Diabetes Care Volume 40, March 2017 291 Basal Glucose Can Be Controlled, Matthew C. Riddle but the Prandial Problem PersistsdIt’stheNextTarget! PERSPECTIVES IN CARE Diabetes Care 2017;40:291–300 | DOI: 10.2337/dc16-2380 Both basal and postprandial elevations contribute to the hyperglycemic exposure of diabetes, but current therapies are mainly effective in controlling the basal compo- nent. Inability to control postprandial hyperglycemia limits success in maintaining overall glycemic control beyond the first 5 to 10 years after diagnosis, and it is also related to the weight gain that is common during insulin therapy. The “prandial problem”dcomprising abnormalities of glucose and other metabolites, weight gain, and risk of hypoglycemiaddeserves more attention. Several approaches to prandial abnormalities have recently been studied, but the patient populations for which they are best suited and the best ways of using them remain incompletely defined. Encouragingly, several proof-of-concept studies suggest that short-acting glucagon- like peptide 1 agonists or the amylin agonist pramlintide can be very effective in controlling postprandial hyperglycemia in type 2 diabetes in specific settings. This article reviews these topics and proposes that a greater proportion of available resources be directed to basic and clinical research on the prandial problem. Widespread self-testing of blood glucose and, more recently, continuous glucose mon- itoring (CGM) have drawn attention to the daily patterns of blood glucose in both type 1 and type 2 diabetes. Seeing these patterns has allowed separate consideration of fasting (basal) hyperglycemia and after-meal (postprandial) increments of glucose above basal levels. In entirely healthy individuals, fasting plasma glucose is rarely .100 mg/dL (5.5 mmol/L). Peak values after meals are ,140 mg/dL (7.8 mmol/L) and return quickly to basal levels. In the early stages of dysglycemia, high basal glucose (described as impaired fasting glucose) is the main abnormality for some people, whereas for others hyperglycemia after meals or an oral glucose load (impaired glucose tolerance) is more evident. These differences reflect varying mechanisms, may predict specific responses to initial treatments, and deserve further study. However, both basal and postprandial hyperglycemia are routinely present later in the natural history of type 2 diabetes, in part because sustained hyperglycemia can impair both the secretion and the various Division of Endocrinology, Diabetes & Clinical actions of insulin. Both are always present in type 1 diabetes. In the last 25 years we Nutrition, Oregon Health & Science University, have become very successful in managing basal hyperglycemia, but postprandial hy- Portland, OR perglycemia and its associated abnormalities remain untamed. Corresponding author: Matthew C. Riddle, riddlem@ ohsu.edu. STUDIES OF BASAL GLYCEMIC THERAPIES IN TYPE 2 DIABETES Received 7 November 2016 and accepted 10 In untreated type 2 diabetes, basal hyperglycemia is usually quantitatively greater than December 2016. further elevation of glucose after meals, especially when A1C is .8.0% (64 mmol/mol) © 2017 by the American Diabetes Association. (1–4). This is fortunate because most treatments for type 2 diabetes are more effective Readers may use this article as long as the work is properly cited, the use is educational and not in controlling basal hyperglycemia. Metformin, sulfonylureas, thiazolidinediones, and for profit, and the work is not altered. More infor- basal insulins (human NPH and insulins glargine, detemir, and degludec) all have rel- mation is available at http://www.diabetesjournals atively modest effects on postprandial hyperglycemia. The same is true for most of the .org/content/license. 292 The Prandial Problem Diabetes Care Volume 40, March 2017 newer agents, including dipeptidyl pepti- 12,500 patients with impaired fasting accompanying the use of glargine 100 dase 4 inhibitors, sodium–glucose co- glucose, impaired glucose tolerance, or units/mL described above suggests that transporter blockers, and longer-acting type 2 diabetes treated with no more individuals who have low BMI and low glucagon-like peptide 1 (GLP-1) receptor than one oral agent (and also selected basal insulin requirements might be agonists. Consequently, in a mixed popu- for high cardiovascular risk) were ran- most likely to have more stable glycemic lation of type 2 diabetes, glycemic expo- domized to either stepwise oral therapy control with a longer-acting insulin (12). sure from basal hyperglycemia is typically (in most cases metformin and glimepiride) When the risk of hypoglycemia is reduced, dominant when A1C is high, and when or insulin glargine added to any prior oral further titration of dosage during long- control is improved by treatment, the therapy and titrated to specific targets. term follow-up might favor more frequent contribution from postprandial hypergly- For the 88% of patients in ORIGIN with attainment of A1C targets, but this expec- cemia becomes more prominent (5). Even overt diabetes at enrollment, the mean du- tation has been difficult to verify (17,18). when dietary or pharmacological treat- ration of diabetes was 4 years and median Long-acting GLP-1 receptor agonists ment maintains A1C values below the A1C was 6.6% (49 mmol/mol) (11). After are an alternative to basal insulin for pa- 7.0% (53 mmol/mol) target, residual post- 7 years of treatment A1C was 6.6% with tients with high risk of hypoglycemia and prandial hyperglycemia commonly limits the regimen based on oral therapy (with can be combined with basal insulins to attainment of A1C ,6.5%, the upper end ;10% needing to add insulin) and 6.3% provide further improvement of glycemic of the normal range (4,6). Persistence of (45 mmol/mol) with the basal insulin regi- control beyond what is possible with ei- postprandial hyperglycemia is most evi- men. Safety findings were reassuring even ther component alone (19). They have a dent when long-acting (basal) insulin is in this high-risk population and similar be- favorable effect on weight but, like basal added to one or more oral agents and tween the regimens except for a threefold insulin, only a modest effect on incre- systematically titrated to a fasting glucose greater frequency of hypoglycemia in the ments of glucose after meals (20,21). target. An analysis of self-measured glu- basal insulin arm. In summary, with an array of oral and cose profiles in type 2 diabetes no longer Hypoglycemia is associated with mor- injectable agents to control basal hyper- well controlled with oral agents, pooled bidity and mortality and is the leading glycemia, as well as the recent addition from six studies, found that 79% of the limitation of basal insulin therapy. In of basal insulins with improved profiles glucose elevation .100 mg/dL was due ORIGIN, younger age, lower BMI, and of action, type 2 diabetes can usually be to basal hyperglycemia (7). Six months lower attained dosage of glargine as basal managed well for the first decade after after initiation of basal insulin, 34% of insulin were independent predictors of diagnosis. In this time frame, the leading the hyperglycemic burden was basal and nonsevere hypoglycemia (12). In contrast, barriers to maintaining A1C ,7.0% are 66% was postprandial. In studies of this and consistent with other studies, events delay in diagnosis, clinical inertia in ad- kind, average fasting glucose after optimi- requiring assistance by another person vancing therapy (22), and difficulty iden- zation of basal insulin generally ranges were associated with older age and evi- tifying patients at greatest risk for between 100 and 130 mg/dL (6.6 and dence of renal or cognitive impairment hypoglycemia to allow use of alternative 7.3 mmol/L) and mean A1C is close to (12,13). Although a causal relationship treatment goals or methods. 7.0% (53 mmol/mol). Even when basal in- between hypoglycemia and poor medical sulin is expertly titrated, significant pran- outcomes has been difficult to verify in THE PRANDIAL PROBLEM PERSISTS dial hyperglycemia may persist. For type 2 diabetes, recurrent or severe hy- After longer duration of type 2 diabetes example, an experienced research group poglycemia calls for measures to mitigate (and for most patients with type 1 diabe- showed that for 61 patients whose mean risks (13,14). The simplest such measure tes), control of postprandial hyperglyce- baseline A1C was 9.5% (80 mmol/mol) on is relaxation of goals for A1C, typically by mia is the main unmet need, and it tends one or two oral agents, 36 weeks of titra- increasing the target range from ,7.0% to become more difficult over time. Be- tion of insulin glargine with continuation to between 7 and 8% for higher-risk pa- cause type 2 diabetes is now often diag- of metformin led to excellent control tients. Use of the new basal insulins (in- nosed before age 40, increasing numbers of fasting glucose (mean 104 mg/dL sulin degludec [Tresiba] and insulin of patients no longer maintain adequate [5.75 mmol/L]). However, the mean A1C glargine 300 units/mL [Toujeo]), both of glycemic control with basal therapies was 7.14% (54 mmol/mol), and half the which have longer and flatter glucose- alone at an age when they should have group still had A1C .7%, mainly because lowering profiles, may reduce the risk several decades of productive life ahead, of daytime hyperglycemia (8). of hypoglycemia while maintaining provided microvascular complications Attainment of A1C levels ,7.0% is desired levels of glycemic control. Di- can be prevented. more likely when basal insulin is started rect comparisons of degludec (15) and The usual recommendation for treat- before A1C is markedly elevated. Analysis glargine 300 units/mL (16) with glargine ment intensification in this setting has of data from .2,000 participants in 100 units/mL (Lantus) as ongoing basal been to start basal-bolus insulin therapy 12 studies showed that when baseline therapy in type 2 diabetes have shown or at least twice-daily injection of pre- A1C was between 7 and 8% (mean 7.6% ;30% lower risk of confirmed hypoglyce- mixed insulins.