Outcomes of Type 2 Diabetes Management: One Center Experience 2015–2023

Abstract

The purpose of this chapter was (1) to identify the frequency of employing different kinds of medication (beta-stimulators, metformin, gliflozins, incretins and/or insulins, pioglitazone, statins, fibrates), (2) to assess global metabolic effectiveness of this medication in a walk-in diabetes center, and (3) to estimate frequency of HbA1c measurements in people admitted to hospital. Methods: In 200 people with T2D (age 24–95 y, 105 men) HbA1c, BM, BMI, blood pressure [BP], lipoproteins HDL, LDL, TAG, eGFR, proteinuria were assessed. Individual observation periods took in the range of 0.5–8.8 years. Student’s t-test, Wilcoxon signed-rank test with Bonferroni correction and Spearman analysis were used to asses changes between the first and the last visit. P < 0.05 was considered as significant. In conclusion, reduction of HbA1c from start values of 52.6 (31.5–173.0) to 46.6 (31.5–116.6) mmol/mol along with reduction of BMI from 26.7 (16.0–45.3) to 25.4 (15.4–42.2) kg/m² (P < 0.0001) and correlation of delta HbA1c with delta BMI (r = 0.209, p = 0.003) confirmed global metabolic effectiveness of medication used in the walk-in diabetes center where the HbA1c was estimated 2–3 times per year in each subject whereas in hospital wards mostly once in up to 15% of admitted T2D patients.

1. Introduction

This chapter is focused on outcomes of routine management of people with type 2 diabetes (T2D) carried out at a diabetes center (Moravský Beroun, Institute of Specialized Treatment Paseka) in close cooperation with the Diabetes Center of the Teaching Hospital and Palacký University Olomouc.

The terminal objective of T2D treatment has been defined as “long active life without frustrating complications.” Clinical and laboratory surrogate markers of metabolic balance and cardiovascular/renal protectivity have served to measure the immediate therapeutic effect.

From the beginning of the third millennium, the pathophysiological approach has offered optimistic perspectives [1]. Important papers [2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62] are cited throughout the entire chapter. Several studies focused on individual drug classes such as insulin preparations [5, 6, 7, 8, 9, 10, 11, 12, 17], incretin preparations [13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29] and gliflozins [30, 31, 32, 33, 34]. New technologies such as SMPG [4], CGM [7, 37, 38], insulin pens [8] and CSII [5, 6] became a part of daily routine. However, assessment of effectiveness of center-related therapeutic methods has not been routinely performed. Therefore, the purpose of this retrospective observational study was (1) to identify how frequently the recent medication with metformin, gliflozins, incretins, insulins and hypolipidemics was prescribed in a single walk-in diabetes center, (2) to assess global effectiveness of this medication on individuals with T2D attending this center and (3) to compare frequency of HbA1c measurements in this center and in people admitted to two independent departments of internal medicine and geriatrics in a teaching hospital.

2. Methods

2.1 Schedule of routine check-ups in the diabetes center

• Routine clinical check-ups including assessment of a recent 10-point PG profile, body mass (BM), BMI, heart rate and BP have been performed in 3-month intervals.

• Laboratory parameters (fasting S-Glucose, HbA1c, blood count, U-glucose, U-protein, serum concentration of uric acid, bilirubin, C-reactive protein, sodium, potassium, chlorides, calcium, magnesium, ALT, AST, GMT, ALP, alfa amylase, lipoproteins cholesterol, HDL, LDL, TAG, total protein, albumin, thyroid-stimulating hormone [TSH], triiodothyronine [T3], free thyroxine [fT4], creatinine, estimated glomerular filtration rate [eGFR] and urinalysis) have been estimated in 6-month intervals or more frequently. Laboratory analyzer COBAS Integra 400 and accredited methods were used [2, 3].

• Eye screening has been performed once a year. Other consultations (neurology, cardiology, gastroenterology, urology, gynecology, etc.) have been provided in specialized centers.

2.2 Characteristics of people with T2D attending the center in the course of the study (January 1, 2015: May 15, 2023)

All adults with T2D who, throughout the entire 9-year study period, have passed at least two routine visits involving estimation of HbA1c, BM and other surrogate markers were regularly followed with their routine check-ups and included in statistical evaluation.

There was a total of 200 T2Ds, but only 66 (33%) of them were routinely followed until 2023, which was a variable period of time. In addition, in 2023, only 97 out of 132 people attended their last check-up before the terminal study date of May 15, 2023 (Tables 1 and 2).

	Absolute numbers (N)	Relative numbers	Age in the year 2023 [years]
			Mean ± SD	Median, min, max
T2D (all)	200	100%	—	—
Men (all)	105	52.5%	—	—
Women (all)	95	47.5%	—	—
HbA1c estimations (all)	2662	100%	—	—
T2D followed continuously over the entire study period	66	33%	68.8 ± 10.6	70; 32.4–91.5

Table 1.

T2Ds who (throughout the entire 9-year study period) have passed at least two routine visits comprising estimation of HbA1c and BM.

Year	2015	2016	2017	2018	2019	2020	2021	2022	2023
No of persons per year	135	163	161	163	151	139	138	132	97
Age mean of N total [years]	64.2	65.1	65.7	65.7	66.7	66.5	66.9	66.9	67.7
SD	10.9	11.2	11.2	11.4	11.3	11.4	11.6	11.5	11.0
Age Median of N total [years]	65.3	66.3	66.7	67.0	67.7	67.9	68.0	67.5	67.3
Min	24.4	25.4	26.4	27.4	28.4	29.4	30.4	31.4	32.4
Max	88.1	89.1	90.1	91.1	92.1	93.1	94.1	95.1	91.6
No of HbA1c per year	415	400	366	358	297	263	279	284	n/a
No of HbA1c per person/year	3.0	2.5	2.3	2.2	2.0	1.9	2.0	2.2	n/a

Table 2.

Number (No) and age [years] of all individuals with T2D attending the diabetes center in respective year.

Mean ± SD, median (min, max). Number of HbA1c estimations per year.

2.3 Clinical and laboratory equipment and investigations

All T2Ds were trained in self-monitoring of plasma glucose (SMPG). Glucometers Calla (recently replaced by Galileo Glu/Ket), Wellion, Austria, employing generally glucose-oxidase strips were used (Figure 1). Glucometers Contour, Ascencia, employing glucose-dehydrogenase strips, were applied to people on the insulin pump paradigm (Figure 2) due to its wireless transfer of glucometer results to the insulin pump. Recently, a hybrid pump MiniMed 780 G, Medtronic, CA, USA, and glucometer Contour Plus One have been introduced.

Figure 1.

Three glucometer strip systems: Galileo Glu/Ket (above), Calla (in the middle) and contour plus one (below). All nine glucometers are showing different values of plasma glucose concentration estimated in the same drop of blood collected from one finger-prick. Variability of the results appears to be lower when comparing the same-name glucometers.

Figure 2.

Insulin pump paradigm 754 MiniMed, Medtronic, CA, USA, displaying: Mean INS/d (31.950 U in a span of 30 days) [5, 6, 7].

Before each visit, each person was expected to provide a 10-point glycemic profile containing data on food and medication Figure 3 [4]. People using hybrid insulin pumps with glucose sensors have their glycemic curves printed using software Carelink (Figure 4).

Figure 3.

Ten-point glycemic profile containing self-monitoring data including nutrition and medication. This document is provided by each person with T2D before each check-up.

Figure 4.

The graph shows data collected with a hybrid pump MiniMed 780G within the span of 1 day. Glycemia-black line, target range (3.9–10.0 mmol/l) highlighted in green, INS basal in pink, INS bolus in blue, meals in brown. Accessible with name and password. Taken from www.carelink.minimed.eu.

In each visit, BP, heart rate and BM were measured (Figures 5 and 6).

Figure 5.

Clinical investigation: Measuring blood pressure and heart rate using a digital tonometer.

Figure 6.

Clinical investigation: Measuring body mass by means of a digital scale.

2.4 Design of the chapter

The data was obtained from electronic files of the walk-in diabetes center, protected with codes and ordered according to two scales, each scale aiming at specific targets:

1. Study-period-related time scale considering all individuals with T2D in each individual year. This scale has been employed to demonstrate the routine capacity of the diabetes center including frequency of individuals treated according to recommended pathophysiology-based principles with beta cell stimulators, metformin, dapagliflozin, DPP4 inhibitors, incretin preparations, insulins and hypolipidemics.

2. The person-related visit scale considers each individual from his/her first visit (V-START) to his/her last visit (V-END). Only visits where HbA1c was measured have been considered. In each individual, 1 to 4 HbA1c measurements per year (along with other surrogate markers) were performed. Mean values of HbA1c calculated in each individual person for each individual year of his/her observational period was considered as a Visit, e.g.: V1 = mean of all HbA1c values estimated in the first year of one’s observation; V2 = mean of HbA1c values estimated in the year following the V1 year, etc. Difference between HbA1c values at V-START and V-END was assessed, as well as differences of BMI and other relevant surrogate markers, to assess effectiveness of global diabetes management on individuals with T2D attending the center.

Next, the frequency of HbA1c estimations in patients admitted to internal (INT) and geriatric (GER) departments in the years 2015–2022 was recognized from the electronic database of the authors’ institution.

2.5 Statistical analysis

Statistical analysis was performed using the IBM SPSS Statistics for Windows, version 23 (IBM Corp., Armonk, NY, USA). Standard descriptive statistics were used to summarize the data for continuous non-normal variables (checked by means of the Shapiro–Wilk test). Wilcoxon signed-rank test with Bonferroni correction was used to assess the changes (Δ delta) of the parameters depicting the therapeutic effectiveness. Spearman correlation analysis was used to find an association between BMI and HbA1c. A significance level of P < 0.05 was considered meaningful.

3. Results

3.1 Frequency of various kinds of medication over the study years 2015–2023

The absolute/relative numbers of individuals with T2D treated with beta-stimulators, metformin, dapagliflozin, incretin preparations, insulins and hypolipidemics are presented according to the study period-related time scale (Table 3, Figures 7 and 8).

Year	2015	2016	2017	2018	2019	2020	2021	2022	2023
N of attending T2D/y	135	163	161	163	151	139	138	132	97
Beta-stimulator (glinide)	2	1	1	1	1	1	1	1	1
Beta-stimulator (S-urea)	0	0	0	0	0	0	1	1	1
Metformina	119	111	105	102	92	106	109	82	54
Metformins’ % of N	88%	68%	65%	63%	61%	76%	79%	62%	56%
Dapagliflozin	32	10	4	3	2	3	2	6	5
Dapagliflozin+Metformin	19	48	47	44	57	53	52	46	43
DAPAs’ sum (n)	51	58	51	47	59	56	54	52	48
DAPAs’ % of N	38%	36%	32%	29%	39%	40%	39%	62%	50%
iDPP4 (gliptin+ met)	32	27	19	22	14	6	6	5	4
Incretin Exenatide	5	6	4	3	3	0	0	0	0
Incretin Liraglutide	15	22	21	12	5	0	0	0	0
Incretin in IDegLira	0	2	11	26	27	28	26	25	19
Incretin Semaglutide sc.	0	0	0	0	14	17	28	33	22
Incretin Semaglutide tbl.	0	0	0	0	0	0	4	10	17
Incretins’ sum (n)	20	30	36	41	49	45	58	68	58
Incretins’ % of N	15%	18%	22%	25%	32%	32%	42%	52%	60%
Insulin Aspart lag	31	33	29	8	3	0	0	0	0
Insulin Aspart pen	33	42	38	14	9	8	5	2	2
Insulin Aspart lag+pen	64	75	67	32	12	8	5	2	2
Insulin Fiasp (lag+pen)	0	0	19	42	38	37	32	29	23
Short INSs’ sum (n)	64	75	88	74	50	45	37	31	25
Short INSs’ % of N	47%	46%	55%	45%	33%	32%	27%	23%	26%
Insulin Detemir	14	28	31	25	9	4	2	2	0
Insulin Degludec	0	0	0	0	18	22	22	18	14
Insulin IDegLira	0	2	11	26	27	28	26	25	19
Long INSs’ sum (n)	14	30	42	51	54	54	50	45	33
Long INSs’ % of N	10%	18%	26%	31%	36%	39%	36%	34%	34%
Pioglitazon	0	0	0	0	1	1	2	3	1
Atorvastatin	N/A	48	79	84	75	69	59	55	46
Rosuvastatin	0	30	34	25	27	28	28	23	22
Statins’ sum (n)	N/A	78	113	109	102	97	87	78	68
Statins’ % of N	N/A	48%	70%	67%	68%	70%	63%	59%	70%
Fibrates	0	0	5	7	11	12	15	14	11

Table 3.

Absolute numbers (N) of all subjects attending the diabetes center and numbers of subjects treated with respective medication (highlighted by colors), in each year from January 1, 2015 to May 15, 2023.

^a

Consider also the numbers of combined preparations DAPA+MET and gliptin +MET.

Data were taken from the electronic database of the center. The percentage is related to the number (N) of all individuals who attended the diabetes center in the given year.

Figure 7.

Relative numbers (% related to N of subjects with T2D attending the diabetes center in the given year) of individuals, who were treated with metformin, dapagliflozin and incretin preparations are plotted according to the study-period-related time scale.

Figure 8.

Relative numbers (% related to N of subjects with T2D attending the diabetes center in the given year) of individuals who were treated with basal insulins and bolus (short-acting) insulins are plotted according to the study-period-related time scale.

3.2 The development of metabolic surrogate markers over person-related observation periods V1–V9

In a total of 200 adults who attended the diabetes center from 2015 to 2023, the following parameters (surrogate markers of therapeutic efficiency) were estimated and assessed:

• Glycated hemoglobin HbA1c (Table 4, Figure 9)

• BM (Table 5, Figure 10)

• BMI (Table 6)

• Heart rate (beats per minute), blood pressure systolic, blood pressure diastolic (Table 7)

• Lipoproteins: high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol (LDLC), TAG; TSH, C-reactive protein (CRP) (Table 8)

• Bilirubin, GMT, AST, ALP, uric acid (Table 9)

• Albumin, creatinine, urea, eGFR (Table 10)

• Blood count, hemoglobin concentration in blood, packed cell volume (Table 11)

• Proteinuria and glycosuria (absolute numbers (N) and percentage (%) of positive findings at respective visits (V1–V9) (Table 12).

Person-related Visit	HbA1c; V1	HbA1c; V2	HbA1c; V3	HbA1c; V4	HbA1c; V5	HbA1c; V6	HbA1c; V7	HbA1c; V8	HbA1c; V9
N	200	199	176	160	142	127	110	100	66
Mean	56.5	50.9	50.9	51.6	50.0	50.5	51.9	51.5	53.8
SD	18.8	12.4	12.6	14.0	12.2	13.7	14.2	14.5	14.7
Minimum	31.5	30.2	33.2	31.5	33.1	29.3	36.3	36.4	36.3
25th percentile	43.0	42.0	42.1	42.2	41.3	41.5	42.0	41.4	43.7
Median	53	48**	49**	48**	46**	46*	48	47	49
75th percentile	65.8	57.3	55.5	55.9	54.9	54.7	57.3	56.9	59.6
Maximum	173.0	98.9	116.4	116.6	100.7	131.9	118.7	114.6	100.1

Table 4.

The development of HbA1c [mmol/mol] from a person-related visit 1 (N = 200) to a person-related visit 9 (N = 66).

*

P = 0.025.

**

P < 0.001.

See Figure 7 for the upper reference limit (URL).

Mean ± SD, Median. Significant differences (compared to V1) are highlighted yellow.

Figure 9.

The development of HbA1c was recorded according to person-related visits (V1–V9) in T2D who attended the diabetes center from 2015 to 2023. Length of person-related observational periods varies from 1 to 9 years. Total number of people N = 200. Number (N) of people in individual visits is equal to the number of each individual person-related mean value of HbA1c in each year (Table 4). Upper reference limit (URL) = 42 mmol/mol.

Person-related visit	BM; V1	BM; V2	BM; V3	BM; V4	BM; V5	BM; V6	BM; V7	BM; V8	BM; V9
N	195	192	173	159	140	129	113	102	81
Mean	91.5	91.1	90	89.6	90.6	90	88.4	86.6	86.4
SD	19.9	19.3	19.1	19.2	19.1	19.4	18.8	19.2	18.5
Minimum	52	52	52	47	50	53	51	49	53
25th percentile	75	75	75	74	75	74	75	73	73
Median	91	91**	90**	90**	91**	91**	89**	87**	86**
75th percentile	104	104	104	103	102	101	98	97	96
Maximum	180	175	172	173	174	180	178	179	167

Table 5.

The development of BM [kg] over the person-related observation period, i.e., from visit 1 to visit 9.

*

P < 0.05.

**

P < 0.001.

Mean ± SD, median (IQR). Significant differences (compared to V1) are highlighted in yellow.

The dates of visits are identical with the dates of visits estimating the HbA1c.

Figure 10.

The development of BM [kg] in T2D individuals who attended the diabetes center from 2015 to 2023. Median (IQR). Number of people (= number of each individual person-related mean values of BM in each individual year) see Table 5. This number need not to be identical with the number of HbA1c estimations due to occasional lack of BM measurement, e.g., the body mass could not be measured in individuals if they were unable to operate the scale.

Person-related visit	BMI; V1	BMI; V2	BMI; V3	BMI; V4	BMI; V5	BMI; V6	BMI; V7	BMI; V8	BMI; V9
N	195	192	173	159	140	129	113	102	80
Mean	32.1	32.0	31.8	31.7	31.8	31.7	31.2	30.6	30.8
SD	6.0	5.8	5.6	5.6	5.5	5.4	5.4	5.4	5.4
Minimum	20.6	19.6	18.5	17.7	19.1	21.5	21.1	20.7	21.9
25th percentile	27.8	28.0	28.0	27.7	27.9	27.7	27.4	26.9	27.0
Median	32.0	31.8**	31.4**	31.1**	31.3**	31.3**	30.1**	29.8**	30.0**
75th percentile	35.7	35.4	35.5	35.6	35.3	35.0	34.0	33.6	33.4
Maximum	55.3	55.8	54.5	54.5	53.1	50.1	48.5	47.8	48.5

Table 6.

The development of BMI [kg/m²] over person-related observation periods, i.e., from visit 1 to visit 9.

**

P < 0.001.

Mean ± SD. Median (IQR). Significant differences (compared to V1) are highlighted in yellow.

		Reference range	Visit 1	Visit 5	Visit 7	Visit 9
Heart rate [BPM]	Median		78	80	79	79
	Min	60	56	51	51	53
	Max	90	109	107	107	112
BP syst [mmHg]	Median		138	147**	144**	150**
	Min	(90)	100	91	105	109
	Max	130	193	188	195	202
BP diast [mmHg]	Median		80	85**	84**	85**
	Min	(40)	50	52	66	67
	Max	85	116	110	107	112

Table 7.

The development of heart rate (BPM – beats per minute) and blood pressure (BP) in person-related visit 1, visit 5, visit 7 and visit 9.

**

P < 0.001.

Median (min, max). Significant differences (compared to V1) are highlighted in yellow.

		Reference range	Visit 1	Visit 5	Visit 7	Visit 9
S-HDLC; [mmol/l]	Median		1.20	1.13**	1.13**	1.17
	Min	1.00	0.56	0.42	0.46	0.56
	Max	2.10	2.86	2.85	2.04	1.93
S-LDLC; [mmol/l]	Median		2.27	1.97	1.80**	1.76**
	Min	1.20	0.79	0.79	0.77	0.87
	Max	2.60	4.79	4.97	3.24	4.37
S-TAG; [mmol/l]	Median		1.49	1.48	1.42	1.33
	Min	0.45	0.61	0.49	0.60	0.59
	Max	1.70	6.71	9.34	5.90	6.06
S-TSH	Median		2.50	2.67	2.53	2.67
	Min	0.27	0.01	0.17	0.01	0.01
	Max	4.20	35.3	64.1	19.0	9.6
S-CRP	Median		2.10	1.70	1.55	1.30
	Min	0.00	0.13	0.05	0.30	0.50
	Max	5.00	58.5	44.3	26.7	92.5

Table 8.

Data on lipoproteins, thyroid function and inflammation: high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol (LDLC), triacylglycerols (TAG), thyroid-stimulating hormone (TSH) and C-reactive protein (CRP) in person-related visit 1, visit 5, visit 7 and visit 9.

**

P < 0.001. No difference in TAG, TSH and CRP.

Median (min, max). Significant differences (compared to V1) are highlighted in yellow.

		Reference range	Visit 1	Visit 5	Visit 7	Visit 9
S-Bil	Median		7.70	7.50	7.48	7.10
	Min	3.4	2.95	3.00	3.15	2.30
	Max	17.0	30.3	28.3	28.5	25.5
S-GMT	Median		0.500	0.378*	0.385*	0.370*
	Min	0.00	0.090	0.105	0.120	0.110
	Max	0.92	26.15	6.17	1.33	7.30
S-AST	Median		0.350	0.385*	0.380	0.353
	Min	0.00	0.180	0.200	0.225	0.210
	Max	0.58	1183	5.980	1.170	1.190
S-ALP	Median		1.23	1.24*	1.17	1.19
	Min	0.66	0.52	0.54	0.57	0.56
	Max	2.20	9.98	4.22	2.88	3.42
S-Uric acid	Median		346	343	332	332
	Min	180.0	167	151	123	152
	Max	420.0	700	648	562	647

Table 9.

Laboratory findings in hepatobiliary disorders: bilirubin (Bil), GMT, AST, ALP and uric acid.

*

P < 0.05. No difference in bilirubin and uric acid.

Significant differences (compared to V1) are highlighted in yellow.

		Reference range	Visit 1	Visit 5	Visit 7	Visit 9
S-albumin; [g/l]	Median		45.9	45.0**	45.5	45.6
	Min	35.00	37.0	31.6	39.4	37.8
	Max	50.00	53.3	51.7	50.9	52.7
S-creatinine [umol/l]	Median		71	77**	79	—
	Min	62.0	38	38	37	—
	Max	115.0	714	486	152	—
S-urea; [mmol/l]	Median		5.1	5.7**	5.8**	5.8**
	Min	2.90	2.5	2.5	2.3	3.1
	Max	7.50	16.7	21.0	15.9	16.1
eGFR; [ml/s]	Median		1.59	1.40**	1.37**	1.38**
	Min	1.000	0.54	0.34	0.36	0.53
	Max	1.500	2.44	2.51	2.17	2.24

Table 10.

Parameters of renal function: Albumin, creatinine, urea, estimated glomerular filtration rate (eGFR) in person-related visit 1, visit 5, visit 7 and visit 9.

**

P < 0.001.

Median (min, max). Occasional small deviations from N (Table 4) need to be considered. Significant differences (compared to V1) are highlighted in yellow.

		Reference range	Visit 1	Visit 5	Visit 7	Visit 9
B-Hb; [g/l]	Median		142	142	140*	143
	Min	135	94	98	96	78
	Max	175	181	178	179	180
B-Ery; [n]	Median		4.78	4.92	4.62*	4.65
	Min	4.0*10^12/l	3.33	3.20	3.22	3.20
	Max	5.8*10^12/l	5.76	6.20	6.76	5.79
B-HTC	Median		0.419	0.426	0.415	0.423
	Min	0.400	0.302	0.296	0.276	0.269
	Max	0.500	0.527	0.545	0.598	0.524
B-Leu; [n]	Median		8.10	8.40*	7.80	7.70
	Min	4.0*10^9/l	4.07	4.95	3.50	3.70
	Max	10.0*10^9/l	15.0	20.0	49.0	17.9
B-Thromb; [n]	Median		238	236*	239*	246*
	Min	150*10^9/l	79	109	100	76
	Max	400*10^9/l	388	517	405	431

Table 11.

Blood count, hemoglobin (B-Hb) and packed cell volume (B-HTC).

*

P < 0.05. No difference in B-HTC.

Significant differences (compared to V1) are highlighted in yellow.

	V 1	V 2	V 3	V 4	V 5	V 6	V 7	V 8	V 9
Measurements of proteinuria (N)	186	186	166	154	136	122	108	95	70
Proteinuria positive (n)	21	17	15	11	10	7	6	9	5
Relative (% n out of N)	11.3	9.1	9.0	7.0	7.4	5.7	5.6	9.5	7.1
Measurements of glycosuria (N)	177	186	168	153	135	122	109	94	73
Glucosuria positive (n)	52	75	68	62	63	58	52	49	36
Relative (% n out of N)	29.4	40.3	40.5	40.5	46.7	47.5	47.7	52.1	49.3

Table 12.

Qualitative urine examination on proteinuria and glucosuria at V1–V9.

The length of person-related observational periods varied. The date (year) of V-START might vary from person to person. Number of people (N) in consequent visits is decreasing as people entering the center later than in 2015 and/or leaving before the terminal visit on May 15, 2023, could attend only a lower number of visits.

3.3 Impact of pathophysiological approach applied over the study period

The study period lasted 9 years (from 2015 to 2023); however, only 66 of 200 attendees took part in all scheduled check-ups.

The person-related observational period started in all individuals (N = 200) at the first measurement (V-START), which might appear in any year, and various timeslapsed until the terminal measurement (V-END) (Table 13).

Observational period	Mean	SD	Median	Minimum	Maximum
Time span [years] between V-START and V-END	5.5	2.4	6.8	0.5	8.8

Table 13.

Length of the person-related observational period in the entire group (N = 200).

Comparison of the descriptive characteristics of principal surrogate markers, namely, HbA1c and BMI estimated at first and at the last person-related measurement and their delta (V-START) minus (V-END), was applied to assess the impact of the therapeutic approach (Table 14).

Parameter	Unit	Mean	SD	Median	Minimum	Maximum	p-value
HbA1c-START	mmol/mol	57.5	20.1	52.6	31.5	173.0	0.0001
HbA1c-END	mmol/mol	51.4	15.0	46.6	31.5	116.6
DELTA HbA1c	mmol/mol	6.09	20.12	3.27	−41.67	116.68
BMI-START	kg/m^2	27.0	5.1	26.7	16.0	45.3	< 0.0001
BMI-END	kg/m^2	25.8	4.9	25.4	15.4	42.2
DELTA BMI	kg/m^2	1.27	2.39	1.21	−5.06	10.37

Table 14.

Descriptive characteristics of HbA1c and BMI at the START (V-START) and at the end (V-END) of subject-related observational periods and statistical analysis of changes START–END.

Spearman correlation analysis revealed a weak positive correlation (r = 0.209, p = 0.003) between delta (START–END) HbA1c and delta (START–END) BMI.

Figures 11 and 12 demonstrate the distribution of values of HbA1c and BMI at the first measurement (V-START) and at the last measurement (V-END) of the study.

Figure 11.

Distribution of values of HbA1c at the first measurement (V-START) and at the last measurement (V-END) of each individual observation period. N = 200 (=100%).

Figure 12.

Distribution of values of BMI at the first measurement (V-START) and at the last measurement (V-END) of each individual observation period. N = 195 (=100%).

3.4 Frequency of HbA1c measurements in people admitted to general hospital

To compare the outcomes of this trial with a routine “state of the art” of every-days’ practice, the frequency of HbA1c estimations in people admitted to internal and geriatric departments of a large hospital in the Czech Republic was sought for (Table 15).

	Parameter	2015	2016	2017	2018	2019	2020	2021	2022
INT	N all admitted patients/year	2980	2797	2852	3028	3358	3570	3444	3581
	N T2D on admission/registry	225	257	252	348	354	641	652	653
	Susp. N T2D (=30% of N all)	864	839	856	908	1007	1071	1033	1074
	N of HbA1c estimations/year	54	35	33	19	23	48	14	16
	% of HbA1c related to susp.N T2D	6.3%	4.2%	3.9%	2.1%	2.3%	4.5%	1.4%	1.6%
	% T2D related to N total	7.6	9.2	8.8	11.5	10.5	18.0	18.9	18.2
	% of HbA1c related to N total	1.8%	1.3%	1.2%	0.6%	0.7%	1.3%	0.4%	0.5%
	Mean Age of admitted T2D (years)	73.3	64.8	70.8	74.7	73.3	76.1	70.7	72.4
GER	N of all admitted patients/year	430	535	459	612	656	679	898	710
	N of T2D on admission/registry	70	118	85	158	137	198	236	176
	Susp. N T2D (=30% of N all	129	161	138	184	197	204	269	213
	N of HbA1c estimations/year	6	29	30	23	19	18	120	7
	% of HbA1c related to susp.N T2D	4.7%	18.0%	21.7%	13.0%	9.6%	8.8%	44.6%	3%
	% T2D related to N total	16.3	22.1	18.5	25.8	20.9	29.2	26.3	24.8
	% of HbA1c related to N total	1.4%	5.4%	6.5%	3.8%	2.9%	2.7%	13.4%	1.0%
	Mean age of admitted T2D (years)	75.5	72.0	77.8	77.7	82.5	78.0	74.7	77.7

Table 15.

Frequency of HbA1c estimations in all patients admitted to internal (INT) and geriatric (GER) departments in the years 2015–2022.

Data from the electronic database of the authors’ institution. N T2D on admission/registry in this table comprises only those people where T2D is registered in the database as the main (principle) condition of admission. The susp. (real) N T2D is assessed to be 30% of N all admitted patients/year to hospital due to various conditions/diagnoses.

So, in individual years 2015–2022, HbA1c was measured in approximately 1.4%–6.3% of patients with T2D admitted to the Department of Medicine and in 3–44.6% of patients with T2D admitted to Department of Geriatrics.

4. Discussion

This chapter focuses on three concerns: (1) to identify the frequency of application of recent drugs, namely, beta-stimulators, metformin, gliflozins, incretins and/or insulins, pioglitazone, statins and fibrates, in a diabetes center and (2) to assess global effectiveness of the T2D management based on medication, physical exercise, meal plan, education, self-monitoring, technical equipment, family background and personal cooperation within the healthcare system and (3) to estimate the frequency of HbA1c measurements in people admitted to hospital (which were used as “control group” attempting to identify potential involvement of non-diabetologists in routine diabetes care).

In the course of previous decades, glycemia and HbA1c were considered to be key markers of therapeutic effectiveness in T2D. Changes in body mass usually took place among marginal side effects of inappropriate diet and lifestyle [17]. On the other hand, changes of current amount of adipose and muscle tissues in the body are associated with availability of endogenous and/or injected insulin along with production of incretins in gut or their therapeutic administering and/or the sensitivity of respective receptors [18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28].

In addition, insulin stimulates appetite. Without insulin, symptoms of T1D including hyperglycemia and reduction of body mass appear. Without incretins, increased appetite leads to obesity and hyperglycemia. In addition, hyperglycemia is supported by escalated activity of SGLT2 in kidneys, resulting in increased reabsorption of glucose from primary urine.

So, euglycemia, optimal body mass and normal lipoproteinemia may be regulated using insulin and/or incretin preparations and/or gliflozins and other medication without delay [16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29].

Despite of frequent discussions dealing with the optimal/acceptable target values of respective metabolic parameters, our attempts aimed to

• good clinical condition without hypoglycemic risks and then

• usual reference range of parameters, i.e., fasting glycemia < 6.0 mmol/l, HbA1c < 42 mmol/mol, BMI < 25 kg/m₂, LDLC < 1.6 mmol/l, etc.

• maximal protection against cardiovascular and renal complications [6, 7, 8, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 51, 52]

The schedule of current clinical and laboratory check-ups, as stated at the beginning of this chapter, was always kept in mind.

The frequency of application of individual drugs (Table 3) allowed us to observe that:

• Metformin (including combinations with DAPA or iDPP4) has been widely used (in >95% of N) throughout the entire study.

• Dapagliflozin has been constantly administered to about 50 subjects, mostly in combination with metformin (even though the relative percentage of subjects on DAPA has increased from about 40 to 60% subjects, Figure 7).

• The percentage of people on incretins (exenatide, liraglutide and semaglutide) has continuously increased from 15% in 2015 to 60% in 2023 (Figure 7).

• The percentage of people on short-acting and faster-acting bolus-insulins decreased from about 50% before 2018 to 26% in 2023 (Figure 8). Based on results of impacted studies [9, 10, 11, 12], insulin aspart was replaced by Fiasp. Even though in the “mini-trial” from 2019 [8] Fiasp did not lead to any significant improvement of metabolic parameters, 29 out of 31 subjects kept administrating Fiasp.

• The percentage of long-acting insulin users increased from 10% in 2015 to 34% in 2023 (Figure 8). We have replaced insulin detemir with insulin degludec in all of them.

• Administrating of beta cells stimulators and/or pioglitazone have always been close to zero.

• Statins have mostly been used in more than 60% of subjects, whereas the LDLC concentration dropped from 2.27 (0.79–4.79) mmol/l at visit 1 to 1.76 (0.87–4.37) mmol/l (P < 0.001) at visit 9 (Table 8).

The development of key metabolic surrogate markers, namely, HbA1c, BM and BMI may be recognized from Tables 4-6, Figures 7 and 8. In general, their changes appear to be substantially impacted by optimized medication indicated in Table 3.

The assessed values of metabolic markers at individual visits are means mostly of two values in each individual year. A significant reduction of HbA1c at V2, V3, V4, V5 and V6 vs. V1 may be seen (Table 4, Figure 9). Similarly, a continuous decrease of BM between V1 and V9 was observed (Table 5, Figure 10).

In Figure 11 (distribution of HbA1c values at the START vs. the END) and in Figure 12 (distribution of BMI at the START vs. the END) is the effect of a complex T2D management clearly recognized: at the end of the study the number of T2D with HbA1c values <60 mmol/mol increased from 135 out of 200 (67%) people with T2D to 185/200 (92%) and only 15/200 (8%) remained higher than 60 mmol/mol. The final BMI < 25 kg/m² reached 93 out of 195 (48%) people with T2D in comparison to 70/195 (36%) individuals at the START visit.

Reduction of HbA1c median from start values of 52.6 (31.5–173.0) to 46.6 (31.5–116.6) mmol/mol (P = 0.0001) along with reduction of BMI median from 26.7 (16.0–45.3) to 25.4 (15.4–42.2) kg/m² (P < 0.0001, Table 14) demonstrated important benefits of a pathophysiology-based management of T2D which has been included into daily routine in the course of subject-related observational period lasting 6.8 (0.5–8.8) years (Table 13).

The current state of the art of precision medicine [16, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52] does not allow the select “the person related optimal medication” as early as the T2D had been recognized. To date, more therapeutic attempts appear to be necessary to find the most effective and acceptable combination of various drugs.

By reading Table 3, it is hard to identify which particular medication resulted in observed metabolic benefits. Two topics appear to be worth the particular assessment, namely, impact of fixed combination IDegLira and incretin receptor agonist semaglutide.

• The impact of combination of incretin with insulin (such as IDegLira) instead of CSII has already been presented [13, 20] and demonstrated the development of HbA1c and BMI over the first period on CSII and over the following period on IDegLira. In the CSII period, the HbA1c decreased in 3/8 T2D individuals and BMI in 4/8. Over the IDegLira period, the HbA1c decreased in 7/8 T2D people (Figure 13) and BMI in 7/8 (Figure 14). Medication with metformin (2000–3000 mg/day) and other drugs remained without substantial changes over the whole study period. Continuing observation of subject No 4 beyond the last study visit revealed progressive cognitive deterioration resulting in the omission of any medication. So, the increase of HbA1c (Figure 13) along with the decrease in BMI (Figure 14) may be explained by this condition (see Case report 1 in [20] for details). Finally, IDegLira was preferred in 7/8 T2Ds due to simplicity. Only one lady found the insulin pump more convenient due to the option of prandial boluses, enabling additional meals at any time.

Figure 13.

Reduction of HbA1c [mmol/mol] following the switch from CSII to IDegLira in 7/8 individuals. The increase of HbA1c in subject No 4 became obvious beyond the end of this study: Cognitive deterioration resulting in unrecognized omitting of any medication [20].

Figure 14.

Reduction of BMI [kg/m²] following the switch from CSII to IDegLira in 7/8 individuals.

So, management of T2D with a fixed combination of insulin degludec and liraglutide appears to be a promising pathophysiologic approach that is equally or even more effective than long-lasting CSII. A person-related approach needs to be considered.

• Therapeutic potential of a GLP1 receptor agonist semaglutide has already been demonstrated by Sustain and Pioneer studies [1]. In the period 2019–2023, we attempted to assess the impact of injectable and oral semaglutide on BMI, HbA1c and insulin needs in people with T2D [1, 14, 15, 20, 52, 53]. In 2023, a total of 48 T2D (28 men, 20 women), median age of 62.8 (45.0–87.4) years, diabetes duration median of 15.8 (0–27.8) years were assessed. Some of them were treated with injectable SEMA (n sc = 33) using doses up to 1.0 mg/week. The oral SEMA dosing (n oral = 15) started with 3 mg/day and was increased to 14 mg/day within 3 months. Table 16 shows a significant reduction of HbA1c, BM and INS/d from the Start Visit A to the End Visit C. At Visit C, there were 2 out of 33 PWD2 who refused further treatment with injectable SEMA (due to maldigestion and increase of HbA1c) and 3/15 PWD2 who refused to continue with oral SEMA (due to maldigestion). Hence, 43/48 (90%) PWD2 appreciate their routine treatment with SEMA.

Parameter	Visit A (Start)			Visit B (check-up)			Visit C (End)
	Median	Min	Max	Median	Min	Max	Median	Min	Max
Days from Visit A	n/a	n/a	n/a	154	64	847	439	64	1414
HbA1c [mmol/mol]	60.1	39.9	129.2	51.9	36.0	86.4	48.0	36.7	108.9
Body mass [kg]	99.2	69.4	181.0	96.3	63.4	172.5	93.0	59.5	172.5
BMI [kg/m^2]	34.0	24.6	53.7	32.0	22.1	50.2	31.3	20.7	47.9
Insulin [U/day]	32.5	0.0	80.0	36.0	8.0	80.0	22.1	0.0	68.0
delta HbA1c (C-A)a							−6.5	−92.4	37.0
delta BM (C-A)b							−5.2	−23.1	4.5
delta BMI (C-A)b							−1.9	−10.3	1.7
delta insulin (C-A)c							−6.0	−43.9	13.0

Table 16.

Changes (delta) of HbA1c, BM, BMI and INS/d.

^a

P = 0.001;

^b

P < 0.0001;

^c

P = 0.019.

Visit A – SEMA start, Visit B – SEMA increase, Visit C – SEMA last check-up. Significant reduction (compared to Visit A) I highlighted in yellow.

Hence, oral or injectable SEMA appears to be effective means of routine, long-lasting T2D management. Higher doses are worthy of consideration [15]. Our observation is consistent with other studies [1, 18, 19, 20] and with recommendations of respected bodies [16]. Preference of its oral or injectable form remains worth further research. Nevertheless, in 5 out of 48 (10%) T2D, maldigestion has not allowed to continue the semaglutide treatment in either form.

Routine check-ups of clinical parameters (Table 7) revealed a significant increase of systolic and diastolic blood pressure at visit 5, visit 7 and visit 9. Hence, when taking into account the WHO Recommendations from 2023 [54], this finding has been a challenge, resulting in a timely implementation of regular blood pressure self-monitoring by means of a personal meter to make adequate antihypertensive therapy more flexible.

Additional clinical and biochemical parameters such as CRP, TSH (Table 8), bilirubin, GMT, alkaline phosphatase, AST, uric acid (Table 9), blood count (Table 11) have occasionally revealed relevant deviations (e.g., acute bronchitis, cholelithiasis, liver cirrhosis, hypothyroid disease, heart failure, anemia, etc.) which were solved in cooperation with general practitioners.

Renal function was measured using eGFR (Table 10). Despite a significant decrease of median eGFR from 1.59 ml/s at visit 1 to 1.38 ml/s at visit 9 the percentage of values in reference range increased. Qualitative urine examination showed the frequency of proteinuria up to 11,3% without any significant change between visit 1 and visit 9 (Table 12).

Adverse side effects such as activation of urinary infection when on DAPA, gastrointestinal discomfort at the beginning of incretin administration, and diarrhea when on metformin, appeared occasionally and mostly mild. Hypoglycemia appeared rarely. These complications were treated by adaptation of therapy as recommended. Nevertheless, maldigestion resulting in interruption of semaglutide therapy appeared in about 10% of T2D which need to be further studied.

HbA1c is a basic parameter assessing the effectiveness of diabetes management. In this trial, the real frequency of HbA1c measurements in a specialized diabetes walk-in center was 1.9–3.0 measurements per person per year (Table 2).

However, not all hospitals/departments are specialized in diabetes. That is why we attempted to compare some data from this specialized trial with 200 T2D with non-specialized diabetes care in routine practice of a hospital ward.

About 3000 people admitted (due to various diagnoses) yearly to internal and geriatric units of a teaching hospital were used as a control group (Table 15). Frequency of HbA1c estimations in admitted patients served as potential marker of involvement of respective professional departments in diabetes care.

In hospital wards, the HbA1c was estimated in 0.4–13.4% of all patients admitted per year, such as about 2 HbA1c estimations in 100 patients per year. There was a slight difference between the two departments: HbA1c was measured in 1.4–6.3% of patients with T2D yearly admitted to the Department of Medicine and in 3 to 44.6% of patients with T2D yearly admitted to Department of Geriatrics. The high number of HbA1c investigations in 2021 is probably related to the COVID-19 epidemics when special attention was paid to early recognition of diabetes and its complications.

Considering the exciting history of medical research, unexpected complications may interfere with any fascinating perspective [55]. More questions, but enough answers remain [56]. However, human life span on insulin has already exceeded 50- and recently even 80 fruitful years [57, 58].

5. Summary and Conclusions

1. A total of 200 adults were treated in a single walk-in diabetes center. Their individual observation periods took in the range of 6.8 (0.5–8.8) years (median, min-max). At the end of the study, individually adapted antidiabetic and hypolipidemic medication contained metformin (in >95% out of 200 subjects) and/or gliflozins (in up to 60%) and/or incretins (in about 60%) and/or insulins (in about 50%) and/or statins (in up to 70%) and fibrates (in up to 15%).

2. The effectiveness of the global T2D management in the walk-in center was assessed by employing the differences of the HbA1c and BMI values between the first and last visit of subjects. Reduction of HbA1c from start values of 52.6 (31.5–173.0) mmol/mol to 46.6 (31.5–116.6) mmol/mol along with reduction of BMI from 26.7 (16.0–45.3) kg/m² to 25.4 (15.4–42.2) kg/m² demonstrated important benefits of complex management comprising variable lifestyle, medication, physical exercise, meal plan, education, self-monitoring, technical equipment, family background and personal cooperation within the healthcare system.

3. Frequency of HbA1c measurements in people admitted to the hospital was used as a blinded attempt to identify the potential involvement of non-diabetes departments in routine diabetes care. HbA1c was mostly investigated in less than 15% of yearly admitted patients with T2D whereas in specialized diabetes walk-in center 2.0–3.0 HbA1c measurements per person per year were performed.

So, the outcomes of the presented global approach focusing on implementation of recent medication in people with T2D are challenging. Last but not least, scheduled education, incretin/insulin pens, glucometers, CGM sensors and a flexible health care systém constitute the background of an effective management.

Parts of this review were presented at the Congress of the German Diabetes Association in Berlin, 2021 [13] and 2022 [15], at the Student Scientific Research Conference, Faculty of Medicine and Dentistry, Palacký University Olomouc, 2023 [52] and at the Annual Research Meeting of the Slovakian Diabetes Society, Topolčianky, 2024 [53].

Acknowledgments

R.C. was in charge of the manuscript design and final text review; H.Z. was responsible for data collection, blood samples and data files; J.G. took care of biochemical investigations; M.T. was in charge of electronic data files and IT operations; J.Z. performed the statistical analysis and provided Figures and Tables; L.H. supervised the performance of therapeutic protocols including HbA1c and 10-point glycemic profiles, R.K., M.B., P.F. and Z.P. supervised the cooperation between walk-in diabetes center and hospital wards, and reviewed the manuscript. There is no conflict of interest.

Special thanks to Stanislava Dudová, Emilia Ďurajková, Lenka Kratochvílová, Michaela Nádvorniková, Jana Polcerová, Svatava Tancosová, Jana Ferancová, Pavel Kolčava, Eva Malá, Dana Masnikosová, Hana Peniaková, Jiří Podivínský, Jana Svobodová, Rastislav Šramko and their teams for outstanding neverending support.

Final acknowledgment belongs to specialists, nursing and other staffs, and students of Palacký University Olomouc (in particular to Zdeněk Ramík, Tzu Hsuan Cheng, Monika Slezáková, Romana Kotačková, Veronika Šálková, Tal Goldstein, Samuel Benyaminov, Biayni Minasyan, Dominika Šimková, Viktória Molnárová, Noemi Nováková, Martin Nezval, Jitka Bačíková), compliant people with diabetes, as well as to Insurance Companies and pharma industry in the Czech Republic.

Those who found this chapter worth of reading surely appreciate the support provided by Palacký University, Teaching Hospital Olomouc, Institute of Specialized Treatment Paseka and other important institutions.

Dedication

This chapter is dedicated to the memory of three professors [59, 60, 61, 62] born in different countries, working at different universities/institutes under oscillating friendly and unfriendly conditions whose lifelong empathy and open minds created fruitful perspectives for people with diabetes and motivated many health care professionals along with students for future diabetes care and research activities:

Abbreviations

ADA	American Diabetes Association
B-HTC	packed cell volume
BP	blood pressure
BM	body mass
BMI	body mass index
CGM	continuous glucose monitoring
CSII	continuous subcutaneous insulin infusion
CRP	C-reactive protein
DAPA	dapagliflozin
EASD	European Association for the Study of Diabetes
eGFR	estimated glomerular filtration rate
Fiasp	faster insulin aspart (insulin aspart + vitamin B3)
fS-glucose	fasting serum glucose concentration
fT4	free thyroxin
GIP	glucose-dependent insulinotropic peptide
GLP1 RA	glucagon-like peptide receptor agonist
HbA1c	hemoglobin A1c, glycated hemoglobin
HDLC	high-density lipoprotein cholesterol
IDegLira	insulin degludec + liraglutide (fixed combination)
iDPP4	inhibitors of dipeptidyl peptidase 4
IQR	interquartile ratio
INS/d	insulin/day (amount of insulin per 24 h)
LDLC	low-density lipoprotein cholesterol
LIRA	liraglutide
MDI	multiple daily insulin injections
MET	metformin
PG	plasma glucose
SD	standard deviation
SEMA	semaglutide
SGLT2	sodium-glucose transporter 2
SMPG	self-monitoring of plasma glucose
T2D	type 2 diabetes
TAG	triacylglycerols
U-glucose	presence of glucose in urine
U-protein	presence of protein in urine
URL	upper reference limit