Johns Hopkins Diabetes GuideOverview

Key Studies in Diabetes Care: Efficacy of Therapies

Thomas Donner, M.D., Rita Rastogi Kalyani, M.D., M.H.S., Christopher Saudek, M.D.
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Medical therapies for type 1 and 2 diabetes

  • Metformin: UKPDS 34 [1] studied the effect of intensive glycemic control with metformin in newly diagnosed, overweight people with type 2 diabetes. 1,704 patients who were hyperglycemic after 3 months of diet alone were randomly continued on "conventional" management mainly with diet alone, or metformin or sulfonylureas or insulin. Metformin reduced any diabetes-related endpoint (p=0.0034), all-cause mortality (p=0.021) and stroke (p=0.032). In an unexpected and unexplained result, early addition of metformin in the sulfonylurea treated group increased diabetes-related deaths (p=.039), although there was no overall association of metformin plus sulfonylurea with increased death risk. Conclusion was that metformin may be the first-line therapy of choice [1].
  • Metformin: The Multicenter Metformin Study Group [2] Randomized trial comparing effect of metformin versus placebo in 289 patients with type 2 diabetes who were moderately obese. After 29 weeks, the metformin group had lower fasting plasma glucose (189 mg/dl versus 244 mg/dl) and hemoglobin A1c (7.1% versus 8.6%) compared to placebo. Combination therapy with glyburide compared to glyburide alone resulted in lower fasting plasma glucose (187 mg/dl versus 261 mg/dl) and HbA1c (7.1% vs 8.6%). However, 18% had hypoglycemia in the combination group, compared to only 2% with metformin alone and 3% with glyburide alone [2].
  • Sulfonylureas: The University Group Diabetes Program [3]An early and much-debated study of new-onset type 2 diabetes, the UGDP randomized to treatment with a first-generation sulfonylurea (SU) (tolbutamide), phenformin or insulin. Found deaths from lactic acidosis in the phenformin group, and slightly but significantly more deaths from cardiovascular disease in the SU group. Serious critiques were leveled regarding methods and conclusions, for instance, by A.R. Feinstein [4]. The UGDP finding of adverse effects of SU have not been confirmed or widely accepted, but continue to prompt a black box warning in the package insert. SUs have been used safely in myriad studies since Meinert [3].
  • Glyburide [5]: Randomized 31 patients with type 2 diabetes previously inadequately controlled on diet alone to once daily NPH insulin or glyburide. Baseline HbA1c ~10% in both groups. After 9 months, HbA1c dropped similarly in both groups by ~3%.
  • Acarbose [6]: Randomized 96 patients with type 2 diabetes and dietary failure to acarbose versus glibenclamide versus placebo. After 24 weeks, mean HbA1c dropped by 1.1% with acarbose and 0.9% with glibenclamide compared to placebo. Acarbose also lower postprandial insulin increase [6].
  • Troglitazone [7]: An early description of how thiazolidinediones (TZDs) (troglitazone in this case) works by reducing insulin resistance in 18 obese patients with either normal or impaired glucose tolerance. While troglitazone is no longer available, this mechanism is a class effect for TZDs.
  • Pioglitazone [8]: Randomized 408 patients to placebo or four different doses of pioglitazone monotherapy. HbA1c decreased on average between 1 - 1.6% on the three highest doses of pioglitazone (15 - 45 mg daily) after 26 weeks compared to placebo. Improvements in fasting glucose were observed after two weeks of therapy, and were maximal at 10-14 weeks but maintained until study completion (-39 to -65 mg/dl versus placebo). The improvement in glycemic control was greatest in those who were treatment naive (HbA1c difference from placebo of -2.55%) [8].
  • Pioglitazone [9]: In the PROActive trial, 5,238 patients with type 2 diabetes and evidence of macrovascular disease were randomized to pioglitazone versus placebo. After an average follow-up of 34.5 months, the primary composite endpoint of all-cause mortality, non-fatal myocardial infarction, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankles was not significantly different between groups. However, the composite secondary endpoint of all-cause mortality, non-fatal myocardial infarction and stroke was 16% lower in the pioglitazone group (p=0.027) [9].
  • Pioglitazone [10]: The PERISCOPE Trial performed coronary intravascular ultrasonography (IVUS) on 543 patients with coronary disease and type 2 diabetes. Patients were then randomized to receive glimepiride (a sulfonylurea) or pioglitazone (a thiazolidinedione) followed by repeat IVUS in 360 patients after 18 months. Percent atheroma volume increased 0.73% (95% CI, 0.33% to 1.12%) with glimepiride and decreased 0.16% (95% CI, -0.57% to 0.25%) with pioglitazone (P = .002). Using this extremely fine measurement, the conclusion was that pioglitazone was more favorable than SU in slowing progression of coronary atherosclerosis [10].
  • Pioglitazone versus Rosiglitazone Effects on Lipids [11]: Many of these studies are company-sponsored. In this, subjects with type 2 diabetes and dyslipidemia, not previously on insulin or lipid lowering-agents, were treated with pioglitazone (n=400) or rosiglitazone (n=402) for 12 weeks. Triglyceride levels fell by 51 ± 7.8 mg/dl with pioglitazone, but increased by 13.1 ± 7.8 mg/dl with rosiglitazone (P < 0.001 between treatments). Pioglitazone also increased HDL cholesterol (5.2 ± 0.5 vs. 2.4 ± 0.5 mg/dl; P < 0.001) and increased LDL cholesterol less (12 ± 1.6 vs. 21 ± 1.6 mg/dl; P < 0.001). LDL particle concentration was reduced and LDL particle size was increased more with pioglitazone (p=0.005), both considered favorable changes, suggesting that pioglitazone and rosiglitazone have significantly different effects on plasma lipids (pioglitazone being more favorable).
  • Rosiglitazone [12]: A meta-analysis of 42 published and unpublished, small and large studies, which found that use of rosiglitazone was associated with a marginally significant increase in deaths from myocardial infarction (odds ratio=1.43, 95% CI 1.03-1.98; p=0.03) and an increase in death from cardiovascular disease that had borderline significance (odds ratio=1.64, 95% CI 0.98 - 2.74; p=0.06). Immediately controversial.
  • Rosiglitazone [13]: An updated meta-analysis of 56 trials of rosiglitazone at least 24 weeks in duration found that rosiglitazone significantly increased risk of myocardial infarction (odds ratio = 1.28, 95%Y. CI 1.02-1.63, p=0.04) but not cardiovascular mortality (odds ratio=1.03, 95%Y. CI 0.78-1.36, p=0.86b).
  • Rosiglitazone [14]: RECORD is a large (n=4,447 patients) randomized trial of the cardiovascular events following addition of rosiglitazone to metformin or sulfonylurea therapy in type 2 diabetes. After 5.5 years, the study found that rosiglitazone treatment was associated with a significant increase in body weight (~4kg), an increased risk of heart failure (hazard ratio 2.10, 95% CI 1.35 - 3.27) and overall bone fractures (relative risk 1.57, 95% CI 1.26-1.97), mainly among women and primarily in upper and lower limb fractures. However, no overall increase in cardiovascular morbidity or mortality was found in this study [14].
  • Comparative Efficacy [15]: The ADOPT study (n=4,360) evaluated longevity of glycemic control with several oral agents in type 2 diabetes over 5 years. Monotherapy failure was defined as fasting plasma glucose of >180 mg/dl. Glyburide had the most significant early hypoglycemic effect but the highest failure rate (34%) at 5 years. 15% failed rosiglitazone, and 21% failed metformin. Rosiglitazone was associated with more weight gain and edema, and an increased rate of new fractures [15].
  • Exenetide versus Insulin Glargine [16]:An early open-label comparison of exenatide (an incretin mimetic) versus insulin glargine in 138 persons with type 2 diabetes who had failed oral agents. Found that exenatide had similar glycemic efficacy after 16 weeks (~38% had HbA1c< 7%), but exenatide had more weight reduction (difference of -2.2 kg between groups, p< 0.001), as well as a higher incidence of gastrointestinal side effects (42.6% versus 3.1% with nausea).
  • Inhaled Insulin [17]: A safety and efficacy trial of inhaled insulin in 580 adults with type 1 diabetes, showing efficacy and safety over 2 years, although a small decrease in FEV1 during the first 3 months that was not progressive thereafter and cough was noted. Inhaled insulin was marketed briefly and then removed from the market, because it was not well accepted, and did not sell. Subsequently, the FDA announced a worrisome finding: while there were few deaths among study participants, there was an imbalance of deaths due to lung cancer in those taking inhaled insulin.
  • Sitagliptin (Study 021 Group) [18]: A safety and efficacy trial of sitagliptin as monotherapy in type 2 diabetes. Randomized 741 patients to sitagliptin (100 or 200 mg) or placebo. After 24 weeks, overall significant reductions in A1c in sitagliptin group (100 or 200 mg) of -0.79 and -0.94%, respectively compared to placebo. A1c lowering effects greatest when baseline A1c >9% (~-1.50%). Sitagliptin was weight neutral, with similar incidence of hypoglycemia and slightly higher GI side effects compared to placebo [18].
  • Canagliflozin [19]: A trial of 755 subjects with type 2 diabetes uncontrolled on metformin and a sulfonylurea. Subjects were randomized to canagliflozin 300 mg daily or sitagliptin 100 mg daily. After 52 weeks, the change in HbA1c was -1.03% with canagliflozin vs -0.66% with sitagliptin. Body weight change was -2.3 kg with canagliflozin vs +0.1 kg with sitagliptin. An increased number of mycotic genital infections and osmotic diuresis-related side effects were seen with canagliflozin use.

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