Pathophysiologic Approach to Therapy in Patients With Newly Diagnosed Type 2 Diabetes

DeFronzo, Ralph A.; Eldor, Roy

doi:10.2337/dcs13-2011

Cited by 253 publications

(266 citation statements)

References 188 publications

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“…31,33 It, therefore, can be argued that the optimum management of type 2 diabetes would involve intensive management of the earlier stages using metformin, pioglitazone 32,34 and GLP-1 receptor agonists, 29 alone or in combination, with a view to achieving a HbA1c less than 6% in order to preserve β-cell function. 18,[29][30][31][32][33][34] In conclusion, in 2015 the accumulated evidence now gives little or no credence to a link between pioglitazone and bladder cancer. At the same time, there is a strong link between pioglitazone and cardiovascular protection.…”

Section: New Perspectivesmentioning

confidence: 99%

“…[29][30][31] Further, pioglitazone has a potent effect to preserve β-cell function. 18,[30][31][32] An ominous octet of factors underlying the pathophysiology of type 2 diabetes has been described ( Figure 1). 31 With regard to these eight factors, sulphonylureas augment insulin secretion but this effect is transient and these agents do not preserve β-cell function.…”

Section: New Perspectivesmentioning

confidence: 99%

“…31 With regard to these eight factors, sulphonylureas augment insulin secretion but this effect is transient and these agents do not preserve β-cell function. [29][30][31] Metformin impacts two members of the ominous octet, while pioglitazone improves four of the abnormalities, and GLP-1 receptor agonists act on five of the eight factors. 31 Metformin reduces hepatic gluconeogenesis and in muscle it provides an additive effect to pioglitazone in promoting glucose uptake.…”

Section: New Perspectivesmentioning

confidence: 99%

“…31 Metformin reduces hepatic gluconeogenesis and in muscle it provides an additive effect to pioglitazone in promoting glucose uptake. 30,31 Pioglitazone reduces hepatic glucose output, increases glucose uptake in muscle, also improves and preserves pancreatic β-cell function, and is a potent inhibitor of lipolysis. 30,31 GLP-1 receptor agonists increase insulin secretion and reduce glucagon secretion, thereby inhibiting hepatic glucose output and also act on the brain, reducing appetite and promoting weight loss.…”

Section: New Perspectivesmentioning

confidence: 99%

“…30,31 Pioglitazone reduces hepatic glucose output, increases glucose uptake in muscle, also improves and preserves pancreatic β-cell function, and is a potent inhibitor of lipolysis. 30,31 GLP-1 receptor agonists increase insulin secretion and reduce glucagon secretion, thereby inhibiting hepatic glucose output and also act on the brain, reducing appetite and promoting weight loss. 31 GLP-1 receptor agonists can, therefore, mitigate the weight increase associated with pioglitazone use.…”

Section: New Perspectivesmentioning

confidence: 99%

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Rehabilitation of pioglitazone

Ryder

DeFronzo

2015

Br J Diabetes

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Section: New Perspectivesmentioning

confidence: 99%

Section: New Perspectivesmentioning

confidence: 99%

Section: New Perspectivesmentioning

confidence: 99%

Section: New Perspectivesmentioning

confidence: 99%

Section: New Perspectivesmentioning

confidence: 99%

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Rehabilitation of pioglitazone

Ryder

DeFronzo

2015

Br J Diabetes

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Initial Choice of Oral Glucose-Lowering Medication for Diabetes Mellitus

et al. 2014

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IMPORTANCE Although many classes of oral glucose-lowering medications have been approved for use, little comparative effectiveness evidence exists to guide initial selection of therapy for diabetes mellitus. OBJECTIVE To determine the effect of initial oral glucose-lowering agent class on subsequent need for treatment intensification and 4 short-term adverse clinical events. DESIGN, SETTING, AND PARTICIPANTS This study was a retrospective cohort study of patients who were fully insured members of Aetna (a large national health insurer) who had been prescribed an oral glucose-lowering medication from July 1, 2009, through June 30, 2013. Individuals newly prescribed an oral glucose-lowering agent who filled a second prescription for a medication in the same class and with a dosage at or above the World Health Organization's defined daily dose within 90 days of the end-of-day's supply of the first prescription were studied. Individuals with interim prescriptions for other oral glucose-lowering medications were excluded. EXPOSURES Initiation of treatment with metformin, a sulfonylurea, a thiazolidinedione, or a dipeptidyl peptidase 4 inhibitor. MAIN OUTCOMES AND MEASURES Time to addition of a second oral agent or insulin, each component separately, hypoglycemia, other diabetes-related emergency department visits, and cardiovascular events. RESULTS A total of 15 516 patients met the inclusion criteria, of whom 8964 (57.8%) started therapy with metformin. In unadjusted analyses, use of medications other than metformin was significantly associated with an increased risk of adding a second oral agent only, insulin only, and a second agent or insulin (P < .001 for all). In propensity score and multivariable-adjusted Cox proportional hazards models, initiation of therapy with sulfonylureas (hazard ratio [HR], 1.68; 95% CI, 1.57-1.79), thiazolidinediones (HR, 1.61; 95% CI, 1.43-1.80), and dipeptidyl peptidase 4 inhibitors (HR, 1.62; 95% CI, 1.47-1.79) was associated with an increased hazard of intensification. Alternatives to metformin were not associated with a reduced risk of hypoglycemia, emergency department visits, or cardiovascular events. CONCLUSIONS AND RELEVANCE Despite guidelines, only 57.8% of individuals began diabetes treatment with metformin. Beginning treatment with metformin was associated with reduced subsequent treatment intensification, without differences in rates of hypoglycemia or other adverse clinical events. These findings have significant implications for quality of life and medication costs.

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Long-term Sustainability of Diabetes Prevention Approaches

et al. 2017

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IMPORTANCE Diabetes prevention is imperative to slow worldwide growth of diabetes-related morbidity and mortality. Yet the long-term efficacy of prevention strategies remains unknown.OBJECTIVE To estimate aggregate long-term effects of different diabetes prevention strategies on diabetes incidence.DATA SOURCES Systematic searches of MEDLINE, EMBASE, Cochrane Library, and Web of Science databases. The initial search was conducted on January 14, 2014, and was updated on February 20, 2015. Search terms included prediabetes, primary prevention, and risk reduction.STUDY SELECTION Eligible randomized clinical trials evaluated lifestyle modification (LSM) and medication interventions (>6 months) for diabetes prevention in adults (age Ն18 years) at risk for diabetes, reporting between-group differences in diabetes incidence, published between January 1, 1990, and January 1, 2015. Studies testing alternative therapies and bariatric surgery, as well as those involving participants with gestational diabetes, type 1 or 2 diabetes, and metabolic syndrome, were excluded. DATA EXTRACTION AND SYNTHESISReviewers extracted the number of diabetes cases at the end of active intervention in treatment and control groups. Random-effects meta-analyses were used to obtain pooled relative risks (RRs), and reported incidence rates were used to compute pooled risk differences (RDs). MAIN OUTCOMES AND MEASURESThe main outcome was aggregate RRs of diabetes in treatment vs control participants. Treatment subtypes (ie, LSM components, medication classes) were stratified. To estimate sustainability, post-washout and follow-up RRs for medications and LSM interventions, respectively, were examined. RESULTS Forty-three studies were included and pooled in meta-analysis (49 029 participants; mean [SD] age, 57.3 [8.7] years; 48.0% [n = 23 549] men): 19 tested medications; 19 evaluated LSM, and 5 tested combined medications and LSM. At the end of the active intervention (range, 0.5-6.3 years), LSM was associated with an RR reduction of 39% (RR, 0.61; 95% CI, 0.54-0.68), and medications were associated with an RR reduction of 36% (RR, 0.64; 95% CI, 0.54-0.76). The observed RD for LSM and medication studies was 4.0 (95% CI, 1.8-6.3) cases per 100 person-years or a number-needed-to-treat of 25. At the end of the washout or follow-up periods, LSM studies (mean follow-up, 7.2 years; range, 5.7-9.4 years) achieved an RR reduction of 28% (RR, 0.72; 95% CI, 0.60-0.86); medication studies (mean follow-up, 17 weeks; range, 2-52 weeks) showed no sustained RR reduction (RR, 0.95; 95% CI, 0.79-1.14). CONCLUSIONS AND RELEVANCEIn adults at risk for diabetes, LSM and medications (weight loss and insulin-sensitizing agents) successfully reduced diabetes incidence. Medication effects were short lived. The LSM interventions were sustained for several years; however, their effects declined with time, suggesting that interventions to preserve effects are needed.

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Pathophysiologic Approach to Therapy in Patients With Newly Diagnosed Type 2 Diabetes

Cited by 253 publications

References 188 publications

Rehabilitation of pioglitazone

Rehabilitation of pioglitazone

Initial Choice of Oral Glucose-Lowering Medication for Diabetes Mellitus

Long-term Sustainability of Diabetes Prevention Approaches

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