a second GLP-1 receptor agonist called liraglutide. In 2012, a new once-weekly formulation of exenatide was approved.14

GLP-1 is an endogenous incretin hormone that acts by enhancing glucose-dependent insulin secretion, suppressing glucagon secretion, slowing gastric emptying, increasing satiety, and preserving beta cells. Endogenous GLP-1 undergoes rapid degradation by dipeptidyl peptidase-4 (DPP-4). However, the synthetic GLP-1 receptor agonists exenatide and liraglutide are partially resistant to breakdown by DPP-4.15

The recommended starting dose of liraglutide is 0.6 mg injected subcutaneously each day for 1 week. The 0.6-mg dose is not effective for glycemic control but rather enhances tolerability and reduces gastrointestinal symptoms in the initial period. After 1 week, the dose of liraglutide is increased to 1.2 mg daily, with a maximum recommended dose of 1.8 mg per day for glycemic control.16 Subcutaneous liraglutide is absorbed slowly; time to reach maximum concentration occurs at approximately 8 to 13 hours after administration. It is metabolized similarly to large proteins with no organ-specific major route of elimination or excretion. There are no recommended dose adjustments for patients with renal or hepatic impairments. However, there are pharmacokinetic studies that demonstrated, on average, a decrease in the area under the curve in patients with varying degrees of renal or hepatic impairments.16,17

A total of 8 phase-3 trials conducted on liraglutide led to its FDA approval.16 Liraglutide was studied as monotherapy and in combination with various oral antihyperglycemic agents as well as insulin. The mean baseline HbA1c for the study populations in the clinical trials ranged from 7.6% to 8.6%. In a 52-week trial, liraglutide 1.2 mg and 1.8 mg daily were evaluated as monotherapy compared to glimepiride 8 mg daily. Liraglutide 1.2 mg and 1.8 mg daily were associated with a statistically significant reduction in HbA1c by 0.8% and 1.1%, respectively, as compared to 0.5% in the glimepiride group. Liraglutide has also been studied in combination with other antihyperglycemic agents, including metformin, metformin and sitagliptin, metformin and insulin, a sulfonylurea, metformin and a sulfonylurea, and metformin and a TZD. It has also been studied in 1 trial for a direct comparison to exenatide in patients already on metformin and/or a sulfonylurea and showed statistically significant HbA1c reductions of 1.1% and 0.8%, respectively. For combination therapy, reduction in HbA1c ranged from about 0.97% to 1.5% in both liraglutide 1.2 mg and 1.8 mg daily.16,17

The newest GLP-1 receptor is the extended-release (ER) formulation of exenatide. The recommended dose is 2 mg subcutaneously once weekly without regard to meals. Compared to an elimination half life of 2.4 hours in the regular-release exenatide, exenatide ER is encapsulated in a biodegradable microsphere polymer that allows slow degradation and release of the drug. After a single injection of exenatide ER, there is an initial peak concentration occurring at around week 2 and a second peak at weeks 6 to 7 representing steady state.13,18 Nonclinical studies have demonstrated that exenatide is primarily eliminated by glomerular filtration with subsequent proteolytic degradation. There are no dose adjustments for patients with creatinine clearance (CrCl) of ≥30 mL/min. Exenatide is not recommended for patients with end-stage renal disease or CrCl <30 mL/min. No adjustment is required for patients with hepatic impairment.18

Once-weekly exenatide has been studied as monotherapy and in combination with metformin, a sulfonylurea, a TZD, and a combination of metformin and sulfonylurea, or a combination of metformin and a TZD.18 In a 24-week randomized, open-label trial, the once-weekly exenatide formulation was compared to the twice-daily exenatide formulation in patients already on an oral antihyperglycemic agent. The once-weekly formulation significantly reduced HbA1c, more than the twice-daily formulation, by 1.6% and 0.9%, respectively.18 In other clinical studies, the ER formulation has demonstrated an HbA1c reduction of about 1.5%.14 The incidence of withdrawal rates of the once-weekly formulation compared to the twice-daily formulation were 4.9% and 4.9%, respectively, in clinical studies.

Another advantage of GLP-1 receptor agonists is the associated reduction of body weight relative to the effects of slow gastric emptying and increased satiety. The average weight loss associated with liraglutide and exenatide ER is 2.5 kg and 2.3 kg, respectively.16,18 Furthermore, GLP-1 receptor agonists are associated with a low rate of hypoglycemia due to its glucose-dependent mechanism for stimulating insulin secretion.14,17

The most common adverse events for GLP-1 receptor agonists are gastrointestinal complaints (nausea, vomiting, and diarrhea).14,16–18 In most patients with nausea on the once-weekly exenatide, this effect diminished about 3 to 4 weeks after the drug reached steady state.14 It is also likely that the transient nauseating effect of GLP-1 receptor agonists may be associated with the onset of delayed gastric emptying, but no clinical studies have focused on this issue.17 Although GLP-1 receptor agonists are contraindicated in patients with a personal or family history of medullary thyroid carcinoma, the association of thyroid C-cell tumors is currently limited to animal studies.16,18 FDA issued a special alert for incretin mimetics in March 2013 for reports of pancreatic toxicity (increased risk of pancreatitis and pancreatic duct metaplasia) from a recently published study.19,20 FDA will announce its final conclusions and recommendations after further investigations.19

Dipeptidyl peptidase-4 inhibitors

Dipeptidyl peptidase-4 (DPP-4) inhibitors are oral agents used for adjunctive treatment of T2DM. The first DPP-4 inhibitor approved by FDA was sitagliptin, followed by saxagliptin.21,22 In 2011, linagliptin was approved as a single-ingredient product.23 In 2012, a fixed-dose combination of linagliptin/metformin was also approved.24 Recently, a new DPP-4, alogliptin, was approved in 3 formulations-a  single-ingredient product, as well as combination products of alogliptin/metformin and alogliptin/pioglitazone.25–27   

DPP-4 is an enzyme that inactivates and degrades incretin hormones, GLP-1 and glucose-dependent insulinotropic polypeptide. DPP-4 inhibitors slow the inactivation of incretin hormones, thereby increasing the concentration of active incretin hormones, which stimulates the release of insulin in a glucose-dependent manner and decreases the level of glucagon in the circulation.21–27

Linagliptin is the third oral DPP-4 inhibitor to be approved in the United States. The recommended dosage of linagliptin is 5 mg once daily, without regard to meals. The majority of linagliptin is excreted unchanged. A small fraction of absorbed linagliptin is metabolized to a pharmacologically inactive metabolite. No dosage adjustment is required in patients with renal impairments, which is an advantage over sitagliptin and saxagliptin. There is no dosage titration recommended. Linagliptin should not be used together with a strong CYP3A4 inducer, such as rifampin, due to the risk for a decrease in the concentration of linagliptin.  In clinical studies, linagliptin has been studied as monotherapy and in combination with metformin, glimepiride, pioglitazone, and insulin. The mean baseline HbA1c for the study populations in the clinical trials ranged from 7.7% to 8.6%. In 2 monotherapy trials of 18 weeks’ and 24-weeks’ duration, linagliptin was compared to placebo and demonstrated statistically significant improvements in HbA1c, by 0.4%, as compared to an increase of 0.1% to 0.3% in the placebo groups. When studied in combination with other antihyperglycemic agents, an HbA1c reduction of 0.2% to 1.6% was observed.23,28

The newest addition to the class of DPP-4 inhibitors is alogliptin. The recommended dosage of alogliptin is 25 mg once daily in patients with normal renal function or mild renal impairment. The recommended adjusted dosage is 12.5 mg once daily for moderate (CrCl 30–60 mL/min) and 6.25 mg once daily for severe (CrCl <30 mL/min) renal impairments. Alogliptin is not extensively metabolized, with 60% to 71% of the dose excreted unchanged in the urine. Alogliptin has been studied in multiple clinical trials as monotherapy and combination therapy with metformin, a sulfonylurea, a TZD (either alone or in combination with metformin or a sulfonylurea), and insulin (either alone or in combination with metformin). The mean baseline HbA1c for the study populations in the clinical trials ranged from 7.9% to 8.8%. When used as initial therapy, all 3 formulations of alogliptin are associated with significant HbA1c reductions of about 0.5% to 1.7%. Currently, there are no studies comparing alogliptin to other DPP-4 inhibitors.29

The most common adverse events for linagliptin in clinical trials were nasopharyngitis, diarrhea, and cough.18 In comparison, nasopharyngitis, headache, and upper respiratory tract infection were the most common adverse events reported for alogliptin.25 The incidence of hypoglycemia for linagliptin and alogliptin were similar to placebo in clinical studies.23,25 As with the GLP-1 receptor agonist, use of DPP-4 has been associated with acute pancreatitis.19

DOPAMINE AGONIST

Bromocriptine has been introduced as a new agent for diabetes. While bromocriptine has been traditionally used for treating hyperprolactinemia, acromegaly, and Parkinson’s disease, a new bromocriptine product was approved by FDA in May 2009 for treating T2DM.30,31 While bromocriptine’s exact mechanism for treating diabetes is unknown, it is suspected to act centrally to affect patterns of food intake and nutrient storage. These effects are suspected to further alter how the body responds physiologically to insulin resistance and obesity.30 Given this hypothesis, bromocriptine is unlikely to cause hypoglycemia or weight gain. In addition, bromocriptine has been shown to decrease fasting and postprandial triglyceride and free fatty acid levels.30 However, despite the novel mechanism, clinical trials only illustrated modest benefit for bromocriptine’s effect on HbA1c and serum glucose levels. Bromocriptine has been studied in multiple trials of various durations (6–52 weeks) resulting in over 4,000 study participants.30,31 These trials often showed a HbA1c reduction of 0.5% to 1% with monotherapy and in combination with other diabetes medications.30,31

The dosing in these trials was variable as bromocriptine was initiated at 0.8 mg once daily within 2 hours of waking, with considerations for increasing the dose by 1 tablet (0.8 mg) per week until maximum tolerance or maximum dosage (4.8 mg/day) was reached.30,31 However, given the dopaminergic activity of bromocriptine, the side-effect profile is unique compared to other agents for diabetes.30 Adverse events or side effects leading to discontinuation pooled in phase 3 clinical trials was 24% in patients treated with bromocriptine compared to 9% for placebo-treated patients. Nausea was the most frequent side effect occurring almost 4 times as often compared to placebo. In addition, given its dopaminergic affinity, bromocriptine should be avoided in patients with hypotension/syncope, psychosis, somnolence, or in patients on other dopaminergic agonists or antagonists.30,31 Bromocriptine may also inhibit lactation in nursing women.31 While bromocriptine does present a novel mechanism for treating diabetes, the modest benefit on HbA1c and its side effect profile may minimize its potential for use.

Thiazolidinediones

Rivoglitazone is a new TZD agent in the pipeline for the treatment of T2DM. When compared with rosiglitazone, rivoglitazone has a longer half-life with in vitro data to show that rivoglitazone has higher potency to activate peroxisome proliferator-activated receptor gamma (PPAR-gamma).  Clinical data have demonstrated that rivoglitazone 1.5 mg or higher may have a greater HbA1c -lowering potential than pioglitazone 30 mg or 45 mg. In addition, low rates of cardiovascular and fracture-related adverse events have been shown in short-term studies. Nevertheless, studies of longer duration are needed to further assess the risks associated with rivoglitazone.32             

SUMMARY

New drug therapies for T2DM (summarized in Table 1, with the exception of rivoglitazone pending FDA approval) are welcomed additions for a disease state that presents so many treatment dilemmas. The DPP-4 class may have the most documented benefit in the literature, as many of these agents are already commercially available as monotherapy or combination products with either metformin or sulfonylureas. The GLP-1 receptor antagonists also provide some additional treatment options; however, as this option still requires a subcutaneous injection, its desirability may ultimately be up to patients’ willingness to comply with an injection versus an oral option. Given the recent approval of canaglifozin, this agent and class (SGLT-2) provide yet another potential option to complement the previously available agents. In addition, rivoglitazone, if approved for use, may provide an alternative to the currently available TZDs. Ultimately, the primary role for prescribers and pharmacists is to recognize that many of these agents may complement previously available oral agents, primarily metformin and/or sulfonylureas.

REFERENCES

1. American Diabetes Association. Executive summary: standards of medical care in diabetes–2013. Diabetes Care. 2013; 36 Suppl 1:S4–S10.

2. Raz I, Riddle MC, Rosenstock J, et al. Personalized management of hyperglycemia in type 2 diabetes: reflections from a Diabetes Care Editors’ Expert Forum. Diabetes Care. 2013;36: 1779–1788.

3. FDA Safety Alert. Thiazolidinediones [Actos (pioglitazone HCl), Avandia (rosiglitazone)]. April 26, 2002. Available at:

http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm154518.htm. Accessed July 28, 2013

4. Krentz AJ, Patel MB, Bailey CJ. New drugs for type 2 diabetes mellitus: what is their place in therapy? Drugs. 2008;68:2131–2162.

5. Aguilar RB. Evaluating treatment algorithms for the management of patients with type 2 diabetes mellitus: a perspective on the definition of treatment success. Clin Ther. 2011;33:408–424.

6. Chao EC, Henry RR. SGLT2 inhibition-a  novel strategy for diabetes treatment. Nat Rev Drug Discov. 2010;9:551–559.

7. Riser Taylor S, Harris KB. The clinical efficacy and safety of sodium glucose cotransporter-2 inhibitors in adults with type 2 diabetes mellitus. Pharmacotherapy. 2013;33:984–999.

8. Invokana® canagliflozin package insert. http://www.invokana.com/prescribing-information.pdf . Titusville, NJ: Janssen Pharmaceuticals, Inc. March 2013.

9. Nisly SA, Kolanczyk DM, Walton AM. Canagliflozin, a new sodium-glucose cotransporter 2 inhibitor, in the treatment of diabetes. Am J Health Syst Pharm. 2013;70:311–319.

10. Stenlof K, Cefalu WT, Kim KA, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab. 2013;15:372–382.

11. Burki TK. FDA rejects novel diabetes drug over safety fears. Lancet. 2012;379:507.

12. FDA. FDA approves Invokana to treat type 2 diabetes. March 29, 2013. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm345848.htm. Accessed June 20, 2013.

13. Byetta® exenatide package insert. http://packageinserts.bms.com/pi/pi_byetta.pdf.  Princeton, NJ: Bristol-Myers Squibb Co. Wilmington, DE: AstraZeneca Pharmaceuticals LP. February 2013.

14. Ryan GJ, Moniri NH, Smiley DD. Clinical effects of once-weekly exenatide for the treatment of type 2 diabetes mellitus. Am J Health Syst Pharm. 2013;70:1123–1131.

15. Tzefos M, Harris K, Brackett A. Clinical efficacy and safety of once-weekly glucagon-like peptide-1 agonists in development for treatment of type 2 diabetes mellitus in adults. Ann Pharmacother. 2012;46:68–78.

16. Victoza® liraglutide package insert. http://www.novo-pi.com/victoza.pdf . Plainsboro, NJ: Novo Nordisk Inc.  April 2013.

17. Joffe D. Liraglutide: a once-daily human glucagon-like peptide-1 analogue for type 2 diabetes mellitus. Am J Health Syst Pharm. 2010;67:1326–1336. 

18. Bydureon®  exenatide extended-release package insert. http://packageinserts.bms.com/pi/pi_bydureon.pdf Princeton, NJ: Bristol-Myers Squibb Co.  Wilmington, DE: AstraZeneca Pharmaceuticals LP.  February 2013.

19. FDA. FDA Drug Safety Communication: FDA investigating reports of possible increased risk of pancreatitis and pre-cancerous findings of the pancreas from incretin mimetic drugs for type 2 diabetes. Updated March 18, 2013. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm343187.htm. Accessed June 20, 2013.

20. Singh S, Chang HY, Richards TM, Weiner JP, Clark JM, Segal JB. Glucagonlike peptide 1-based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus: a population-based matched case-control study. JAMA Intern Med. 2013;173:534–539.

21. Sitagliptin and combination drug package inserts. http://www.januvia.com/sitagliptin/januvia/hcp/januvia/clinical_experience/clinical_experience.jsp?WT.srch=1&WT.mc_id=JA80D&utm_source=google&utm_medium=cpc&utm_term=sitagliptin&utm_campaign=Januvia+Branded+2013&utm_content=sKeGWnIS4|dc_pcrid_26867477798. Whitehouse Station, NJ: Merck & Co., Inc. August  2013.

22. Onglyza® saxagliptin package insert. http://packageinserts.bms.com/pi/pi_onglyza.pdf. Princeton, NJ: Bristol-Myers Squibb Co. Wilmington, DE: AstraZeneca Pharmaceuticals LP. May 2013.

23. Tradjenta® linagliptin package insert. http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing+Information/PIs/Tradjenta/Tradjenta.pdf . Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.  Indianapolis, IN: Eli Lilly and Co. sJune 2013.

24. Jentadueto® linagliptin and metformin HCl package insert. http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing+Information/PIs/Jentadueto/Jentadueto.pdf. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc. Indianapolis, IN: Eli Lilly and Co.  September 2013.

25. Nesino® alogliptin package insert. https://www.takedadiabetes.com/?gclid=CNzywcj29rkCFcxAMgodJH4A0g. Deerfield, IL: Takeda Pharmaceuticals America, Inc.  June 2013.

26. Kazano® alogliptin and metformin HCl package insert. https://www.takedadiabetes.com/?gclid=CNzywcj29rkCFcxAMgodJH4A0g. Deerfield, IL: Takeda Pharmaceuticals America, Inc. June 2013.

27. Oseni® alogliptin and pioglitazone package insert. https://www.takedadiabetes.com/?gclid=CNzywcj29rkCFcxAMgodJH4A0g. Deerfield, IL: Takeda Pharmaceuticals America, Inc. June 2013.

28. Neumiller JJ. Pharmacology, efficacy, and safety of linagliptin for the treatment of type 2 diabetes mellitus. Ann Pharmacother. 2012;46:358–367.

29. Alogliptin (nesina) for type 2 diabetes. Med Lett Drugs Ther. 2013;55:41–43.

30. Sando KR, Taylor J. Bromocriptine: its place in type 2 diabetes Tx. J Fam Pract. 2011;60:e1–5.

31. Cycloset® bromocriptine mesylate package insert. http://www.cycloset.com/assets/pdf/cycloset-pi-final.pdf. Tiverton, RI: VeroScience, LLC. September 2010.

32. Koffarnus RL, Wargo KA, Phillippe HM. Rivoglitazone: a new thiazolidinedione for the treatment of type 2 diabetes mellitus. Ann Pharmacother. 2013;47:877–885.

 

Dr Chen, at the time of writing this manuscript, was a post graduate year-2 pharmacy resident in internal medicine and is now a clinical pharmacy specialist in internal medicine, MedStar Union Memorial Hospital, Baltimore, Md. Dr Norwood is pharmacy clinical coordinator and director of the pharmacy residency programs, Pharmacy Department, MedStar Union Memorial Hospital, Baltimore, Md.

The authors report no financial disclosures as related to products discussed in this article.

 

Table 1: Comparing new agents for treatment of T2DM

 

DrugDoseDose adjustmentHbA1c reductionEstimated cost/mo*Adverse drug reactions/comments

Sodium glucose cotransporter-2

CanagliflozinInitial: 100 mg oral once dailyeGFR 45 to <60 mL/min/1.73 m0.63% to 1.06%$263Genital fungal infection, urinary tract infection, increased urination and thirst, constipation, nausea

Glucagon-like peptide-1 receptor agonists

LiraglutideInitial: 0.6 mg subcutaneous once  daily x 1 week to reduce GI symptoms. Then increase to 1.2 mg subcutaneous once daily.Renal impairments: no dosage adjustment recommended0.97% to 1.5%$164GI complaints (nausea, vomiting, diarrhea)
Exenatide ERInitial: 2 mg subcutaneous once weeklyCrCl ≥30 mL/min: no dosage adjustment1.5%$342

Dipeptidyl peptidase-4 inhibitors

LinagliptinInitial: 5 mg oral once dailyRenal impairments: no dosage adjustment recommended0.2% to 1.6%$242Nasopharyngitis, diarrhea, cough, headache, upper respiratory tract infection
AlogliptinInitial: 25 mg once dailyCrCl ≥30 to 60 mL/min: 12.5 mg once daily0.5% to 1.7%$246

Dopamine agonist

BromocriptineInitial: 0.8 mg once dailyNo pharmacokinetic studies have been conducted in patients with renal or hepatic impairment0.5% to 1%$69Syncope and/or hypotension (most frequent during dose titration)

*Prices based on wholesale acquisition cost for 30-day supply.

Abbreviations: CrCl, creatinine clearance; eGFR, estimated glomerular filtration rate; GI, gastrointestinal; HbA1c, hemoglobin A1c; T2DM, type 2 diabetes mellitus.

Formulary/Source: Refs 8,16,18,23,25,31