Type 2 diabetes mellitus is an ongoing medical problem that clinicians deal with on a daily basis. The necessity of treating diabetes adequately is essential because of the many comorbidities and complications associated with uncontrolled diabetes. These comorbidities are very costly to the healthcare system and to the patient. In 2012, 28.9 million adult patients in the United States were diagnosed or undiagnosed with diabetes; of these, 15.5 million were men and 11.2 million were aged ≥65 years.1 The number of newly diagnosed patients with diabetes in 2012 was approximately 1.7 million, the majority of whom were aged 45 to 64 years.1 The prevalence of diabetes is still increasing. The number of US adults (aged 18-79 years) with newly diagnosed diabetes has nearly tripled in the past few decades, from 493,000 in 1980 to more than 1.5 million in 2011.2 At the current pace, approximately 1 in 3 US adults will have diabetes in their lifetime.1
The numerous comorbidities associated with diabetes include, but are not limited to, kidney failure, obesity, coronary artery disease, peripheral vascular disease, hypertension, stroke, and amputations.1 In the years 2003-2006, cardiovascular (CV) disease mortality rates were approximately 1.7 times higher among adults aged ≥18 years with diagnosed diabetes than among adults without diagnosed diabetes.1 In 2010, after adjusting for population age differences, hospitalization rates for heart attack and stroke were 1.8 times and 1.5 times higher, respectively, among adults aged ≥20 years with diagnosed diabetes than among adults without diagnosed diabetes.1 The estimated total cost for type 2 diabetes mellitus was $245 billion in 2012, of which $176 billion was in direct medical expenditures.1 With these trends, the cost and debilitating effects of this disease are only going to escalate, unless better glycemic control is achieved.
The older medications for diabetes, especially insulin and sulfonylureas, are associated with the common side effects of weight gain and hypoglycemia, which can be costly to the healthcare system. A retrospective study evaluated the incidence and cost of hypoglycemic events in patients with type 2 diabetes during 4 years.3 The analysis showed that the mean cost per 1 inpatient admission was $17,564, including $1387 for an emergency department visit and $394 for an outpatient visit. The total direct medical cost of hypoglycemia during the 4-year study was $52,223,675, which accounted for approximately 1% of all the inpatient costs, 2.7% of emergency department costs, and 0.3% of outpatient costs.3
The annual medical cost of obesity is currently estimated to be approximately $147 billion.4 Using drugs for the treatment of diabetes that can aid in weight loss rather than increase weight gain is cost-effective and can aid in patient adherence. In one study, researchers estimated that 1% of weight loss in 1 year could decrease a patient’s total healthcare cost by approximately $213 per patient who is using antidiabetic medications.5 Another study ascertained that patients with type 2 diabetes mellitus who lost weight with a treatment regimen are more likely to adhere to their regimen than patients who gain weight with their medication.6 Increased adherence to oral antihyperglycemic agents has been shown to be associated with reduced healthcare utilization as well as cost.7
As many as 14 classes of drugs are currently available for the treatment of type 2 diabetes mellitus.8 Despite the availability of pharmacotherapies, an estimated 3.1 million (14.9%) US adults with type 2 diabetes were still not taking a medication for diabetes in 2011.9 According to the 1999-2000 National Health and Nutrition Examination Survey, only approximately 36% of patients with type 2 diabetes achieve glycemic control—defined as a hemoglobin (Hb)A1c level of <7%—with the currently available therapies.10 New medications with different mechanisms of action or with novel approaches to therapy are needed to improve patient outcomes and to reduce the clinical burden of this condition.
The current article reviews some of the newly approved therapies by the US Food and Drug Administration (FDA), as well as those that are currently being tested as new options for the treatment of type 2 diabetes mellitus. Most drugs in this review have voucher and coupon programs provided by the manufacturer to offset the cost of the medications (Table).
The risks and benefits of each drug discussed in this article should be weighed appropriately when a drug regimen is chosen for a particular patient with diabetes. In addition, because many of these drugs have only recently become available in the United States, long-term evidence from real-world utilization is lacking. Furthermore, the FDA has requested postmarketing studies for some of these new agents, to investigate the potential risks for patients with diabetes to ensure that these new classes of drugs are safe for long-term use in this patient population.
Sodium Glucose Cotransporter-2 Inhibitors
The most recent class to be approved by the FDA for the treatment of type 2 diabetes mellitus is sodium glucose cotransporter-2 (SGLT-2) inhibitors. SGLT-2 proteins are primarily found in the proximal convoluted tubule of the kidneys and are responsible for reabsorbing approximately 90% of the glucose that is filtered through the kidneys.11 By inhibiting SGLT-2, urinary glucose excretion is increased, thereby lowering the plasma glucose concentration. This drug class can be used as monotherapy or in combination with other antihyperglycemic agents as a result of its distinct mechanism of action.12
The first SGLT-2 inhibitor to be approved by the FDA was canagliflozin (Invokana), which received FDA approval in March 2013. Canagliflozin is indicated as an adjunct to diet and exercise for the improvement of glycemic control in adult patients with type 2 diabetes mellitus.13 Supplied as tablets for oral administration, the recommended starting dose of canagliflozin is 100 mg once daily, taken before the first meal of the day. In patients tolerating canagliflozin 100 mg once daily and who have an estimated glomerular filtration rate (eGFR) of ≥60 mL/min/1.73 m2 and require additional glycemic control, the dose can be increased to 300 mg once daily.
Clinical results. In a randomized, double-blind, placebo-controlled study over 26 weeks, 584 patients were randomized to canagliflozin 100 mg, canagliflozin 300 mg, or placebo, administered once daily.14 At week 26, there was a significant reduction of HbA1c from baseline with canagliflozin 100 mg and 300 mg compared with placebo (−0.77%, −1.03%, and +0.14%, respectively; P <.001).14 In addition, both doses of canagliflozin significantly reduced fasting plasma glucose (FPG), 2-hour postprandial glucose, body weight, and systolic blood pressure.
There were few adverse events in the groups receiving canagliflozin, including genital mycotic infections, urinary tract infections, and osmotic diuresis, which can lead to orthostatic hypotension and syncope. The incidence of hypoglycemia was low across all groups. Overall, treatment with canagliflozin improved glycemic control and was generally well-tolerated in patients with type 2 diabetes who had inadequate glycemic control with diet and exercise.14
Canagliflozin was also assessed in a randomized, double-blind, active-controlled study of 755 patients inadequately controlled on the combination of metformin and a sulfonylurea.15 Patients received canagliflozin 300 mg in combination with metformin and a sulfonylurea or sitagliptin 100 mg in combination with metformin and a sulfonylurea. At week 52, canagliflozin 300 mg demonstrated superiority to sitagliptin 100 mg in reducing HbA1c (−1.03% vs −0.66%, respectively). Combination therapies including canagliflozin also demonstrated greater reductions in FPG, body weight, and systolic blood pressure than those with sitagliptin (P <.001).15
The overall adverse event rates were similarly low with canagliflozin and sitagliptin (76.7% vs 77.5%, respectively), but higher incidences of genital mycotic infections and osmotic diuresis were reported with canagliflozin, which led to 1 patient’s discontinuation of the drug.15 The trial’s findings demonstrate that canagliflozin is superior to sitagliptin in providing glycemic control and body-weight reduction in patients with type 2 diabetes who are already using metformin plus a sulfonylurea.15
Considering its site of action at the renal SGLT-2 transporters, canagliflozin is not expected to be effective in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2), those with end-stage renal disease, or those who are undergoing dialysis, even though studies have not been conducted on these patient populations.
The efficacy and safety of canagliflozin were evaluated in a randomized, double-blind, placebo-controlled study that included 269 patients with moderate renal impairment (eGFR ≥30 to <50 mL/min/1.73 m2).16 These patients had less overall glycemic efficacy at 26 weeks and a higher incidence of adverse events related to reduced intravascular volume (ie, postural dizziness and orthostatic hypotension), renal-related adverse reactions, and decreases in eGFR compared with patients with mild renal impairment or with normal renal function (eGFR ≥60 mL/min/1.73 m2). Patients using canagliflozin 300 mg were also more likely to experience an elevation in potassium. Hence, the assessment of renal function is recommended before the initiation of canagliflozin, and periodically thereafter.16
Finally, among the ongoing postmarketing studies required by the FDA for these agents is the phase 3 clinical trial Canagliflozin Cardiovascular Assessment Study (CANVAS) that is set to compare canagliflozin with placebo regarding CV events, including CV-related death, myocardial infarction, and stroke.17 A total of 4330 patients with type 2 diabetes whose diabetes was not well-controlled at the beginning of the study and who had a history of, or were at a high risk for, CV events were enrolled; they will be followed up for up to 9 years.
In January 2013, preliminary data from the CANVAS trial suggested that canagliflozin was not associated with an increased risk for CV events. Canagliflozin also caused a slight increase in low-density lipoprotein cholesterol, but the mechanism for this has yet to be elucidated.17
In January 2014, dapagliflozin (Farxiga) was the second SGLT-2 inhibitor to receive FDA approval to improve glycemic control, along with diet and exercise, in adult patients with type 2 diabetes.18 Similar to canagliflozin, dapagliflozin works in the renal tubules by inhibiting SGLT-2 transporters, resulting in the removal of excess glucose and its associated calories in the urine. Dapagliflozin has been studied as a monotherapy and in combination with other therapies for type 2 diabetes, including metformin, pioglitazone, glimepiride, sitagliptin, and insulin.19,20
Clinical results. One major study assessing the safety and efficacy of dapagliflozin monotherapy was a 24-week, parallel-group, double-blind, placebo-controlled phase 3 trial involving 558 patients with type 2 diabetes.19 Patients were divided into 2 groups based on their HbA1c levels: 485 patients were in the main cohort with an HbA1c of 7% to 10%, and 73 patients were in the group with an HbA1c of 10.1% to 12%. The patients with an HbA1c of 7% to 10% were randomly assigned to 1 of 7 arms to receive placebo or 2.5-mg, 5-mg, or 10-mg dapagliflozin once daily in the morning (main cohort) or evening (exploratory cohort). The patients with an HbA1c of 10.1% to 12% (the high-HbA1c exploratory cohort) were randomly assigned to receive placebo or 5-mg or 10-mg dapagliflozin once daily in the morning.
At week 24, the mean HbA1c changes from baseline in the main cohort were −0.23% with placebo and −0.58, −0.77, and −0.89% with 2.5-mg, 5-mg (P = .005), and 10-mg dapagliflozin, respectively (P <.001). Data from exploratory cohorts yielded similar and consistent results. No major episodes of hypoglycemia were reported with dapagliflozin, but urinary tract infections and genital infections were more common in the arms receiving dapagliflozin than with placebo.19
In another randomized, double-blind, active-controlled, multicenter 52-week trial, dapagliflozin was compared with glipizide as an add-on therapy in diabetic patients who had inadequate glycemic control with metformin.20 Sulfonylureas are known to cause hypoglycemia and weight gain, and to have poor glycemic durability, although they are initially effective. The study aimed to assess whether dapagliflozin causes fewer of these adverse events.
A total of 814 patients with type 2 diabetes were divided into 2 groups to receive either dapagliflozin and metformin or glipizide and metformin.20 The mean HbA1c reduction in the dapagliflozin cohort (–0.52%) was statistically noninferior at week 52 compared with glipizide (–0.52%). In addition, dapagliflozin produced a significant weight loss of 3.2 kg compared with a weight gain of 1.2 kg with glipizide (P <.001). Furthermore, only 3.5% of patients receiving combination therapy with dapagliflozin and metformin had hypoglycemic episodes compared with 40.8% of patients in the glipizide group (P <.001). However, genital infections and lower urinary tract infections were more frequent with dapagliflozin than with glipizide, but patients with these infections responded to standard treatment and this rarely led to study discontinuation.20
Before its approval by the FDA, dapagliflozin was declined twice by the FDA, in July 2011 and January 2012, because of insufficient data on the drug’s safety profile. The concern was of an increased number of bladder cancers diagnosed among dapagliflozin users in the initial trials.21 At the time of the July 2011 Endocrinology and Metabolic Drugs Advisory Committee meeting, 9 total patients who were diagnosed with bladder cancer were receiving dapagliflozin (0.06 per 100 patient-years), and 1 patient with bladder cancer was in the control group (0.03 per 100 patient-years).22 The drug manufacturer argued that the increase in bladder cancers seen in patients taking dapagliflozin resulted from preexisting cancers. Nonetheless, at this time, the drug’s manufacturer and the FDA do not recommend dapagliflozin for patients with active bladder cancer.18,23
Similar to canagliflozin, dapagliflozin should not be used in patients with moderate or severe renal impairment, patients with end-stage renal disease, or patients on dialysis. Dapagliflozin can also cause dehydration, leading to hypotension, dizziness, fainting, and a decline in renal function.
The FDA is requiring 6 postmarketing studies to be conducted by the manufacturers of dapagliflozin, including further investigation on its CV risk, bladder cancer risk, effects on urinary flow and composition changes on bladder tumor promotion in rodents, efficacy and safety in pediatric patients, risk of liver damage, and pregnancy outcomes. These postmarketing studies will likely provide better insight into dapagliflozin’s benefit-risk profile.23
In August 2014, empagliflozin (Jardiance) became the third SGLT-2 inhibitor to receive FDA approval for the treatment of type 2 diabetes as an adjunct to diet and exercise. Used as a tablet for oral administration, the recommended dose is 10 mg once daily in the morning, taken with or without food. In patients tolerating empagliflozin, the dose may be increased to 25 mg. The FDA approval of empagliflozin was based on a monotherapy study24 and in a combination study with metformin, sulfonylurea, pioglitazone, and insulin.25,26
Clinical results. The safety and efficacy of empagliflozin was shown to have linear pharmacokinetics with dose increases with respect to time.24 Empagliflozin was associated with an increase in urine glucose excretion compared with virtually no urine glucose excretion in the placebo group. It also significantly decreased blood glucose in the active drug group versus the placebo group. The amount of glucose in the urine increased from baseline to day 1 by 74 g, 90 g, and 81 g, with 10-mg, 25-mg, and 100-mg doses of empagliflozin, respectively. The adverse events observed with empagliflozin included excessive urination (10.3%), nasopharyngitis (9%), constipation (9%), and headache (7.7%). The increase in urinary glucose excretion remained elevated at similar levels during the 28-day trial period.24
The efficacy and safety of empagliflozin in patients with type 2 diabetes have been studied in conjunction with metformin in a 12-week, double-blind, placebo-controlled trial that compared the results with those of placebo and open-label sitagliptin 100 mg daily.25 Empagliflozin’s dosing was 1 mg, 5 mg, 10 mg, 25 mg, and 50 mg daily. The trial demonstrated a significant reduction of HbA1c with empagliflozin (–0.09 to –0.56%) compared with placebo (+0.15%). Furthermore, empagliflozin in conjunction with metformin had significant reductions of blood glucose levels (–2 to –28 mg/dL) compared with placebo (+5 mg/dL; P <.001), as well as significant benefits of body-weight reductions (–2.3 to –2.9 kg) compared with placebo (–1.2 kg; P <.01).
Empagliflozin had similar overall adverse event rates (29.6%-48.6%) compared with placebo (36.6%) and sitagliptin (35.2%). Empagliflozin had more urinary tract infections than placebo (4% vs 2.8%, respectively) and greater increase in urination (2.5% vs 1.4%, respectively). Genital infections were only reported with empagliflozin, at a rate of 4.0%.
The once-daily dosing of empagliflozin was welltolerated and was associated with significantly decreased levels in HbA1c, decreased fasting blood glucose, and decreased body weight in poorly controlled patients with type 2 diabetes who had been receiving metformin monotherapy.25
Empagliflozin was also investigated as an add-on to pioglitazone with or without metformin in patients with type 2 diabetes in a 24-week trial.26 A significant reduction of HbA1c was seen with empagliflozin 10 mg and 25 mg (–0.6% and –0.7%, respectively) compared with placebo (–0.1%; P <.001). In addition to reductions in fasting blood glucose levels in this trial, empagliflozin 10 mg and 25 mg was associated with significant weight loss (–1.62 kg and –1.47 kg, respectively) compared with increased weight (+0.34 kg; P <.001) with placebo. Significantly more patients with HbA1c levels of ≥7% had their HbA1c level reduced to <7 by the end of the trial with the 10-mg (23.8%) and 25-mg (30%) doses of empagliflozin than with placebo (7.7%; P <.001). Finally, similar proportions of patients reported adverse events with empagliflozin (67.3%-71.4%) and with placebo (72.7%). Confirmed hypoglycemia was reported by 1.2% to 2.4% of patients receiving empagliflozin and by 1.8% of patients receiving placebo.26
A special population trial was also conducted to determine the efficacy and tolerability of empagliflozin monotherapy in Japanese patients with type 2 diabetes mellitus.27 A total of 547 patients were randomized to empagliflozin 5 mg, 10 mg, 25 mg, 50 mg, or to placebo for 12 weeks. Significant reductions in HbA1c levels (approximately –0.7% to –0.95%), FPG, and body weight were reported in patients receiving empagliflozin compared with those receiving placebo. More patients with an HbA1c level of ≥7% at baseline reached an HbA1c level of <7% with empagliflozin (19%-33%) than with placebo (3%). Adverse events were reported by 33% to 38% of patients receiving empagliflozin and by 42% of patients receiving placebo.27
Empagliflozin has been studied with other therapies, such as for lipid control with simvastatin, in healthy volunteers.28 No serious adverse reactions or drug–drug interactions were observed when empagliflozin was combined with simvastatin. The pharmacokinetic results suggest that no dose adjustments for either drug are necessary when empagliflozin and simvastatin are coadministered.28
Ipragliflozin (Suglat) is an SGLT-2 inhibitor that gained regulatory approval in Japan in January 2014 for the treatment of patients with type 2 diabetes, but is not yet approved by the FDA. It is the first SGLT-2 inhibitor on the Japanese market, and is currently available only in Japan.29 Ipragliflozin is available in doses of 25-mg and 50-mg tablets, taken daily, and the dosing can be increased to 100 mg daily if lower doses are inefficient. Ipragliflozin has been studied in 6 phase 3 clinical trials in Japan and has demonstrated significant reductions in HbA1c, decreases in FPG, and decreases in total body weight without many adverse events. All the clinical trials were conducted in Japan, because the manufacturer decided to focus on the Asian market for ipragliflozin.29 Because ipragliflozin is still not available in the United States, and for lack of space, details of the trials are not included in this review.
Tofogliflozin (CSG452) is an investigational, potent, and highly selective SGLT-2 inhibitor that is currently in phase 3 clinical trials. It has the highest selectivity toward SGLT-2 compared with the other SGLT-2 inhibitors (canagliflozin, ipragliflozin, empagliflozin, luseogliflozin, and PF-04971729).30 The clinical data published on tofogliflozin are currently limited; however, early reports of tofogliflozin suggest that it is a true SGLT-2 inhibitor. The SGLTs have several functions in the body. The inhibition of SGLTs that are not involved in renal glucose absorption would lead to undesirable side effects. Therefore, the high selectivity of tofogliflozin to SGLT-2s, if approved by the FDA, is expected to play an important role in terms of safety.30
Glucagon-Like Peptide-1 Drugs
Incretins are hormones that are secreted by cells in the small intestine during an oral nutrient load. Glucagon-like peptide-1 (GLP-1) is an incretin that has potent antihyperglycemic effects. In the presence of hyperglycemia, GLP-1 causes the release of insulin from the pancreas, shuts down glucagon secretion, slows down gastric emptying, and acts on the hypothalamus to increase satiety.31 Currently, 4 GLP-1 agents are approved by the FDA—exenatide (which also has an extendedrelease version), albiglutide, dulaglutide, and liraglutide. The first 3 of these GLP-1 drugs recently had significant marketing changes.
Exenatide Extended-Release Pen
The new exenatide extended-release for injectable suspension pen (Bydureon) that was approved by the FDA for the treatment of type 2 diabetes on March 3, 2014, is a prefilled, single-use, once-weekly pen injector.32 The pen contains the same formulation and dose of exenatide as the original, single-dose tray that was approved by the FDA in 2012. It provides the same continuous supply of the drug as the original formulation, but the new pen is designed to be more user-friendly. Patients attach the needle, twist the base of the pen to mix the drug, then tap the pen firmly against the palm of their hand for 80 times or more, while rotating the pen until the solution is completely mixed.32 This new process is a significant improvement from the manual mixing of the drug in the 2012 version.
Each weekly dose in the pen is made up of microspheres that house exenatide and slowly dissolve over the span of a week. It requires no titration and can be administered at any time of the day, with or without meals. The exenatide extended-release pen improves glycemic control by reducing fasting and postprandial glucose concentrations in patients with type 2 diabetes. The original single-dose tray version of Bydureon has been shown to provide powerful HbA1c reduction and weight loss.33 The exenatide extended-release pen aims to provide an easier method of delivery for patients.
Albiglutide (Tanzeum) subcutaneous injection is a long-acting GLP-1 receptor agonist approved by the FDA in April 2014 as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.34 The recommended dose is 30 mg once weekly given as a subcutaneous injection in the abdomen, thigh, or upper arm region. The dose may be increased to 50 mg once weekly if the glycemic response is inadequate.26 Albiglutide may be administered at any time of day, without regard to meals. As a once-weekly subcutaneous injection, it requires fewer injections than short-acting GLP-1 agonists.34
Clinical results. The clinical efficacy of albiglutide is demonstrated in a series of phase 3 trials named the HARMONY series.
HARMONY 2 demonstrated the efficacy of albiglutide as monotherapy in a 52-week, randomized, doubleblind, placebo-controlled multicenter trial.35 Patients were randomized to 3 different groups, including (1) placebo, (2) albiglutide 30 mg weekly, and (3) albiglutide 30 mg weekly titrated to 50 mg weekly at week 12. The mean patients’ age was 53 years, 55% of patients were men, the mean duration of diabetes was 4 years, and the mean baseline eGFR was 84 mL/min/1.73 m2. All 3 groups had approximately 100 patients, with a baseline HbA1c of approximately 8%.
Albiglutide achieved –0.7% and –0.9% reductions in HbA1c in the 30-mg and 50-mg groups, respectively, whereas patients receiving placebo had a 0.2% increase in HbA1c. A study extension to 3 years revealed a durable reduction in HbA1c.35
In the longest duration comparative study of albiglutide to date, HARMONY 3 compared the efficacy and safety of albiglutide versus sitagliptin, glimepiride, and placebo in patients whose glycemic levels were inadequately controlled with metformin.36 At week 104, the mean difference in HbA1c reduction when albiglutide was added to metformin was significantly superior to the comparator treatment: the reduction was –0.9% greater than in the placebo group (P <.001); –0.4% greater than in the sitagliptin group (P = .001); and 0.3% greater than in the glimepiride group (P = .003).36 Weight loss was also significantly greater (–2.4 kg) in the albiglutide group than in the glimepiride group (P <.001), but it was similar to the sitagliptin group (–0.4 kg) and the placebo group (–0.2 kg).37
Gastrointestinal adverse events during 2 years of observation across the placebo, sitagliptin, glimepiride, and albiglutide arms included nausea (11%, 7%, 6%, and 10%, respectively), vomiting (1%, 4%, 4%, and 6%, respectively), and diarrhea (11%, 9%, 9%, and 13%, respectively). There were no reports of severe hypoglycemia in the albiglutide arm.37
The HARMONY 4 study compared the use of albiglutide and insulin therapy in patients with diabetes. In a 52-week, randomized, open-label, noninferiority study, HARMONY 4 compared albiglutide with insulin glargine in patients receiving metformin with or without a sulfonylurea.38 Both groups achieved a similar reduction in HbA1c (–0.7% in the albiglutide group and –0.8% in the insulin glargine group), indicating the noninferiority of albiglutide to insulin glargine. In addition, patients receiving albiglutide lost weight (–1.1 kg), whereas those receiving insulin glargine gained weight (+1.6 kg), resulting in a treatment difference of 2.6 kg (P <.001) between the 2 groups.38
Similar results were seen when albiglutide was compared with prandial lispro insulin 3 times daily in patients using background glargine ≥20 U in a 26-week, randomized, noninferiority trial. The HbA1c levels were reduced by –0.82% in the group using albiglutide versus –0.66% in the group taking lispro insulin, meeting the noninferiority end point of the trial.39 Furthermore, patients receiving albiglutide lost weight (–0.73 kg), whereas those using insulin lispro experienced weight gain (+0.81 kg).39
Albiglutide has also been studied as an add-on therapy to other drugs, including pioglitazone. In HARMONY 1, patients whose glycemic control was inadequate with pioglitazone, with or without metformin, were administered either albiglutide 30 mg or placebo.40 At the 52-week primary end point, albiglutide combined with pioglitazone demonstrated a significant reduction in HbA1c levels from baseline compared with placebo (for a difference of –0.8% between the 2 treatments; P <.001). Of the patients receiving albiglutide, 44% achieved the HbA1c target of <7% compared with 15% of patients receiving placebo. Weight changes were not significantly different between the 2 groups. Adverse reactions of nausea and vomiting were comparable between the albiglutide and the placebo groups, but were higher with albiglutide than with placebo in diarrhea (11.3% vs 8.6%, respectively) and injection-site reactions (11.3% vs 7.9%, respectively).40
Finally, as a new member of the GLP-1 drug class, it is important to compare albiglutide with other drugs in this class. HARMONY 7 was a 32-week, randomized, open-label noninferiority phase 3 clinical trial comparing albiglutide with liraglutide in patients with uncontrolled type 2 diabetes.41 The results revealed a lower
reduction of HbA1c levels with albiglutide than with liraglutide (–0.8% vs –1.0), which did not meet the noninferiority upper margin of 0.3% in this trial. In addition, patients in the albiglutide group had more injection-site reactions and fewer gastrointestinal events than patients in the liraglutide group.41
The FDA approved dulaglutide (Trulicity) as a once-weekly subcutaneous injection to improve glycemic control, along with diet and exercise, in adults with type 2 diabetes on September 18, 2014.42 Dulaglutide is administered once weekly, any time of day, independent of meals, and should be injected subcutaneously in the abdomen, thigh, or upper arm. The recommended starting dose is 0.75 mg, which can be increased to a 1.5-mg dose for patients who need additional blood glucose control.42 Dulaglutide has been studied in 6 clinical trials (AWARD 1-6) as a stand-alone therapy and in combination with other type 2 diabetes therapies, including metformin, sulfonylurea, thiazolidinedione, and prandial insulin.42,43 Significant reductions in HbA1c were seen in patients receiving dulaglutide.43
In AWARD-6, a head-to-head, phase 3, randomized, noninferiority trial of dulaglutide versus liraglutide in patients with uncontrolled type 2 diabetes receiving metformin, the least-squares mean reduction in HbA1c was –1.42% in the dulaglutide group and –1.36% in the liraglutide group.44 The mean treatment difference in HbA1c was –0.06% between the groups, which met the noninferiority criteria of the trial (margin, 0.4%).44 To our knowledge, this is the first time a once-weekly GLP-1 agent has achieved a noninferiority status versus a once-daily GLP-1 drug in a phase 3 clinical trial.
Dulaglutide has also been studied as a monotherapy versus metformin in patients with uncontrolled type 2 diabetes.45 At 26 weeks, changes from baseline in HbA1c levels were –0.78%, –0.71%, and –0.56% for dulaglutide 1.5 mg, dulaglutide 0.75 mg, and metformin, respectively. Nausea, diarrhea, and vomiting were the most common adverse events and occurred at similar rates in both the dulaglutide and metformin treatment groups. No severe hypoglycemia was reported.45
New Insulin Agents
Technosphere insulin human (Afrezza) is a recombinant regular human insulin inhalation powder approved by the FDA in June 2014 for the treatment of type 1 and type 2 diabetes mellitus. When the insulin is inhaled through the device, the powder is aerosolized and delivered to the lung. Afrezza should be administered at each mealtime and is touted as an alternative to injectable short-acting insulin.
Clinical results. The pharmacokinetics for the powder was studied in 11 healthy nonsmokers who were randomized to either a dose of single inhalation consisting of 25 U, 50 U, or 100 U of inhaled human insulin or to a fixed dose of 10 IU of regular human insulin. When comparing the 2 groups, it was noted that the inhaled insulin achieved peak concentration approximately 2 hours earlier than the regular human insulin. The pharmacokinetics measured by the area under the curve was found to be linear with the doses that were studied. No treatment- related adverse events were reported with the inhaled human insulin. It was concluded that this inhaled regular insulin had a more rapid absorption than the subcutaneous regular human insulin with linear pharmacokinetics.46
The regular human insulin inhaled powder has been studied in patients with type 1 and type 2 diabetes. Across a broad spectrum of diabetes severity, inhaled human insulin was noninferior to active comparators in 2 of 3 trials and was superior to placebo in HbA1c reduction, as was demonstrated in 24-week to 52-week clinical trials.47
A total of 334 patients receiving inhaled insulin with a basal insulin dose of glargine were compared with 343 patients receiving biaspart insulin given twice daily in patients with type 2 diabetes mellitus.48 The randomized, multicenter, noninferiority trial compared the treatments and their changes in HbA1c from baseline to the end of the 52-week trial. At the end of 52 weeks, the change in HbA1c with inhaled insulin plus insulin glargine was –0.68% and was similar and noninferior to that with biaspart insulin (–0.76%). The between-group difference was 0.07% (the noninferiority margin was 0.4%).
The inhaled insulin group demonstrated fewer adverse events of mild-to-moderate and severe hypoglycemic events and significantly less weight gain. The safety profiles of the drugs were similar, except the inhaled insulin demonstrated an increase in forced expiratory volume in 1 second (FEV1) and an increase in the occurrence of cough.48 Changes in FEV1 do not progress over time with use, and they reverse with the cessation of the medication.49
The FDA has approved the medication with a box warning that states that inhaled human insulin may cause acute bronchospasm and is not recommended for use by patients with asthma or chronic obstructive pulmonary disease.50 The most common adverse events, such as hypoglycemia, are similar to that of short-acting subcutaneous insulin. Other common side effects include throat pain or irritation (4.4%) and cough (25.6%).51
Miscellaneous Drugs with a Potential to Regulate Glucose Dysregulation
Ranolazine is a novel antiangina drug used in the treatment of patients with chronic angina, and has also been shown to lower HbA1c and FPG levels in clinical trials. Ranolazine inhibits the cardiac late-phase sodium current during cardiac repolarization, thus improving sodium-calcium homeostasis and resulting in reduced myocardial ischemia. In patients with coronary artery disease and diabetes, ranolazine has been shown to decrease HbA1c levels in 2 clinical trials—the Combination Assessment of Ranolazine in Stable Angina (CARISA) trial52 and the Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndromes-Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) trial.53
In the CARISA trial, ranolazine was associated with a statistically significant decline in HbA1c in a dose-dependent manner.52 After 12 weeks of treatment with ranolazine 750 mg or 1000 mg twice daily, the HbA1c level was reduced by 0.48% (P = .008) and 0.7% (P = .002) compared with placebo.52 This was further confirmed in the MERLIN-TIMI 36 trial. The double-blind study included 6560 patients with non–ST-segment elevation myocardial infarction acute coronary syndrome and at least 1 indicator of moderate-to-high risk of a recurrent ischemic event who were randomized in a 1:1 ratio to ranolazine or to placebo.53 The results showed a significant reduction in HbA1c with ranolazine in addition to standard antidiabetic therapy. Ranolazine had a placebo-adjusted reduction in HbA1c of 0.28% in patients with an HbA1c of 6% to 8% and by 0.59% in patients with an HbA1c of 8% to 10%. In addition, ranolazine also had a placebo-corrected reduction in FPG of 25.7 mg/dL in patients with an initial FPG of ≥150 to 400 mg/dL and no change in FPG in patients with an initial FPG of <150 mg/dL.53
The exact mechanism of the reduction of HbA1c with ranolazine is not known, but experimental models have suggested that ranolazine increases glucose-stimulated insulin secretion in isolated pancreatic islet cells.54 In mice with streptozotocin-induced diabetes that were treated with ranolazine, the peak insulin levels were higher during the oral glucose tolerance test (P <.05), the islet morphology appeared healthier, there was higher beta-cell mass, and there were significantly less apoptotic cells in the pancreas.54
Many patients with diabetes have concurrent nephropathy. In patients with chronic kidney disease, sevelamer is used in the management of hyperphosphatemia. In a single-center, randomized, crossover, open-label, intention-to-treat study, sevelamer was shown to lower HbA1c, total cholesterol, and triglycerides compared with calcium carbonate (P <.05).55 The mechanism behind sevelamer’s effect on HbA1c is unknown. Sevelamer is also a bile sequestrant in addition to being a phosphate binder. Thus, sevelamer’s effect on HbA1c is possibly related to its bile acid–binding ability.
Colesevelam is a bile sequestrant that is approved by the FDA for the management of diabetes and has been shown to lower HbA1c and FPG.56 Sevelamer enhances the delivery of bile acids to the distal colon via its bile sequestration capability, thereby promoting GLP-1 release and modulating HbA1c.57
The problem of diabetes in the United States will continue to wreak heavy human and financial tolls. The complications stemming from diabetes will continue to climb if they are not stemmed. The most common obstacle a physician faces in clinical practice is patient adherence. Aside from efficacy and safety, the common themes seen with these new and emerging drugs are the convenience of administration and the convenient dosing frequency.
All the oral drugs discussed in this review article are once-daily medications, with the exception of ranolazine. All new injections for diabetes are coming out in a pen format to improve patient adherence. A new inhaled insulin was found to work more quickly than the injectable version of the drug, and it has shown to be as effective as other short-acting subcutaneous insulin agents.
Perhaps the most exciting aspects of these novel developments in diabetes management are that the new agents are either weight-friendly or can induce weight loss, or they have lower risks for hypoglycemia. At a mean total cost of $17,564 per hypoglycemic episode requiring hospitalization,3 this is a meaningful improvement to the healthcare system as a whole.
Weight gain in patients with diabetes is counterproductive, because substances related to insulin resistance are upregulated in obese patients. Weight loss promotes HbA1c reduction, with a loss of 10% body weight potentially reducing HbA1c by 0.81%.58 This, in turn, improves insulin sensitivity potentiating other therapies.
Postmarketing data are continuing to be collected for these drugs to address safety concerns. No macrovascular outcomes data are currently available for the antidiabetes drugs that are mentioned in this review, although each drug will have to conduct a dedicated CV safety trial to meet the 2008 updated FDA guidance recommendations. The risks and benefits of each drug should be appropriately weighed when a diabetes regimen is chosen for a particular patient.
Author Disclosure Statement
Dr Miller, Dr H. Nguyen, Dr Hu, and Dr Lin reported no conflicts of interest. Dr Q.T. Nguyen is on the Speaker’s Bureau for AstraZeneca.
Dr Miller is Resident, Department of Internal Medicine, Valley Hospital Medical Center, Las Vegas, NV; Dr H. Nguyen is Resident, Department of Internal Medicine, Valley Hospital Medical Center, Las Vegas, NV; Dr Hu is Resident, Department of Internal Medicine, Valley Hospital Medical Center, Las Vegas, NV; Dr Lin is Resident, Department of Internal Medicine, Valley Hospital Medical Center, Las Vegas, NV; Dr Q.T. Nguyen is Medical Director, Las Vegas Endocrinology, Clinical Associate Professor, Clinical Education, AZCOM, Adjunct Associate Professor of Endocrinology, Touro University Nevada.
1. Centers for Disease Control and Prevention. National diabetes statistics report: estimates of diabetes and its burden in the United States, 2014. 2014. www.cdc.gov/diabe tes/pubs/statsreport14/national-diabetes-report-web.pdf. Accessed October 3, 2014.
2. Centers for Disease Control and Prevention. Annual number (in thousands) of new cases of diagnosed diabetes among adults aged 18-79 years, United States, 1980-2011. Updated September 24, 2012. www.cdc.gov/diabetes/statistics/incidence/fig1.htm. Accessed September 22, 2014.
3. Quilliam BJ, Simeone JC, Ozbay AB, Kogut SJ. The incidence and costs of hypoglycemia in type 2 diabetes. Am J Manag Care. 2011;17:673-680.
4. Finkelstein EA, Trogdon JG, Cohen JW, Dietz W. Annual medical spending
attributable to obesity: payer- and service-specific estimates. Health Aff (Millwood). 2009;28:w822-w831.
5. Yu AP, Wu EQ, Birnbaum HG, et al. Short-term economic impact of body weight change among patients with type 2 diabetes treated with antidiabetic agents: analysis using claims, laboratory, and medical record data. Curr Med Res Opin. 2007;23:2157-2169.
6. Grandy S, Fox KM, Hardy E; for the SHIELD Study Group. Association of weight loss and medication adherence among adults with type 2 diabetes mellitus: SHIELD (Study to Help Improve Early Evaluation and Management of Risk Factors Leading to Diabetes). Curr Ther Res Clin Exp. 2013;75:77-82.
7. White TJ, Vanderplas A, Chang E, et al. The costs of non-adherence to oral antihyperglycemic medication in individuals with diabetes mellitus and concomitant diabetes mellitus and cardiovascular disease in a managed care environment. Dis Manag Health Outcomes. 2004;12:181-188.
8. American Diabetes Association. Standards of medical care in diabetes—2014. Diabetes Care. 2014;37(suppl 1):S14-S80. Erratum in: Diabetes Care. 2014;37:887.
9. Centers for Disease Control and Prevention. Number (in millions) of adults with diabetes by diabetes medication status, United States, 1997-2011. Updated December 7, 2012. www.cdc.gov/diabetes/statistics/meduse/fig1.htm. Accessed September 22, 2014.
10. Koro CE, Bowlin SJ, Bourgeois N, Fedder DO. Glycemic control from 1988 to 2000 among U.S. adults diagnosed with type 2 diabetes: a preliminary report. Diabetes Care. 2004;27:17-20.
11. Idris I, Donnelly R. Sodium–glucose co-transporter-2 inhibitors: an emerging new class of oral antidiabetic drug. Diabetes Obes Metab. 2009;11:79-88.
12. Ferrannini E, Solini A. SGLT2 inhibition in diabetes mellitus: rationale and clinical prospects. Nat Rev Endocrinol. 2012;8:495-502.
13. US Food and Drug Administration. FDA approves Invokana to treat type 2 diabetes. Press release. March 29, 2013. www.fda.gov/NewsEvents/Newsroom/Press
Announcements/ucm345848.htm. Accessed October 30, 2014.
14. Stenlöf K, Cefalu WT, Kim K-A, 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.
15. Schernthaner G, Gross JL, Rosenstock J, et al. Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52-week randomized trial. Diabetes Care. 2013;36:2508-2515. Erratum in: Diabetes Care. 2013;36:4172.
16. Yale J-F, Bakris G, Cariou B, et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab. 2013;15:463-473.
17. Neal B, Perkovic V, de Zeeuw D, et al; for the CANVAS Trial Collaborative Group. Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS)—a randomized placebo-controlled trial. Am Heart J. 2013;166:217-223.e11.
18. US Food and Drug Administration. FDA approves Farxiga to treat type 2 diabetes. Press release. January 8, 2014. www.fda.gov/NewsEvents/Newsroom/Press Announcements/ucm380829.htm. Accessed September 23, 2014.
19. Ferrannini E, Jimenez Ramos S, Salsali A, et al. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care. 2010,33:2217-2224.
20. Nauck MA, Del Prato S, Meier JJ, et al. Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes Care. 2011;34:2015-2022.
21. US Food and Drug Administration. FDA briefing document. NDA 202293. Dapagliflozin tablets, 5 and 10 mg. July 19, 2011. www.fda.gov/downloads/advisory committees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugs advisorycommittee/ucm262994.PDF. Accessed October 10, 2014.
22. US Food and Drug Administration. Background document. Dapagliflozin. NDA 202293. November 4, 2013. www.fda.gov/downloads/drugs/endocrinologicandmeta bolicdrugsadvisorycommittee/ucm378079.pdf. Accessed October 27, 2014.
23. Farxiga (dapagliflozin) tablets [prescribing information]. Princeton, NJ: Bristol-
Myers Squibb; January 2014.
24. Heise T, Seewaldt-Becker E, Macha S, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics following 4 weeks’ treatment with empagliflozin once daily in patients with type 2 diabetes. Diabetes Obes Metab. 2013;15:613-621.
25. Rosenstock J, Seman LJ, Jelaska A, et al. Efficacy and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, as add-on to metformin in type 2 diabetes with mild hyperglycaemia. Diabetes Obes Metab. 2013;15:1154-1160.
26. Kovacs CS, Seshiah V, Swallow R, et al; for the EMPA-REG PIO trial investigators. Empagliflozin improves glycaemic and weight control as add-on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: a 24-week, randomized, placebo-controlled trial. Diabetes Obes Metab. 2014;16:147-158.
27. Kadowaki T, Haneda M, Inagaki N, et al; for the EMPA-REG DOSEJAPAN trial investigators. Empagliflozin monotherapy in Japanese patients with type 2 diabetes mellitus: a randomized, 12-week, double-blind, placebo-controlled, phase II trial. Adv Ther. 2014;31:621-638.
28. Macha S, Lang B, Pinnetti S, Broedl UC. Pharmacokinetics of empagliflozin, a sodium glucose cotransporter 2 inhibitor, and simvastatin following co-administration in healthy volunteers. Int J Clin Pharmacol Ther. 2014;52:973-980.
29. Astellas Pharma. Approval of Suglat tablets, a selective SGLT2 inhibitor for treatment of type 2 diabetes, in Japan. Press release. January 17, 2014. www.astellas.com/en/corporate/news/detail/approval-of-suglat-tablets-a-s.html. Accessed September 28, 2014.
30. Suzuki M, Honda K, Fukazawa M, et al. Tofogliflozin, a potent and highly specific sodium/glucose cotransporter 2 inhibitor, improves glycemic control in diabetic rats and mice. J Pharmacol Exp Ther. 2012;341:692-701.
31. Holst JJ. Treatment of type 2 diabetes mellitus with agonists of the GLP-1 receptor or DPP-IV inhibitors. Expert Opin Emerg Drugs. 2004;9:155-166.
32. Bydureon (exenatide) pen [prescribing information]. Wilmington, DE: Astra Zeneca Pharmaceuticals; October 2014.
33. Blevins T, Pullman J, Malloy J, et al. DURATION-5: exenatide once weekly resulted in greater improvements in glycemic control compared with exenatide twice daily in patients with type 2 diabetes. J Clin Endocrinol Metab. 2011;96:1301-1310.
34. Tanzeum (albiglutide) for injection [prescribing information]. Wilmington, DE: GlaxoSmithKline; June 2014.
35. Rendell M, Scott R, Ye J, et al. Harmony 2 year 3 results: albiglutide monotherapy in drug naïve patients with T2DM. Poster presented at the American Diabetes Association’s 74th Scientific Sessions; June 13-17, 2014; San Francisco, CA.
36. Ahrén B, Johnson SL, Stewart M, et al; for the HARMONY 3 Study Group. HARMONY 3: 104-week randomized, double-blind, placebo- and active-controlled trial assessing the efficacy and safety of albiglutide compared with placebo, sitagliptin, and glimepiride in patients with type 2 diabetes taking metformin. Diabetes Care. 2014;37:2141-2148.
37. GlaxoSmithKline. GSK announces data from five phase III studies of albiglutide, an investigational once-weekly treatment for type 2 diabetes. Press release. June 24, 2013. http://us.gsk.com/en-us/media/press-releases/2013/gsk-announces-data-from-five-phase-iii-studies-of-albiglutide-an-investigational-once-weekly-treatment-for-type-2-diabetes/. Accessed September 24, 2014.
38. Weissman PN, Carr MC, Ye J, et al. HARMONY 4: randomised clinical trial comparing once-weekly albiglutide and insulin glargine in patients with type 2 diabetes inadequately controlled with metformin with or without sulfonylurea. Diabetologia. 2014;57:2475-2484.
39. Rosenstock J, Fonseca VA, Gross JL, et al; for the Harmony 6 Study Group. Advancing basal insulin replacement in type 2 diabetes inadequately controlled with insulin glargine plus oral agents: a comparison of adding albiglutide, a weekly GLP-1 receptor agonist, versus thrice-daily prandial insulin lispro. Diabetes Care. 2014;37:2317-2325.
40. Reusch J, Stewart MW, Perkins CM, et al. Efficacy and safety of once-weekly glucagon-like peptide 1 receptor agonist albiglutide (HARMONY 1 trial): 52-week primary endpoint results from a randomized, double-blind, placebo-controlled trial in patients with type 2 diabetes mellitus not controlled on pioglitazone, with or without metformin. Diabetes Obes Metab. 2014;16:1257-1264.
41. Pratley RE, Nauck MA, Barnett AH, et al; for the HARMONY 7 study group. Once-weekly albiglutide versus once-daily liraglutide in patients with type 2 diabetes inadequately controlled on oral drugs (HARMONY 7): a randomised, open-label, multicentre, non-inferiority phase 3 study. Lancet Diabetes Endocrinol. 2014;2:289-297. Erratum in: Lancet Diabetes Endocrinol. 2014;2:e5.
42. Eli Lilly and Company. FDA approves Trulicity (dulaglutide), Lilly’s once-weekly therapy for adults with type 2 diabetes. Press release. September 18, 2014. https://investor.lilly.com/releasedetail.cfm?releaseid=871658. Accessed September 28, 2014.
43. US Food and Drug Administration. FDA approves Trulicity to treat type 2 diabetes. Press release. September 18, 2014. www.fda.gov/NewsEvents/Newsroom/Press Announcements/ucm415180.htm. Accessed September 28, 2014.
44. Dungan KM, Povedano ST, Forst T, et al. Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial. Lancet. 2014;384:1349-1357. Erratum in: Lancet. 2014;384:1348.
45. Umpierrez G, Tofé Povedano S, Pérez Manghi F, et al. Efficacy and safety of dulaglutide monotherapy versus metformin in type 2 diabetes in a randomized controlled trial (AWARD-3). Diabetes Care. 2014;37:2168-2176.
46. Rave K, Potocka E, Boss AH, et al. Pharmacokinetics and linear exposure of Afresa compared with the subcutaneous injection of regular human insulin. Diabetes Obes Metab. 2009;11:715-720. Erratum in: Diabetes Obes Metab. 2009;11:1175.
47. MannKind Corporation. Afrezza (insulin human [rDNA origin]) inhalation powder: an ultra-rapid acting insulin treatment to improve glycemic control in adult patients with diabetes mellitus. Briefing document. NDA 022472. April 1, 2014. www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM390865.pdf. Accessed September 29, 2014.
48. Rosenstock J, Lorber DL, Gnudi L, et al. Prandial inhaled insulin plus basal insulin glargine versus twice daily biaspart insulin for type 2 diabetes: a multicentre randomised trial. Lancet. 2010;375:2244-2253.
49. Santos Cavaiola T, Edelman S. Inhaled insulin: a breath of fresh air? A review of inhaled insulin. Clin Ther. 2014;36:1275-1289.
50. US Food and Drug Administration. FDA approves Afrezza to treat diabetes. Press release. June 27, 2014. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm403122.htm. Accessed September 29, 2014.
51. Afrezza (insulin human) inhalation powder [prescribing information]. Danbury, CT: MannKind Corporation; June 2014
52. Timmis AD, Chaitman BR, Crager M. Effects of ranolazine on exercise tolerance and HbA1c in patients with chronic angina and diabetes. Eur Heart J. 2006;27:42-48.
53. Chisholm JW, Goldfine AB, Dhalla AK, et al. Effect of ranolazine on A1C and glucose levels in hyperglycemic patients with non-ST elevation acute coronary syndrome. Diabetes Care. 2010;33:1163-1168.
54. Ning Y, Zhen W, Fu Z, et al. Ranolazine increases β-cell survival and improves glucose homeostasis in low-dose streptozotocin-induced diabetes in mice. J Pharmacol Exp Ther. 2011;337:50-58.
55. Vlassara H, Uribarri J, Cai W, et al. Effects of sevelamer on HbA1c, inflammation, and advanced glycation end products in diabetic kidney disease. Clin J Am Soc Nephrol. 2012;7:934-942.
56. Bays HE, Goldberg RB, Truitt KE, Jones MR. Colesevelam hydrochloride therapy in patients with type 2 diabetes mellitus treated with metformin: glucose and lipid effects. Arch Intern Med. 2008;168:1975-1983.
57. Brønden A, Hansen M, Sonne DP, et al. Sevelamer in a diabetologist’s perspective: a phosphate-binding resin with glucose-lowering potential. Diabetes Obes Metab. 2014 Jul 9 [Epub ahead of print].
58. Shantha GP, Kumar AA, Kahan S, Cheskin LJ. Association between glycosylated hemoglobin and intentional weight loss in overweight and obese patients with type 2 diabetes mellitus: a retrospective cohort study. Diabetes Educ. 2012;38:417-426.