Michael A. Nauck

Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)

Erratum to: DiabetologiaDOI 10.1007/s00125-012-2534-0In the text box ‘Properties of currently available glucose-lowering agents that may guide treatment choice in individualpatients with type 2 diabetes mellitus ’ vildagliptin was incor-rectly assigned footnote ‘a’ (Limited use in the USA/Europe)instead of footnote ‘b’ (Not licensed in the USA).

The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes.

Glucagon-like peptide 1 (GLP-1) is a gut-derived incretin hormone that stimulates insulin and suppresses glucagon secretion, inhibits gastric emptying, and reduces appetite and food intake. Therapeutic approaches for enhancing incretin action include degradation-resistant GLP-1 receptor agonists (incretin mimetics), and inhibitors of dipeptidyl peptidase-4 (DPP-4) activity (incretin enhancers). Clinical trials with the incretin mimetic exenatide (two injections per day or long-acting release form once weekly) and liraglutide (one injection per day) show reductions in fasting and postprandial glucose concentrations, and haemoglobin A1c (HbA1c) (1-2%), associated with weight loss (2-5 kg). The most common adverse event associated with GLP-1 receptor agonists is mild nausea, which lessens over time. Orally administered DPP-4 inhibitors, such as sitagliptin and vildagliptin, reduce HbA1c by 0.5-1.0%, with few adverse events and no weight gain. These new classes of antidiabetic agents, and incretin mimetics and enhancers, also expand beta-cell mass in preclinical studies. However, long-term clinical studies are needed to determine the benefits of targeting the incretin axis for the treatment of type 2 diabetes.

Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus.

In type-2 diabetes, the overall incretin effect is reduced. The present investigation was designed to compare insulinotropic actions of exogenous incretin hormones (gastric inhibitory peptide [GIP] and glucagon-like peptide 1 [GLP-1] [7-36 amide]) in nine type-2 diabetic patients (fasting plasma glucose 7.8 mmol/liter; hemoglobin A1c 6.3 +/- 0.6%) and in nine age- and weight-matched normal subjects. Synthetic human GIP (0.8 and 2.4 pmol/kg.min over 1 h each), GLP-1 [7-36 amide] (0.4 and 1.2 pmol/kg.min over 1 h each), and placebo were administered under hyperglycemic clamp conditions (8.75 mmol/liter) in separate experiments. Plasma GIP and GLP-1 [7-36 amide] concentrations (radioimmunoassay) were comparable to those after oral glucose with the low, and clearly supraphysiological with the high infusion rates. Both GIP and GLP-1 [7-36 amide] dose-dependently augmented insulin secretion (insulin, C-peptide) in both groups (P < 0.05). With GIP, the maximum effect in type-2 diabetic patients was significantly lower (by 54%; P < 0.05) than in normal subjects. With GLP-1 [7-36 amide] type-2 diabetic patients reached 71% of the increments in C-peptide of normal subjects (difference not significant). Glucagon was lowered during hyperglycemic clamps in normal subjects, but not in type-2 diabetic patients, and further by GLP-1 [7-36 amide] in both groups (P < 0.05), but not by GIP. In conclusion, in mild type-2 diabetes, GLP-1 [7-36 amide], in contrast to GIP, retains much of its insulinotropic activity. It also lowers glucagon concentrations.

Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient-Centered Approach: Update to a Position Statement of the American Diabetes Association and the European Association for the Study of Diabetes

In 2012, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) published a position statement on the management of hyperglycemia in patients with type 2 diabetes (1,2). This was needed because of an increasing array of antihyperglycemic drugs and growing uncertainty regarding their proper selection and sequence. Because of a paucity of comparative effectiveness research on long-term treatment outcomes with many of these medications, the 2012 publication was less prescriptive than prior consensus reports. We previously described the need to individualize both treatment targets and treatment strategies, with an emphasis on patient-centered care and shared decision making, and this continues to be our position, although there are now more head-to-head trials that show slight variance between agents with regard to glucose-lowering effects. Nevertheless, these differences are often small and would be unlikely to reflect any definite differential effect in an individual patient. The ADA and EASD have requested an update to the position statement incorporating new data from recent clinical trials. Between June and September of 2014, the Writing Group reconvened, including one face-to-face meeting, to discuss the changes. An entirely new statement was felt to be unnecessary. Instead, the group focused on those areas where revisions were suggested by a changing evidence base. This briefer article should therefore be read as an addendum to the previous full account (1,2). Glucose control remains a major focus in the management of patients with type 2 diabetes. However, this should always be in the context of a comprehensive cardiovascular risk factor reduction program, to include smoking cessation and the adoption of other healthy lifestyle habits, blood pressure control, lipid management with priority to statin medications, and, in some circumstances, antiplatelet therapy. Studies have conclusively determined that reducing hyperglycemia decreases the onset and progression of …

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

BACKGROUND The cardiovascular effect of liraglutide, a glucagon-like peptide 1 analogue, when added to standard care in patients with type 2 diabetes, remains unknown. METHODS In this double-blind trial, we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo. The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome, with a margin of 1.30 for the upper boundary of the 95% confidence interval of the hazard ratio. No adjustments for multiplicity were performed for the prespecified exploratory outcomes. RESULTS A total of 9340 patients underwent randomization. The median follow-up was 3.8 years. The primary outcome occurred in significantly fewer patients in the liraglutide group (608 of 4668 patients [13.0%]) than in the placebo group (694 of 4672 [14.9%]) (hazard ratio, 0.87; 95% confidence interval [CI], 0.78 to 0.97; P<0.001 for noninferiority; P=0.01 for superiority). Fewer patients died from cardiovascular causes in the liraglutide group (219 patients [4.7%]) than in the placebo group (278 [6.0%]) (hazard ratio, 0.78; 95% CI, 0.66 to 0.93; P=0.007). The rate of death from any cause was lower in the liraglutide group (381 patients [8.2%]) than in the placebo group (447 [9.6%]) (hazard ratio, 0.85; 95% CI, 0.74 to 0.97; P=0.02). The rates of nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure were nonsignificantly lower in the liraglutide group than in the placebo group. The most common adverse events leading to the discontinuation of liraglutide were gastrointestinal events. The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group. CONCLUSIONS In the time-to-event analysis, the rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo. (Funded by Novo Nordisk and the National Institutes of Health; LEADER ClinicalTrials.gov number, NCT01179048.).

Reduced incretin effect in Type 2 (non-insulin-dependent) diabetes

SummaryIntegrated incremental immunoreactive insulin and connecting peptide responses to an oral glucose load of 50 g and an “isoglycaemic” intravenous glucose infusion, respectively, were measured in 14 Type 2 (non-insulin-dependent) diabetic patients and 8 age- and weight-matched metabolically healthy control subjects. Differences between responses to oral and intravenous glucose administration are attributed to factors other than glucose itself (incretin effect). Despite higher glucose increases, immunoreactive insulin and connecting peptide responses after oral glucose were delayed in diabetic patients. Integrated responses were not significantly different between both groups. However, during “isoglycaemic” intravenous infusion, insulin and connecting peptide responses were greater in diabetic patients than in control subjects as a consequence of the higher glycaemic stimulus. The contribution of incretin factors to total insulin responses was 72.8 ± 6.9% (100% = response to oral load) in control subjects and 36.0 ± 8.8% in diabetic patients (p ≦ 0.05). The contribution to connecting peptide responses was 58.4 ± 7.6% in control subjects and 7.6 ± 14.5% (p ≦ 5 0.05) in diabetic patients. Ratios of integrated insulin to connecting peptide responses suggest a reduced (hepatic) insulin extraction in control subjects after oral as compared to intravenous glucose. This was not the case in diabetic patients. Immunoreactive gastric inhibitory polypeptide responses were not different between control subjects and diabetic patients. A reduced or lost incretin effect in the face of normal gastric inhibitory polypeptide response in Type 2 diabetic patients may be explained by decreased sensitivity of the B cells towards the insulinotropic effect of gastric inhibitory polypeptide or to hyposecretion or reduced effectiveness of as yet unidentified humoral or nervous gut factors with incretin activity.

Efficacy and Safety Comparison of Liraglutide, Glimepiride, and Placebo, All in Combination With Metformin, in Type 2 Diabetes: The LEAD (Liraglutide Effect and Action in Diabetes)-2 study

OBJECTIVE—The efficacy and safety of adding liraglutide (a glucagon-like peptide-1 receptor agonist) to metformin were compared with addition of placebo or glimepiride to metformin in subjects previously treated with oral antidiabetes (OAD) therapy. RESEARCH DESIGN AND METHODS—In this 26-week, double-blind, double-dummy, placebo- and active-controlled, parallel-group trial, 1,091 subjects were randomly assigned (2:2:2:1:2) to once-daily liraglutide (either 0.6, 1.2, or 1.8 mg/day injected subcutaneously), to placebo, or to glimepiride (4 mg once daily). All treatments were in combination therapy with metformin (1g twice daily). Enrolled subjects (aged 25–79 years) had type 2 diabetes, A1C of 7–11% (previous OAD monotherapy for ≥3 months) or 7–10% (previous OAD combination therapy for ≥3 months), and BMI ≤40 kg/m2. RESULTS—A1C values were significantly reduced in all liraglutide groups versus the placebo group (P < 0.0001) with mean decreases of 1.0% for 1.8 mg liraglutide, 1.2 mg liraglutide, and glimepiride and 0.7% for 0.6 mg liraglutide and an increase of 0.1% for placebo. Body weight decreased in all liraglutide groups (1.8–2.8 kg) compared with an increase in the glimepiride group (1.0 kg; P < 0.0001). The incidence of minor hypoglycemia with liraglutide (∼3%) was comparable to that with placebo but less than that with glimepiride (17%; P < 0.001). Nausea was reported by 11–19% of the liraglutide-treated subjects versus 3–4% in the placebo and glimepiride groups. The incidence of nausea declined over time. CONCLUSIONS—In subjects with type 2 diabetes, once-daily liraglutide induced similar glycemic control, reduced body weight, and lowered the occurrence of hypoglycemia compared with glimepiride, when both had background therapy of metformin.

Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients.

SummaryGlucagon-like peptide 1 (GLP-1) (7-36 amide) is a physiological incretin hormone that is released after nutrient intake from the lower gut and stimulates insulin secretion at elevated plasma glucose concentrations. Previous work has shown that even in Type 2 (non-insulin-dependent) diabetic patients GLP-1 (7-36 amide) retains much of its insulinotropic action. However, it is not known whether the magnitude of this response is sufficient to normalize plasma glucose in Type 2 diabetic patients with poor metabolic control. Therefore, in 10 Type 2 diabetic patients with unsatisfactory metabolic control (HbAlc 11.6±1.7%) on diet and sulphonylurea therapy (in some patients supplemented by metformin or acarbose), 1.2 pmol ×kg−1×min−1 GLP-1 (7-36 amide) or placebo was infused intravenously in the fasting state (plasma glucose 13.1±0.6 mmol/l). In all patients, insulin (by 17.4±4.7 nmol ×1−1×min; p=0.0157) and C-peptide (by 228.0±39.1 nmol×1−1×min; p=0.0019) increased significantly over basal levels, glucagon was reduced (by -1418±308 pmol ×1−1×min) and plasma glucose reached normal fasting concentrations (4.9±0.3 mmol/l) within 4 h of GLP-1 (7-36 amide) administration, but not with placebo. When normal fasting plasma glucose concentrations were reached insulin returned towards basal levels and plasma glucose concentrations remained stable despite the ongoing infusion of GLP-1 (7-36 amide). Therefore, exogenous GLP-1 (7-36 amide) is an effective means of normalizing fasting plasma glucose concentrations in poorly-controlled Type 2 diabetic patients. The glucose-dependence of insulinotropic actions of GLP-1 (7-36 amide) appears to be retained in such patients.

Both Subcutaneously and Intravenously Administered Glucagon-Like Peptide I Are Rapidly Degraded From the NH2-Terminus in Type II Diabetic Patients and in Healthy Subjects

To fate of exogenous glucagon-like peptide I (GLP-I)(7–36) amide was studied in nondiabetic and type II diabetic subjects using a combination of high-pressure liquid chromatography (HPLC), specific radioimmunoassays (RIAs), and a sensitive enzyme-linked immunosorbent assay (ELISA), whereby intact biologically active GLP-I and its metabolites could be determined. After GLP-I administration, the intact peptide could be measured using an NH2-terminally directed RIA or ELISA,while the difference in concentration between these assays and a COOH-terminal–specific RIA allowed determination of NH2-terminally truncated metabolites. Subcutaneous GLP-I was rapidlydegraded in a time-dependent manner, forming a metabolite, which co-eluted on HPLC with GLP-I(9–36) amide and had the same immunoreactive profile. Thirty minutes after subcutaneous GLP-I administration to diabetic patients (n = 8), the metabolite accounted for 88.5 ± 1.9% of the increase in plasma immunoreactivity determined by the COOH-terminal RIA, which was higher than the levels measured in healthy subjects (78.4 ± 3.2%; n = 8; P < 0.05). Intravenously infused GLP-I was also extensively degraded, but no significant differences were seen between the two groups. Intact GLP-I accounted for only 19.9 ± 3.4% of the increase in immunoreactivity measured with the COOH-terminal RIA in normal subjects (n = 8), and 25.0 ± 4.8% of the increase in diabetic subjects (n = 8), the remainder being the NH2-terminally truncated metabolite.

Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans

Glucagon-like peptide 1 (GLP-1) has been shown to inhibit gastric emptying of liquid meals in type 2 diabetic patients. It was the aim of the present study to compare the action of physiological and pharmacological doses of intravenous GLP-1-(7-36) amide and GLP-1-(7-37) on gastric emptying in normal volunteers. Nine healthy subjects participated (26 ± 3 yr; body mass index 22.9 ± 1.6 kg/m2; hemoglobin A1C 5.0 ± 0.2%) in five experiments on separate occasions after an overnight fast. A nasogastric tube was positioned for the determination of gastric volume by use of a dye-dilution technique (phenol red). GLP-1-(7-36) amide (0.4, 0.8, or 1.2 pmol ⋅ kg-1 ⋅ min-1), GLP-1-(7-37) (1.2 pmol ⋅ kg-1 ⋅ min-1), or placebo was infused intravenously from -30 to 240 min. A liquid meal (50 g sucrose, 8% amino acids, 440 ml, 327 kcal) was administered at 0 min. Glucose, insulin, and C-peptide were measured over 240 min. Gastric emptying was dose dependently slowed by GLP-1-(7-36) amide ( P < 0.0001). Effects of GLP-1-(7-37) at 1.2 pmol ⋅ kg-1 ⋅ min-1were virtually identical. GLP-1 dose dependently stimulated fasting insulin secretion (-30 to 0 min) and slightly reduced glucose concentrations. After the meal (0-240 min), integrated incremental glucose ( P < 0.0001) and insulin responses ( P = 0.01) were reduced (dose dependently) rather than enhanced. In conclusion, 1) GLP-1-(7-36) amide or -(7-37) inhibits gastric emptying also in normal subjects, 2) physiological doses (0.4 pmol ⋅ kg-1 ⋅ min-1) still have a significant effect, 3) despite the known insulinotropic actions of GLP-1-(7-36) amide and -(7-37), the net effect of administering GLP-1 with a meal is no change or a reduction in meal-related insulin responses. These findings suggest a primarily inhibitory function for GLP-1 (ileal brake mechanisms).Glucagon-like peptide 1 (GLP-1) has been shown to inhibit gastric emptying of liquid meals in type 2 diabetic patients. It was the aim of the present study to compare the action of physiological and pharmacological doses of intravenous GLP-1-(7-36) amide and GLP-1-(7-37) on gastric emptying in normal volunteers. Nine healthy subjects participated (26 +/- 3 yr; body mass index 22.9 +/- 1.6 kg/m2; hemoglobin A1C 5.0 +/- 0.2%) in five experiments on separate occasions after an overnight fast. A nasogastric tube was positioned for the determination of gastric volume by use of a dye-dilution technique (phenol red). GLP-1-(7-36) amide (0.4, 0.8, or 1.2 pmol.kg-1.min-1), GLP-1-(7-37) (1.2 pmol.kg-1.min-1), or placebo was infused intravenously from -30 to 240 min. A liquid meal (50 g sucrose, 8% amino acids, 440 ml, 327 kcal) was administered at 0 min. Glucose, insulin, and C-peptide were measured over 240 min. Gastric emptying was dose dependently slowed by GLP-1-(7-36) amide (P < 0.0001). Effects of GLP-1-(7-37) at 1.2 pmol.kg-1.min-1 were virtually identical. GLP.1 dose dependently stimulated fasting insulin secretion (-30 to 0 min) and slightly reduced glucose concentrations. After the meal (0-240 min), integrated incremental glucose (P < 0.0001) and insulin responses (P = 0.01) were reduced (dose dependently) rather than enhanced. In conclusion, 1) GLP-1-(7-36) amide or -(7-37) inhibits gastric emptying also in normal subjects, 2) physiological doses (0.4 pmol.kg-1.min-1) still have a significant effect, 3) despite the known insulinotropic actions of GLP-1-(7-36) amide and -(7-37), the net effect of administering GLP-1 with a meal is no change or a reduction in meal-related insulin responses. These findings suggest a primarily inhibitory function for GLP-1 (ileal brake mechanisms).