Kaiser Permanente Northwest (KPNW) is a group-model health maintenance organization that provides integrated health care to approximately 475,000 members in the Portland, Oregon area. KPNW maintains electronic databases containing information on all inpatient admissions, pharmacy dispenses, outpatient visits, and laboratory tests. All such information is stored in an electronic medical record in use since 1996. To complete each patient visit, the clinician is required to enter in the electronic medical record at least 1 diagnosis and may enter up to 20 diagnoses.

The organization also provides online medical guidelines to assist clinicians in patient management. One such guideline recommends lipid screening for men aged more than 35 years and women aged more than 45 years. Fasting plasma glucose tests are routinely ordered with these lipid panels.

For this study, we identified KPNW members aged more than 40 years who had a fasting plasma glucose test result of less than 100 mg/dL between January 1, 1997, and December 31, 2000, and who had health plan eligibility for at least 6 months before and 12 months after the test (n=53,356). For patients with multiple tests, we selected the first available result. We excluded 4856 potential subjects who had a previous test result of more than 100 mg/dL and 1922 potential subjects who had diagnosed diabetes. We followed the remaining 46,578 patients until they developed diabetes (inpatient or outpatient International Classification of Diseases, 9th Revision-Clinical Modification diagnosis 250.xx or fasting plasma glucose test result>125 mg/dL), died, or left the health plan, or until April 30, 2007.

To determine whether the risk of diabetes increased with fasting plasma glucose, we analyzed fasting plasma glucose both as a continuous variable and in 4 categories: less than 85 mg/dL, 85 to 89 mg/dL, 90 to 94 mg/dL, and 95 to 99 mg/dL. To isolate the independent contribution of fasting plasma glucose to diabetes risk, we collected a number of control variables. From diagnoses contained in the electronic medical record, we identified comorbidities (International Classification of Diseases, 9th Revision-Clinical Modification codes) present at the time of the glucose test: myocardial infarction (410.xx); stroke (430.xx-432.xx, 434.xx-436.xx, 437.1); other atherosclerotic cardiovascular disease (411.1, 411.8, 413.xx, 414.0, 414.8, 414.9, 429.2); and congestive heart failure (428.xx). These comorbidities were combined into a single variable indicating cardiovascular disease. We also identified hypertension diagnoses (401.xx-404.xx).

Age was calculated as of the date of the fasting plasma glucose test. Smoking history, height, weight, and blood pressure were obtained from the electronic medical record. Lipid values were extracted from the laboratory database. For this study, we used the height, weight, blood pressure, and lipid values recorded on the date closest to the fasting plasma glucose test date either before or up to 3 months after the test date.

By using these variables, we constructed a Cox regression model to estimate the adjusted risk of diabetes incidence. Interaction terms for fasting plasma glucose with age, sex, and body mass index (BMI) were found to be nonsignificant so were not included in the final model. All data were analyzed using SAS, version 8.2 (SAS Institute, Cary, NC).

Study subjects' age averaged 57.5 years, and 40.4% were men (Table 1Table 1). Mean follow-up time was similar across fasting plasma glucose categories, averaging 81.0 months. Mean age, BMI, systolic blood pressure, low-density lipoprotein and total cholesterol, and triglycerides all increased with fasting plasma glucose, whereas high-density lipoprotein cholesterol decreased (P <.001 for all comparisons). The proportion who were male, had cardiovascular disease, or had hypertension also increased with fasting plasma glucose.

Table 1Baseline Characteristics of Total Study Sample by Fasting Plasma Glucose Category

	<85 mg/dL	85-89 mg/dL	90-94 mg/dL	95-99 mg/dL	Total
n (%)	8705 (18.7%)	10,983 (23.6%)	13,704 (29.4%)	13,186 (28.3%)	46,578
Age	55.4 (11.0)	56.6 (10.7)	57.8 (11.0)	59.1 (11.1)	57.5 (10.9)
% Male	28.7%	35.5%	42.9%	49.4%	40.4%
BMI	28.0 (5.8)	28.6 (5.8)	29.2 (5.9)	29.9 (6.0)	29.0 (5.9)
Systolic blood pressure	128 (19)	130 (18)	131 (19)	134 (19)	131 (19)
Diastolic blood pressure	79 (10)	79 (10)	80 (10)	81 (10)	80 (10)
HDL cholesterol	57 (17)	56 (17)	54 (16)	52 (16)	54 (16)
LDL cholesterol	123 (34)	126 (34)	129 (35)	130 (34)	128 (34)
Triglycerides	142 (122)	147 (115)	156 (106)	164 (114)	154 (114)
Total cholesterol	208 (42)	210 (39)	213 (41)	214 (40)	212 (41)
Current smoker	20.3%	19.4%	20.4%	21.2%	20.4%
Cardiovascular disease††	4.8%	5.2%	6.6%	7.6%	6.2%
Hypertension	21.6%	24.0%	26.7%	31.7%	26.5%
Mean months of follow-up (SD)	79.0 (28.4)	80.1 (29.8)	82.0 (30.1)	82.1 (31.1)	81.0 (30.0)

BMI=body mass index; HDL=high-density lipoprotein; LDL=low-density lipoprotein; SD=standard deviation.

Data are means (standard deviation) or percent.

All comparisons of glucose categories are statistically significantly different (P <.001).

†All comparisons of glucose categories are statistically significantly different (P <.001), except<85 mg/dL versus 85-89 mg/dL (not significant).

The characteristics of the 4.0% (n=1854) of subjects who developed diabetes are shown in Table 2Table 2. Diabetes developed after a mean of 54.6 months. The mean time to diabetes did not differ among categories, but the proportion developing diabetes increased significantly with fasting plasma glucose (P <.001 for all comparisons, except between the<85 mg/dL and 85-89 mg/dL categories). All risk factors were less favorable among individuals who developed diabetes compared with the total sample. However, their risk profiles were similar regardless of initial fasting plasma glucose levels. Mean hemoglobin A_1c at diagnosis was greater than 7% in all categories.

Table 2Baseline Characteristics of Subjects Who Developed Diabetes

	<85 mg/dL	85-89 mg/dL	90-94 mg/dL	95-99 mg/dL	Total
n (%)	175 (9.4%)	264 (14.2%)	520 (28.1%)	895 (48.3%)	1854
Proportion of baseline FPG category	2.0%	2.4%	3.8%	6.8%	4.0%
Age	56.6 (9.7)	57.4 (9.5)	58.7 (10.4)	59.1 (10.5)	58.5 (10.3)
% Male	42.9%	45.5%	46.5%	49.8%	47.6%
BMI	32.7 (6.7)	33.5 (7.2)	33.4 (7.3)	33.0 (6.8)	33.2 (7.0)
Systolic blood pressure	134 (18)	137 (18)	136 (20)	136 (19)%	136 (19)
Diastolic blood pressure	82 (10)	82 (11)	82 (11)	82 (10)	82 (10)
HDL cholesterol	49 (15)	46 (15)	47 (14)	47 (14)	47 (14)
LDL cholesterol	123 (37)	124 (36)	127 (37)	125 (34)	125 (36)
Triglycerides	239 (364)	213 (257)	212 (149)	209 (131)	213 (191)
Total cholesterol	216 (54)	210 (45)	216 (48)	212 (43)	213 (46)
Current smoker	27.4%	25.8%	25.0%	22.0%	23.9%
Cardiovascular disease	9.7%	8.3%	11.9%	11.7%	11.1%
Hypertension	41.1%	49.6%	43.7%	43.6%	44.2%
Months to diabetes development	59.0 (28.3)	54.6 (28.3)	54.4 (28.3)	53.8 (29.9)	54.6 (29.2)
Mean fasting glucose at diagnosis	150 (63)	145 (52)	141 (53)	142 (51)	143 (53)
Mean HbA1c at diagnosis	7.3% (1.5)	7.1% (1.5)	7.3% (1.8)	7.1% (1.5)	7.2% (1.6)

FPG=fasting plasma glucose; BMI=body mass index; HDL=high-density lipoprotein; LDL=low-density lipoprotein; HbA_1c=hemoglobin A1c.

All comparisons of glucose categories are statistically significantly different (P <.001), except<85 mg/dL versus 85 to 89 mg/dL (not significant).

Kaplan-Meier plots of the unadjusted cumulative diabetes incidence for each of the 4 categories are displayed in Figure 1Figure 1. Subjects in the 95 to 99 mg/dL category developed diabetes at a rate of 9.9 per 1000 person-years (95% confidence interval [CI], 9.3-10.6). Subjects in the 90 to 94 mg/dL category developed diabetes at a rate of 5.6 per 1000 person-years (95% CI, 5.1-6.1). Subjects in the 85 to 89 mg/dL and less than 85 mg/dL groups developed diabetes at rates of 3.6 (95% CI, 3.2-4.1) and 3.1 (95% CI, 2.6-3.5), respectively. The log-rank test indicated statistically significant differences (P <.0001) in the incidence of diabetes among the 4 categories.

Figure 1

Kaplan-Meier plot of cumulative diabetes incidence by category of normal fasting plasma glucose.

View Large Image | View Hi-Res Image | Download PowerPoint Slide

In a multivariable model that included all subjects, each milligram per deciliter of fasting plasma glucose was associated with an increased risk of diabetes incidence of 6% (hazard ratio [HR] 1.06; 95% CI, 1.05-1.07) (Table 3Table 3). Except for male sex, all other risk factors were highly statistically significant. Each kilogram per meter squared of BMI was associated with an increased risk of diabetes of 8% (HR 1.08; 95% CI, 1.07-1.09; P <.0001), whereas the presence of hypertension was associated with an increased risk of 51% (HR 1.51; 95% CI, 1.35-1.68; P <.0001).

Compared with subjects with fasting plasma glucose levels less than 85 mg/dL, those in the 85 to 89 mg/dL category were not at significantly greater risk of diabetes after adjustment for other risk factors (Figure 2Figure 2). However, those in the 90 to 94 mg/dL group had a 49% greater diabetes risk relative to the subjects in the less than 85 mg/dL group (HR 1.49; 95% CI, 1.23-1.79), and diabetes risk was 2.33 (1.95-2.79) times greater in the 95 to 99 mg/dL group. Other risk factors performed identically to the model presented in Table 3Table 3.

Figure 2

HRs (95% CIs) from Cox regression analysis of diabetes incidence, adjusted for risk factors displayed in Table 3Table 3.

View Large Image | View Hi-Res Image | Download PowerPoint Slide

In an observational cohort analysis of 46,578 community-based health maintenance organization subjects, we found a strong association between level of normal fasting plasma glucose and diabetes incidence after controlling for a large number of other known risk factors. The overall risk of diabetes (4.0%) among these subjects was relatively low compared with patients with impaired fasting glucose levels in the same study setting (11.3%).⁹x9Nichols, G.A., Hillier, T.A., and Brown, J.B. Progression from newly acquired impaired fasting glucose to type 2 diabetes. Diabetes Care. 2007; 30: 228–233

CrossRef | PubMed | Scopus (94)See all References9 However, we found that each milligram per deciliter of fasting plasma glucose was associated with a 6% increased risk of diabetes in the subjects with fasting plasma glucose levels in the normal range, similar to the 7% risk increase we reported in patients with impaired fasting glucose levels. Furthermore, the other risk factors analyzed in the current study performed nearly identically to the previous study. Thus, fasting plasma glucose levels seem to impart diabetes risk that begins well below the currently accepted normal level.

In a study conducted on the island of Mauritius, Shaw et al¹⁰x10Shaw, J.E., Zimmet, P.Z., Hodge, A.M. et al. Impaired fasting glucose: how low should it go?. Diabetes Care. 2000; 23: 34–39

CrossRef | PubMedSee all References10 concluded that the risk of diabetes (when diagnosed by fasting plasma glucose alone) starts to increase at a fasting plasma glucose level of greater than 5.2 mmol/L (∼94 mg/dL).¹⁰x10Shaw, J.E., Zimmet, P.Z., Hodge, A.M. et al. Impaired fasting glucose: how low should it go?. Diabetes Care. 2000; 23: 34–39

CrossRef | PubMedSee all References10 Our results suggest that the threshold is lower. In our data, a fasting plasma glucose level of 90 to 94 mg/dL conferred a 49% greater risk of developing diabetes compared with a level less than 85 mg/dL. Furthermore, although the HR of 1.08 in the 85 to 89 mg/dL category did not reach statistical significance, it was nonetheless elevated, suggesting that the upper portion of this range may also carry additional risk. This is consistent with the study of young Israeli men, which found significantly greater risk at the level of 87 to 90 mg/dL (relative to<81 mg/dL).¹¹x11Tirosh, A., Shai, I., Tekes-Manova, D. et al. Normal fasting plasma glucose levels and type 2 diabetes in young men. N Engl J Med. 2005; 353: 1454–1462

CrossRef | PubMed | Scopus (198)See all References11

Up to 70% of individuals with abnormal glucose regulation, defined as impaired fasting glucose or impaired glucose tolerance, may ultimately progress to diabetes.²x2Nathan, D.M., Davidson, M.B., DeFronzo, R.A. et al. Impaired fasting glucose and impaired glucose tolerance: implications for care. Diabetes Care. 2007; 30: 753–759

CrossRef | PubMed | Scopus (433)See all References2 Whether diabetes risk is best identified by fasting or post-challenge glucose tests remains controversial, but it is agreed that impaired fasting glucose and impaired glucose tolerance do not define the same individuals.¹²x12Unwin, N., Shaw, J., Zimmet, P., and Alberti, K.G.M.M. Impaired glucose tolerance and impaired fasting glycaemia: the current status on definition and intervention. Diabet Med. 2002; 19: 708–723

CrossRef | PubMed | Scopus (586)See all References12 Because no subjects in the current study had impaired fasting glucose, it is likely that some of those who progressed to diabetes had impaired glucose tolerance. This would not be surprising given the higher sensitivity of impaired glucose tolerance in predicting progression to diabetes.¹³x13Shaw, J.E., Zimmet, P.Z., de Courten, M. et al. Impaired fasting glucose or impaired glucose tolerance (What best predicts future diabetes in Mauritius) . Diabetes Care. 1999; 22: 399–402

CrossRef | PubMedSee all References13 Indeed, the lowering of the criterion for impaired fasting glucose from 110 to 100 mg/dL was done primarily to equalize the population risk of developing diabetes between impaired fasting glucose and impaired glucose tolerance states.⁴x4Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Follow-up Report on the Diagnosis of Diabetes Mellitus. Diabetes Care. 2003; 26: 3160–3167

CrossRef | PubMed | Scopus (1845)See all References^{, 12}x12Unwin, N., Shaw, J., Zimmet, P., and Alberti, K.G.M.M. Impaired glucose tolerance and impaired fasting glycaemia: the current status on definition and intervention. Diabet Med. 2002; 19: 708–723

CrossRef | PubMed | Scopus (586)See all References

The ADA currently recommends the use of fasting glucose tests to diagnose diabetes. Thus, from the standpoint of US clinical practice, monitoring fasting plasma glucose in at-risk patients is necessary. In the present study, all subjects had apparently normal fasting glucose levels that did not suggest diabetes risk by the current definition. However, those who developed diabetes had other adverse characteristics that may help identify their increased risk, namely, high BMI, hypertension, and poor lipid profiles. The univariate comparisons of these risk factors across fasting plasma glucose categories among those who developed diabetes yielded no significant differences. Thus, a consistent profile of predictive characteristics emerged that may assist clinicians in identifying patients for targeted diabetes screening. Although widespread screening with oral glucose tolerance tests is burdensome, performing this test on patients with the high-risk profile we identified might be an appropriate course of action. In addition to this risk profile, smoking increased the risk of diabetes by 36% independently of other factors, a result consistent with previous studies that have found an association between smoking and diabetes.¹⁴x14Meisinger, C., Doring, A., Thorand, B., and Lowel, H. Association of cigarette smoking and tar and nicotine intake with development of type 2 diabetes mellitus in mean and women from the general population: the MONICA/KORA Augsburg Cohort Study. Diabetologia. 2006; 49: 1770–1776

CrossRef | PubMed | Scopus (29)See all References^{, 15}x15Rimm, E.B., Manson, J.E., Stampfer, M.J. et al. Cigarette smoking and the risk of diabetes in women. Am J Pub Health. 1993; 83: 211–214

CrossRef | PubMedSee all References^{, 16}x16Manson, J.E., Ajani, U.A., Liu, S. et al. A prospective study of cigarette smoking and the incidence of diabetes mellitus among US male physicians. Am J Med. 2000; 109: 538–542

PubMed | Scopus (129)See all References^{, 17}x17Willi, C., Bodenmann, P., Ghali, W.A. et al. Active smoking and the risk of type 2 diabetes: A systematic review and meta-analysis. JAMA. 2007; 298: 2654–2664

CrossRef | PubMed | Scopus (343)See all References Patients with this high-risk profile would likely benefit from lifestyle modifications known to reduce diabetes risk.¹⁸x18Pan, X.R., Li, G.W., Hu, Y.H. et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance (The Da Qing IGT and Diabetes Study) . Diabetes Care. 1997; 20: 537–544

CrossRef | PubMedSee all References^{, 19}x19Tuomilehto, J., Eriksson, J.G., Valle, T.T. et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001; 344: 1343–1350

CrossRef | PubMed | Scopus (5530)See all References^{, 20}x20Knowler, W.C., Barrett-Connor, E., Fowler, S.E. et al. Reduction in the incidence of type 2 diabetes with life-style intervention or metformin. N Engl J Med. 2002; 346: 393–403

CrossRef | PubMed | Scopus (8392)See all References

Our study has several limitations. First, we defined diabetes as the entry into the electronic medical record of a diagnosis or by a single fasting plasma glucose level greater than 125 mg/dL. Neither of these criteria necessarily defines clinically confirmed diabetes. Oral glucose tolerance tests, which may be a stronger predictor of diabetes, were not available for our subjects. Among those who developed diabetes by our criteria, however, the mean hemoglobin A_1c at diagnosis was more than 7%, a level that strongly suggests that abnormal glucose metabolism has been maintained for several months. Second, because of the observational design, we cannot conclude that higher fasting plasma glucose within the normal range actually causes diabetes; we can only report the strong independent association. Third, it is possible that risk factors we could not include, such as insulin resistance and family history of diabetes, would have accounted for the reported difference in diabetes incidence across fasting plasma glucose categories. We also did not assess the use of drugs known to affect glucose levels (eg, thiazide diuretics, glucocorticosteroids) as covariates. Fourth, we did not randomly select participants for fasting plasma glucose testing. Although most of our results were ascertained from routine lipid screening, the study was nonetheless limited to patients who sought health care. Thus, whether our study sample is representative of all individuals with normal fasting plasma glucose levels cannot be determined.

The debate over the “correct” cut-point for defining impaired fasting glucose has not been settled. Our results demonstrate that increased risk of diabetes extends well below the ADA's current maximum limit of normal plasma glucose of 99 mg/dL. Although impaired fasting glucose may be a useful construct, seemingly normal fasting plasma glucose levels also provide information regarding the future risk of diabetes, especially in conjunction with other known risk factors.