The Rationale for Paired Pre- and Postprandial Self-monitoring of Blood Glucose: The Role of Glycemic Variability in Micro- and Macrovascular Risk

Gerich JE, Odawara M, Terauchi Y. Curr Med Res Opin. 2007;23:1791-1798.

Glycemic control based on A1C levels remains far from optimal in patients with type 1 and type 2 diabetes, even though landmark studies have shown that intensive therapy to improve overall glycemic control (as measured by A1C) is associated with a reduction in disease complications. Nevertheless, placing the focus of patient-management decisions exclusively on achieving certain A1C targets (such as < 7% or ≤ 6.5 %) has ignored the fact that postprandial hyperglycemia (PPHG) contributes the bulk of glycemic exposure at A1C levels < 8.4%, and fasting hyperglycemia is the main contributor to A1C at higher levels. In addition to its contribution to overall glycemic control, PPHG appears to be independently linked to macrovascular complications of diabetes. Although no randomized, prospective data are available, the available observational data provide compelling evidence for the importance of controlling PPHG. The authors of this commentary present the view, based on their MEDLINE search of relevant primary articles and meta-analyses, that postprandial glycemic spikes, rather than glycemic exposure over 2 to 3 months (A1C level), are key to the development of macrovascular complications and suggest more attention be paid to minimizing PPHG and glycemic variability as an approach to improving patient outcomes.

PPHG (or post-challenge hyperglycemia [PCHG]) is common in patients with both type 1 diabetes and type 2 diabetes and has been linked to complications of cardiovascular disease (CVD) and hypertension. Despite A1C levels < 7.5%, patients with type 2 diabetes have high 2-hour postprandial glucose values (> 144 mg/dL) after 57% of all meals. Insulin-treated type 1 and type 2 patients who were monitored continuously with sensors for high (≥ 200 mg/dL) and low (≤ 80 mg/dL) glucose alerts spent 21% less time with hypoglycemia (≤ 55 mg/dL), 23% less time with hyperglycemia (≥ 240 mg/dL), 26% more time in the target glucose range (81-140 mg/dL, P < .001 each), and displayed significantly reduced nocturnal hypoglycemia compared with patients who performed self-monitoring of blood glucose (SMBG) alone, indicating a benefit of more frequent glucose sampling. Indeed, according to the German Retrospective (ROSSO) Study Self-monitoring of Blood Glucose and Outcome in Patients With Type 2 Diabetes, SMBG is associated with decreased diabetes-related morbidity and all-cause mortality, possibly due to changes in eating behavior or activity levels that may have resulted in improved glycemic control. The Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in Europe (DECODE) study (whose results were confirmed by the DECODA study of people of Japanese and Asian-Indian origin) concluded that impaired glucose tolerance (IGT), defined as 2-hour post-challenge (75-g oral glucose tolerance test) glucose ≥ 200 mg/dL was an independent risk factor for death from CVD and all causes. A 1-hour postprandial glucose level was an independent risk factor for death in patients with newly detected type 2 diabetes according to the Diabetes Intervention Study. Targeting PPHG with acarbose appeared to effect a significant reduction in cardiovascular events (P = .03; 95% CI: 0.28-0.95) and cases of hypertension (P = .006; 95% CI: 0.49-0.89) in the Study to Prevent Non-Insulin Dependent Diabetes Mellitus (STOP-NIDDM) trial.

Postprandial blood glucose has also been linked to retinopathy and neuropathy as demonstrated by the Diabetes Control and Complications Trial (DCCT), in which the risk of progression of retinopathy over time was greater for conventionally-treated patients than for intensively managed patients who received more frequent insulin injections. Risk for progression of retinopathy may therefore be more readily explained by the amplitude of postprandial glycemic spikes (excursions) or glycemic variability than by A1C level. The largest number of excess deaths in the DECODE study occurred in individuals who had a fasting glucose level ≤ 6.1 mmol/L and higher spike in terms of increase from baseline to 2-hour glucose value. Acute glucose fluctuations also showed a positive correlation with an increased production of a prostaglandin marker of free radical production, thought to be the key factor underlying 4 major biochemical pathways linking hyperglycemia to microvascular and macrovascular complications of diabetes. In contrast, no such correlation was observed with A1C or fasting plasma glucose levels or chronic hyperglycemia. Still other studies such as the DCCT trial failed to find these associations. Consequently, the current perception of professional diabetes associations regarding management of the hyperglycemic patient continues to revolve around measurement of A1C levels, although their recommendations include a need for monitoring both pre- and postprandial glucose levels to effect a maximal reduction of A1C levels.

In addition to acarbose, which improved overall glycemic control and significantly reduced the risk for myocardial infarction (P = .012) while displaying a high association with undesirable gastrointestinal side effects, agents that delay carbohydrate absorption form the gut (including a-glucosidase inhibitors), short-acting insulin secretagogs (eg, sulfonylureas and meglitinide analogs), rapid-acting insulin analogs (eg, lispro, aspart, and glulisine), the amylin and glucagon-like peptide-1 (GLP-1) analogs pramlintide and exenatide, respectively, as well as the dipeptidyl peptidase 4 (DPP-4) inhibitors sitagliptin and vildagliptin, have each demonstrated an ability to control PPHG and thus have the potential to reduce CVD complications in both type 1 and type 2 diabetes.

Managing glycemic levels by focusing on PPHG and postprandial glycemic excursions—combined with patient education designed to influence the effects of meal choices, medications, and activity levels on blood glucose, and paired-meal testing and occasional glucose profiles to provide healthcare professionals with a tool to evaluate specific glycemic defects—can help patients with diabetes achieve normoglycemic levels and avoid cardiovascular risks.