"All models are wrong, but some are useful": On the non-bayesianstatistical robustness of Hilton's law

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Comparison of Safety and Efficacy of Glimepiride-Metformin and Vildagliptin- Metformin Treatment in Newly Diagnosed Type 2 Diabetic Patients.

OBJECTIVES: To compare the safety and efficacy of combination of Glimepiride - Metformin with Vildagliptin - Metformin in type 2 diabetic patients with HbA1c between 7.5to10. METHODS: A randomized, prospective, comparative and interventional study was conducted at Indira Gandhi Medical College, Shimla. The level of hemoglobin A1c (HbA1c), fasting blood sugar (FBS) and postprandial blood sugar (PP) were the primary outcomes, whereas, the evidence of hypoglycemia, quality of life and weight gain were recorded as secondary outcomes. 215 patients newly diagnosed with type 2 diabetes mellitus were randomized into Glimepiride-Metformin group (Group1) having 111 patients and Vildagliptin-Metformin group (Group 2) having 106 patients. Patients were followed up at 3 month, 12 month, 24 month and then after completion of 30 month of treatment. RESULTS: A comparable FPG, PPPG and HbA1c were observed from baseline at the end of 12 weeks in both groups. However, at the 130-week endpoint a significantly more pronounced reduction in HbA1c was observed in vildagliptin-metformin (1.96%) arm compared to Glimepiride-metformin (1.67%) arm. A similar significant more pronounced reduction was demonstrated in both FPG (48.25% vs. 41.70%) and PPPG (49.40% vs. 42.95%) in vildagliptin-metformin group compared to Glimepiride-metformin group. The proportion of patients who achieved an A1C < 7% at 130-weeks was 49% in the vildagliptin group and 41% in the Glimepiride group. Statistically significant more weight gain was observed in Glimepiride arm compared to vildagliptin arm (2.09 kg vs. 0.69 kg) and 8-fold lower incidence was observed in vildagliptin group. Conclusion: Vildagliptin -metformin represent a more effective combination in terms of number of patients achieving guidelines recommended A1C target of less than 7% at the end of 30 months, less weight gain, and a lower risk of hypoglycemia in newly diagnosed type 2 diabetic patients with moderate hypoglycemia. CONCLUSIONS: Vildagliptin -metformin represent a more effective combination in terms of number of patients achieving guidelines recommended A1C target of less than 7% at the end of 30 months, less weight gain, and a lower risk of hypoglycemia in newly diagnosed type 2 diabetic patients with moderate hypoglycemia.

To compare the effect of Telmisartan with Metoprolol on arterial stiffness in hypertension: prospective randomized parallel group trial.

BACKGROUND: Hypertension is often complicated by increased arterial stiffness and is an independent predictor of adverse cardiovascular (CV) outcome. Beta blockers and angiotensin receptor blockers (ARBs) are commonly used antihypertensive agents. The effect of beta blockers and ARBs on arterial stiffness has not been compared adequately. The aim of the present study is to compare the effect of telmisartan with metoprolol on arterial stiffness in hypertensive patients in prospective open label randomized parallel group intervention study. METHODS: 100 patients of hypertension, not on any antihypertensive agents, were enrolled after obtaining informed consent. Baseline recording of data related to demographics, CV risk factors, anthropometry and BP were made. Arterial stiffness was measured noninvasively by recording pulse wave velocity (PWV) using periscope (Genesis medical system). Left ventricular (LV) mass was measured using 2D guided M-mode echocardiography. Blood sugar, renal function, lipids and uric acid estimations were done in fasting state. Patients were randomized to receive metoprolol and telmisartan using stratified randomization technique. Dose of the study drugs were titrated to achieve target BP of <140/90 mmHg. Data related to PWV, BP, anthropometry and blood biochemistry was repeated after 6 months of treatment with study drugs. RESULTS: Telmisartan resulted in significantly greater reduction in arterial stiffness index (ASI) in left and right lower limb arterial bed (39.9 ± 11.7 vs. 46.8 ± 17.0 m/s, p < 0.02) and (36.4 ± 9.6 vs. 44.86 ± 15.1 m/s, p < 0.002) respectively and systolic blood pressure (SBP) (-4.9 mmHg with 95% C.I. of -8.0-1.7 mmHg, p < 0.003) compared to metoprolol. Reduction in diastolic blood pressure (DBP) in telmisartan and metoprolol groups was not different statistically (-1.0 mmHg with 95% C.I. of -3.3-1.2 mmHg, p < 0.3). The change in LV mass was not significantly different between the study groups (135.5 ± 37.6 vs. 143.2 ± 41.5, p < 0.3).

Nicotine reversal of anticonvulsant action of topiramate in kainic acid-induced seizure model in mice.

INTRODUCTION: Tobacco smoking is a widespread phenomenon, and nicotine is the addictive component of tobacco. Nicotine acts through nicotinic cholinergic receptors and has been associated with different types of psychophysical disorders in human beings. The present study had explored the proconvulsive action of nicotine and its effect on the antiseizure efficacy of topiramate against kainic acid (KA)-induced seizures in mice. METHODS: The study had evaluated the dose-response curves for nicotine and KA and for KA in nicotine-pretreated mice and for topiramate against KA-induced seizures. Mecamylamine was used to antagonize the nicotinic receptor-mediated actions of nicotine. CD50 (convulsive dose in 50% of animals) for KA and nicotine and ED50 (effective dose in 50% of animals as anticonvulsant) for topiramate were determined. Brain lipid peroxidation studies were also undertaken in the treated mice. RESULTS: Nicotine significantly potentiated the convulsive action of KA acid and reduced the CD50 (95% confidence limits [CL]) value for KA from 2.6 mg/kg (2.3-3.1) to 1.4 mg/kg (0.9-2.1), intraperitoneally (i.p.). Topiramate pretreatment significantly inhibited KA-induced seizures and brain lipid peroxidation with ED50 (95% CL) value of 21.90 mg/kg (17.3-28.2), i.p. Nicotine pretreatment caused dose-dependent antagonism to the antiseizure and antilipid peroxidative actions of topiramate. Mecamylamine had antagonized the proconvulsant action of nicotine. CONCLUSION: The study highlights the fact that intake of nicotine, through agonism to nAChR, might predispose epileptic patients to lower seizure threshold and induce a state of refractoriness to the protective effects of the antiepileptic drugs, resulting in possible breakthrough seizure attacks.

Dose-finding study with nicotine as a proconvulsant agent in PTZ-induced seizure model in mice.

The present study was conducted to investigate the possible interaction between low doses of nicotine and pentylenetetrazole (PTZ) in vivo and also to evaluate the influence of nicotine on the antiseizure efficacy of topiramate and sodium valproate in the PTZ-induced seizure model in mice. Graded dose-response study with nicotine showed the CD50 value for nicotine at 6.76 mg/kg. i.p. Subtheshold dose of nicotine (4 mg/kg, i.p.) pretreatment significantly decreased the CD50 value for PTZ from 47.86 mg/kg, i.p. (of PTZ per se) to 31.62 mg/kg, i.p. Sodium valproate but not topiramate, significantly inhibited PTZ-induced seizures in mice with an ED50 value of 177.83 mg/kg, i.p. Nonconvulsive dose of nicotine (1 mg/kg, i.p.) significantly antagonized the protective efficacy of sodium valproate against PTZ-induced seizures and increased the ED50 value to 338.84 mg/kg, i.p. PTZ-induced seizures significantly increased the mouse brain levels of MDA and reduced the level of GSH while sodium valproate reversed such changes. Nicotine pretreatment reversed the anti-lipid peroxidative action of sodium valproate in the PTZ-induced seizure model in mice. The study highlighted the convulsant as well as proconvulsant role of nicotine and established dose discrimination for nicotine as a proconvulsant agent and an anti-antiseizure agent. The study bears significant clinical relevance particularly amongst epileptic smokers who may show failure of efficacy of antiepileptic agents and present with breakthrough seizure attacks on exposure to nicotine.

Evaluating the role of confounding in pharmacoeconomic studies.

Confounding may be present in nonrandomized etiological research involving human populations. It can result in erroneous conclusions about the effect of exposure on a disease outcome or about any form of causality between predictors and outcomes. Confounding can wholly or partially account for the apparent effect of the risk factor under consideration or mask the underlying, true association. Not controlling for the effects of confounding can lead to biased results, thus compromising the validity of study conclusions. The three goals of this article are: (1) to define a confounder or a confounding variable, (2) to discuss strategies for controlling the effects of confounding, and (3) to illustrate the perverse effects of confounding with the help of an example.