Table 1.

Summary of current medications to treat prediabetes.23–40 T2DM: type 2 diabetes mellitus; MI: myocardial infarction; CVD: cardiovascular disease

MEDICATION (BRAND EXAMPLES)	MECHANISM OF ACTION	STUDY OUTCOMES	CARDIOPROTECTIVE FEATURES
Metformin (Glucophage, Glumetza, Fortamet)	Metformin reduces glucose production by inhibiting the mitochondrial respiratory chain in the liver and thus activating AMPK (5′ adenosine monophosphate-activated protein kinase, an enzyme that plays a role in cellular energy homeostasis); this enhances insulin sensitivity and lowers cAMP, which then reduces the expression of gluconeogenic enzymes. AMPK-independent effects of metformin include inhibition of fructose-1,6- bisphosphatase by AMP.23	Salpeter et al. (meta-analysis) 4,560 participants Metformin reduced the incidence of new onset diabetes by 40% (OR 0.6; CI, 0.5–0.8) with an absolute risk reduction of 6% (CI, 4–8) during a mean trial duration of 1.8 years.24 Ramachandran et al. (study of native Asian Indians) 531 participants A relative risk reduction in the incidence of T2DM was seen in both the lifestyle (28.5%), and metformin (26.4%) groups compared to control group.25	In Svensson et al., investigators studied the association between lowering HbA1c levels and cardiovascular events or death in patients with T2DM on metformin. This study included 24,752 metformin initiators. A mean follow-up of 2.6 years showed a lower risk of cardiovascular events and death when patients achieved an HbA1c of < 6.5% within 6 months of starting metformin.26 Further research will need to be applied to the prediabetes population, but a potential promising cardioprotective effect could also be attributed with metformin.
Pioglitazone (Actos)	Pioglitazone is a synthetic ligand for peroxisome proliferator-activated receptors (PPARs), which allows it to alter the transcription of genes that influence carbohydrate and lipid metabolism. Through its action at PPAR gamma 1 and 2, pioglitazone enhances insulin sensitivity. Additional benefits include an increase in glucose transporters 1 and 4 and enhanced insulin signaling.27	Defronzo et al. (ACT NOW Study) 602 participants Received either pioglitazone 30 mg once daily (increased to 45 mg/day after 1 month) or placebo. At 2.4 years, the incidence of diabetes was 2.1% with pioglitazone versus 7.6% with placebo.28	In the IRIS trail, Actos showed a reduced risk of stroke and MI. When comparing the treatment and control groups, the first event of MI to stroke was 9% vs 11.8%. In addition, T2DM incidence was 3.8% (treatment) vs 7.7% (placebo).29 This drug appears safe for the prediabetes population as long as they do not have an increased risk for bone fracture and complication from weight gain. Adverse side effects included an increase in bone fractures, weight gain of greater than 4.5 kg, and edema.
Acarbose (Precose)	Acarbose inhibits alpha-glucosidase and is most effective against glucoamylase, followed by sucrase, maltase, and dextranase. It is a diabetic agent that delays carbohydrate digestion and absorption in the intestine.30	Chiasson et al. (randomized trial) 1,429 participants 714 patients received acarbose (100 mg TID) and 715 received placebo. In the arcarbose group, 32% developed diabetes vs 42% in the placebo group (P = .0015, NNT 10). However, the acarbose group experienced increased flatulence and diarrhea, which could account for early treatment discontinuation.31	Further analysis of the Chiasson et al. study group showed that the risk of CVD in patients with impaired glucose tolerance was 2.2% in the treatment group vs 4.7% in the control group (0.15% vs 1.75% for MI, respectively). The differences were not as significant in other study areas.31
Liraglutide (Victoza)	Liraglutide is an incretin mimetic of the glucagon-like peptide-1 (GLP-1) receptor agonist and has similar biochemical features. The most important aspect of this therapy is that it increases insulin secretion in response to oral ingestion of carbohydrates while also slowing gastric emptying, suppressing glucagon secretion, reducing food intake, and promoting beta-cell proliferation.32	SCALE Obesity and Prediabetes trial (randomized controlled trial) 2,254 participants Prediabetic individuals with a body mass index (BMI) ⩾ 30 kg/m2 or ⩾ BMI 27 kg/m2 with comorbidities were recruited. Although the withdrawal rate was significantly high (47% in liraglutide group, 55% in placebo group), the data obtained at 160 weeks showed a decreased incidence of diabetes in the treatment vs placebo group (2% vs 6%; P < .0001, NNT 25) as well as increased normoglycemia (66% vs 36%; P < .0001, NNT 4), significant weight loss (6.1% vs 1.9%; P < .0001), and close rate of adverse events (15% vs 13%).33	The cardioprotective effect of liraglutide has not been fully studied in the prediabetes population. However, the LEADER trial showed significant cardiovascular outcomes in patients with T2DM after a 3.8-year follow-up. In the primary end point of first occurrence of death from cardiovascular causes, nonfatal MI, or nonfatal stroke, the study showed lower incidence in the treatment group vs control (13.0% vs 14.9%; HR 0.87; 95% CI, 0.78–0.97; P < .001 for noninferiority; P = .01 for superiority).34 Despite the high withdrawal rate, liraglutide shows promise in the treatment of prediabetes and cardiovascular health and will surely be studied with other agents in this class.
Orlistat (Alli, Xenical)	Orlistat is a semisynthetic derivative of lipstatin, a potent and selective inhibitor of gastric and pancreatic lipase. By binding to the serine residue of lipase, orlistat inhibits the hydrolysis of triglycerides, thus reducing the absorption of monoacylglycerides and free fatty acids.35	Torgerson et al. (randomized prospective trial) 3,305 participants Participants with BMI ⩾ 30 kg/m2 and normal or impaired glucose tolerance were randomized to either lifestyle + placebo or lifestyle + orlistat 120 mg 3 times/day. At 4 years, the incidence of T2DM in those receiving orlistat vs placebo was 6.2% vs 9% (P < .0032, NNT 36), mean weight loss was 5.8 vs 3 kg (P < .001), and progression from normal to impaired glucose tolerance was 27.6% vs 30.5%. The biggest limitation was the high dropout rate of 48% with orlistat and 66% with placebo; however, 99% of randomized patients were included in intention-to-treat analysis.36	No studies have been conducted to establish potential cardioprotective features of orlistat.
Phentermine/Topiramate (Qsymia)	Qsymia is one of the newer agents for treating obesity in the United States. Its properties consist of two known pharmacologic agents used in combination: Phentermine, a centrally acting appetite suppressant that uses sympathomimetic pathway while increasing metabolism, and Topiramate, with a proposed mechanism of neurotransmitter-mediated appetite suppression and enhanced satiety.37	Guo et al. (randomized controlled trials) 3,040 participants The authors pooled data from three RCTs (CONQUER, SEQUEL, and EQUIP). Patients who were overweight or obese without diabetes received 7.5 mg/46 mg vs 15 mg/92 mg of phentermine/topiramate vs placebo once daily for > 1 year. Patients were risk-stratified based on Cardiometabolic Disease Staging score. The 1-year risk of incidence of diabetes in the treatment vs placebo groups was 0.67% vs 1.51% for those at low risk, 2.37% vs 4.67% for those at moderate risk, and 6.29% vs 10.43% for those at high risk.38	No studies have been conducted to establish potential cardioprotective features of phentermine/topiramate. Teratogenic potentials and elevations in heart rate are possible concerns.
Lorcaserin (Belviq)	Lorcaserin is a small-molecule agonist of the 5-HT2C receptor designed to promote weight loss in obese/overweight patients as an adjunct to a reduced-calorie diet and increased physical activity. It acts on the 5-HT2C receptors in the central nervous system, mainly the hypothalamus, to suppress appetite.39	Nesto et al. (post hoc analysis) 6,136 participants The authors performed a post hoc analysis from two phase 3 studies (Bloom and Blossom) with the goal of monitoring weight and glycemic parameters for 52 weeks in the subpopulation of obese or overweight prediabetic patients. The percentage who progressed to T2DM in the lorcaserin vs placebo group was 3.2% vs 5.0% (P = .032) based on HbA1c but was insignificant based on fasting blood glucose.40 In addition, a greater percentage of lorcaserin vs placebo-treated patients reverted to euglycemia based on both HbA1c (40% vs 29.5%, P < .001) and FPG (52.4% vs 46.5%, P = .047)	No studies have been conducted to establish potential cardioprotective features of lorcaserin.