Glycemic Control for Patients With Type 2 Diabetes Mellitus: Our Evolving Faith in the Face of Evidence

Abstract

Background: We sought to determine the concordance between the accumulating evidence about the impact of tight versus less tight glycemic control in patients with type 2 diabetes mellitus since the publication of UKPDS (UK Prospective Diabetes Study) in 1998 until 2015 with the views about that evidence published in journal articles and practice guidelines.

Methods and results: We searched in top general medicine and specialty journals for articles referring to glycemic control appearing between 2006 and 2015 and identified the latest practice guidelines. To summarize the evidence, we included all published systematic reviews and meta-analyses of contemporary randomized trials of glycemic control measuring patient-important microvascular and macrovascular outcomes, and completed a meta-analysis of their follow-up extensions. We identified 16 guidelines and 328 statements. The body of evidence produced estimates warranting moderate confidence. This evidence reported no significant impact of tight glycemic control on the risk of dialysis/transplantation/renal death, blindness, or neuropathy. In the past decade, however, most published statements (77%-100%) and guidelines (95%) unequivocally endorsed benefit. There is also no significant effect on all-cause mortality, cardiovascular mortality, or stroke; however, there is a consistent 15% relative-risk reduction of nonfatal myocardial infarction. Between 2006 and 2008, most statements (47%-83%) endorsed the benefit; after 2008 (ACCORD), only a minority (21%-36%) did.

Conclusions: Discordance exists between the research evidence and academic and clinical policy statements about the value of tight glycemic control to reduce micro- and macrovascular complications. This discordance may distort priorities in the research and practice agendas designed to improve the lives of patients with type 2 diabetes mellitus.

Keywords: blindness; complications; evidence-based medicine; myocardial infarction; type 2 diabetes mellitus.

Figure 1

Body of evidence and statements published in journals and guidelines in favor of tight glycemic control in patients with type 2 diabetes mellitus. A. Microvascular complications. The number of guideline statements is presented in parenthesis. ESRD, end-stage renal disease; GC, glycemic control. Black, randomized clinical trials; red, follow-up studies of included randomized clinical trials; green, meta-analyses; orange; meta-analyses of follow-up studies. † Meta-analysis including follow-up UKPDS 33 and excluding follow-up UKPDS 34. B. Macrovascular complications. The number of guideline statements is presented in parenthesis. CV, cardiovascular; GC, glycemic control; MI, myocardial infraction; PVE, peripheral vascular events. Black, randomized clinical trials; red, follow-up studies of included randomized clinical trials; green, meta-analyses; orange; meta-analyses of follow-up studies. As UKPDS 33 control patients also participated as controls in UKPDS 34, two pooled estimates were constructed including either one or the other study. †Meta-analysis including follow-up UKPDS 33 and excluding follow-up UKPDS 34 §Meta-analysis including follow-up UKPDS 34 and excluding follow-up UKPDS 33. *UKPDS 33 Follow-up (c) includes both fatal and nonfatal-MI. *UKPDS 33, UKPDS 34, Kelly et al., Trák I., Boussageon et al., Hemmingsen et al., Buehler et al. and VADT Follow-Up report only nonfatal strokes. *UKPDS 34 was not included in the 2015 meta-analysis of follow-up studies for cardiovascular mortality and nonfatal MI outcomes, as these outcomes were not reported.

Figure 1

Body of evidence and statements published in journals and guidelines in favor of tight glycemic control in patients with type 2 diabetes mellitus. A. Microvascular complications. The number of guideline statements is presented in parenthesis. ESRD, end-stage renal disease; GC, glycemic control. Black, randomized clinical trials; red, follow-up studies of included randomized clinical trials; green, meta-analyses; orange; meta-analyses of follow-up studies. † Meta-analysis including follow-up UKPDS 33 and excluding follow-up UKPDS 34. B. Macrovascular complications. The number of guideline statements is presented in parenthesis. CV, cardiovascular; GC, glycemic control; MI, myocardial infraction; PVE, peripheral vascular events. Black, randomized clinical trials; red, follow-up studies of included randomized clinical trials; green, meta-analyses; orange; meta-analyses of follow-up studies. As UKPDS 33 control patients also participated as controls in UKPDS 34, two pooled estimates were constructed including either one or the other study. †Meta-analysis including follow-up UKPDS 33 and excluding follow-up UKPDS 34 §Meta-analysis including follow-up UKPDS 34 and excluding follow-up UKPDS 33. *UKPDS 33 Follow-up (c) includes both fatal and nonfatal-MI. *UKPDS 33, UKPDS 34, Kelly et al., Trák I., Boussageon et al., Hemmingsen et al., Buehler et al. and VADT Follow-Up report only nonfatal strokes. *UKPDS 34 was not included in the 2015 meta-analysis of follow-up studies for cardiovascular mortality and nonfatal MI outcomes, as these outcomes were not reported.

Figure 2

A. End-of-study mean HbA1c and rate of microvascular complications and macrovascular complications in the tight (red) and less tight (black) glycemic control groups (square: UKPDS 33; triangle: UKPDS 34; circle: ACCORD; diamond: ADVANCE; Cross: VADT). GC, glycemic control; ESRD, end-stage renal disease; NNH, Number needed to harm; NNT, number needed to treat. B. End-of-study mean HbA1c and risk of macrovascular complications and severe hypoglycemia (Panel B) in the tight (red) and conventional (black) glycemic control groups of included studies (square: UKPDS 33; triangle: UKPDS 34; circle: ACCORD; diamond: ADVANCE; Cross: VADT). GC, glycemic control; MI, myocardial infarction; NNH, number needed to harm; NNT, number needed to treat.

Figure 2

A. End-of-study mean HbA1c and rate of microvascular complications and macrovascular complications in the tight (red) and less tight (black) glycemic control groups (square: UKPDS 33; triangle: UKPDS 34; circle: ACCORD; diamond: ADVANCE; Cross: VADT). GC, glycemic control; ESRD, end-stage renal disease; NNH, Number needed to harm; NNT, number needed to treat. B. End-of-study mean HbA1c and risk of macrovascular complications and severe hypoglycemia (Panel B) in the tight (red) and conventional (black) glycemic control groups of included studies (square: UKPDS 33; triangle: UKPDS 34; circle: ACCORD; diamond: ADVANCE; Cross: VADT). GC, glycemic control; MI, myocardial infarction; NNH, number needed to harm; NNT, number needed to treat.