The results from clinical trials have been mixed. Most clinical trials have indicated the risk for bladder cancer in patients on pioglitazone is no different than for patients given a placebo.

However, it is recommended that it should not be used in patients with active bladder cancer and the benefits of glycemic control versus unknown risks for cancer recurrence with piaglitazone should be weighed in patients with a prior history of bladder cancer.

The triglyceride lowering effect of pioglitazone is greater than that of rosiglitazone, presumably due to its stimulatory effects on PPAR-α. A similar effect has not been observed in men Habib et al, Management of heart failure should be initiated, and discontinuation or dose reduction of Actos must be considered in such cases.

com Actos ®. Acarbose Trade Names: Precose ®. inhibits the activity of enzymes required to break carbohydrates down into simple sugars within the intestine.

Miglitol Glyset ® is six times more potent in inhibiting sucrase than acarbose. Non-FDA approved: potentially beneficial in Type 1 diabetes. Acarabose has been found to decrease the amplitude of postprandial excursions and lower Hb A1c values in Type 1 diabetics by ~0. not very efficacious at lowering A1c levels when used as monotherapy.

poorly absorbed. Should be taken with the first bite of breakfast, lunch, and dinner. the hypoglycemic goal in diabetics typically cannot be met with these drugs alone. bloating, gas, abdominal discomfort, diarrhea.

these side effects develop due to the fermenting of undigested carbohydrate in the colon to fatty acids, with resultant release of gas. McCulloch DK : Alpha-glucosidase inhibitors and lipase inhibitors for treatment of diabetes mellitus.

In: UpToDate. Basow, DS Ed , UpToDate, Waltham, MA. com Precose ®. Miglitol Pharmacology:. com Glyset ®. Sitagliptin Trade Name: Januvia ®. An inhibitor of dipeptidyl peptidase-4 DPP-4 , a protease that degrades the incretin GLP Incretins are hormones released from the GI tract in response to nutrient ingestion.

Incretins potentiate glucose-stimulated insulin secretion from beta cells in the pancreas. As a result of inhibiting DPP-4, increased or prolonged GLP-1 levels are able to potentiate the secretion of insulin by the pancreas. The effect produced by DPP-4 inhibitors is dependent on endogenous GLP-1 levels, and produce a modest effect on GLP-1 activity compared to giving GLP-1 receptor agonists hence DPP-4 inhibitors do not have the same impact to produce weight loss as GLP-1 agonists.

Sitagliptin works ONLY when blood sugar is elevated, to address diminished insulin levels due to β-cell dysfunction and uncontrolled production of glucose by the liver due to pancreatic α-cell and β-cell dysfunction. FDA approved: Type II diabetes - monotherapy or combination therapy.

Because it does not work when your blood sugar is low, it is unlikely to produce dangerous levels of hypoglycemia. diabetic ketoacidosis it would not be effective for treating this condition. an association between DPP-4 inhibitors and heart failure has been observed for two members of this drug class in patients with type 2 DM and atherosclerosis.

The risk vs benefit of these agents should be considered before prescribing these drugs to patients at risk for CHF. pancreatitis - there have been post-marketing reports of acute pancreatitis. Patients should be observed carefully for signs and symptoms of pancreatitis e.

stomach pain , and treatment discontinued if it is suspected. A similar increased risk for heart failure was also observed for alogliptin 3. The risk may be particularly high in patients with underlying heart failure or kidney disease.

Clinicians should consider taking patients off these drugs if they develop signs of heart failure. Charbonnel B, Cariou B : Pharmacological management of type 2 diabetes: the potential of incretin-based therapies.

Diabetes, Obesity and Metabolism Dungan K, DeSantis : Dipeptidyl peptidase DPP-4 inhibitors for the treatment of type 2 diabetes mellitus. In: UpToDate Basow, DS Ed , Waltham, MA. Hansotia T, Drucker DJ : Therapeutic Potential of the DPP-4 Inhibitors. FDA Patient Information Sheet.

com Januvia ®. Saxagliptin Trade Name: Onglyza ®. a DPP-4 inhibitor, similar to Sitagliptin. com Onglyza ®. a synthetic analog of glucagon-like-polypeptide 1 GLP-1 that is resistant to breakdown by DPP-IV.

It has multiple actions including:. this effect is mediated by reduced parasympathetic tone, and undergoes tachyphylaxis with chronic GLP-1 stimulation.

potentiation of glucose-mediated insulin secretion. because the GLP-1 effect is glucose-dependent there is more insulin release when glucose levels are elevated, but less effect when glucose levels are normal , GLP-1 agonists have a lower risk for producing hypoglycemia compared to sulfonylureas that chronically stimulate insulin release, independent of glucose concentration.

suppression of postprandial glucagon release. reduction in liver fat content. liver fat accumulation is correlated with several metabolic disturbances including low HDL and elevated triglyceride levels Tushuizen et al, reaches a peak concentration in ~2 hours, with a duration of action of up to 10 hours.

exenatide incorporated into an extended-release microsphere formulation once weekly injection. there is an increased risk of hypoglycemia when exenatide is used with a sulfonylurea. The dose of the sulfonylurea may need to be reduced if hypoglycemia occurs when combined with exenatide.

When initiating patients on Byetta, watch for signs and symptoms of pancreatitis including persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting.

Discontinue Byetta if pancreatitis is suspected. The discovery of DPP-IV-resitant GLP-1 analogs was pursued in parallel with the discovery of DPP-IV inhibitors. Exenatide is a synthetic form of a protein originally isolated from the saliva of the Gila monster poisonous lizard that lives in the deserts of Arizona.

Dungan K, DeSantis A : Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes mellitus. Guo XH : The value of short- and long-acting glucagon-like peptide-1 agonists in the management of type 2 diabetes mellitus: experience with exenatide.

Curr Med Res Opin. Holt RIG, Hanley NA : Essential Endocrinology and Diabetes. Blackwell Publishing. ISBN: Madsbad S : Review of head-to-head comparisons of glucagon-like peptide-1 receptor agonists.

Diabetes Obes Metab. Meier JJ : GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus.

Nat Rev Endocrinol. Nauck MA et al : Rapid tachyphylaxis of the glucagon-like peptide 1-induced deceleration of gastric emptying in humans. Diabetes — Tushuizen ME et al : Incretin mimetics as a novel therapeutic option for hepatic steatosis.

Liver Int 26 8 : Wettergren A et al : Glucagon-like peptide-1 inhibits gastropancreatic function by inhibiting central parasympathetic outflow. Am J Physiol. com Byetta ®. com Byduron ® extended release formulation.

Liraglutide Trade Name: Victoza ®. mechanism of action is the same as exenatide. an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus. to reduce the risk of major adverse cardiovascular events cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke in adults with type 2 diabetes mellitus and established cardiovascular disease.

Most common : nausea, diarrhea, vomiting similar to exenatide. Black Box Warning: RISK OF THYROID C-CELL TUMORS Liraglutide has been found to cause a dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice.

Whether it produces similar carcinogenic effects in humans is unknown, and can not be ruled out with available data. Liraglutide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 MEN 2.

com Victoza ®. Pramlintide injection Trade Name: Symlin ®. CNS-mediated hypothalamic mediated anorectic effects to decrease food intake; mediated by stimulation of central amylin receptors, which are different from the receptors mediating the anorectic effects of GLP suppresses glucagon secretion from pancreatic α cells by a neuroendocrine pathway that is not well understood; this results in suppression of endogenous glucose output from the liver Ryan et al, pramlintide's multiple effects reduce postprandial rises in glucose when injected 3 times a day.

it has been reported to reduce HbA1c by ~0. Type 1 diabetes - as an adjunct treatment in patients who use mealtime insulin therapy but have failed to achieve desired glucose control despite optimal insulin therapy. a similar reduction in secretagogue doses may also be necessary in patients with Type 2 diabetes.

Modest weight loss ~ 1 kg. Amylin is a small peptide hormone that is normally co-released with insulin into the bloodstream by β-cells, in response to meals. Endogenous amylin is not suitable for pharmacologic use because it is insoluble and aggregates in solution.

Substitution of a few amino acids of amylin results in pramlintide, a stable, soluble synthetic analog of amylin Ryan et al, In patients with Type 1 or Type 2 diabetes β-cells are either absent or dysfunctional, resulting in decreased secretion of both insulin and amylin in response to food.

Dungan K : Amylin analogs for the treatment of diabetes mellitus. In: UpToDate, Basow, DS Ed , Waltham, MA. Ryan GJ, Jobe LJ, Martin R : Pramlintide in the treatment of Type 1 and Type 2 diabetes mellitus.

Clin Therap 27 10 com Symlin ®. Canagliflozin Invokana ® Trade Names: Invokana ®. Drug Class: Anti-diabetic drug, Hypoglycemic, SGLT-2 inhibitor. Inhibits the Na-glucose co-transporter 2 SGLT-2 in the kidney to reduce glucose reabsorption, resulting in increased urinary glucose excretion, and lower plasma glucose.

Adjunct therapy in patients not meeting their glycemic goal with other agents e. To reduce the risk of cardiovascular death in adult patients with type 2 diabetes mellitus and established cardiovascular disease. Severe renal impairment - its efficacy depends on renal function. NOT recommended for treatment of type 1 diabetes or treatment of diabetic ketoacidosis.

Weight loss potential kg. Glucose loss acts as an osmotic diuretic which is the cause for polyuria in type diabetes. While rapid weight loss may be beneficial in some patients, the loss of glucose can also result in dehydration and tiredness.

Low incidence of hypoglycemia - when used as monotherapy or with metformin. Decrease in blood pressure by mm Hg in patients with hypertension ; due to its effects as an osmotic diuretic with associated volume loss. More long-term studies with multiple SGLT-2 inhibitors is needed. Urinary Tract Infections the most common side effect for this drug class ; increased glucose in the urine can stimulate the growth of microorganisms e.

yeast, bacteria. Serious infections of the genital area. The FDA has published a Drug Safety Warning concerning SGLT-2 inhibitors having an associated increased risk for developing serious genital infections, including necrotizing fasciitis of the perineum FDA safety warning, ; Kumar et al ; O'Malley, ,.

the mechanisms by which SGLT-2 inhibitors affect bone are poorly understood, in part due to the complex biology of bone, and multiple comorbidities in diabetic patients that can affect bone health.

Increased risk for lower limb amputation. Use of SGLT-2 inhibitors has been associated with a ~2-fold increased risk for limb amputation when compared with the use of sulfonylureas, metformin, and thiazolidinediones Chang et al, The mechanisms by which SGLT-2 inhibitors increase the risk for lower limb amputation is poorly understood.

It has been speculated that by promoting glucosuria and volume depletion, they can cause hemo-concentration in patients that are already at increased risk for peripheral artery disease, resulting in an increased risk for amputation Das et al, ; Chang et al, These studies were conducted with patients at high risk of heart problems, and compared the effects of canagliflozin with placebo.

Canagliflozin was one of the most commonly prescribed diabetes medications in and heavily advertised too. Blau JE, Taylor SI : Adverse effects of SGLT2 inhibitors on bone health. Nature Reviews Nephrology.

Chang H-Y et al : Association Between Sodium-Glucose Cotransporter 2 Inhibitors and Lower Extremity Amputation Among Patients With Type 2 Diabetes.

JAMA Intern Med. Das L et al : Unmasking and aggravation of polycythemia vera by canagliflozin. Case Report. Diabetic Medicine. Karagiannis T et al : Canagliflozin in the treatment of type 2 diabetes: an evidence-based review of its place in therapy.

Core Evid. Kumar S et al : Fournier's gangrene in a man on empagliflozin for treatment of Type 2 diabetes. Kuriyama C et al : Analysis of the Effect of Canagliflozin on Renal Glucose Reabsorption and Progression of Hyperglycemia in Zucker Diabetic Fatty Rats. J Pharmacol Exp Ther McCulloch DK : Management of persistent hyperglycemia in type 2 diabetes mellitus.

Neal B et al : Rationale, design and baseline characteristics of the CANagliflozin cardioVascular Assessment Study-Renal CANVAS-R : A randomized, placebo-controlled trial. O'Malley OA : Sodium-Glucose Cotransporter 2 Inhibitors and Fournier Gangrene.

A Rare and Lethal Adverse Event. Clin Nurse Spec. com Invokana ®. Wikipedia canagliflozin. Wikipedia SLC5A2 gene.

The reported frequency of lactic acidosis in all patients is three cases per , patient-years. Metformin should not be used in patients with elevated serum creatinine levels, specifically, 1. In patients undergoing contrast studies, metformin therapy should be withheld for approximately 48 hours following the procedure or until it has been determined that renal function has returned to baseline.

Other situations in which metformin therapy should be avoided include cardiogenic or septic shock, congestive heart failure that requires pharmacologic therapy, severe liver disease, pulmonary insufficiency with hypoxemia or severe tissue hypoperfusion. Metformin is unusual among the oral antidiabetic drugs in that therapy has been associated with a lack of weight gain and even weight loss in some overweight patients.

Metformin therapy should be initiated at mg twice daily with meals and can be increased by mg maximum dosage of 2, mg daily at two-week intervals to minimize gastrointestinal side effects. A new extended release formulation of metformin was recently introduced to the market Glucophage XR , allowing a more convenient once-daily dosing regimen.

Until recently, the agents in this drug class approved by the U. Food and Drug Administration FDA included troglitazone Rezulin , rosiglitazone Avandia and pioglitazone Actos.

Subsequently, in March , the FDA asked the manufacturer Parke-Davis, Warner-Lambert of troglitazone, the first agent in this class to receive labeling approval, to remove the product from the market.

This request occurred following more than 60 reports of severe liver toxicity in patients taking this agent. A majority of the data reporting the efficacy of this class comes from studies with troglitazone, although results from more recent studies with the newer agents rosiglitazone and pioglitazone demonstrate similar properties.

These agents have a notable effect on improving insulin resistance, particularly when used in combination with other antidiabetic drugs, but have no effect on insulin secretion.

Monotherapy with these agents has been associated with a 0. Results from studies with troglitazone consistently show a decrease in triglyceride levels—in some cases by as much as 33 percent.

Patients treated with pioglitazone have displayed mean decreases in triglyceride levels, mean increases in HDL cholesterol levels, and no consistent mean changes in LDL and total cholesterol levels.

Because these agents do not increase insulin secretion, hypoglycemia does not pose a risk when thiazolidinediones are taken as monotherapy.

Significant weight gain has been reported with all three agents. The thiazolidinediones are relatively safe in patients with impaired renal function because they are highly metabolized by the liver and excreted in the feces; however, caution should be used in patients with hepatic dysfunction because troglitazone and its metabolites have been shown to accumulate in this setting.

The manufacturers recommend that these agents not be prescribed for patients with serum transaminase levels that exceed 2. Mild to moderate edema has been reported in 5 to 7 percent of patients treated with rosiglitazone and pioglitazone. The use of thiazolidinediones should be avoided in these patients.

As referred to earlier, of greatest concern are the reports of an idiosyncratic drug reaction with troglitazone. This reaction is initially characterized by increased serum transaminase levels, which in some cases progressed to hepatitis, hepatic failure and death.

Preliminary attempts before troglitazone was withdrawn from the market in March to prevent such incidents included a request by the FDA that Parke-Davis strengthen the drug's labeling and require stringent monitoring of transaminase levels in patients taking this agent.

In March , the FDA's Endocrine and Metabolic Drugs Advisory Committee reviewed the status of troglitazone and the potential toxicities and recommended continued availability in a select group of patients: those who are not well controlled with other antidiabetic agents.

Since then, it has been determined that patients requiring the use of an insulin sensitizer should be treated with one of the alternative agents. Although results from pre-marketing trials revealed no evidence of hepatotoxicity with the newer agents rosiglitazone and pioglitazone , two recent case reports demonstrated that rosiglitazone may be associated with hepatic failure following just 14 days of therapy, although a true cause-and-effect relationship has not been established.

The FDA recommends that serum transaminase levels be monitored every other month for the first year in all patients receiving a thiazolidinedione. Following one year of therapy with the newer agents, the incidence of serum transaminase elevations has been reported to be similar to placebo.

The time to achieve a desired effect with the thiazolidinediones is somewhat longer than the other classes of hypoglycemic agents discussed thus far.

Intervals of at least three to four weeks should be allowed before increasing the dosage of these agents. Smaller dosages can be initiated if used as part of a combination regimen with a sulfonylurea or a sulfonylurea plus metformin. In patients receiving insulin therapy, the addition of a thiazolidinedione has resulted in significant reductions in daily insulin requirements.

Acarbose Precose and miglitol Glycet are the two agents available in this class. Alpha-glucosidase inhibitors act by inhibiting the enzyme alpha-glucosidase found in the brush border cells that line the small intestine, which cleaves more complex carbohydrates into sugars.

Because they inhibit the breakdown and subsequent absorption of carbohydrates dextrins, maltose, sucrose and starch; no effect on glucose from the gut following meals, the largest impact of these drugs is on postprandial hyperglycemia.

Their effect on FPG levels is modest. They have been associated with a reduction in HbA 1c by 0. The most bothersome side effects observed with these agents are gastrointestinal, including abdominal discomfort, bloating, flatulence and diarrhea but are reversible with discontinuation.

Therapy with acarbose has been linked to elevations in serum transaminase levels and the use of this agent is contraindicated in patients with liver cirrhosis. Likewise, concentrations of the alpha-glucosidase inhibitors have been shown to increase proportionally to the degree of renal dysfunction and their use in patients with a serum creatinine level more than 2.

Other contraindications include patients with inflammatory bowel disease or a history of bowel obstruction. Therapy should be initiated with the lowest effective dose and titrated slowly over intervals of two to four weeks. Patients should be instructed to take this medication with food.

For maximum efficacy, the dietary carbohydrate intake should exceed 50 percent. Although hypoglycemia is not typically associated with monotherapy with the alpha-glucosidase inhibitors, it can occur in combination with other drugs. It is important, therefore, to inform patients that the traditional treatment for hypoglycemia may be blocked while using this therapy and to consume only glucose.

If adequate control is not obtained with the use of a single agent, combination therapy is an option Figure 1. Several of the available oral agents have been studied in combination and have been shown to further improve glycemic control when compared to monotherapy.

Reasonable combinations of agents include a sulfonylurea plus metformin, a sulfonylurea plus an alpha-glucosidase inhibitor, a sulfonylurea plus a thiazolidinedione, metformin plus repaglinide, biguanide plus alpha-glucosidase inhibitor, and metformin plus a thiazolidinedione.

A newer formulation Glucovance combines glyburide and metformin in one tablet, allowing a more convenient dosing schedule. Some physicians advocate therapy combining three oral agents, sulfonylurea, metformin, thiazolidinedione or sulfonylurea, metformin, alpha-glucosidase inhibitor , although this approach has not been extensively studied.

Several other combinations have recently been reviewed. Harris MI, Flegal KM, Cowie CC, Eberhardt MS, Goldstein DE, Little RR, etal. Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U. S adults. The Third National Health and Nutrition Examination Survey, — Diabetes Care.

Nathan DM, Kitrick C, Larkin M, Schaffran R, Singer DE. Glycemic control in diabetes mellitus: have changes in therapy made a difference?.

Am J Med. United Kingdom Prospective Diabetes Study UKPDS Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes UKPDS DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus.

Ann Intern Med. Feinglos MN, Bethel MA. Treatment of type 2 diabetes mellitus. Med Clin North Am. American Diabetes Association. The pharmacological treatment of hyperglycemia in NIDDM. Berger M, Jorgens V, Muhlhauser I. Rationale for the use of insulin therapy alone as the pharmacological treatment of type 2 diabetes.

Luna B, Hughes AT, Feinglos MN. The use of insulin secretagogues in the treatment of type 2 diabetes. Prim Care. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Therapy of type 2 diabetes, cardiovascular death, and the UGDP. Am Heart J. Meinert CL, Knatterud GL, Prout TE, Klimt CR.

A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. Mortality results. Gerich JE. Oral hypoglycemic agents. N Engl J Med. DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus.

The Multicenter Metformin Study Group. Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE. The metabolic effects of metformin in non-insulin-dependent diabetes mellitus.

Hermann LS, Schersten B, Bitzen PO, Kjellstrom T, Lindgarde F, Melander A. Therapeutic comparison of metformin and sulfonylurea, alone and in various combinations. A double-blind controlled study. Campbell IW, Menzies DG, Chalmers J, McBain AM, Brown IR.

One year comparative trial of metformin and glipizide in type 2 diabetes mellitus. Diabetes Metab. Dornan TL, Heller SR, Peck GM, Tattersall RB. Double-blind evaluation of efficacy and tolerability of metformin in NIDDM. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes UKPDS Nolan JJ, Jones NP, Patwardhan R, Deacon LF.

Rosiglitazone taken once daily provides effective glycaemic control in patients with type 2 diabetes mellitus. Diabet Med. Raskin P, Rappaport EB, Cole ST, Yan Y, Patwardhan R, Freed MI. Rosiglitazone short-term monotherapy lowers fasting and post-prandial glucose in patients with type II diabetes.

Saltiel AR, Olefsky JM.

Natiglinide Starlix is a very short-acting glucose lowering drug whose mode of action is similar to the sulfonylureas and is nearing approval by the FDA. The first phase of insulin release is brisk, of short duration and occurs within minutes of ingesting food.

The usual dose is mg before meals. Metformin has been used in Europe for over thirty years, and has been available in the United States since March It is effective only in the presence of insulin but, in contrast to sulfonylureas, it does not directly stimulate insulin secretion.

Its major effect is to increase insulin action. How metformin increases insulin action is not known but it is known to affect many tissues.

One important effect appears to be suppression of glucose output from the liver. Clinical Use — Metformin is most often used in patients with type 2 diabetes who are obese, because it promotes modest weight reduction or at least weight stabilization. This is in contrast to the increased appetite and weight gain often induced by insulin and sulfonylureas.

Metformin typically lowers fasting blood glucose concentrations by approximately 20 percent, a response similar to that achieved with a sulfonylurea. Metformin given in combination with a sulfonylurea lowers blood glucose concentrations more than either drug alone. In addition to causing modest weight loss, metformin has two other advantages as compared with sulfonylureas.

There are, however, two disadvantages to metformin: the risk for lactic acidosis described below and its prominent gastrointestinal side effects. Pharmacokinetics — Metformin should be taken with meals and should be started at a low dose to avoid intestinal side effects.

Side Effects — The most common side effects of metformin are gastrointestinal, including a metallic taste in the mouth, mild anorexia, nausea, abdominal discomfort, and diarrhea. These symptoms are usually mild, transient, and reversible after dose reduction or discontinuation of the drug.

A rare problem is lactic acidosis, which may be fatal in as many as one-half of cases. The risk is much less than with another biguanide, phenformin, which was withdrawn from use in the United States in the s because of this complication.

Serious lactic acid accumulation usually occurs only in the presence of a predisposing conditions including:. A potential drug interaction exists between metformin and cimetidine Tagamet resulting in an increase in metformin blood levels.

This interaction could increase the risk of hypoglycemia in patients taking metformin plus a sulfonylurea or insulin, and could increase the risk of lactic acidosis in those with impaired renal function.

These risks could increase now that cimetidine is available over-the-counter. Other H2-blockers are less likely to cause this problem. The manufacturer also recommends discontinuing metformin for 48 hours after any radiologic procedure involving the administration of iodinated contrast material into the blood.

The rationale for this recommendation is to avoid the potential for high plasma metformin concentrations if the patient develops contrast-induced acute renal failure. The thiazolidinediones such as Avandia Rosiglitazone and Actos Pioglitazone reverse insulin resistance by acting on muscle, fat and to a lesser extent liver to increase glucose utilization and diminish glucose production.

The mechanism by which the thiazolidinediones increase insulin action is not well understood but they may be acting by redistributing fat from the visceral compartment to the subcutaneous compartment.

We know that visceral fat is associated with insulin resistance. The HbA1c value in the troglitazone group fell from 8. Thiazolidinediones are also effective when given in combination with metformin, although they are not currently approved for this purpose.

Safety — There have been reports of severe liver injury in small numbers of patients receiving Rezulin and this product has now been removed from the market. The important goal of the treatment of T2DM is to maintain blood glucose management and decrease the incidence of T2DM complications especially CVD Rosenstock et al.

HbA 1c is a vital indicator of blood glucose management and diabetes complications American, Metformin has been one of the most popular oral hypoglycemic drugs for the past 60 years, and is still the first-line drug for the initial therapy of most T2DM patients Sanchez-Rangel and Inzucchi, ; Flory and Lipska, ; Feng et al.

In recent years, the approval of a large number of new hypoglycemic drugs has brought more options for the therapy of T2DM patients, including DPP-4i, GLP-1RA, and SGLT-2i.

To fully understand the role of new hypoglycemic drugs in T2DM including prediabetes , it is necessary to conduct a comprehensive study of their antidiabetic capacity, additional benefits and risks, how to use for maximum potential, and their role in new drug development. SGLT-2i have a special hypoglycemic pathway, which does not rely on insulin, but reduces the glucose reabsorption by the proximal renal tubules, resulting in increased excretion of glucose from the urine, thereby controlling the blood glucose of patients with T2DM Das et al.

In the case of hyperglycemia, this inhibitory effect of glucose reabsorption is more obvious Riddle, GLP-1 receptor exists in a variety of tissues and cells, including brain, kidney, cardiomyocytes, and vascular endothelial cells Ban et al.

When blood glucose level is high, GLP-1RA activate GLP-1 receptor to stimulate pancreatic β cells to secrete insulin while reduce the secretion of glucagon from pancreatic α cells, thereby improving blood glucose levels.

When blood glucose level is low, GLP-1RA have no stimulating effect on insulin secretion, which helps decrease the risk of hypoglycemia Farilla et al. Considering the overlapping hypoglycemic mechanisms, it is recommended to discontinue DPP-4i when T2DM patients are intensified from DPP-4i to GLP-1 RA American Diabetes Association Professional Practice et al.

We list combination therapy trials involving new hypoglycemic drugs mostly traditional stepwise therapy in Supplementary Table S1 and Table 1 , which are summarized in terms of HbA 1c and weight management. There are many clinical studies of GLP-1RA in T2DM, and the efficacy of different GLP-1RA is different Supplementary Table S1.

The current evidence suggests that 1. In addition, semaglutide 1. Further, dulaglutide 1. Finally, exenatide 2 mg once per week is better than exenatide 10 μg twice-daily Wysham et al. TABLE 1. Table 1 lists blood glucose and weight management differences in other cases, including: GLP-1RA vs.

DPP-4i, GLP-1RA vs. glimepiride or insulin. The main advantages of new hypoglycemic drugs are their significant hypoglycemic effect and low incidence of hypoglycemic adverse reactions, especially when compared with insulin and sulfonylureas.

In addition, SGLT2i and GLP-1RA have obvious cardio-renal protective effects, and DPP-4i has advantages in patients who do not need to lose weight. Recently, the meta-analysis of medium to high certainty evidence by Kanie et al. Unlike SGLT-2i, GLP-1RA does not have a clinical study with kidney as the main outcome.

The ongoing FLOW trial has studied the effects of semaglutide injection on the renal outcome of T2DM patients with CKD, and will provide further treatment and mechanism insights NCT The effect of GLP-1RA on the progression of CKD needs to be further studied Brown et al.

In fact, in patients with non-T2DM, SGLT-2i, and GLP-1RA also have convincing data to support their cardiac benefits. For example, the findings of the DAPA-HF study showed that dapagliflozin lowered the risk of worsening HF and death due to cardiovascular events in non-diabetic patients with HF reduced ejection fraction, HFrEF HR 0.

Similarly, the results of the EMPEROR-Reduced study showed that empagliflozin reduced the risk of hospitalization or death due to HF in the empagliflozin group was lower, regardless of whether diabetes was present or not HR 0.

There has been little progress in the treatment of patients with HF preserved ejection fraction, HFpEF , and SGLT-2i has broad prospects for the therapy of HFpEF. For example, the results of the EMPEROR-Preserved study indicated that empagliflozin decreased the risk of hospitalization or death due to worsening HF HR 0.

Similarly, dapagliflozin treatment for 12 weeks obviously improved the symptoms, motor function, and physical limitations reported by patients with chronic HFpEF, and it was well tolerated NCT Nassif et al.

The beneficial effects of empagliflozin and dapagliflozin are also not related to diabetes status Anker et al. In addition, in the SOLOIST-WHF study all patients have T2DM , the benefits of sotagliflozin in patients with HFrEF and HFpEF are consistent Bhatt et al.

The ongoing DELIVER trial NCT will further determine the effect of dapagliflozin added to the routine therapy of patients with HF reserved or slightly reduced ejection fraction Solomon et al. TABLE 2. The effect of SGLT-2i on cardiorenal outcome and GLP-1RA on cardiovascular outcome.

Liraglutide GLP-1RA has been approved for weight management in many countries Brown et al. Similarly, semaglutide is also being assessed as a drug for the therapy of obesity Figure 1B. For example, among non-diabetic adult overweight or obese participants, after 68 weeks of treatment, the weight change of 2.

In addition, subjects in the semaglutide group had greater improvements in cardiovascular and metabolic risk factors Wilding et al. SGLT-2i can reduce weight approximately 2 kg , systolic blood pressure SBP approximately 2. Similarly, GLP-1RA have shown consistent efficacy in blood pressure 2—3 mmHg Brown et al.

These effects of improving cardiovascular metabolic risk factors provide a theoretical basis for GLP-1RA treatment in patients with CV risk factors or CVD. FIGURE 1. Combined use of hypoglycemic drugs in different situations.

On this basis, the FDA and EMA in the United States and Europe announced that there are no drugs recommended for T2DM prevention.

GLP-1RA may be better than SGLT2i in controlling blood glucose and body weight, for differences between different GLP-1RAs, please see the second paragraph of 2.

Abbreviations: CKD, chronic kidney disease; CV, cardiovascular; DPP-4i, dipeptidyl peptidase-4 inhibitors; EMPA, empagliflozin; GLP-1RA, glucagon-like peptide 1 receptor agonists; HF, heart failure; Met, metformin; OAM, oral antihyperglycemic medication; SGLT-2i, sodium-glucose cotransporter 2 inhibitors; T2DM, type 2 diabetes.

The meta-analysis of Kanie et al. In fact, GLP-1RA is a type of incretin, which plays a hypoglycemic effect by increasing the insulin secretion of pancreatic β cells stimulated by glucose Farilla et al. Insulin secretion only increases when glucose is higher than about 3. Because GLP-1RA action is glucose-dependent, they have a low risk of hypoglycemia, unless combined with sulfonylureas or insulin Brown et al.

This highlights the need to follow the recommendations for reducing the dose of sulfonylurea drugs when starting DPP-4i Salvo et al.

canagliflozin, empagliflozin, and dapagliflozin have a higher risk of genital infections ORs 3. Among these SGLT-2i, only dapagliflozin was associated with an obviously higher Urinary Tract Infections UTIs risk compared with other active treatments or placebo OR 1.

Compared with dapagliflozin, empagliflozin was associated with a significant decrease in UTIs OR 0. The genital infections and UTIs caused by SGLT-2i mainly occurred in the 24—26 weeks of treatment Li et al. Compared with men, women have obviously higher risks of genital infections and UTIs, regardless of whether SGLT-2i is used or not Li et al.

Observational studies and meta-analysis have indicated that SGLT-2i do not increase the risk of bacterial UTIs, including pyelonephritis Li et al. In the CANVAS and CANVAS-R study, compared with placebo, patients treated with canagliflozin at higher risk of amputation HR 1.

Similarly, T2DM patients with CVD who started hypoglycemic therapy in the United States Department of Defense military health system were followed up for a median of 1.

The results showed that the use of SGLT-2i increased the risk of lower knee amputation HR 1. The findings highlight the potential benefits and risks that need to be considered when launching SGLT-2i Udell et al. However, canagliflozin increased the risk of amputation and was not found in other subsequent CVOT or CREDENCE Perkovic et al.

In addition, Paul et al. The results showed that compared with GLP 1-RA, DPP-4i or other anti-diabetic drugs ADD , the risk of lower limb amputations LLAs in SGLT2i is not higher or even lower [HR are: 0. And there was no obvious difference in the incidence of LLA between empagliflozin, canagliflozin, or dapagliflozin.

Patients with pre-existing peripheral arterial disease PAD had the highest risk more than fourfold of developing LLA. These results indicate that SGLT-2i do not increase amputation risk Paul et al. Does this mean that PAD patients should be more cautious when using SGLT-2i?

The findings of Bonaca et al. No significant difference between placebo and dapagliflozin in any limb outcome including limb ischemic adverse events and amputation. These results indicate that dapagliflozin may be safe in T2DM patients with PAD in terms of limb outcome Bonaca et al.

Nonetheless, when using SGLT2i, carefully monitor the lower extremity ulcers. If the patient develops lower extremity complications, consider stopping treatment at least suspend use until symptoms are relieved.

Sometimes, injection site reactions, headaches, and nasopharyngitis may occur Brown et al. The weekly preparation of GLP-1RA seems to be more advantageous in lowering glucose and reducing gastrointestinal discomfort Nauck and Meier, The C-cell proliferation and medullary thyroid carcinogenesis observed in rodents has not been clinically demonstrated this may be due to low or absent GLP-1R expression in normal human thyroid tissue.

Nevertheless, GLP-1RA should not be recommended when patients at risk of developing medullary thyroid cancer Brown et al. GLP-1RA treatment may increase the risk of gallbladder and bile duct disease, and it is more likely to undergo cholecystectomy Faillie et al. The good news is that GLP-1RA treatment does not appear to increase the risk of pancreatic cancer or acute pancreatitis compared to other ADD treatments Storgaard et al.

It has been reported that diabetic ketoacidosis occurs in patients with T2DM who use GLP-1RA and insulin at the same time when the simultaneous use of insulin is rapidly reduced or stopped. Insulin should be lowered cautiously and gradually, and capillary blood glucose should be monitored GLP-1 receptor agonists, Risk factors include concurrent use of insulin, concurrent diseases, and major elective surgery or emergency Brown et al.

Although the rapid glycemic control effect of semaglutide may be responsible for the temporary deterioration of diabetic eye disease, the direct effect of drug cannot be ruled out. A clinical trial investigating the long-term effects of semaglutide in diabetic eye disease is ongoing NCT It should be noted that we listed most of the risks of the new hypoglycemic drugs, but there may be other risks that have not been discussed.

Earlier studies supported initial combination therapy to achieve glycemic goals more rapidly while reducing the incidence of hypoglycemia compared to traditional stepwise therapy Phung et al.

The 5-years treatment period is divided into 3 study periods. Finally, 1, In period 1, the number of initial treatment failures in the combination treatment group and monotherapy group was The median time to medication failure observed in the two groups was In addition, both treatments are safe and well tolerated.

These results indicate that for newly diagnosed T2DM patients, the early use of vildagliptin combined with metformin will provide greater, longer-lasting long-term benefits compared to traditional stepwise therapy Figure 1C Matthews et al.

TABLE 3. Randomized controlled trial of early combination therapy with new hypoglycemic drugs in T2DM and prediabetes. Moreover, the research results of Hadjadj et al.

And it is significantly better than once daily empagliflozin 25 mg or twice daily metformin 1 g treatment. This suggests that low-dose empagliflozin and high-dose metformin combined therapy is superior to high-dose empagliflozin or metformin in controlling blood glucose and weight.

The study by Rosenstock et al. Prediabetes is a very common health problem that progresses to T2DM and the risk of T2DM complications are high. Lifestyle interventions a combination of diet and exercise aimed at reducing weight and increasing activity levels can improve glucose tolerance and prevent progression from impaired glucose tolerance IGT to T2DM.

Nevertheless, there may still be value in combination therapy with new hypoglycemic agents for prediabetes. The results indicated that glucose levels during oral glucose tolerance test OGTT in the LM group were significantly improved.

The OGTT disposition index DI of the LM group increased from 1. In addition, the LM group is more likely to reach normal blood glucose [Odds Ratio OR 3.

No obvious adverse reactions were observed during the study. This suggests that in patients with prediabetes, the early combination of SGLT-2i and metformin may further reduce the incidence of T2DM Figure 1A.

Research by Yusuf et al. The research results of Chow et al. The benefits of polypill and quadpill in participants with moderate CV risk or initial antihypertensive therapy reducing the dose of the drug may help reduce adverse reactions and cancel the requirement for dose adjustment , which has important reference value for the combination therapy of hypoglycemic drugs increase patient compliance, reduce the failure rate of single-drug hypoglycemic, reduce single-drug dose to control costs.

The latest data IDF diabetes atlas 10th edition shows that million adults worldwide have IGT. It is particularly important to effectively reduce their risk of developing T2DM.

More than three-quarters of adults with diabetes live in countries with low and moderate incomes. Therefore, it is also very important to control the cost of diabetes treatment. Undoubtedly, as the new hypoglycemic drugs become widely available and their patents expire, their prices will be greatly reduced.

On the other hand, adjusting the dosage of hypoglycemic drugs and the initial combination therapy both in prediabetes and newly diagnosed T2DM patients may help improve efficacy and reduce costs including reducing the cost of expensive drugs and the medical burden due to treatment failure.

In fact, DPP-4i and metformin, and the combination of SGLT-2i and metformin have been approved in some countries and regions such as the European Union and Japan , but are mainly used in patients with poor monotherapy or those who are taking the drugs in the combination separately eg empagliflozin and metformin hydrochloride.

Therefore, studies of approved or unapproved combination drugs for the initial treatment of prediabetes and T2DM should be accelerated. The approval of oral GLP-1RA semaglutide will help to promote this process.

In general, the cardioprotective mechanism of SGLT-2i is mainly divided into two parts: indirect and direct effects Figure 2 : indirect effects mainly include lowering blood pressure and weight, ketogenesis, and lowering glucose.

The results of DAPA-HF, EMPEROR-Reduced and EMPEROR-Preserved indicate that SGLT-2i has similar benefits in diabetic and non-diabetic patients, suggesting that the protective effect of SGLT-2i on HF may be independent of its hypoglycemic effect.

However, SGLT-2i decreases the risk of conversion to T2DM in the prediabetes stage Brown et al. As we all know, the SGLT-2i hypoglycemic pathway is significantly different from other hypoglycemic drugs.

Whether this special glucose-lowering pathway improving energy balance is beneficial for HF remains unclear. Therefore, the protective mechanism of SGLT-2i on HF in non-diabetic patients cannot be completely ruled out for its hypoglycemic effect. Sotagliflozin as a non-selective SGLT-2i should have similar effects].

Although SGLT-2i have obvious protective effects against HF, their direct cardioprotective mechanism may be different.

FIGURE 2. The mechanism of SGLT-2i in cardioprotection. The comprehensive cardioprotective mechanism of SGLT-2i including indirect and direct effects : SGLT-2i promotes urinary glucose excretion by inhibiting SGLT-2 on the kidneys, lowers insulin, increases glucagon, and then promotes the increase of ketone bodies through the ketogenic effect of the liver; In addition, SGLT-2i increases urinary sodium excretion, reduces blood volume and blood pressure, and reduces preload and afterload of the heart.

These indirect effects on vascular cells including endothelial cells and macrophages are shown to reduce arterial stiffness and improve vascular and endothelial functions.

Metformin can increase the beneficial effects of SGLT-2i on atherosclerosis. At the same time, canagliflozin inhibits cardiac SGLT Sotagliflozin, a non-selective SGLT2i, is speculated to have this effect.

The above-mentioned indirect and direct cardioprotective effects have improved heart function and decreased the rate of hospitalization for HF and cardiovascular mortality. active liver disease or elevated transaminase levels - due to increased risk of hepatic injury. Several previous clinical trials suggested that rosiglitazone but not pioglitazone may increase the risk of myocardial infarction.

Consequently the FDA issued a drug-specific black box warning for rosiglitazone concerning an increased risk of ischemic cardiovascular events separate from the warning for increased risk of heart failure, which remains in effect.

This also resulted in the FDA imposing restrictions on its prescribed use in In , after reviewing newer evidence, the FDA removed the rosiglitazone specific black box warning regarding ischemic CV risk, and ended its restricted access program.

However, concerns about its adverse effects remained, and its use declined Hickson et al, ; Inzucchi, Weight gain : all TZDs cause weight gain.

Weight gain is caused in part by fluid retention, and may also result from PPAR-gamma activation that results in increased adipose tissue mass, and a central effect to increase feeding McCulloch, Management of heart failure should be initiated, and discontinuation or dose reduction of Avandia must be considered in such cases.

Habib ZA, Havstad SL, Wells K, Divine G, Pladevall M, Williams LK : Thiazolidinedione use and the longitudinal risk of fractures in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 95 2 : J Manag Care Spec Pharm. PMCID: PMC Inzucchi SE, Lupsa B : Thiazolidinediones in the treatment of type 2 diabetes mellitus.

McCulloch DK : Thiazolidinediones in the treatment of diabetes mellitus. com Avandia ®. Pioglitazone Trade Name: Actos ®. activates PPAR-γ see Rosiglitazone. Pioglitazone also activates PPAR-α in contrast to Rosiglitazone , which can explain its ability to also lower triglyceride levels.

because the actions of these drugs involves changes in gene expression, they have a slow onset of therapeutic action , requiring weeks or even months to achieve maximal effect. patients with heart failure see black box warning. The results from clinical trials have been mixed.

Most clinical trials have indicated the risk for bladder cancer in patients on pioglitazone is no different than for patients given a placebo. However, it is recommended that it should not be used in patients with active bladder cancer and the benefits of glycemic control versus unknown risks for cancer recurrence with piaglitazone should be weighed in patients with a prior history of bladder cancer.

The triglyceride lowering effect of pioglitazone is greater than that of rosiglitazone, presumably due to its stimulatory effects on PPAR-α. A similar effect has not been observed in men Habib et al, Management of heart failure should be initiated, and discontinuation or dose reduction of Actos must be considered in such cases.

com Actos ®. Acarbose Trade Names: Precose ®. inhibits the activity of enzymes required to break carbohydrates down into simple sugars within the intestine.

Miglitol Glyset ® is six times more potent in inhibiting sucrase than acarbose. Non-FDA approved: potentially beneficial in Type 1 diabetes. Acarabose has been found to decrease the amplitude of postprandial excursions and lower Hb A1c values in Type 1 diabetics by ~0.

not very efficacious at lowering A1c levels when used as monotherapy. poorly absorbed. Should be taken with the first bite of breakfast, lunch, and dinner.

the hypoglycemic goal in diabetics typically cannot be met with these drugs alone. bloating, gas, abdominal discomfort, diarrhea. these side effects develop due to the fermenting of undigested carbohydrate in the colon to fatty acids, with resultant release of gas.

McCulloch DK : Alpha-glucosidase inhibitors and lipase inhibitors for treatment of diabetes mellitus. In: UpToDate. Basow, DS Ed , UpToDate, Waltham, MA. com Precose ®. Miglitol Pharmacology:. com Glyset ®. Sitagliptin Trade Name: Januvia ®. An inhibitor of dipeptidyl peptidase-4 DPP-4 , a protease that degrades the incretin GLP Incretins are hormones released from the GI tract in response to nutrient ingestion.

Incretins potentiate glucose-stimulated insulin secretion from beta cells in the pancreas. As a result of inhibiting DPP-4, increased or prolonged GLP-1 levels are able to potentiate the secretion of insulin by the pancreas.

The effect produced by DPP-4 inhibitors is dependent on endogenous GLP-1 levels, and produce a modest effect on GLP-1 activity compared to giving GLP-1 receptor agonists hence DPP-4 inhibitors do not have the same impact to produce weight loss as GLP-1 agonists.

Sitagliptin works ONLY when blood sugar is elevated, to address diminished insulin levels due to β-cell dysfunction and uncontrolled production of glucose by the liver due to pancreatic α-cell and β-cell dysfunction.

FDA approved: Type II diabetes - monotherapy or combination therapy. Because it does not work when your blood sugar is low, it is unlikely to produce dangerous levels of hypoglycemia. diabetic ketoacidosis it would not be effective for treating this condition. an association between DPP-4 inhibitors and heart failure has been observed for two members of this drug class in patients with type 2 DM and atherosclerosis.

The risk vs benefit of these agents should be considered before prescribing these drugs to patients at risk for CHF. pancreatitis - there have been post-marketing reports of acute pancreatitis. Patients should be observed carefully for signs and symptoms of pancreatitis e.

stomach pain , and treatment discontinued if it is suspected. A similar increased risk for heart failure was also observed for alogliptin 3.

The risk may be particularly high in patients with underlying heart failure or kidney disease. Clinicians should consider taking patients off these drugs if they develop signs of heart failure. Charbonnel B, Cariou B : Pharmacological management of type 2 diabetes: the potential of incretin-based therapies.

Diabetes, Obesity and Metabolism Dungan K, DeSantis : Dipeptidyl peptidase DPP-4 inhibitors for the treatment of type 2 diabetes mellitus. In: UpToDate Basow, DS Ed , Waltham, MA.

Hansotia T, Drucker DJ : Therapeutic Potential of the DPP-4 Inhibitors. FDA Patient Information Sheet. com Januvia ®. Saxagliptin Trade Name: Onglyza ®. a DPP-4 inhibitor, similar to Sitagliptin. com Onglyza ®. a synthetic analog of glucagon-like-polypeptide 1 GLP-1 that is resistant to breakdown by DPP-IV.

It has multiple actions including:. this effect is mediated by reduced parasympathetic tone, and undergoes tachyphylaxis with chronic GLP-1 stimulation.

potentiation of glucose-mediated insulin secretion. because the GLP-1 effect is glucose-dependent there is more insulin release when glucose levels are elevated, but less effect when glucose levels are normal , GLP-1 agonists have a lower risk for producing hypoglycemia compared to sulfonylureas that chronically stimulate insulin release, independent of glucose concentration.

suppression of postprandial glucagon release. reduction in liver fat content. liver fat accumulation is correlated with several metabolic disturbances including low HDL and elevated triglyceride levels Tushuizen et al, reaches a peak concentration in ~2 hours, with a duration of action of up to 10 hours.

exenatide incorporated into an extended-release microsphere formulation once weekly injection. there is an increased risk of hypoglycemia when exenatide is used with a sulfonylurea.

The dose of the sulfonylurea may need to be reduced if hypoglycemia occurs when combined with exenatide. When initiating patients on Byetta, watch for signs and symptoms of pancreatitis including persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting.

Discontinue Byetta if pancreatitis is suspected. The discovery of DPP-IV-resitant GLP-1 analogs was pursued in parallel with the discovery of DPP-IV inhibitors.

Exenatide is a synthetic form of a protein originally isolated from the saliva of the Gila monster poisonous lizard that lives in the deserts of Arizona. Dungan K, DeSantis A : Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes mellitus.

Guo XH : The value of short- and long-acting glucagon-like peptide-1 agonists in the management of type 2 diabetes mellitus: experience with exenatide.

Curr Med Res Opin. Holt RIG, Hanley NA : Essential Endocrinology and Diabetes. Blackwell Publishing. ISBN: Madsbad S : Review of head-to-head comparisons of glucagon-like peptide-1 receptor agonists.

Diabetes Obes Metab. Meier JJ : GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol. Nauck MA et al : Rapid tachyphylaxis of the glucagon-like peptide 1-induced deceleration of gastric emptying in humans.

Diabetes — Tushuizen ME et al : Incretin mimetics as a novel therapeutic option for hepatic steatosis. Liver Int 26 8 : Wettergren A et al : Glucagon-like peptide-1 inhibits gastropancreatic function by inhibiting central parasympathetic outflow.

This Issue. Citations View Metrics. Share X Facebook Email LinkedIn. Controversies in Internal Medicine. Alan J. Garber, MD, PhD. Author Affiliations Article Information From the Baylor College of Medicine, Houston, Tex. visual abstract icon Visual Abstract.

Insulin and Oral Hypoglycemic Agents Should Not Be Used in Combination in the Treatment of Type 2 Diabetes. Access through your institution. Add or change institution. Read More About Diabetes Diabetes and Endocrinology. Download PDF Full Text Cite This Citation Garber AJ.

Select Your Interests Customize your JAMA Network experience by selecting one or more topics from the list below. Save Preferences. Privacy Policy Terms of Use. Access your subscriptions. Free access to newly published articles. Aroda, V. Efficacy and Safety of Once-Weekly Semaglutide versus Once-Daily Insulin Glargine as Add-On to Metformin With or without Sulfonylureas in Insulin-Naive Patients with Type 2 Diabetes SUSTAIN 4 : a Randomised, Open-Label, Parallel-Group, Multicentre, Multinational, Phase 3a Trial.

Lancet Diabetes Endocrinol. With the Special Contribution of the Heart Failure Association HFA of the ESC. Heart Fail 24, 4— Ban, K. Cardioprotective and Vasodilatory Actions of Glucagon-like Peptide 1 Receptor Are Mediated through Both Glucagon-like Peptide 1 Receptor-dependent and -independent Pathways.

Circulation , — Bergenstal, R. Efficacy and Safety of Exenatide once Weekly versus Sitagliptin or Pioglitazone as an Adjunct to Metformin for Treatment of Type 2 Diabetes DURATION-2 : a Randomised Trial.

Lancet , — Bhatt, D. Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure. Blevins, T. DURATION Exenatide once Weekly Resulted in Greater Improvements in Glycemic Control Compared with Exenatide Twice Daily in Patients with Type 2 Diabetes. Bonaca, M. Dapagliflozin and Cardiac, Kidney, and Limb Outcomes in Patients with and without Peripheral Artery Disease in DECLARE-TIMI Bosi, E.

Vildagliptin Plus Metformin Combination Therapy Provides Superior Glycaemic Control to Individual Monotherapy in Treatment-Naive Patients with Type 2 Diabetes Mellitus. Bouthoorn, S. The Prevalence of Left Ventricular Diastolic Dysfunction and Heart Failure with Preserved Ejection Fraction in Men and Women with Type 2 Diabetes: A Systematic Review and Meta-Analysis.

Diab Vasc. Brown, E. SGLT2 Inhibitors and GLP-1 Receptor Agonists: Established and Emerging Indications. Buse, J. Exenatide once Weekly versus Liraglutide once Daily in Patients with Type 2 Diabetes DURATION-6 : a Randomised, Open-Label Study. Liraglutide once a Day versus Exenatide Twice a Day for Type 2 Diabetes: a week Randomised, Parallel-Group, Multinational, Open-Label Trial LEAD Lancet , 39— Cannon, C.

Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes. Capehorn, M. Efficacy and Safety of Once-Weekly Semaglutide 1. Diabetes Metab. Chow, C. Quarter-dose Quadruple Combination Therapy for Initial Treatment of Hypertension: Placebo-Controlled, Crossover, Randomised Trial and Systematic Review.

Das, S. Dave, C. Sodium-Glucose Cotransporter-2 Inhibitors and the Risk for Severe Urinary Tract Infections: A Population-Based Cohort Study. Intern Med. Davies, M. Effect of Oral Semaglutide Compared with Placebo and Subcutaneous Semaglutide on Glycemic Control in Patients with Type 2 Diabetes: A Randomized Clinical Trial.

Jama , — Dungan, K. 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.

Faillie, J. Association of Bile Duct and Gallbladder Diseases with the Use of Incretin-Based Drugs in Patients with Type 2 Diabetes Mellitus. JAMA Intern Med. Farilla, L. Glucagon-like Peptide-1 Promotes Islet Cell Growth and Inhibits Apoptosis in Zucker Diabetic Rats.

Endocrinology , — Feng, X. Metformin, Macrophage Dysfunction and Atherosclerosis. Flory, J. Metformin in JAMA , — Frías, J. Efficacy and Safety of Once-Weekly Semaglutide 2·0 Mg versus 1·0 Mg in Patients with Type 2 Diabetes SUSTAIN FORTE : a Double-Blind, Randomised, Phase 3B Trial.

Tirzepatide versus Semaglutide once Weekly in Patients with Type 2 Diabetes. Gerstein, H. Dulaglutide and Cardiovascular Outcomes in Type 2 Diabetes REWIND : a Double-Blind, Randomised Placebo-Controlled Trial.

Glp-1 receptor agonists, Reports of Diabetic Ketoacidosis when Concomitant Insulin Was Rapidly Reduced or Discontinued. Accessed June 19, Google Scholar. Guardado-Mendoza, R. The Combination of Linagliptin, Metformin and Lifestyle Modification to Prevent Type 2 Diabetes PRELLIM. A Randomized Clinical Trial.

Metabolism , Hadjadj, S. Initial Combination of Empagliflozin and Metformin in Patients with Type 2 Diabetes. Diabetes Care 39, — Hernandez, A.

Albiglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Cardiovascular Disease Harmony Outcomes : a Double-Blind, Randomised Placebo-Controlled Trial. Holman, R. Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes.

Husain, M. Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. Jabbour, S. Efficacy and Safety over 2 Years of Exenatide Plus Dapagliflozin in the DURATION-8 Study: A Multicenter, Double-Blind, Phase 3, Randomized Controlled Trial.

Diabetes Care 43, — Jia, G. Diabetic Cardiomyopathy: An Update of Mechanisms Contributing to This Clinical Entity. Frias, J. Efficacy and Safety of Dulaglutide 3. CrossRef Full Text Google Scholar.

Kanie, T. Dipeptidyl Peptidase-4 Inhibitors, Glucagon-like Peptide 1 Receptor Agonists and Sodium-Glucose Co-transporter-2 Inhibitors for People with Cardiovascular Disease: a Network Meta-Analysis.

Cochrane Database Syst. Konduracka, E. Myocardial Dysfunction and Chronic Heart Failure in Patients with Long-Lasting Type 1 Diabetes: a 7-year Prospective Cohort Study. Acta Diabetol. Li, D.

Urinary Tract and Genital Infections in Patients with Type 2 Diabetes Treated with Sodium-Glucose Co-transporter 2 Inhibitors: A Meta-Analysis of Randomized Controlled Trials.

Lingvay, I. Efficacy and Safety of Once-Weekly Semaglutide versus Daily Canagliflozin as Add-On to Metformin in Patients with Type 2 Diabetes SUSTAIN 8 : a Double-Blind, Phase 3b, Randomised Controlled Trial.

Ludvik, B. Dulaglutide as Add-On Therapy to SGLT2 Inhibitors in Patients with Inadequately Controlled Type 2 Diabetes AWARD : a week, Randomised, Double-Blind, Placebo-Controlled Trial. Marso, S. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes.

Matthews, D. Glycaemic Durability of an Early Combination Therapy with Vildagliptin and Metformin versus Sequential Metformin Monotherapy in Newly Diagnosed Type 2 Diabetes VERIFY : a 5-year, Multicentre, Randomised, Double-Blind Trial.

McMurray, J. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. Nassif, M. The SGLT2 Inhibitor Dapagliflozin in Heart Failure with Preserved Ejection Fraction: a Multicenter Randomized Trial. Nauck, M. Once-Daily Liraglutide versus Lixisenatide as Add-On to Metformin in Type 2 Diabetes: A Week Randomized Controlled Clinical Trial.

Neal, B. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. Neuen, B. SGLT2 Inhibitors for the Prevention of Kidney Failure in Patients with Type 2 Diabetes: a Systematic Review and Meta-Analysis.

Olansky, L. A Treatment Strategy Implementing Combination Therapy with Sitagliptin and Metformin Results in Superior Glycaemic Control versus Metformin Monotherapy Due to a Low Rate of Addition of Antihyperglycaemic Agents.

Packer, M. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. Pasternak, B. Use of Sodium-Glucose Co-transporter 2 Inhibitors and Risk of Serious Renal Events: Scandinavian Cohort Study.

BMJ , m Paul, S. The Association of Amputations and Peripheral Artery Disease in Patients with Type 2 Diabetes Mellitus Receiving Sodium-Glucose Cotransporter Type-2 Inhibitors: Real-World Study. Heart J. Perkovic, V. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy.

Pfeffer, M. Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome. Pfützner, A.

Initial Combination Therapy with Saxagliptin and Metformin Provides Sustained Glycaemic Control and Is Well Tolerated for up to 76 Weeks.

Philippaert, K. Phung, O. Early Combination Therapy for the Treatment of Type 2 Diabetes Mellitus: Systematic Review and Meta-Analysis. Pieber, T. Efficacy and Safety of Oral Semaglutide with Flexible Dose Adjustment versus Sitagliptin in Type 2 Diabetes PIONEER 7 : a Multicentre, Open-Label, Randomised, Phase 3a Trial.

Pratley, R. Oral Semaglutide versus Subcutaneous Liraglutide and Placebo in Type 2 Diabetes PIONEER 4 : a Randomised, Double-Blind, Phase 3a Trial.

Semaglutide versus Dulaglutide once Weekly in Patients with Type 2 Diabetes SUSTAIN 7 : a Randomised, Open-Label, Phase 3b Trial.

Liraglutide versus Sitagliptin for Patients with Type 2 Diabetes Who Did Not Have Adequate Glycaemic Control with Metformin: a week, Randomised, Parallel-Group, Open-Label Trial. 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.

Ridderstråle, M. Empagliflozin Compared with Glimepiride in Metformin-Treated Patients with Type 2 Diabetes: week Data from a Masked Randomized Controlled Trial. Riddle, M. Effects of Intensive Glucose Lowering in the Management of Patients with Type 2 Diabetes Mellitus in the Action to Control Cardiovascular Risk in Diabetes ACCORD Trial.

Rodbard, H. Oral Semaglutide versus Empagliflozin in Patients with Type 2 Diabetes Uncontrolled on Metformin: The PIONEER 2 Trial , 42, — Rosano, G. Heart Failure in Patients with Diabetes Mellitus , Buckinghamshire: Card Fail Rev , 52— Rosenstock, J.

Effect of Additional Oral Semaglutide vs Sitagliptin on Glycated Hemoglobin in Adults with Type 2 Diabetes Uncontrolled with Metformin Alone or with Sulfonylurea: The PIONEER 3 Randomized Clinical Trial. Initial Combination Therapy with Canagliflozin Plus Metformin versus Each Component as Monotherapy for Drug-Naïve Type 2 Diabetes.

Efficacy and Safety of Lixisenatide once Daily versus Exenatide Twice Daily in Type 2 Diabetes Inadequately Controlled on Metformin: a week, Randomized, Open-Label, Active-Controlled Study GetGoal-X. Diabetes Care 36, — Salvo, F. Addition of Dipeptidyl Peptidase-4 Inhibitors to Sulphonylureas and Risk of Hypoglycaemia: Systematic Review and Meta-Analysis.

BMJ , i Sanchez-Rangel, E. Metformin: Clinical Use in Type 2 Diabetes. Diabetologia 60, — Schiattarella, G. Canagliflozin and Myocardial Oxidative Stress: SGLT1 Inhibition Takes Centre Stage.

Sfairopoulos, D. Clinical Pharmacology of Glucagon-like Peptide-1 Receptor Agonists. Athens 17, — Sharma, D. Solomon, S. Dapagliflozin in Heart Failure with Preserved and Mildly Reduced Ejection Fraction: Rationale and Design of the DELIVER Trial.

Heart Fail 23, — Sorli, C. Efficacy and Safety of Once-Weekly Semaglutide Monotherapy versus Placebo in Patients with Type 2 Diabetes SUSTAIN 1 : a Double-Blind, Randomised, Placebo-Controlled, Parallel-Group, Multinational, Multicentre Phase 3a Trial.

Sposito, A. GLP-1RAs in Type 2 Diabetes: Mechanisms that Underlie Cardiovascular Effects and Overview of Cardiovascular Outcome Data. Cardiovasc Diabetol. Storgaard, H. Glucagon-like Peptide-1 Receptor Agonists and Risk of Acute Pancreatitis in Patients with Type 2 Diabetes.

Stumvoll, M. Type 2 Diabetes: Principles of Pathogenesis and Therapy. Tamborlane, W. Liraglutide in Children and Adolescents with Type 2 Diabetes.

Udell, J. Cardiovascular Outcomes and Risks after Initiation of a Sodium Glucose Cotransporter 2 Inhibitor: Results from the EASEL Population-Based Cohort Study Evidence for Cardiovascular Outcomes with Sodium Glucose Cotransporter 2 Inhibitors in the Real World.

Uthman, L. Diabetologia 61, — Vilsbøll, T. Dapagliflozin Plus Saxagliptin Add-On Therapy Compared with Insulin in Patients with Type 2 Diabetes Poorly Controlled by Metformin with or without Sulfonylurea Therapy: A Randomized Clinical Trial.

Diabetes Care 42, — Weng, J. Wilding, J. Once-Weekly Semaglutide in Adults with Overweight or Obesity. Williams-Herman, D. Efficacy and Safety of Initial Combination Therapy with Sitagliptin and Metformin in Patients with Type 2 Diabetes: a week Study.

Wiviott, S. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes , , — Wysham, C. Efficacy and Safety of Dulaglutide Added onto Pioglitazone and Metformin versus Exenatide in Type 2 Diabetes in a Randomized Controlled Trial AWARD Diabetes Care 37, — Yabe, D.

Safety and Efficacy of Oral Semaglutide versus Dulaglutide in Japanese Patients with Type 2 Diabetes PIONEER 10 : an Open-Label, Randomised, Active-Controlled, Phase 3a Trial. Yusuf, S. Polypill with or without Aspirin in Persons without Cardiovascular Disease. Zinman, B. Efficacy, Safety, and Tolerability of Oral Semaglutide versus Placebo Added to Insulin with or without Metformin in Patients with Type 2 Diabetes: The PIONEER 8 Trial.

Semaglutide once Weekly as Add-On to SGLT-2 Inhibitor Therapy in Type 2 Diabetes SUSTAIN 9 : a Randomised, Placebo-Controlled Trial.

Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. Citation: Ni X, Zhang L, Feng X and Tang L New Hypoglycemic Drugs: Combination Drugs and Targets Discovery. doi: Received: 17 February ; Accepted: 10 May ; Published: 08 June Copyright © Ni, Zhang, Feng and Tang.