United States experience of insulin degludec alone or in combination for type 1 and type 2 diabetes.

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pioglitazone 2 endocrinologydiseasesdrugs
Insulin 9 endocrinologydiseasesdrugs
Liraglutide 4 endocrinologydiseasesdrugs
hyperglycemia 1 endocrinologydiseases
hypoglycemia 54 endocrinologydiseases
metformin 7 endocrinologydiseasesdrugs
obesity 1 endocrinologydiseases

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Select Drug Character Offset Drug Term Instance
Insulin 339 Investigators, Newport Coast, CA, USAPublication date (collection): /2017Publication date (epub): 4/2017Abstract Insulin degludec has been the product of a sophisticated and systematic biochemical engineering program which
Insulin 4655 the human insulin peptide B chain with lysine substituted at position 28 and proline at position 29. Insulin tends to self-associate into dimers. Three dimers combine with two zinc ions to form hexamers in β
Insulin 5215 insulin, resulting in more rapid absorption and a shorter duration of action than regular human insulin.[7] Insulin glargine was an insulin analog developed in 2000 to produce a long-acting, stable release of insulin
Insulin 7109 long-acting insulin for well over a decade, efforts to discover new synthetic basal insulins have continued. Insulin detemir was designed by Novo Nordisk (Bagsværd, Denmark) to promote increased self-association of hexamers
Insulin 8160 variability.[20],[21]Novo Nordisk pursued further modifications of the long-acting insulin analogs. Insulin degludec, developed by Novo Nordisk in a continuation of the development program which produced detemir,
Insulin 8326 the development program which produced detemir, has been a recent addition to the available options. Insulin degludec has a similar structure to detemir in the deletion of threonine in the ThrB30 on the insulin
Insulin 29513 This decision led to approval of marketing of degludec in the US.[44]Comparing degludec with glargine Insulin glargine has been the dominant form of basal insulin since its initial approval in 2000. The extended
Insulin 31489 than the U100 preparation, and release of monomeric insulin also shows less variability.[45]–[47] Insulin combined with GLP-1 agonistsHowever, the single most important advantage that degludec possesses is
Insulin 37539 liraglutide certainly provide a substantial advantage for degludec in their coformulation.Conclusion Insulin degludec has been the product of a sophisticated and systematic biochemical engineering program that
Liraglutide 31797 liraglutide, which suggests a new approach to the use of basal insulin, at least in type 2 diabetes. Liraglutide is a GLP-1 receptor agonist. GLP-1 is a 37-amino acid peptide secreted from the L cells of the ileum
Liraglutide 44796 (G)0.8% (G)NN9068-3697 (DUAL-I)[53]Type 2 diabetes on metformin or metformin-pioglitazoneDegludec– Liraglutide 1.9% (D-L)1.8% (D-L)not reportedDegludec1.4% (D)2.6% (D)Liraglutide1.3% (L)0.2% (L)NN9068-3697 (DUAL-II)[54]Type
Liraglutide 44863 metformin-pioglitazoneDegludec–Liraglutide1.9% (D-L)1.8% (D-L)not reportedDegludec1.4% (D)2.6% (D) Liraglutide 1.3% (L)0.2% (L)NN9068-3697 (DUAL-II)[54]Type 2 diabetes patients inadequately controlled on glargineDegludec–Liraglutide0.74%0.30%0.10%Glargine
Liraglutide 44986 (L)NN9068-3697 (DUAL-II)[54]Type 2 diabetes patients inadequately controlled on glargineDegludec– Liraglutide 0.74%0.30%0.10%Glargine to maximum dose0.45%0.61%0.31%Notes: For each of these major studies, the study
metformin 15880 years; baseline HbA1c: 8.2%) were randomized 3:1 to receive once-daily degludec or glargine, both with metformin .[31] The reduction in HbA1c with degludec was similar (noninferior) to that with glargine (1.06% vs
metformin 34089 individual components. In a key proof-of-concept trial, type 2 diabetes patients inadequately controlled on metformin or metformin + pioglitazone were assigned to daily injections of degludec–liraglutide, degludec alone,
metformin 34102 components. In a key proof-of-concept trial, type 2 diabetes patients inadequately controlled on metformin or metformin + pioglitazone were assigned to daily injections of degludec–liraglutide, degludec alone, or liraglutide
metformin 35838 tested in patients with type 2 diabetes (HbA1c: 7.5%–10.0% on basal insulin [20–40 units]) and metformin with or without Sulfonylurea/Glinides.[55] The maximal dose of degludec allowed in this trial was 50
metformin 44057 agentsReduction in HbA1cHypoglycemic events (PYE)Nocturnal hypoglycemiaNN1250-3579[31]Type 2 diabetes on metformin Degludec1.06% (D)1.52% (D)0.25% (D)Glargine1.19% (G)1.85% (G)0.39% (G)*NN1250-3582[32]Type 2 on basal
metformin 44750 (DF)3.6% (DF)0.6% (DF)Glargine−1.26% (G)3.5% (G)0.8% (G)NN9068-3697 (DUAL-I)[53]Type 2 diabetes on metformin or metformin-pioglitazoneDegludec–Liraglutide1.9% (D-L)1.8% (D-L)not reportedDegludec1.4% (D)2.6%
metformin 44763 (DF)0.6% (DF)Glargine−1.26% (G)3.5% (G)0.8% (G)NN9068-3697 (DUAL-I)[53]Type 2 diabetes on metformin or metformin -pioglitazoneDegludec–Liraglutide1.9% (D-L)1.8% (D-L)not reportedDegludec1.4% (D)2.6% (D)Liraglutide1.3%
pioglitazone 34114 proof-of-concept trial, type 2 diabetes patients inadequately controlled on metformin or metformin + pioglitazone were assigned to daily injections of degludec–liraglutide, degludec alone, or liraglutide alone (1.8
pioglitazone 44773 (DF)Glargine−1.26% (G)3.5% (G)0.8% (G)NN9068-3697 (DUAL-I)[53]Type 2 diabetes on metformin or metformin- pioglitazone Degludec–Liraglutide1.9% (D-L)1.8% (D-L)not reportedDegludec1.4% (D)2.6% (D)Liraglutide1.3% (L)0.2%
Select Disease Character Offset Disease Term Instance
hyperglycemia 21896 stable flat insulin concentration, the more possible it is to raise insulin levels to reduce fasting hyperglycemia without engendering hypoglycemia. The prolonged duration of action suggested that degludec could be
hypoglycemia 848 unpredictable copolymerization of added aspart. In several studies, degludec has shown lower rates of nocturnal hypoglycemia than glargine. Degludec can be administered flexibly with a very flat insulin concentration curve at
hypoglycemia 1433 times weekly resulted in less effective lowering of glycated hemoglobin and an increased incidence of hypoglycemia compared to daily glargine. Conversely the coformulation of degludec and liraglutide has proven very
hypoglycemia 1607 degludec and liraglutide has proven very successful in reducing glycated hemoglobin levels with less hypoglycemia and less weight gain than with degludec alone and with less gastrointestinal symptoms than with liraglutide
hypoglycemia 4401 release of insulin and in glucose-lowering effects, with unpredictable insulin peaks that promoted hypoglycemia .A new era began in 1995 with the development of insulin analogs with modified peptide sequences. The
hypoglycemia 6396 insulin does not have as long a duration of action as glargine and develops peak concentrations at which hypoglycemia is more likely to occur. The most important advantage of glargine over NPH is reduction in the risk
hypoglycemia 6512 more likely to occur. The most important advantage of glargine over NPH is reduction in the risk of hypoglycemia , primarily at night. This advantage derives from the very flat pharmacokinetic profile of glargine,
hypoglycemia 6877 insulin therapy in patients with type 1 and type 2 diabetes and is associated with less severe nocturnal hypoglycemia and less weight gain.[12]–[16]Design of insulin degludecAlthough glargine has remained the dominant
hypoglycemia 13742 baseline, the primary endpoint in all trials, 2) fasting plasma glucose (FPG), and 3) episodes of confirmed hypoglycemia and nocturnal confirmed hypoglycemia. Hypoglycemia was defined as a measured glucose of <56 mg/dL (3.1
hypoglycemia 13779 2) fasting plasma glucose (FPG), and 3) episodes of confirmed hypoglycemia and nocturnal confirmed hypoglycemia . Hypoglycemia was defined as a measured glucose of <56 mg/dL (3.1 mmol/L), regardless of symptoms. Novo
hypoglycemia 13955 (3.1 mmol/L), regardless of symptoms. Novo Nordisk has historically used this cut-off level to define hypoglycemia , rather than the American Diabetes Association criteria (<70 mg/dL (3.9 mmol/L), because <56 mg/dL is
hypoglycemia 14162 mg/dL is typically where counterregulatory mechanisms begin and patients report clinical symptoms of hypoglycemia . Furthermore, the cutoff of 56 mg/dL was sufficiently below the target prebreakfast self-measured plasma
hypoglycemia 14550 Typically, the glucose measurements were specified at given times between dosing intervals. Severe hypoglycemia was defined as episodes requiring assistance from another person.Nocturnal hypoglycemia was prospectively
hypoglycemia 14638 intervals. Severe hypoglycemia was defined as episodes requiring assistance from another person.Nocturnal hypoglycemia was prospectively defined as episodes occurring between midnight and 6 AM to allow consistent evaluation
hypoglycemia 14792 occurring between midnight and 6 AM to allow consistent evaluation across trials. Although episodes of hypoglycemia may go unnoticed and therefore be unreported, especially at night when patients are asleep, this is
hypoglycemia 16146 degludec to glargine of 0.09% (95% confidence interval [CI]: −0.04 to 0.22). Overall rates of confirmed hypoglycemia were similar, with degludec and glargine at 1.52 vs 1.85 episodes/patient-year of exposure (PYE). Nocturnal
hypoglycemia 16277 degludec and glargine at 1.52 vs 1.85 episodes/patient-year of exposure (PYE). Nocturnal confirmed hypoglycemia in the overall population occurred at a lower rate with degludec vs glargine (0.25 vs 0.39 episodes/PYE;
hypoglycemia 16487 episodes/PYE; P=0.038). A similar percentage of patients in both groups achieved HbA1c levels <7% without hypoglycemia . End-of-trial mean daily insulin doses were 0.59 units/kg for degludec and 0.60 units/kg for glargine.[32]In
hypoglycemia 16919 in the degludec group and 1.2% in the glargine group (P: nonsignificant). Rates of overall confirmed hypoglycemia were lower with degludec than glargine (11.1 vs 13.6 episodes per PYE; estimated rate ratio 0.82, 95%
hypoglycemia 17099 PYE; estimated rate ratio 0.82, 95% CI: 0.69–0.99; P=0.0359), as were rates of nocturnal confirmed hypoglycemia (1.4 vs 1.8 episodes per PYE; 0.75, CI: [0.58–0.99]; P=0.0399).Degludec was also compared to glargine,
hypoglycemia 17636 (43%) participants achieved a target HbA1c of less than 7% (<53 mmol/mol). Rates of overall confirmed hypoglycemia were similar in the degludec and glargine groups (42.5 vs 40.2 episodes per PYE; estimated rate ratio
hypoglycemia 17835 estimated rate ratio [degludec to glargine] 1.07 [0.89–1.28]; P=0.48). The rate of nocturnal confirmed hypoglycemia was 25% lower with degludec than with glargine (4.41 vs 5.86 episodes per PYE; relative rate [RR]: 0.75
hypoglycemia 19103 similar HbA1c but greater FPG reductions than glargine subjects (−1.07 mmol/L) (P=0.005). Confirmed hypoglycemia rates (plasma glucose <3.1 mmol/L or severe hypoglycemia) were similar at weeks 26 and 52. Nocturnal
hypoglycemia 19160 subjects (−1.07 mmol/L) (P=0.005). Confirmed hypoglycemia rates (plasma glucose <3.1 mmol/L or severe hypoglycemia ) were similar at weeks 26 and 52. Nocturnal confirmed hypoglycemia occurred less frequently with degludec
hypoglycemia 19227 (plasma glucose <3.1 mmol/L or severe hypoglycemia) were similar at weeks 26 and 52. Nocturnal confirmed hypoglycemia occurred less frequently with degludec Forced-Flex vs degludec fixed dose (37%; P=0.003) and glargine
hypoglycemia 19979 for glargine (P: nonsignificant for the three treatments). There were no significant differences in hypoglycemia .[36]A meta-analysis of hypoglycemia risk of degludec compared to glargine was performed over seven trials,
hypoglycemia 20015 the three treatments). There were no significant differences in hypoglycemia.[36]A meta-analysis of hypoglycemia risk of degludec compared to glargine was performed over seven trials, five in type 2 diabetes and two
hypoglycemia 21230 no statistically significant difference between degludec–aspart and detemir in the rates of severe hypoglycemia (0.33 and 0.42 episodes/patient-year, respectively), but the rate of nocturnal confirmed hypoglycemia
hypoglycemia 21332 hypoglycemia (0.33 and 0.42 episodes/patient-year, respectively), but the rate of nocturnal confirmed hypoglycemia was 37% lower with degludec–aspart (3.71 vs 5.72 episodes/patient-year, P<0.05). Weight gain was 2.3
hypoglycemia 21930 the more possible it is to raise insulin levels to reduce fasting hyperglycemia without engendering hypoglycemia . The prolonged duration of action suggested that degludec could be administered three times weekly rather
hypoglycemia 22221 trials between degludec given three times weekly and glargine given daily showed a greater tendency to hypoglycemia with degludec and worse glycemic control.[39],[40] In these studies, mean HbA1c decreased by 0.9% on
hypoglycemia 22631 cases favoring glargine. Degludec administered three times weekly was associated with higher rates of hypoglycemia than daily administration, presumably due to requirement for a larger initial dose. Overall hypoglycemic
hypoglycemia 23967 Nordisk program.[41] The issues raised by the FDA included the validity of claims of reduced risk of hypoglycemia with degludec, but, of even greater concern, what they considered a clear signal of questionable cardiovascular
hypoglycemia 24160 of questionable cardiovascular safety of this insulin.The FDA statisticians carefully analyzed the hypoglycemia meta-analysis submitted by Novo Nordisk. Markedly different results in subpopulations of study subjects
hypoglycemia 24357 subpopulations of study subjects were noted. For example, degludec demonstrated significantly lower frequency of hypoglycemia than glargine, but only in type 2 diabetes patients with estimated rate ratio favoring degludec of 0.84,
hypoglycemia 24726 rate ratio in type 2 diabetes did not occur in US subjects as compared to a 20% lower frequency of hypoglycemia in non-US patients. Moreover, the favorable rate ratio outside the US was primarily attributable to
hypoglycemia 25016 1.27 in US patients. Dr Jean-Marc Guettier, the clinical reviewer, disputed the interpretability of hypoglycemia claims, calling into question the definition of confirmed hypoglycemia offered by Novo Nordisk, which
hypoglycemia 25087 disputed the interpretability of hypoglycemia claims, calling into question the definition of confirmed hypoglycemia offered by Novo Nordisk, which included asymptomatic low glucose values. He noted that in the 3579 trial[32],
hypoglycemia 25426 asymptomatic events were recorded by glargine participants. He also pointed out that the favorable hypoglycemia data offered by Novo Nordisk related to type 2 patients receiving only basal insulin. In these patients,
hypoglycemia 25544 offered by Novo Nordisk related to type 2 patients receiving only basal insulin. In these patients, hypoglycemia is much less frequent than in type 1 patients or in type 2 patients receiving mealtime rapidacting insulin.
hypoglycemia 25731 receiving mealtime rapidacting insulin. He also strongly challenged the claim of lower rates of nocturnal hypoglycemia with degludec, pointing out the difference in pharmacokinetics compared to glargine. Degludec injection
hypoglycemia 25984 insulin levels compared to glargine, which rapidly attains its peak value. Novo Nordisk defined nocturnal hypoglycemia as low glucose recorded between the hours of midnight and 6 AM. Dr Guettier suggested that the forced
hypoglycemia 26406 there was no longer a difference favoring degludec.However, it was not the disagreements regarding hypoglycemia that delayed the US approval of degludec. Rather, marketing approval was initially withheld due to concern
hypoglycemia 30574 several days was not realized. Degludec administered three times weekly resulted in a higher rate of hypoglycemia with less reduction in HbA1c than with glargine given daily. The release of degludec is more invariant
hypoglycemia 30850 variability has been argued as more advantageous in preventing hypogycemic events. However, the definition of hypoglycemia proposed by Novo Nordisk, in particular nocturnal hypoglycemia, is somewhat biased by the pharmacokinetics
hypoglycemia 30913 hypogycemic events. However, the definition of hypoglycemia proposed by Novo Nordisk, in particular nocturnal hypoglycemia , is somewhat biased by the pharmacokinetics of degludec in the overnight period. It is relevant to note
hypoglycemia 36411 3.5% for insulin alone).So, by combining liraglutide and degludec, patients achieve lower HbA1c, less hypoglycemia , less gastrointestinal symptoms, and relative weight loss. The clear superiority of combined degludec–liraglutide
hypoglycemia 38423 NPH–Lispro mixtures. Novo Nordisk data suggested that degludec was even less likely than glargine to provoke hypoglycemia . In particular, nocturnal hypoglycemia was recorded as lower in both type 1 and type 2 patients. FDA
hypoglycemia 38462 that degludec was even less likely than glargine to provoke hypoglycemia. In particular, nocturnal hypoglycemia was recorded as lower in both type 1 and type 2 patients. FDA reviewers did not agree with Novo Nordisk
hypoglycemia 38750 study design. They raised many objections, including the interesting observation that lower rates of hypoglycemia were only seen in non-US type 2 patients. They also questioned whether the rate of clinically serious
hypoglycemia 38865 were only seen in non-US type 2 patients. They also questioned whether the rate of clinically serious hypoglycemia , as opposed to asymptomatic hypoglycemia, might not actually be higher for degludec than for glargine.The
hypoglycemia 38906 They also questioned whether the rate of clinically serious hypoglycemia, as opposed to asymptomatic hypoglycemia , might not actually be higher for degludec than for glargine.The most disquieting issue raised in the
hypoglycemia 40557 (Figure 1).Degludec provides a very stable release of insulin, suggesting that it is less likely to cause hypoglycemia due to peaks than glargine. However, in clinical use, there may not be a major advantage of degludec
hypoglycemia 40905 in several studies, including the flexible time administration studies, there was no difference in hypoglycemia frequency comparing degludec to glargine. Futhermore, the advent of U300 glargine blurs the purported
hypoglycemia 44011 degludecStudyStudy populationComparison agentsReduction in HbA1cHypoglycemic events (PYE)Nocturnal hypoglycemia NN1250-3579[31]Type 2 diabetes on metforminDegludec1.06% (D)1.52% (D)0.25% (D)Glargine1.19% (G)1.85%
obesity 32611 2009.[51] Very recently, liraglutide given at doses up to 3 mg daily was approved for treatment for obesity as a separate indication.[52] The benefits of GLP-1 analog treatment have been somewhat counterbalanced

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