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Newer oral and noninsulin therapies to treat type 2 diabetes mellitus

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SODIUM-GLUCOSE COTRANSPORTER-2 INHIBITORS

In 2013, canagliflozin became the first sodium-glucose cotransporter-2 (SGLT-2) inhibitor to be FDA-approved for treating patients with type 2 DM, followed in 2014 by dapagliflozin and empagliflozin. Several other drugs in this class are available outside the US or are currently undergoing clinical development, including ipragliflozin, luseogliflozin, tofogliflozin, and ertugliflozin. Currently, no SGLT-2 inhibitors are FDA-approved for type 1 DM, although they have been used off-label and in trials in this patient population.

Oral pharmacologic agents for treatment of type 2 diabetes mellitus

These drugs work by targeting the SGLT-2 protein in the kidney. In healthy individuals, 99% of filtered glucose is reabsorbed by the kidney with a filtered load of approximately 180 g/day.23 Glucosuria occurs with glucose concentrations above this threshold. In patients with type 2 DM, this threshold and the ability to reabsorb glucose is increased, contributing to hyperglycemia.24 Located in the proximal tubule, the SGLT-2 protein is responsible for 80% to 90% of glucose reabsorption, with SGLT-1 responsible for the other 10% to 20%.25 Inhibition of SGLT-2 reduces the renal threshold for glucose, thus leading to glucosuria and reduction in serum glucose levels.24Table 4 lists dosing regimens, HbA1c effects, and side-effect profiles for the SGLT-2 inhibitors.

As a monotherapy, SGLT-2 inhibitors significantly reduce HbA1c levels by 0.4% to 1.1% when compared with placebo.26–28 Reductions may be more significant in patients with HbA1c levels greater than 8.5%, and even more so in patients with HbA1c levels above 10%.29 When compared with other therapeutic options for type 2 DM, SGLT-2 inhibitors have efficacy similar to metformin, sitagliptin, and glipizide; however, some studies have shown superiority to glimepiride and sitagliptin at reducing HbA1c, depending on the dose and duration of treatment.26,27

The SGLT-2 inhibitors do not rely on insulin activity, allowing for their use at any stage of type 2 DM and in combination with other therapies, including insulin. As an add-on medication, SGLT-2 inhibitors reduce HbA1c by 0.5% to 0.7%.27,28 Given that the mechanism of action depends on the filtered load of glucose, they are less effective in patients with a reduced glomerular filtration rate (GFR).

The SGLT-2 inhibitors have bene­fits beyond that of glycemic control. Studies report weight loss of 1 to 3 kg, which is maintained up to 104 weeks.27–31 Sustained weight loss is secondary to glucosuria, which amounts to a caloric loss of 200 to 300 kcal/day.30 Also, SGLT-2 inhibitors lead to modest reductions in systolic and diastolic blood pressure of approximately 3 to 6 mm Hg and 1 to 2 mm Hg, respectively, due to their diuretic effect.27,31 The risk of hypoglycemia is low—similar to that of metformin and DPP-4 inhibitors—and only slightly higher than placebo when used as monotherapy.26,31 When added to sulfonylureas or insulin, however, the risk of hypoglycemia is increased.26,29

Meta-analyses of SGLT-2 inhibitors showed rates of death and other serious adverse effects were no different than placebo.26,27 A 2015 study on the CV safety of empagliflozin showed lower rates of CV death (38% relative risk [RR] reduction), lower rates of hospitalization due to heart failure (35% RR reduction), and lower rates of all-cause mortality (32% RR reduction) when compared with placebo, with no difference in nonfatal stroke and MI.32 CV safety trials for dapagliflozin and canagliflozin are ongoing, although some trials have shown an increased incidence in CV events in the first 30 days of treatment with canagliflozin.4

Common side effects include genital infections, such as vaginitis and balanitis, as well as urinary tract infections. In a 2013 meta-analysis,27 genital infections carried an odds ratio of 3.5 for SGLT-2 inhibitors compared with placebo, while urinary tract infections carried a 1.34 odds ratio. The increased risk of infection is thought to be secondary to glucosuria combined with immune dysfunction and altered glycosylation uroepithelium cells.30

During clinical trials, more cases of bladder cancer were diagnosed in patients on dapagliflozin than on placebo, leading to a delay in FDA approval. No causal relationship was established, but dapagliflozin is not recommended in patients with active bladder cancer.30

Treatment with SGLT-2 inhibitors can lead to a decrease in GFR, likely secondary to the diuretic effect. In patients with GFR greater than 60 mL/min, this decrease is transient. In patients with GFR below 60 mL/min (moderate renal impairment) who were treated with dapagliflozin, GFR did not quite return to baseline, and they did not show an improvement in HbA1c relative to placebo.33 Canagliflozin at a dose of 300 mg/day caused renal-related adverse events with GFR 45 to 60 mL/min, but a lower dose of 100 mg/day did not.27 A decrease in GFR also occurred in patients with chronic kidney disease treated with empagliflozin, which returned to baseline after discontinuing the drug.31 Despite these findings, renal function stabilizes in patients on SGLT-2 inhibitors over time, whereas it continues to decrease with placebo, suggesting there may be a renal protective effect.30 Their diuretic effect can also lead to volume depletion in patients at risk such as elderly patients or those already taking diuretics.31

Some studies have shown mild increases in low-density lipoprotein (LDL) and high-density lipoprotein (HDL) levels with no change in triglycerides, though long-term effects of this are unknown.31

There are case reports of euglycemic diabetic ketoacidosis occurring in patients with type 1 DM and type 2 DM treated with SGLT-2 inhibitors, which led the FDA in May 2015 to issue a warning that SGLT-2 inhibitors may increase the risk of ketoacidosis.34 There are several possible mechanisms for this increased risk. The SGLT-2 inhibitors may decrease renal clearance of ketones, stimulate glucagon secretion leading to hepatic ketogenesis, or suppress glucose-mediated insulin secretion leading practitioners to decrease insulin doses thus resulting in increased ketone production via lipolysis.34 More studies are needed, but patients and healthcare providers should be aware of potential euglycemic ketoacidosis associated with SGLT-2-inhibitors, as the lack of hyperglycemia can delay the diagnosis.

BILE ACID SEQUESTRANTS

Bile acid sequestrants have been used for years in hyperlipidemia to reduce LDL concentration; however, colesevelam is the only drug in this class approved (2009) for treating type 2 DM, after studies showed colesevelam improves glycemic control.35–37 Though several possibilities have been proposed, the precise mechanism of action for lowering blood glucose levels is unknown.35 Colesevelam is not absorbed systemically and does not affect endogenous insulin levels.4Table 4 lists dosing regimens, HbA1c effects, and side-effect profiles for colesevelam.

As monotherapy, studies have shown varying effectiveness in reducing HbA1c relative to placebo ranging from no statistical difference to 0.54% reduction.36,37 As an add-on to other diabetic medications, a Cochrane review of six randomized controlled trials showed a decrease in HbA1c by 0.3% to 0.5% and decrease in fasting glucose of 15 mg/dL.37 Additional benefits of colesevelam include low risk for hypoglycemia, weight neutrality, and reduction in LDL.4 No serious adverse events or deaths have been associated with colesevelam, including CV events; however, more trials on macrovascular outcomes are needed to clarify its side-effect profile.35

Common side effects include constipation, flatulence, and dyspepsia.35 Colesevelam has shown a statistically significant increase in triglycerides, so its use in patients with triglycerides above 500 mg/dL or with hypertriglyceridemia-induced pancreatitis is contraindicated.4 Caution should be used prior to starting treatment in patients with triglyceride levels above 200 mg/dL.35 Colesevelam is contraindicated in patients with a history of small-bowel obstruction, and caution is recommended in patients with decreased gastric motility. This drug may reduce absorption of fat-soluble vitamins and some medications.4

Although further research into the long-term effects of colesevelam is needed, its relatively good safety profile makes it a reasonable choice in diabetic patients with hyperlipidemia not controlled with statins.

DOPAMINE-RECEPTOR AGONIST

Bromocriptine, a dopamine-receptor agonist, was FDA-approved for the treatment of Parkinson disease, hyperprolactinemia, and acromegaly in the 1970s. In 2009, a quick-release formulation of bromocriptine (bromocriptine QR) was approved for treatment of type 2 DM. Table 4 lists dosing regimens, HbA1c effects, and side-effect profiles for bromocriptine.

The precise mechanism of action is unclear, but an American Association of Clinical Endocrinologists expert panel recommendation suggests that it may lower glucose levels by improving hypothalamic-mediated, postprandial insulin sensitivity via increasing morning dopaminergic activity (decreased in patients with type 2 DM) and by reducing hypothalamic adrenergic tone.38 It is not currently recommended as monotherapy, although a study of 154 patients showed monotherapy reduced HbA1c by 0.55%.39 When added to other diabetic medications, it reduced HbA1c by 0.4% to 0.7%.4,38

Bromocriptine QR is weight neutral and carries a low risk of hypoglycemia.4 A safety trial with 3,095 patients showed fewer adverse CV events in patients treated with bromocriptine QR compared with placebo, which may be secondary to reduced sympathetic tone or to reduced systemic inflammation.40 Some studies have shown reductions in blood pressure, free fatty acid levels, and triglycerides, with no change in LDL or HDL.38

Common side effects include nausea, headache, dizziness, diarrhea, and fatigue. Administration is recommended with food to reduce GI side effects. It is contraindicated in women who are nursing and those with syncopal migraines. Furthermore, it may be prudent to avoid this medication in patients with a history of psychosis, those currently treated with dopamine agonists or antagonists, or those at risk for hypotension.4

CONCLUSION

The pathophysiology of type 2 DM involves at least seven organs and tissues—the brain, liver, pancreas, intestines, kidneys, fat, and muscle—and no single medication addresses all seven of them. Most patients require more than one medication to adequately treat their diabetes, making availability and development of drugs with unique and complementary mechanisms of action of paramount importance. The medications described here—DPP-4 inhibitors, GLP-1 agonists, SGLT-2 inhibitors, colesevelam, and bromocriptine QR—provide therapeutic options with novel mechanisms of action, all while avoiding weight gain and providing a low risk of hypoglycemia. While not appropriate for every patient, these medications give healthcare providers additional options to individualize treatment and optimize care for patients.


Acknowledgments. The authors gratefully thank Julie Benke-Bennett for assistance with manuscript formatting and transcription. The contents of this article do not represent the views of the Department of Veterans Affairs or the United States Government.

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