Saxagliptin - An Overview | Sciencedirect Topics
Thundiparambil Azeez Sonia, Chandra P. Sharma, in Oral Delivery of Insulin , 2014 Saxagliptin was approved by the FDA in July 2009 as a once-daily tablet. It can be taken either as a monotherapy or in combination with hypoglycaemic drugs such as metformin, SUs or thiazolidinediones. A combination of either sitagliptin or vildagliptin with metformin was recently approved; HbA1c is decreased by an additional 0.7% compared with metformin alone [203, 204]. Nowicki et al. reported that once-daily dosage (2.5mg) of saxagliptin is a well-tolerated treatment option for patients with inadequately controlled T2DM and renal impairment . Risks associated with the use of these agents include urinary tract and sinus infections, gastrointestinal disorders, musculoskeletal disorders, hypoglycaemia, fatigue, depression and increased risk of bone fractures. Saxagliptin is metabolized by the cytochrome P450 isoenzyme CYP 3A4; hence it carries a higher risk for pharmacokinetic interactions . In view of the above limitations, metformin will be the drug of choice for initial treatment of type 2 diabetes. Incretin mimetics and enhancers may be established as first-line treatment; however, their exact place in therapy remains to be explored. DPP-4 inhibitors could eventually be used in prediabetic stages and in early stages of diabetes in order to prevent the progression of type 2. Since incretin failure may occur early, and can address many pathophysiological features of type 2 diabetes that lead to progression despite use of existing treatments, incretin therapy should be used in early diabetes (prophylactic use). Important issues with regard to practicalities such as oral or parenteral route of administration, long-term safety and efficacy may determine which of the proposed opti Continue reading >>
Acute Pancreatitis in Type 2 Diabetes Treated With Exenatide or Sitagliptin: A retrospective observational pharmacy claims analysis. Rajesh Garg et al. Diabetes Care Diabetes Care November 2010 vol. 33 no. However, this was a relatively short study, and it was run under the auspices of a commercial organization that profits from selling this very expensive drug. A far more conclusive, and damaging, study was conducted by highly regarded researchers at UCLA's Medical School. They carefully autopsied the pancreases of people with diabetes who had died of strokes and head injuries. About half of these people had been taking an incretin drug for at least a year. All but one were on Januvia, the other was on Byetta. The most troubling finding of this study was that all the people with diabetes who had taken these incretin drugs for a year or more had very abnormal findings when their pancreases were examined. The abnormalities included the presence of an abnormally high number of both beta cells and alpha cells--more than three times greater than normal and the fact that these cells were arranged in "eccentric" islets that were proliferating into the pancreatic ducts in an unusual way. The people taking these incretin drugs were also found to have tiny glandular tumors scattered throughout their pancreases. None of the pancreases of the people who had had diabetes but had not taken these drugs displayed any of these abnormalities. The proliferative changes observed were of the type associated with pancreatitis. Most of the tumors found in people taking Januvia were adenomas--a type of glandular tumor that starts out benign but can over time turn cancerous. They also found a 1 cm neuroendocrine tumor in the pancreas of one patient who had been taking Januvia. The scientists Continue reading >>
Detail-document: Pharmacist's Letter
Combining a GLP-1 Agonist and a DPP-4 Inhibitor for Type 2 Diabetes Clinicians are curious about the utility of combining the incretin-based therapies GLP-1 agonists (e.g., exenatide [Byetta, Bydureon-U.S.], liraglutide [Victoza]) and DPP-4 inhibitors (e.g., linagliptin [Tradjenta-U.S., Trajenta-Canada], saxagliptin [Onglyza], sitagliptin [Januvia]). This combination might seem useful for patients who need multiple drugs to manage type 2 diabetes but want to avoid side effects such as weight gain or hypoglycemia with other medications like sulfonylureas or insulin. This document reviews the evidence for using a GLP-1 agonist with a DPP-4 inhibitor in patients with type 2 diabetes. Patients with diabetes have lower levels and impaired action of glucagon-like peptide-1 (GLP-1).1 GLP-1 agonist drugs (incretin mimetics) mimic the action of this incretin hormone. They are structurally similar, but not exactly the same as endogenous GLP-1.2 (Liraglutide is more similar to endogenous GLP-1 than exenatide.) Endogenous GLP-1 is quickly broken down by the enzyme dipeptidyl peptidase-4 (DPP-4). Modification of the structure of these GLP-1 analogs is a strategy to increase the half-life while retaining the physiologic effects of endogenous GLP-1.1 Endogenous GLP-1 is produced in response to food intake. It stimulates glucose-dependent insulin release and suppresses postprandial glucagon secretion. It also delays gastric emptying, which helps increase satiety. GLP-1 agonists not only help reduce A1C by approximately 1% to 1.5%, but they also can help patients lose weight.3,4 DPP-4 inhibitor drugs (gliptins) reduce the breakdown of endogenous GLP-1 by inhibiting the action of DPP-4. DPP-4 rapidly degrades endogenous GLP-1. It has minimal to no effect on GLP-1 agonist drugs. Exenatid Continue reading >>
What Everyone With Type 2 Diabetes Should Know
Nearly 20 million Americans have type 2 diabetes, also known as adult-onset diabetes, a condition where a person’s body does not respond well to sugar or store it properly. Diabetes can cause many very serious health problems, including kidney disease, blindness, amputation and, most notably, heart disease. Diabetes can even increase your risk of developing cancer. These health problems that are caused by diabetes are more dangerous than the diabetes itself. Diabetes is becoming more and more common, and is estimated to affect more than 9% of the U.S. population in 2014. The fact that people often take diabetes medication for many years, has meant that a diabetes drug can make a lot of money for a pharmaceutical company. As a result, many drugs to treat diabetes have come on the market in the last several years. But unfortunately, it’s not clear if the new drugs are better than the old ones – in fact, all the newer drugs have serious safety concerns (see below for more details). There is also uncertainty about the best way to treat diabetes, especially among older adults. Recent studies suggest that using drugs to keep blood sugar very tightly controlled in type 2 diabetes patients, especially older adults, may not always be beneficial. If blood sugar gets too low, this can cause serious health problems in older adults. And the benefits of tight blood sugar control are likely to only help younger people. In other words, older adults may be less likely to benefit, and more likely to be harmed, by the traditional guidelines for blood sugar (glucose). Medical experts are now starting to change their recommendations by relaxing blood sugar level goals for older adults. New Warnings about Drugs Containing Saxagliptin and Alogliptin In April 2016, the FDA issued a wa Continue reading >>
Sitagliptin (INN; /sɪtəˈɡlɪptɪn/ ( listen), previously identified as MK-0431 and marketed as the phosphate salt under the trade name Januvia) is an oral antihyperglycemic (antidiabetic drug) of the dipeptidyl peptidase-4 (DPP-4) inhibitor class. It was developed, and is marketed, by Merck & Co. This enzyme-inhibiting drug is used either alone or in combination with other oral antihyperglycemic agents (such as metformin or a thiazolidinedione) for treatment of diabetes mellitus type 2. Adverse effects Side effects are as common with sitagliptin (whether used alone or with metformin or pioglitazone) as they were with placebo, except for rare nausea and common cold-like symptoms, including photosensitivity. No significant difference exists in the occurrence of hypoglycemia between placebo and sitagliptin. In those taking sulphonylureas, the risk of low blood sugar is increased. The existence of rare case reports of renal failure and hypersensitivity reactions is noted in the United States prescribing information, but a causative role for sitagliptin has not been established. Several postmarketing reports of pancreatitis (some fatal) have been made in people treated with sitagliptin and other DPP-4 inhibitors, and the U.S. package insert carries a warning to this effect, although the causal link between sitagliptin and pancreatitis has not yet been fully substantiated. One study with lab rats published in 2009 concluded that some of the possible risks of pancreatitis or pancreatic cancer may be reduced when it is used with metformin. However, while DPP-4 inhibitors showed an increase in such risk factors, as of 2009, no increase in pancreatic cancer has been reported in individuals taking DPP-4 inhibitors. The updated (August 20 Continue reading >>
18-week Add-on To Metformin Comparison Of Saxagliptin And Sitagliptin In Adult Patients With Type 2 Diabetes (t2d)
You have reached the maximum number of saved studies (100). Please remove one or more studies before adding more. 18-week add-on to Metformin Comparison of Saxagliptin and Sitagliptin in Adult Patients With Type 2 Diabetes (T2D) The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. ClinicalTrials.gov Identifier: NCT00666458 Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information Saxagliptin is a new investigational medication being developed for treatment of type 2 diabetes. This study is designed to assess the efficacy and tolerability of saxagliptin in addition to metformin and compare to sitagliptin in addition with metformin. Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) 18-wk, International, Multi-centre, Randomized, Parallel-group, Double-Blind, Active-Controlled Phase IIIb Study to Evaluate the Efficacy and Safety of Saxagliptin in Combination With Metformin in Comparison With Sitagliptin in Combination With Metformin in Adult Patients With T2D Who Have Inadequate Glycaemic Control on Metformin Alone Hemoglobin A1c (HbA1c) Change From Baseline to Week 18 [TimeFrame:Baseline, Week 18] Adjusted mean change from baseline in HbA1c achieved with saxagliptin added on to metformin versus sitagliptin added on to metformin at Week 18 (Per Protocol Analysis Set). HbA1c is a continuous measure, the change from baseline for each participant is calculated as the Week 18 value minus the baseline value. Proportion of Patients Achieving Therapeutic Glycaemic Response Defined as HbA1c <= 6.5% at Continue reading >>
New Fda Warning That Januvia, Onglyza, Tradjenta, And Nesina Are Associated With "joint Pain That Can Be Severe And Disabling"
Label Changes About Side Effects For These Type 2 Diabetes Medicines In The Drug Class Called Dipeptidyl Peptidase-4 (DPP-4) Inhibitors In August 2015 the FDA announced that it has found indications of a new side effect for a class of diabetes drugs -- dipeptidyl peptidase-4 (DPP-4) inhibitors -- that includes Januvia, Onglyza, Tradjenta, and Nesina. The FDA found drug adverse event reports of arthralgia, or severe pain in one or more joints, associated with the use of DPP-4 inhibitor diabetes drugs, with Januvia being the one implicated most often, followed by Onglyza. According to the FDA, patients started having symptoms of the new side effect from one day to years after they started taking Januvia, Onglyza, Tradjenta, Nesina or one of the "combination" DPP-4 inhibitors, e.g., Janumet (sitagliptin and metformin). In more detail, the FDA reported that after the DPP-4 inhibitor medicine was discontinued, the patients' symptoms were usually relieved within less than a month of stopping the subject drug. Furthermore, some patients developed severe joint pain again when they restarted the same medicine or another DPP-4 inhibitor. This last fact provides some substantiation for linking this severe joint pain side effect with Januvia, Onglyza, Tradjenta, Nesina, and the other drugs in this DPP-4 inhibitors class. ____________________________________________________ Januvia / Onglyza / Tradjenta / Nesina Free Case Evaluation Strictly Confidential, No Obligation. _____________________________________________________ We get the following more detailed information from the "FDA Drug Safety Communication: FDA warns that DPP-4 inhibitors for type 2 diabetes may cause severe joint pain" document that was issued on August 28, 2015: In a search of the FDA Adverse Event Reporting Sys Continue reading >>
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Steps: Saxagliptin (onglyza) For Type 2 Diabetes Mellitus - American Family Physician
2.5 or 5.0 mg once daily; 2.5 mg in patients with moderate to severe renal dysfunction * Estimated retail price of one month's treatment based on information obtained at (accessed May 18, 2010). Few adverse effects have been associated with saxagliptin. Unlike some other oral hypoglycemics, when saxagliptin is used alone it does not increase the likelihood of hypoglycemia. 1 , 3 , 4 When used as monotherapy or add-on therapy with metformin or thiazolidinediones, saxagliptin has an incidence of hypoglycemia that is comparable with placebo. 1 , 3 7 The manufacturer states that hypoglycemia is more common when saxagliptin is combined with glyburide (formerly Micronase), although the frequency is not significantly higher than with glyburide alone (13.3 to 14.6 percent versus 10.1 percent, respectively). 2 , 3 In 0.5 to 1.5 percent of patients, saxagliptin decreases lymphocyte count and causes lymphocytopenia (i.e., lymphocyte count of 750 cells per L [0.75 109 per L] or less). Decreases in lymphocyte count have not caused any clinical sequelae; however, the effects of saxagliptin in patients with preexisting lymphocyte abnormalities (e.g., human immunodeficiency virus infection) are unknown. 3 Patients with moderate to severe renal dysfunction (creatinine clearance of less than 50 mL per minute per 1.73 m2 [0.83 mL per second per m2]) require a dosage reduction to 2.5 mg once daily. The lower dosage also should be used in patients receiving strong cytochrome P450 3A4 and 3A5 inhibitors, such as clarithromycin (Biaxin), ketoconazole, and the antivirals ritonavir (Norvir), nelfinavir (Viracept), and atazanavir (Reyataz). Saxagliptin is U.S. Food and Drug Administration pregnancy category B. 3 Saxagliptin is well tolerated and produces bothersome adverse effects to a similar Continue reading >>
Best Treatments For Type 2 Diabetes
At-a-glance Six classes of oral medicines (and 12 individual drugs) are now available to help the 25.8 million people in the U.S. with type 2 diabetes control their blood sugar when diet and lifestyle changes are not enough. Our evaluation of these medicines found the following: Newer drugs are no better. Two drugs from a class called the sulfonylureas and a drug named metformin have been around for more than a decade and work just as well as newer medicines. Indeed, several of the newer drugs, such as Januvia and Onglyza, are less effective than the older medications. Newer drugs are no safer. All diabetes pills have the potential to cause adverse effects, both minor and serious. The drugs’ safety and side effect “profiles” may be the most important factor in your choice. The newer drugs are more expensive. The newer diabetes medicines cost many times more than the older drugs. Taking more than one diabetes drug is often necessary. Many people with diabetes do not get enough blood sugar control from one medicine. Two or more may be necessary. However, taking more than one diabetes drug raises the risk of adverse effects and increases costs. Taking effectiveness, safety, adverse effects, dosing, and cost into consideration, we have chosen the following as Consumer Reports Best Buy Drugs if your doctor and you have decided that you need medicine to control your diabetes: Metformin and Metformin Sustained-Release — alone or with glipizide or glimepiride Glipizide and Glipizide Sustained-Release — alone or with metformin Glimepiride — alone or with metformin These medicines are available as low-cost generics, costing from $4 to $35 a month. If you have been diagnosed with diabetes, we recommend that you try metformin first unless it's inappropriate for your hea Continue reading >>
Dpp-4 Inhibitors Charts & Dosing Information For Special Populations
Forms, dosages and dosing considerations for pregnancy, breastfeeding, hepatic and renal. brand name preparation manufacturer route form dosage^ Januvia sitagliptin phosphate (Plus Metformin) Merck oral tablet 25 mg oral tablet 50 mg oral tablet 100 mg Onglyza Saxagliptin (Plus with metformin) Bristol-Myers Squibb oral tablet 2.5 mgD oral tablet 5 mg Tradjenta Linagliptin (Plus with metformin) Eli Lilly oral tablet 5 mg Janumet sitagliptin phosphate + metformin hydrochloride Merck Sharp & Dohme Corp. oral tablet 50/500 mg oral tablet 50/1000 mg Nesina alogliptin Takeda oral tablet 6.25 mg oral tablet 12.5 mg oral tablet 25 mg Dosing (Oral Tablet) Sitagliptin: recommended dose is 25-100 mg once a day. Can be taken with or without food. Saxagliptin: recommended dose is 2.5 or 5 mg once a day. Can be taken with or without food. Linagliptin: recommended dose is 5 mg once a day. Can be taken with or without food. Sitagliptin + metformin: co-formulated as Janumet 50/500 mg twice a day, with meals. Can increase to 50/1000 mg twice a day, with meals (maximum dose). Saxagliptin + metformin XR: co-formulated as Kombiglyze. 2.5/1000 mg, 5/1000 mg, or 5/2000 mg once daily with evening meal. Alogliptin: recommended dose is 25 mg once daily. DPP-4 inhibitors are FDA approved for use as monotherapy in type 2 diabetes (T2DM). DPP-4 inhibitors can also be added to patients already on metformin, sulfonylureas, thiazolidinediones, or insulin. If adding DPP-4 inhibitors to sulfonylurea/insulin therapy, consider decreasing the sulfonylurea/insulin dose, to reduce hypoglycemia risk. DOSING IN SPECIAL POPULATIONS – RENAL Sitagliptin GFR ≥ 50 mL/min, no dosage adjustment needed GFR 30-50 mL/min, do not exceed 50 mg daily GFR < 30 mL/min, do not exceed 25 mg daily For patients on hemodialys Continue reading >>
Inhibits the degradation of incretins such as GLP-1 by inhibiting the enzyme dipeptidyl peptidase IV (DPP-IV). The incretin effect is prolonged, enhancing glycemic control through various mechanisms, primarily by stimulating insulin synthesis and secretion in a glucose-dependant manner and by reducing glucagon secretion. brand name preparation manufacturer route form dosage^ cost* Januvia sitagliptin phosphate Merck oral tablet 25 mg $885 for 90 tabs oral tablet 50 mg $885 for 90 tabs oral tablet 100 mg $295 for 30 tabs Onglyza saxagliptin Bristol-Myers Squibb oral tablet 2.5 mg $295 for 30 tabs oral tablet 5 mg $885 for 90 tabs Tradjenta linagliptin Eli Lilly oral tablet 5 mg $870 for 90 tabs Janumet sitagliptin phosphate + metformin hydrochloride Merck Sharp & Dohme Corp. oral tablet 50/500 mg $885 for 180 tabs oral tablet 50/1000 mg $885 for 180 tabs Nesina alogliptin Takeda oral tablet 6.25 mg $374 for 30 tabs oral tablet 12.5 mg $374 for 30 tabs oral tablet 25 mg $374 for 30 tabs **Patient Assistant Programs: ** Information gathered by Heather Tran and Gladimir Elysee *Prices represent cost per unit specified, are representative of "Average Wholesale Price" (AWP). ^Dosage is indicated in mg unless otherwise noted. Continue reading >>
Onglyza: Just Like Januvia But With More Serious Side Effects?
NOTE (April 2, 2013): Before you take Onglyza or Januvia please read about the new research that shows that they, and probably all incretin drugs, cause severely abnormal cell growth in the pancreas and precancerous tumors. You'll find that information HERE. When the FDA approves a new drug it requires no proof that the drug is more effective than similar, existing drugs, only that it is better than placebo. Which is something to keep in mind as Bristol-Myers Squibb unveils what is sure to be a saturation advertising campaign for its new DPP-4 inhibitor, Onlgyza. This mellifluous moniker is the brand name for Saxagliptin, which alert followers of drug news remember as the Januvia clone developed at the same times as Januvia whose release has been blocked due to its ability to cause "skin lesions" some of which necrotized (i.e. died and fell off) in monkeys. I have read through the Prescribing Information for Onglyza and cannot see any benefit it offers in comparison to Januvia, the other DPP-4 inhibitor currently on the market. Setting aside for the time being the advisability of controlling your blood sugar by turning off a tumor suppressor gene Onglyza offers nothing not offered by Januvia. Both inhibit the expression of the DPP-4 gene for a full 24 hours--which means that if your body was fighting a new, very small DPP-4 sensitive tumor, like ovarian cancer, melanoma, prostate cancer or lung cancer, the drug would keep DPP-4 from killing off the tumor cells. 1. Feeble impact on blood sugar: Onglyza lowered A1cs that averaged 8% by .5%, which does not bring them anywhere near a safe level even by the anemic standards of the ADA. When the highest dose of Onglyza was compared to a placebo, it allowed only 14% more of those taking it to achieve 7% A1cs. To better underst Continue reading >>
Dpp-4 Inhibitors - Dipeptidyl Peptidase-4 Inhibitor - Gliptins - Globalrph
DPP-4 INHIBITORS - Dipeptidyl peptidase-4 inhibitor - Gliptins Typical reductions in A1C values DPP-4 INHIBITORS: NESINA is a dipeptidyl peptidase-4 (DPP-4) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitation of Use: Not for treatment of type 1 diabetes or diabetic ketoacidosis. The recommended dose in patients with normal renal function or mild renal impairment is 25 mg once daily. Adjust dose if moderate or severe renal impairment or end-stage renal disease (ESRD). History of a serious hypersensitivity reaction to alogliptin-containing products, such as anaphylaxis, angioedema or severe cutaneous adverse reactions. TRADJENTA is a dipeptidyl peptidase-4 (DPP-4) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. -Should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. -Has not been studied in combination with insulin. The recommended dose of TRADJENTA is 5 mg once daily. TRADJENTA can be taken with or without food. History of hypersensitivity reaction to linagliptin, such as urticaria, angioedema, or bronchial hyperreactivity. When used with an insulin secretagogue (e.g., sulfonylurea), consider lowering the dose of the insulin secretagogue to reduce the risk of hypoglycemia. There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with TRADJENTA or any other antidiabetic drug. 5% of patients treated with TRADJENTA and more commonly than in patients treated with placebo included nasopharyngitis. -Hypoglycemia was more commonly reported in patients treated with the combination of TRADJENTA and sulfonylurea compared with those treat Continue reading >>
Diabetes Treatment: Medications For Type 2 Diabetes
Healthy lifestyle choices — including diet, exercise and weight control — provide the foundation for managing type 2 diabetes. However, you may need medications to achieve target blood sugar (glucose) levels. Sometimes a single medication is effective. In other cases, a combination of medications works better. The list of medications for type 2 diabetes is long and potentially confusing. Learning about these drugs — how they're taken, what they do and what side effects they may cause — will help you discuss treatment options with your doctor. Diabetes treatment: Lowering blood sugar Several classes of type 2 diabetes medicines exist. Each class of medicine works in different ways to lower blood sugar. A drug may work by: Stimulating the pancreas to produce and release more insulin Inhibiting the production and release of glucose from the liver Blocking the action of stomach enzymes that break down carbohydrates Improving the sensitivity of cells to insulin Inhibiting the reabsorption of glucose in the kidneys Slowing how quickly food moves through the stomach Each class of medicine has one or more drugs. Some of these drugs are taken orally, while others must be injected. Compare diabetes medications Here's an at-a-glance comparison of common diabetes medications. More medications are available depending on your needs and situation. Ask your doctor about your options and the pros and cons of each. Oral medications Meglitinides Medications Repaglinide (Prandin) Nateglinide (Starlix) Action Stimulate the release of insulin Advantages Work quickly Possible side effects Low blood sugar (hypoglycemia) Weight gain Nausea or vomiting, when interacting with alcohol Sulfonylureas Medications Glipizide (Glucotrol) Glimepiride (Amaryl) Glyburide (DiaBeta, Glynase) Action S Continue reading >>
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Which Diabetes Drug Is Best?
TUESDAY, July 19, 2016 -- No single drug to treat type 2 diabetes stands out from the pack when it comes to reducing the risks of heart disease, stroke or premature death, a new research review finds. The analysis of hundreds of clinical trials found no evidence that any one diabetes drug, or drug combination, beats out the others. Researchers said the results bolster current recommendations to first try an older, cheaper drug -- metformin (Glumetza, Glucophage) -- for most patients with type 2 diabetes. "There are very few things experts agree on, but this is one of them," said Dr. Kevin Pantalone, a diabetes specialist at the Cleveland Clinic and a member of the Endocrine Society. "Metformin, in the absence of contraindications or intolerability, should be the first-line agent to treat patients with type 2 diabetes," he said. Metformin can cause upset stomach and diarrhea, so some patients are unable to stick with it day to day, explained Pantalone, who wasn't involved in the study. And people with kidney disease generally shouldn't take it, he said. More than 29 million Americans have diabetes -- mostly type 2, according to the U.S. Centers for Disease Control and Prevention. The disease, which is often linked to obesity, causes blood sugar levels to be chronically high. Over time, that can lead to complications, such as heart disease, stroke, kidney failure and nerve damage, the CDC says. There are numerous classes of medications that lower blood sugar levels. What's been unclear is whether any of those drugs work better than others in warding off diabetes complications and extending people's lives. The new analysis found no obvious winners. But the researchers also cautioned against drawing conclusions: The trials in the review were not specifically designed to see Continue reading >>