approximately a 1% reduction in hba1c when compared to placebo. glp-1 agonists also show improvement of beta-cell function, but this effect does not last after treatment is stopped. due to shorter duration of studies, this review did not allow for long-term positiver or negative effects to be assessed. exenatide (also exendin-4, marketed as byetta) is the first glp-1 agonist approved for the treatment of type 2 diabetes. exenatide is not an analogue of glp but rather a glp agonist. exenatide has only 53% homology with glp, which increases its resistance to degradation by dpp-4 and extends its half-life. a 2011 cochrane review showed a hba1c reduction of 0.20% more with exenatide 2 mg compared to insulin glargine, exenatide 10 µg twice daily, sitagliptin and pioglitazone. exenatide, together with liraglutide, led to greater weight loss than glucagon-like peptide analogues. liraglutide, a once-daily human analogue (97% homology), has been developed by novo nordisk under the brand name victoza. the product was approved by the european medicines agency (emea) on july 3, 2009, and by the u.s. food and drug administration (fda) on january 25, 2010. a 2011 cochrane review showed a hba1c reduction of 0.24% more with liraglutide 1.8 mg compared to insulin glargine, 0.33% more than exenatide 10 µg twice daily, sitagliptin and rosiglitazone. liraglutide, together with exenatide, led to greater weight loss than glucagon-like peptide analogues. taspoglutide is presently in phase iii clinical trials with hoffman-la roche. lixisenatide (lyxumia) sanofi aventis semaglutide (ozempic) (oral version is rybelsus) dulaglutide (trulicity) - once weekly albiglutide (tanzeum) - once weekly these agents may also cause a decrease in gastric motility, responsible for the common side-effect of nausea, which tends to subside with time. dipeptidyl peptidase-4 inhibitors main article: dipeptidyl peptidase-4 inhibitor glp-1 analogs resulted in weight loss and had more gastrointestinal side-effects, while in general dipeptidyl peptidase-4 (dpp-4) inhibitors were weight-neutral and increased risk for infection and headache, but both classes appear to present an alternative to other antidiabetic drugs. however, weight gain and/or hypoglycemia have been observed when dipeptidyl peptidase-4 inhibitors were used with sulfonylureas; effects on long-term health and morbidity rates are still unknown. dpp-4 inhibitors increase blood concentration of the incretin glp-1 by inhibiting its degradation by dpp-4. examples are: vildagliptin (galvus) eu approved 2008 sitagliptin (januvia) fda approved oct 2006 saxagliptin (onglyza) fda approved july 2009 linagliptin (tradjenta) fda approved may 2, 2011 alogliptin septagliptin teneligliptin gemigliptin (zemiglo) dpp-4 inhibitors lowered hemoglobin a1c values by 0.74%, comparable to other antidiabetic drugs. a result in one rct comprising 206 patients aged 65 or older (mean baseline hgba1c of 7.8%) receiving either 50 or 100 mg/d of sitagliptin was shown to reduce hba1c by 0.7% (combined result of both doses). a combined result of 5 rcts enlisting a total of 279 patients aged 65 or older (mean baseline hba1c of 8%) receiving 5 mg/d of saxagliptin was shown to reduce hba1c by 0.73%. a combined result of 5 rcts enlisting a total of 238 patients aged 65 or older (mean baseline hba1c of 8.6%) receiving 100 mg/d of vildagliptin was shown to reduce hba1c by 1.2%. another set of 6 combined rcts involving alogliptin (approved by fda in 2013) was shown to reduce hba1c by 0.73% in 455 patients aged 65 or older who received 12.5 or 25 mg/d of the medication. injectable amylin analogues amylin agonist analogues slow gastric emptying and suppress glucagon. they have all the incretins actions except stimulation of insulin secretion. as of 2007, pramlintide is the only clinically available amylin analogue. like insulin, it is administered by subcutaneous injection. the most frequent and severe adverse effect of pramlintide is nausea, which occurs mostly at the beginning of treatment and gradually reduces. typical reductions in a1c values are 0.5–1.0%. glycosurics main article: gliflozin sglt-2 inhibitors block the re-uptake of glucose in the renal tubules, promoting loss of glucose in the urine. this causes both mild weight loss, and a mild reduction in blood sugar levels with little risk of hypoglycemia. oral preparations may be available alone or in combination with other agents. along with glp-1 agonists, they are considered preferred second or third agents for type 2 diabetics sub-optimally controlled with metformin alone, according to most recent clinical practice guidelines. because they are taken by mouth, rather than injected (like glp-1 agonists), patients who are injection-averse may prefer these agents over the former. they may be considered first line in diabetic patients with cardiovascular disease, especially heart failure, as these medications have been shown to reduce the risk of hospitalization in patients with such comorbidities. because they are not available as generic medications, however, cost may limit their feasibility for many patients. furthermore, there has been growing evidence that the effectiveness and safety of this drug class could depend on genetic variability of the patients. examples include: dapagliflozin canagliflozin empagliflozin remogliflozin the side effects of sglt-2 inhibitors are derived directly from their mechanism of action; these include an increased risk of: ketoacidosis, urinary tract infections, candidal vulvovaginitis, and hypoglycemia. comparison the following table compares some common anti-diabetic agents, generalizing classes, although there may be substantial variation in individual drugs of each class. when the table makes a comparison such as "lower risk" or "more convenient" the comparison is with the other drugs on the table. comparison of anti-diabetic medication drug class mechanism of action advantages disadvantages sulfonylureas (glyburide, glimepiride, glipizide) stimulating insulin release by pancreatic beta cells by inhibiting the katp channel inexpensive fast onset of action no effect on blood pressure no detrimental effect on low-density lipoprotein lower risk of gastrointestinal side effects than metformin convenient dosing cause an average of 5–10 pounds weight gain increase the risk of hypoglycemia glyburide increases risk of hypoglycemia slightly more compared to glimepiride and glipizide metformin acts on the liver to reduce gluconeogenesis and causes a decrease in insulin resistance via increasing ampk signalling. associated with weight loss lower risk of hypoglycemia compared to other antidiabetics decreases low-density lipoprotein decreases triglycerides no effect on blood pressure lowered all-cause mortality in diabetics inexpensive higher risk of gastrointestinal side effects due to the risk of potentially fatal lactic acidosis, contraindicated in people with shock; with acute or chronic, moderate or severe kidney disease or at risk for impaired kidney function from intravenous dye; and with acute or chronic metabolic acidosis risk of lactic acidosis also is increased for people with unstable or acute heart failure, liver disease, or alcoholism, or who are recovering from major surgery increased risk of vitamin b12 deficiency metallic taste alpha-glucosidase inhibitors (acarbose, miglitol, voglibose) inhibit carbohydrate digestion in the small intestine by inhibiting enzymes that break down polysaccharides slightly lower risk of hypoglycemia compared to sulfonylureas associated with modest weight loss decreases triglycerides no detrimental effect on cholesterol less effective than most other diabetes pills in lowering glycated hemoglobin increased risk of gi side effects than other diabetes pills except metformin inconvenient dosing thiazolidinediones (pioglitazone, rosiglitazone) reduce insulin resistance by activating ppar-γ in fat and muscle lower the risk of hypoglycemia may slightly increase high-density lipoprotein rosiglitazone linked to decreased triglycerides convenient dosing increase the risk of heart failure cause an average of 5–10 pounds weight gain are associated with a higher risk of edema, anemia and bone fractures can increase low-density lipoprotein rosiglitazone has been linked to increased triglycerides and an increased risk of a heart attack pioglitazone has been linked to an increased risk of bladder cancer have a slower onset of action require monitoring for hepatotoxicity expensive sglt2 inhibitors generic many anti-diabetes drugs are available as generics. these include: sulfonylureas – glimepiride, glipizide, glyburide biguanides – metformin thiazolidinediones (tzd) – pioglitazone, actos generic alpha-glucosidase inhibitors – acarbose meglitinides – nateglinide combination of sulfonylureas plus metformin – known by generic names of the two drugs no generics are available for dipeptidyl peptidase-4 inhibitors (januvia, onglyza), the glifozins, the incretins and various combinations. alternative medicine the effect of ayurvedic treatments has been researched, however due to methodological flaws of studies it has not been possible to draw conclusion regarding efficacy of these treatments and there is insufficient evidence to recommend them.