Barbara N. Campaigne

Effects of Prandial Versus Fasting Glycemia on Cardiovascular Outcomes in Type 2 Diabetes: The HEART2D trial

OBJECTIVE—Hyperglycemia and Its Effect After Acute Myocardial Infarction on Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus (HEART2D) is a multinational, randomized, controlled trial designed to compare the effects of prandial versus fasting glycemic control on risk for cardiovascular outcomes in patients with type 2 diabetes after acute myocardial infarction (AMI). RESEARCH DESIGN AND METHODS—Patients (type 2 diabetes, aged 30–75 years) were randomly assigned within 21 days after AMI to the 1) prandial strategy (PRANDIAL) (three premeal doses of insulin lispro targeting 2-h postprandial blood glucose <7.5 mmol/l) or the 2) basal strategy (BASAL) (NPH twice daily or insulin glargine once daily targeting fasting/premeal blood glucose <6.7 mmol/l). RESULTS—A total of 1,115 patients were randomly assigned (PRANDIAL n = 557; BASAL n = 558), and the mean patient participation after randomization was 963 days (range 1–1,687 days). The trial was stopped for lack of efficacy. Risks of first combined adjudicated primary cardiovascular events in the PRANDIAL (n = 174, 31.2%) and BASAL (n = 181, 32.4%) groups were similar (hazard ratio 0.98 [95% CI 0.8–1.21]). Mean A1C did not differ between the PRANDIAL and BASAL groups (7.7 ± 0.1 vs. 7.8 ± 0.1%; P = 0.4) during the study. The PRANDIAL group showed a lower daily mean postprandial blood glucose (7.8 vs. 8.6 mmol/l; P < 0.01) and 2-h postprandial blood glucose excursion (0.1 vs. 1.3 mmol/l; P < 0.001) versus the BASAL group. The BASAL group showed lower mean fasting blood glucose (7.0 vs. 8.1 mmol/l; P < 0.001) and similar daily fasting/premeal blood glucose (7.7 vs. 7.3 mmol/l; P = 0.233) versus the PRANDIAL group. CONCLUSIONS—Treating diabetic survivors of AMI with prandial versus basal strategies achieved differences in fasting blood glucose, less-than-expected differences in postprandial blood glucose, similar levels of A1C, and no difference in risk for future cardiovascular event rates.

Natural History of Cardiovascular Disease in Patients With Diabetes: Role of hyperglycemia

Atherosclerotic vascular disease is more common in diabetic than in nondiabetic individuals. Diabetic macrovascular disease also has a more severe course with greater prevalence of multiple-vessel coronary artery disease and more diffuse elongated atheromas in affected blood vessels. In this review, we discuss possible reasons for increased incidence of cardiovascular (CV) events in individuals with diabetes. Although an increased prevalence of standard CV risk factors has been clearly documented in association with diabetes, diabetes-related abnormalities, particularly hyperglycemia, also play an important role. Epidemiological studies suggest that the effect of hyperglycemia on CV risk is independent of other known risk factors, but no data from primary interventional trials are available yet. Analysis of datasets from populations that included individuals with impaired glucose tolerance and impaired fasting glucose suggest that the pathogenic role of hyperglycemia on the blood vessel wall already exists in the early stages of glucose intolerance. The effect of postprandial or postchallenge hyperglycemia seems to be greater than the effect of fasting blood glucose abnormalities. The relationship of postprandial glycemia, fasting blood glucose, and CV risk in individuals with diagnosed (or overt) diabetes is less clear, although most reports indicate a greater pathogenic potential of postprandial hyperglycemia rather than fasting hyperglycemia. Based on the results of epidemiological reports, the most appropriate targets in interventional trials are postprandial hyperglycemia or A1C.

Effects of Exercise Training on Insulin Sensitivity in Adolescents with Type I Diabetes

We investigated the influence of a program of exercise training consisting of three weekly sessions, each 45 min long, for 12 wk, on indices of physical fitness, glycemic control, and insulin sensitivity in nine adolescents with type I diabetes; six age-matched adolescents with diabetes of equivalent duration served as nonexercised controls. All subjects were instructed not to change dialy insulin dose or caloric intake. In the exercised group, maximal oxygen uptake during graded cycle ergometry to volitional exhaustion increased by 9 ± 2.7% (P < 0.01) and lean body mass increased by 4 ± 1.8% (P < 0.05). Insulin sensitivity, assessed via the euglycemic clamp technique at insulin infusion rates of 100 mU/M2/min, showed an increase of insulin-mediated glucose disposal from 274 ± 33 to 338 ± 28 mg/M2/min, representing an increase in insulin sensitivity of 23 ± 5% (P < 0.01). None of these indices changed in the control group. Despite increased insulin sensitivity, glycohemoglobin levels remained at 12 ± 1% before and after the 12 wk of exercise training, indicating no improvement in overall glycemic control. No increase in hypoglycemic reactions was reported in either group. We conclude that exercise training may be a valuable adjunct in managing type I diabetes providing there is concomitant attention to diet and insulin. Exercise training alone, however, does not improve glycemic control, although it improves physical fitness and insulin sensitivity.

Glucose and Insulin Responses in Relation to Insulin Dose and Caloric Intake 12 h After Acute Physical Exercise in Men With IDDM

Acute exercise in insulin-dependent diabetic patients may perturb glycemic control, and adjustments of insulin and diet might be required to avoid postexercise hypoglycemia. The aim of this study was to assess the role of alterations in insulin dose or caloric intake on blood glucose and free-insulin levels during 12 h after an evening bout of exercise. Nine insulin-dependent diabetic men (28–42 yr of age) receiving two daily injections with a combination of intermediate-acting and soluble insulin participated in the study. Patients were randomly assigned to four treatment protocols: A, 50% reduction in intermediate-acting insulin dose; B, 50% reduction in soluble insulin dose; C, extra caloric intake (1700 kj) 1 h after exercise; and D, no change. Exercise consisted of 45 min of cycling at 60% of maximal oxygen uptake at each occasion. Glucose and insulin responses were similar for the four protocols. There was a significant (P < .001) time effect found regardless of treatment, with lowest blood glucose values 75 min after exercise. Hypoglycemia occurred in six of the nine patients at some time during the study, with half of the occurrences on the control night (protocol D). Consistent individual plasma insulin and glucose patterns were observed independent of protocol used. In some patients, hypoglycemia was evident after reductions in insulin dose, and in others it was evident on the night increases in caloric intake were to occur; thus, none of the interventions were totally adequate in preventing exercise-induced hypoglycemia. In conclusion, general recommendations on how to adjust insulin or diet before exercise are difficult to give. Individualized recommendations for treatment modification appear most appropriate.

Effects of a fixed mixture of 25% insulin lispro and 75% NPL on plasma glucose during and after moderate physical exercise in patients with type 2 diabetes.

Summary Objective: To compare the plasma glucose (PG) response with a fixed mixture of 25% insulin lispro and 75% NPL (Mix25), prior to a meal and 3 h before exercise, to human insulin 30/70 (30/70) in patients with type 2 diabetes. Research design and methods: Thirty-seven patients were treated in a randomized, open-label, 8-week, two-period crossover study. Mix25 was injected 5 min before breakfast and dinner throughout the study, as was 30/70 on inpatient test days and on outpatient dose titration days. Following the 4-week outpatient phase, patients were hospitalized, and exercised at a heart rate of 120 beats/min on a cycle ergometer two times for 30 min, separated by 30 min rest, starting 3 h after a 339 kcal breakfast. Results: The 2-h postprandial PG was significantly lower with Mix25 ((mean ± SEM) 10.5 ± 0.4 mmol/lvs 11.6 ± 0.4 mmol/l; p = 0.016). Maximum decrease in PG from onset of exercise to end of exercise was significantly less with Mix25 (-3.6 ± 0.29 mmol/l vs -4.7 ± 0.31 mmol/l; p = 0.001). The maximum decrease in PG over 6 h, after exercise onset, was significantly less with Mix25 (-4.3 ± 0.4 mmol/l vs -5.9 ± 0.4 mmol/l; p < 0.001). The frequency of hypoglycemia (blood glucose (BG) < 3 mmol/l or symptoms) during the inpatient test was not different between treatments. During the outpatient phase, the frequency of patient-recorded hypoglycemia was significantly lower with Mix25 (0.7 ± 0.2 episodes/30d vs 1.2 ± 0.3 episodes/30 d; p = 0.042). Conclusions: Mix25 resulted in better postprandial PG control without an increase in exercise-induced hypoglycemia. The smaller decrease in PG during the postprandial phase after exercise may suggest a lower risk of exercise-induced hypoglycemia with Mix25 than with human insulin 30/70, especially for patients in tight glycemic control.

Impact of prandial plus basal vs basal insulin on glycemic variability in type 2 diabetic patients.

OBJECTIVE To determine whether metformin-treated patients with type 2 diabetes given an analogue mixture of basal and rapid-acting insulins (insulin lispro protamine suspension plus insulin lispro) would have less glycemic variability than patients given basal insulin glargine. METHODS Two post hoc analyses were used to compare 7-point blood glucose profiles from 3 published studies comparing basal plus prandial premixed insulin lispro mixtures with insulin glargine in metformin-treated patients with type 2 diabetes. Glycemic variability indices used included standard deviation of mean daily blood glucose, coefficient of variation, M-value, mean amplitude of glycemic excursion, and J-index. RESULTS Patients on the twice-daily insulin lispro mix 75/25 (75% insulin lispro protamine suspension/25% insulin lispro) plus metformin regimen had significantly lower standard deviation, M-value, and J-index than patients on the insulin glargine plus metformin regimen, but not lower coefficient of variation or mean amplitude of glycemic excursion. Patients on the 3 times daily insulin lispro mix 50/50 (50% insulin lispro protamine suspension/50% insulin insulin lispro) plus metformin regimen had significantly lower values for all 5 indices than patients on the insulin glargine plus metformin regimen. CONCLUSION Use of basal plus prandial insulin lispro mixtures at 2 or 3 meals was associated with lower glycemic variability in metformin-treated patients with type 2 diabetes.

Sravnenie kombinatsiy insulina lizpromiks 25 s metforminom i insulina glarginas metforminom pri lechenii patsientovs sakharnym diabetom 2 tipa,ranee ne poluchavshikh insulinoterapii(16-nedel'noe randomizirovannoe otkrytoeperekrestnoe issledovanie)

Цель. Оценка гликемического ответа при назначении лизпро микс 25 2 раза в сутки в комбинации с метформином по сравнению с терапией инсулином гларгином один раз в сутки в комбинации с метформином у пациентов с СД 2 типа. Материалы и методы. Данное исследование было рандомизированным проспективным открытым перекрестным исследованием, проведенным в 12 центрах в США. Исследование начиналось с вводного периода продолжительностью 8?2 нед для ознакомления пациентов с введением инсулина и стандартизации предрандомизационной терапии. После вводного периода пациенты были случайным образом распределены либо в группу лечения сначала комбинацией лизпро микс 25, вводимого перед завтраком и ужином, с метформином в дозе от 1500 до 2550 мг в день в течение 16 нед, а затем комбинацией инсулина гларгина, вводимого перед сном, с метформином в дозе от 1500 до 2550 мг в день в течение последующих 16 недель, либо в группу лечения в обратной последовательности. данное исследование было проведено в условиях, имитирующих естественную клиническую ситуацию, когда исследователи для коррекции дозы инсулина использовали целевые параметры гликемии, но не алгоритм введения инсулина. Основной переменной эффективности был уровень HbAlc в конце каждого периода лечения. Результаты. В обеих группах лечения было отмечено достоверное снижение уровня HbAlc в конечной точке по сравнению с исходным. Однако в группе лечения лизпро микс 25 снижение среднего (СО) показателя HbAlc было больше (?1,3% и -0,9%). При терапии исследуемыми комбинациями препаратов среднее значение (? СО) уровня ГКН исходно составило 152,8?47,2 мг/дл; средний уровень ГКН в конечной точке был достоверно ниже на фоне лечения инсулином гларгином. На фоне проводимой терапии ни у одного пациента не было отмечено тяжелой гипогликемии. Выводы. В исследованной популяции пациентов с СД 2 типа применение лизпро микс 25 в сочетании с мет-формином позволило добиться более низкого уровня HbA1c, чем терапия инсулином гларгином в комбинации с метформином, обеспечить достижение целевого уровня HbA1c<7,0% у большинства пациентов и способствовало меньшему подъему ППГК после завтрака и ужина при незначительном увеличении общей частоты эпизодов гипогликемии (но не ночных эпизодов гипогликемии). В настоящем исследовании введение лизпро микс 25 в комбинации с метформином оказалось эффективным вариантом лечения у пациентов с СД 2 типа, которым впервые назначена инсулинотерапия.