# Abstract

 

## OBJECTIVE After intensive insulin treatment, many obese African American patients with new-onset diabetic ketoacidosis (DKA) and severe hyperglycemia are able to achieve near-normoglycemia remission. The optimal treatment to prevent hyperglycemic relapses after remission is not known. 

## RESEARCH DESIGN AND METHODS This prospective, 4-year, placebo-controlled study randomly assigned 48 African American subjects with DKA and severe hyperglycemia to metformin 1,000 mg daily (*n* = 17), sitagliptin 100 mg daily (*n* = 16), or placebo (*n* = 15) after normoglycemia remission. Hyperglycemic relapse was defined as fasting glucose >130 mg/dL (7.2 mmol/L) and HbA~1c~ >7.0% (53 mmol/mol). Oral glucose tolerance tests were conducted at randomization and at 3 months and then every 6 months for a median of 331 days. Oral minimal model and incremental area under the curve for insulin (AUCi) were used to calculate insulin sensitivity (Si) and β-cell function, respectively. Disposition index (DI) was calculated as a product of Si and incremental AUCi. 

## RESULTS Relapse-free survival was higher in sitagliptin and metformin (*P* = 0.015) compared with placebo, and mean time to relapse was significantly prolonged in the metformin and sitagliptin groups compared with the placebo group (480 vs. 305 days, *P* = 0.004). The probability of relapse was significantly lower for metformin (hazard ratio 0.28 [95% CI 0.10--0.81]) and sitagliptin (0.31 [0.10--0.98]) than for placebo. Subjects who remained in remission had a higher DI (*P* = 0.02) and incremental AUCi (*P* < 0.001) than those with hyperglycemia relapse without significant changes in Si. 

## CONCLUSIONS This study shows that near-normoglycemia remission was similarly prolonged by treatment with sitagliptin and metformin. The prolongation of remission was due to improvement in β-cell function. # Results Forty-eight African American subjects with DKA (*n* = 22) and severe hyperglycemia (*n* = 26) were included in the study. Seventeen subjects were randomly assigned to metformin 1,000 mg daily, 16 to sitagliptin 100 mg daily, and 15 to placebo. Four subjects in the metformin group, 6 in the sitagliptin group, and 1 in the placebo group were lost to follow-up. One subject in the sitagliptin group and one subject in the placebo group withdrew from the study. The overall median follow-up after insulin discontinuation was 331 days (interquartile range 102, 612 days) with no differences between randomized groups ([Table 1](#)). The subjects lost to follow-up or who withdrew from the study were in near-normoglycemia remission during their last documented study visit. There were no significant differences in baseline characteristics at presentation between subjects who withdrew and those who stayed in the study, except for HbA~1c~. HbA~1c~ was lower at presentation of DKA/hyperglycemia in subjects who withdrew compared with those who stayed (12.0 ± 2.3% [107 ± 25 mmol/mol] vs. 13.5 ± 2.0% [124 ± 22 mmol/mol], *P* = 0.03) but was similar at randomization. ::::table-wrap

::: caption
Clinical characteristics of obese African American subjects with DKA and
severe hyperglycemia
:::

```
                                       Metformin (*n* = 17)   Sitagliptin (*n* = 16)   Placebo (*n* = 15)   *P* value
```

______________________________________________________________________

Sex (*n*) 0.70
Male 11 11 8\
Female 6 5 7\
Age (years) 48 ± 9 50 ± 11 46 ± 13 0.73
At diagnosis of diabetes\
BMI (kg/m^2^) 35.0 ± 4.3 37.3 ± 10.0 34.9 ± 5.2 0.96
DKA/severe hyperglycemia (*n*) 7/10 10/6 5/10 0.26
Family history of type 2 diabetes (%) 71 88 80 0.56
FBG 0.49
mmol/L 40.8 ± 13.5 41.7 ± 18.7 43.7 ± 12.2\
mg/dL 735 ± 243 750 ± 336 787 ± 219\
GAD antibody positivity \[*n* (%)\] 2 (12) 0 (0)[\*](#) 3 (23)[\*](#) 0.20
HbA~1c~ 0.85
% 13.1 ± 2.0 13.1 ± 2.5 13.1 ± 2.3\
mmol/mol 120 ± 21 120 ± 27 120 ± 25\
Fasting C-peptide (pg/L) 2.8 ± 1.1 3.4 ± 1.2 3.1 ± 1.2 0.43
At randomization\
FBG 0.21
mmol/L 6.3 ± 1.0 6.2 ± 0.9 7.0 ± 1.3\
mg/dL 114 ± 18 111 ± 16 125 ± 24\
HbA~1c~ 0.28
% 6.2 ± 0.9 6.5 ± 0.7 6.6 ± 0.5\
mmol/mol 44 ± 10 48 ± 8 49 ± 6\
Insulin dose (units/kg/day) 0.5 ± 0.2 0.6 ± 0.3 0.8 ± 0.4 0.08
Length of insulin use (weeks) 9.5 ± 3.0 7.6 ± 3.2 9.2 ± 2.7 0.14
ΔWeight from enrollment (kg) 1.8 (−1.0, 5.9) −0.1 (−3.5, 5.1) −4.6 (−6.3, 0.5) 0.08
At end of study---all subjects\
Duration of treatment[†](#) (days) 472 (242, 716) 194 (92, 613) 194 (91, 579) 0.19
ΔWeight from randomization (kg) 0 (−3.6, 3.5) 3.3 (−0.7, 6.0) 1.4 (−2.2, 2.9) 0.10
FBG 0.10
mmol/L 6.7 ± 1.2 6.9 ± 1.5 8.5 ± 3.2\
mg/dL 121 ± 22 124 ± 27 153 ± 58\
HbA~1c~ 0.04
% 6.4 ± 1.2 6.6 ± 1.1 7.6 ± 1.6\
mmol/mol 46 ± 13 48 ± 12 55 ± 22\
Near-normoglycemia remission (*n*) 12 12 4\
End-of-study FBG 0.04
mmol/L 6.2 ± 1.1 6.1 ± 0.4 7.4 ± 0.8\
mg/dL 112 ± 19 110 ± 7 134 ± 15\
End-of-study HbA~1c~ 0.80
% 5.8 ± 0.7 6.1 ± 0.7 6.1 ± 0.5\
mmol/mol 40 ± 8 43 ± 8 43 ± 6\
Hyperglycemia relapse (*n*) 5 4 11\
End-of-study FBG 0.51
mmol/L 7.9 ± 0.4 9.1 ± 1.3 8.9 ± 3.8\
mg/dL 142 ± 7 163 ± 23 160 ± 68\
End-of-study HbA~1c~ 0.94
% 8.0 ± 0.9 8.0 ± 0.9 8.2 ± 1.5\
mmol/mol 64 ± 10 64 ± 10 66 ± 16

Data are mean ± SD or median (interquartile range) unless otherwise
indicated. FBG, fasting blood glucose.

\*Missing GAD antibody levels for one subject in the sitagliptin group
and two subjects in the placebo group.

†Median time of follow-up after randomization and insulin
discontinuation.:::: At presentation of DKA and severe hyperglycemia, there were no differences in age and BMI among the metformin, sitagliptin, or placebo groups ([Table 1](#)). Although not statistically significant, both the sitagliptin and metformin groups had more men than women, whereas the placebo group had similar proportions of men and women. In the proportion of subjects with DKA or severe hyperglycemia, length and dose of insulin use before randomization (time to near-normoglycemia remission) did not differ between groups. At randomization, there were no significant changes in weight or differences in fasting glucose or HbA~1c~ levels. At the end of the study, there was a significant difference in HbA~1c~ (*P* = 0.04) between the groups ([Table 1](#)). In the patients who remained in near-normoglycemia remission, there was a significant difference in fasting glucose at the end of the study ([Table 1](#)). There were no differences at diagnosis of diabetes in the subjects who remained in near-normoglycemia remission compared with those with hyperglycemia relapse at presentation ([Table 2](#)). At randomization, fasting glucose levels were higher in subjects who experienced hyperglycemia relapse than in those who remained in remission ([Table 2](#)). At the end of the study, fasting glucose and HbA~1c~ levels were higher in the subjects who experienced hyperglycemia relapse ([Table 2](#)). ::::table-wrap
::: caption
Clinical characteristics of obese African American patients with DKA and
severe hyperglycemia with near-normoglycemia remission compared with
those with hyperglycemia relapse
:::

```
                                           Near-normoglycemia remission (*n* = 28)   Hyperglycemia relapse (*n* = 20)   *P* value
```

______________________________________________________________________

Sex (*n*) 0.38
Male 19 11\
Female 9 9\
Age (years) 48 ± 10 49 ± 12 0.73
At diagnosis of diabetes\
BMI (kg/m^2^) 35.2 ± 5.0 36.6 ± 9.0 0.96
DKA/severe hyperglycemia (*n*) 15/13 7/13 0.24
Family history of type 2 diabetes (%) 82 90 0.68
FBG 0.95
mmol/L 42.5 ± 16 41.4 ± 13.2\
mg/dL 765 ± 288 745 ± 239\
GAD antibody positivity[†](#) \[*n* (%)\] 2 (7) 3 (17) 0.64
HbA~1c~ 0.75
% 13.2 ± 2.2 13.0 ± 2.2\
mmol/mol 121 ± 24 119 ± 24\
Fasting C-peptide (pg/L) 3.3 ± 1.1 2.8 ± 1.3 0.25
At randomization\
FBG 0.007
mmol/L 6.1 ± 0.9 7.0 ± 1.1\
mg/dL 110 ± 17 126 ± 20\
HbA~1c~ 0.14
% 6.3 ± 0.8 6.7 ± 0.5\
mmol/mol 49 ± 12 60 ± 16\
Insulin dose (units/kg/day) 0.6 ± 0.2 0.7 ± 0.4 0.67
Length of insulin use (weeks) 8.6 ± 3.1 9.1 ± 2.9 0.57
ΔWeight from enrollment (kg) −0.4 (−6.9, 1.8) 0.8 (−5.4, 4.5) 0.24
At end of study\
ΔWeight from randomization (kg) −0.4 (−2.5, 3.1) 2.1 (−0.4, 5.6) 0.11
FBG \<0.0001
mmol/L 6.3 ± 0.9 8.7 ± 2.8\
mg/dL 114 ± 17 156 ± 50\
HbA~1c~ \<0.0001
% 6.0 ± 0.7 8.1 ± 1.2\
mmol/mol 42 ± 8 65 ± 13

Data are mean ± SD or median (interquartile range) unless otherwise
indicated. FBG, fasting blood glucose.

†Missing GAD antibody levels for one subject in the near-normoglycemia
remission group and two subjects in the hyperglycemia relapse group.:::: Hyperglycemia relapse-free survival was significantly higher in the metformin and sitagliptin groups than in the placebo group (*P* = 0.015) ([Fig. 1](#)). The 2-year failure rate was higher in the placebo than in the sitagliptin (77% vs. 44%, *P* = 0.113) or metformin (77% vs. 34%, *P* = 0.013) groups. Compared with placebo, patients randomized to metformin (hazard ratio 0.28 [95% CI 0.10--0.814]) and sitagliptin (0.31 [0.10--0.98]) were ∼70% less likely to have a hyperglycemia relapse. However, there was no difference in hyperglycemia relapse-free survival between metformin and sitagliptin (*P* = 0.75) ([Fig. 1](#)). The restricted mean time to hyperglycemia relapse in the combined metformin and sitagliptin groups was significantly higher than placebo (480 vs. 305 days, *P* = 0.004). <figure> <p><img src="" /></p> <figcaption>Cox proportional hazards of failure-free survival among metformin, sitagliptin, and placebo in obese African American patients presenting with DKA and severe hyperglycemia. A significant difference was found among the placebo, metformin, and sitagliptin groups (<em>P</em> = 0.015), but no significant difference was found between the sitagliptin and metformin groups (<em>P</em> = 0.75).</figcaption> </figure> We also assessed whether being on medication decreased the severity of hyperglycemia relapse. Because only a small number of subjects experienced relapse in the medication groups (metformin \[*n* = 5\], sitagliptin \[*n* = 4\]) compared with placebo (*n* = 11), we combined the metformin and sitagliptin groups. There were no significant differences in HbA~1c~ (8.0 ± 0.8% [64 ± 9 mmol/mol] vs. 8.2 ± 1.5% [66 ± 16 mmol/mol], *P* = 0.79) or blood glucose (152 ± 18 mg/dL [8.4 ± 1 mmol/L] vs. 160 ± 68 mg/dL [8.9 ± 3.8 mmol/L], *P* = 0.65) levels at the time of hyperglycemia relapse between the placebo group and the combined metformin and sitagliptin group. In the placebo group, 3 of the 11 subjects who experienced hyperglycemia relapse presented to the emergency department with a glucose level >400 mg/dL (22.2 mmol/mol) or DKA. None of the patients in the metformin and sitagliptin group had a hyperglycemia relapse necessitating a visit to the emergency department or admission to the hospital. The difference in hyperglycemia relapse was explained by improvements in β-cell function. Over the course of the study, DI (*P* = 0.02) and incremental AUCi (*P* < 0.001) were significantly higher in subjects who remained in near-normoglycemia remission compared with those who had a hyperglycemia relapse without any differences in Si (*P* = 0.75). There was a significant interaction between remission status and study visit for both Si (*P* = 0.01) and DI (*P* = 0.02), suggesting a different pattern of change in Si and DI over time between subjects with near-normoglycemia remission and hyperglycemia relapse. The difference in DI and incremental AUCi was not present at randomization in the subjects who stayed in near-normoglycemia remission compared with those who experienced a hyperglycemia relapse ([Fig. 2*A* and *B*](#)). At the last documented follow-up, there were no differences in Si ([Fig. 2*C*](#)); however, DI (*P* = 0.02) and incremental AUCi (*P* < 0.001) were significantly higher in subjects who stayed in near-normoglycemia remission than in those who had a hyperglycemia relapse at the end of the study ([Fig. 2*A* and *B*](#)). Comparison across treatment groups showed no differences at randomization, over the course of the study, or at the last follow-up for DI, incremental AUCi, or Si (data not shown). Similarly, a comparison of subjects with an initial presentation of DKA and severe hyperglycemia showed no differences in Si, incremental AUCi, or DI at randomization, over the course of the study, or at the last follow-up (data not shown). Although there were no significant changes in weight, we performed analyses adjusting for changes in weight throughout the course of the study. No differences were found in Si, incremental AUCi, or DI compared with unadjusted analyses. <figure> <p><img src="" /></p> <figcaption>DI, incremental AUCi, and Si at randomization and last follow-up. At randomization OGTT, no significant differences were found in DI, incremental AUCi, or Si in subjects who remained in near-normoglycemia remission at the end of the study compared with those with hyperglycemia relapse. During the last follow-up OGTT, subjects who remained in remission had higher DI and incremental AUCi than those who had a relapse (<em>A</em> and <em>B</em>) without a difference in Si (<em>C</em>).</figcaption> </figure>


Extracted trial result:
Outcome: The 2-year failure rate (binary)
Intervention: metformin 1,000 mg daily, sitagliptin 100 mg daily
Comparator: placebo
Intervention events: 13
Intervention group size: 33
Comparator events: 12
Comparator group size: 15
Notes: Used percentage to calculate events as binary outcome.