Pathophysiology-Oriented Treatment of Type 2 Diabetes: 10 Case Reports

Abstract

The effects of pathophysiology-oriented treatment using metformin and/or insulin analogs and/or incretin GLP-1 receptor agonists and/or dapagliflozin and/or pioglitazone were individually evaluated in ten people with type 2 diabetes (T2D) at an urban diabetes center. Some of them had microangiopathy and/or neuropathy and/or nephropathy. The observation period ranged from 2 to 12 years. Treatment efficiency was estimated according to changes in HbA_1c, body mass, insulin dose per day, blood pressure, lipoproteins, albuminuria, estimated glomerular filtration rate (eGFR), and general clinical condition. The results suggest that adequate education, early implementation of self-monitoring of capillary plasma glucose (SMPG)/continuous glucose monitoring (CGM), and long-term carefully selected/combined medication (see above) appears to result in improved metabolic control and enhanced quality of life for people with T2D.

1. Introduction

Type 2 diabetes (T2D) is the predominant form of diabetes, accounting for approximately 90–95% of all diabetes cases. A distinctive feature of type 2 diabetes is that many individuals may not require insulin treatment for their survival, particularly in the early stages and often throughout their lives [1]. The establishment of therapeutic goals encompasses individual preferences, coexisting medical conditions, age, duration of diabetes, life expectancy, quality of life, psychosocial circumstances, and the individual’s capabilities [2, 3].

The rising prevalence of T2D has led to the emergence of numerous novel approaches aimed at safely managing hyperglycemia. Nevertheless, individual responses to treatment modalities may vary due to the diverse and complex pathophysiology underlying T2D. Correct understanding and addressing this heterogeneity may influence the choice of therapeutic approach [4]. As per the guidelines provided by the ADA/EASD, older adults who are in good health with minimal coexisting chronic conditions and intact cognitive and functional abilities should aim for lower glycemic targets, typically with an HbA_1c level of <53–58 mmol/mol. For older adults facing multiple chronic illnesses, cognitive impairment, or functional dependence, goals with HbA_1c < 64 mmol/mol are recommended [5, 6, 7].

Prompt initiation of pharmacotherapy is recommended at the time when T2D is diagnosed unless contraindications exist. Metformin or other agents, including combination therapy, should be considered. Agents that reduce cardiorenal risk should be included in the treatment regimen for adults with a high risk of atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), and/or chronic kidney disease (CKD). These involve consideration of agents such as dulaglutide, semaglutide (SEMA), insulin, and gliflozins should be considered [3, 8].

In people with T2D and obesity, the medication’s impact on body mass should be considered [9, 10].

In addition to pharmacological therapy, people with T2D should adopt their physical activity and well-balanced diet [2].

In this chapter, we present ten case reports that demonstrate the application of pathophysiology-oriented treatment strategies in individuals with T2D [11]. These case reports were created at an urban diabetes center. The observation period ranged from 2 to 12 years. The effectiveness of the pathophysiology-oriented treatment was evaluated based on various parameters, including changes in HbA_1c, body mass, amount of insulin per day, and general clinical condition. Additionally, the importance of adequate education and early implementation of self-monitoring of capillary plasma glucose (SMPG) or continuous glucose monitoring (CGM) is plays a significant role [12].

2. Case reports

This collection of case reports aims to demonstrate the diverse challenges and various aspects of T2D treatment. We have selected six men and four women. Their age varies between 52 and 78 years, and the duration of diabetes from 2 years to 27 years. Case reports were ordered according to the duration of T2D. The overview of these ten cases is in Table 1.

No	Name	Age (years)	T2D (years)	Study period (years)	BM start (kg)	BM end (kg)	HbA1c start (mmol/mol)	HbA1c end (mmol/mol)
1	Amy	78	27	9	82	79	84	53
2	Benjamin	60	25	11	123	103	81	59
3	Connor	72	24	12	113	99	76	85
4	David	72	24	3	116	98	60	51
5	Emma	65	23	12	108	90	88	83
6	Fatima	73	16	11	83	79	65	52
7	Gerry	71	16	5	106	107	82	45
8	Henry	52	5	5	111	102	66	48
9	Irene	65	2	2	112	105	110	58
10	Jacob	52	2	2	130	112	129	37

Table 1.

Overview of the individual case reports, ordered according to the duration of T2D.

Each case report serves a specific focus, presenting the unique reason for its inclusion in this collection. They offer a glimpse into the medical history and pharmacological background of each individual, shedding light on their specific challenges and treatment journeys, and future plans marked as looking ahead. The case reports are complemented by graphical representations of absolute values, illustrating the progress of HbA_1c (glycated hemoglobin), BMI (body mass index), and INS/d (insulin dosage) over time.

Relative values are depicted in a graph where 100% corresponds to the highest physiological range for HbA_1c, BMI, and INS/d. This allows for a better understanding of each individual’s progress in relation to the optimal target range.

2.1 Case report Amy

Focus: Crucial role of the family in ensuring medication intake adherence of IDegLira and DAPA by the subject with T2D and progressing cognitive impairment [13].

History: Amy, a 78-year-old woman, was diagnosed with T2D in 1995 when she was 51 years of age. Despite attempts to control her diabetes with an MDI regimen, her HbA_1c remained persistently high, around 80 mmol/mol, coupled with fluctuating BM, and polyneuropathy.

In 2014, Amy was referred to our center. MDI was replaced with CSII and introduced to the fixed combination of dapagliflozin and metformin (DAPA/MET) in 2016. This was followed by the replacement of her insulin pump with a combination of degludec and liraglutide (IDegLira) in June 2018. However, the unrecognized progression of the cognitive impairment led to difficulties in keeping up with the new treatment, resulting in worsening glycemic control.

To further investigate the issue, Amy was hospitalized (H1), which led to a decrease in HbA_1c from 90 to 70. Her GP refused home care service due to Amy’s ability to administer medication herself; therefore, family members were asked to ensure Amy adheres to her medication schedule, and they agreed.

Despite these precautions, Amy’s glycemic control rapidly deteriorated during outpatient care. As Amy lives alone and was usually only supervised remotely through phone calls from her family, her intellectual dysfunction interfered with her ability to accurately report her medication adherence, leading to an alarming HbA_1c of 131 mmol/mol by December 2020.

Addressing this, the healthcare team implemented a more comprehensive approach. Amy was admitted to the hospital for rehabilitation including diabetes control (H2, H3, and H4), see Figure 1. During her hospital stay, her family members were educated about her condition and the importance of their active involvement in her care. A home care service was also arranged to ensure regular monitoring and assistance. With these interventions, Amy’s HbA_1c dropped to 51 mmol/mol in May 2023; see Figures 2 and 3 for data values.

Figure 1.

Four hospitalizations (H1-H4) marked as four green boxes, with marked admission (A) values of HbA1c and dismission (D) values of HbA1c. Green and red numbers indicate the change between each measurement.

Figure 2.

Absolute values of HbA_1c, BM, and INS/d over 9 years period showing that the first hospitalization (H1) led to a decrease in HbA_1c, yet due to poorly managed self-care and inability to adhere to the prescribed medication, the HbA_1c value escalated to 131 mmol/mol. Following further hospitalizations, coupled with family support and home care, a noticeable decrease in HbA_1c was achieved (see also Figure 1). Insulin usage was constant, with 60 IU/d, and then, decreased to 50 IU/d.

Figure 3.

Relative values of HbA_1c, BMI, and INS/d over the last 9 years show that none of the observed parameters reached under the upper limit of the reference range (URL), depicted as a line on 100% level.

Looking ahead: Regular check-ups at in-home care senior house.

2.2 Case report Benjamin

Focus: remarkable influence of CGM/hybrid insulin pump, DAPA, and SEMA on reduction of BM and HbA_1c and on improving overall metabolic health.

History: Benjamin, 60 years-old-man, was first diagnosed with DM2 in 1998. A subsequent diagnosis of polyneuropathy in 2007 suggests that his diabetes was most likely not optimally controlled.

Benjamin began our regimen of care in August 2012, presenting with an HbA_1c of 81 mmol/mol and a daily insulin requirement of 80 IU. The introduction of an insulin pump in early 2013 led to a commendable decrease in his HbA_1c to 71 mmol/mol and a reduction in his daily insulin requirement to 70 IU by the beginning of 2014 [14]. Nevertheless, Benjamin grappled with personal challenges in controlling his eating habits, which he found particularly difficult to overcome.

In an effort to curb his overeating, we strategically reduced Benjamin’s daily insulin intake. Despite this, his glycated HbA_1c remained around 80 mmol/mol from 2017 to 2019. To address this, we introduced a combination of dapagliflozin/metformin (DAPA/MET) into his treatment plan in 2019, which successfully brought down his HbA_1c. (Figures 4 and 5).

Figure 4.

CareLink Statistics: A comparison between the date range of 1 month A (blue) and B (orange). Progress between both date ranges, time in range (TIR), blood glucose (BG), insulin usage, and saccharides consumed.

Figure 5.

Absolute values of HbA_1c, BM, INS, since Benjamin has been in our care. The daily dose of insulin has been reduced from 88 to 71 IU by the implementation of an insulin pump. After lowering the INS/d and adding liraglutide to the treatment plan, HbA_1c increased, but body mass decreased by 7 kg. There is an apparent body mass decreasing trend, with a further decrease after SEMA was added to the treatment plan.

In early 2021, SEMA s.c. (once weekly) was added to his regimen. This led to a notable improvement in his glycemic control, with HbA_1c dropping to a promising 56 mmol/mol. However, Benjamin’s struggle with overeating resurfaced. Later in the same year (November 2021), flash glucose monitoring started. In 2022, a hybrid insulin pump MiniMed 780G, replaced the previous pump Paradigm Veo [15]. CareLink statistics can be seen in Figure 6.

Figure 6.

Relative values of HbA_1c, BMI, INS/d over the last 11 years showing that all the parameters are above the upper reference limit (URL). The BMI values show a decreasing trend.

Despite this setback, Benjamin’s glycemic control has remained commendably stable over the last 3 years, with HbA_1c maintaining below 60 mmol/mol. Moreover, his Body Mass Index (BMI) has also been reduced to below 30.

Looking Ahead: Reducing insulin intake and BM while maintaining/improving his glycemic control (HbA_1c). Improvement in his overall health and well-being.

2.3 Case report Connor

Focus: Unfortunate case with the focus on BM and HbA_1c reduction with no sustainable effect of CSII, exenatide, liraglutide, DAPA, >MET, SEMA.

History: A 72-year-old man, diagnosed with T2D in 1999 and on insulin therapy since 2007, was registered in our diabetes center on May 30, 2011. Upon admission, Connor’s treatment plan comprised insulin lispro (86 ID/d), insulin glargine (48 IU/d) (LIS + GLA in Figure 7), and MET (1700 mg daily). Soon after, insulin adjustments were made: insulin lispro was replaced with insulin aspart and insulin glargine with insulin detemir. This case will be further described using Figures 8–11.

Figure 7.

Absolute values of HbA_1c, BM, INS, in 2011–2013.

Figure 8.

Overview of Connor’s relative values from 2011 until 2023.

Figure 9.

Absolute values of HbA_1c, BM, INS/d over time.

Figure 10.

Absolute values of HbA_1c, BM, INS/d in 2018–2021.

Figure 11.

Absolute values of HbA_1c, BM, INS/d in 2021–2023.

September 30, 2011, the INS/d was reduced from 134 to 81 IU. April 13, 2012, in line with the special study, Connor was given an insulin pump, with 81 IU/d of insulin aspart; also MET increased to 3 g/day [14]. The outcome of the special study, which ended on October 12, 2012: despite reducing INS/d by 12 IU, HbA_1c decreased from 92 to 69 mmol/mol, and his body mass remained unchanged. Connor continues to use CSII [15].

January 21, 2013, liraglutide (LIRA) 6 mg/ml was prescribed, but on November 18, 2013, LIRA was replaced with exenatide (EX) (10–0-10 mg s.c./d) (as shown on Figure 9). March 3, 2014, exenatide was discontinued, but after a month exenatide QW (EX QW) was prescribed again. As the body mass was 111 kg, he was advised on the need for physical activity and a healthy lifestyle. Treatment with exenatide, metformin, and insulin delivery via the insulin pump led to improvement of HbA_1c, but its value still did not drop 60 mmol/mol below, so on November 23, 2015, dapagliflozin was added to the therapeutic plan. Exenatide and dapagliflozin were discontinued on February 29, 2016, due to gastric issues. June 27, 2016, exenatide therapy was restarted, which was interrupted due to surgery on the biliary tract, resulting in HbA_1c dropping below 50 mmol/mol after 6 months.

In 2017, the basal insulin dose was gradually reduced. April 22, 2018, insulin Fiasp was prescribed for the insulin pump. Due to persistently elevated blood pressure (157/80) and HbA_1c (57 mmol/mol) despite insulin pump, exenatide, and metformin treatment, dapagliflozin was added again on September 21, 2018. This treatment combination led to a slight improvement in HbA_1c to 55 mmol/mol. HbA_1c value shows a slight decrease, but as no change in body mass occurs, exenatide was replaced with s.c. SEMA on May 20, 2019. On July 29, 2020, HbA_1c values increased from 54 to 61 mmol/mol, and body mass remained unchanged; thus, SEMA dose was increased from 0.5–1 mg.

BM remained unchanged, HbA_1c decreased to 59 mmol/mol (by 2 mmol/mol). Therefore, the basal rate is reduced from 27 to 16.5 IU per day. With concurrent DAPA and SEMA, BM decreased by 2.5 kg in 3 months, and treatment continues.

March 22, 2021: With this treatment, where the total daily insulin dose was 34 IU/day, there was a slight decrease in HbA_1c to 58 mmol/mol, and body mass decreased by 5.5 kg – now 104.5 kg. After another 3 months, June 14, 2021, there is a BM reduction of 4 kg (i.e., to 100.7 kg). Due to favorable body mass development, the basal insulin dose was reduced by 0.1 IU every hour to 14.1 IU per day – INS/d is 25 IU.

Insulin pump was discontinued on September 21, 2021, with no other supply of endogenous insulin. Then, BM decreased from 100 to 96 kg, and HbA_1c increased from 66 to 75 mmol/mol in 3 months. Medication includes MET, DAPA, and SEMA.

Due to an increase in HbA_1c from 75 mmol/mol to 95 mmol/mol, with body mass reduced from 96 kg to 94 kg since the last check, a fixed combination of IDegLira at a dose of 22 units was initiated on February 21, 2022.

Since the last check-up, while on IDegLira treatment of 22 units, dapagliflozin, and metformin 1-0-1, HbA_1c decreased from 95 to 80 mmol/mol, but body mass increased to 96 kg. IDegLira dose increased to 26 units on May 16, 2022.

After 6 months (November 7, 2022) with this treatment combination, HbA_1c decreased from 80 mmol/mol to 66 mmol/mol but also led to an increase in body mass (now 99 kg).

Looking Ahead: Adequate algorithm for DAPA, MET, incretin, and insulin administration resulting in HbA_1c decrease without BM increase should be sought. Bariatric surgery should be discussed.

2.4 Case report David

Focus: Effective replacement of insulin with IDegLira followed by DAPA and SEMA: challenging reduction of both BM and HbA_1c, higher satisfaction, no insulin.

History: David, a 72-year-old man, sought medical care at our clinic after relocating to a new area. At the time of his visit, he was facing challenges with his diabetes management. His daily insulin requirement exceeded 100 units, and he experienced a body mass increase, with an elevated HbA_1c of around 60 mmol/mol. David had a history of mononeuropathy of the left peroneal nerve and had developed advanced axonal sensory-motor diabetic polyneuropathy in both lower limbs since 2019. Additionally, he was already taking fibrates for hyperlipidemia.

To optimize his insulin therapy, his daily insulin dose was gradually reduced from 102 IU to 76 IU.

During a subsequent follow-up, adjustments were made to his insulin regimen. Insulin glargine at a dose of 40 IU was replaced with insulin degludec at a dose of 30 IU, while maintaining insulin aspart at a dose of 30 IU. This modification resulted in a total daily insulin dose of 60 IU. Despite 6 months of intensive insulin therapy, there were no notable improvements in HbA_1c or body mass.

In light of the unsatisfactory outcomes, both insulin aspart (30 IU) and degludec (30 IU) were substituted with a fixed combination of insulin degludec and the incretin liraglutide (IDegLira), totaling 16 units. David was educated on the need for titration and diligently adjusted his daily dose to stabilize it at 50 units. Unfortunately, even with this medication change, the desired reduction in clinical and laboratory parameters was not achieved (see Figures 12 and 13).

Figure 12.

Absolute values of HbA_1c, BM, INS/d over time. By the admission, David’s daily use of insulin was 102 IU. Insulin usage was reduced, and eventually, IDegLira was prescribed with a starting dose of 16 units with a final titration of 50 units per day. During this period, his body mass remained relatively stable. After exogenous insulin intake was stopped and the SEMA dose was increased to 1 mg, HbA_1c started to drop along with his body mass.

Figure 13.

Relative values of HbA_1c, BMI, INS/d over time showing red values of given parameters that represent being above the upper reference limit (URL). After exogenous insulin doses were decreased to 0, a treatment consisting of dapagliflozin (DAPA) and semaglutide 1 mg (SEMA 1 mg) and increased physical activity, the values of HbA_1c and BMI are getting closer to the URL line, indicating an improvement.

Considering David’s intolerance to MET, DAPA 10 mg was introduced as an additional treatment option. However, after a year of this regimen, David began experiencing fatigue during daily activities, which resulted in a decrease in his physical activity level. Consequently, his HbA_1c once again reached 63 mmol/mol, while his body mass remained around 110 kg. At this point, David received further education on the importance of energy intake restriction and increasing physical activity.

During a subsequent check-up, his body mass increased by 3 kg, and his HbA_1c rose to 71 mmol/mol. To address these concerns, treatment with 0.5 mg of SEMA was initiated for David, with his explicit preference for the injectable form. After 3 months of SEMA 0.5 mg treatment (once weekly), his body mass decreased by 9 kg. Since there was no simultaneous decrease in HbA_1c, the SEMA dose was increased to 1 mg, subcutaneously.

Following 6 months of treatment with SEMA 1 mg subcutaneously (s.c.), pioglitazone 15 mg, and dapagliflozin 10 mg, David’s body mass decreased from 103 kg to 97 kg, and his HbA_1c dropped from 72 mmol/mol to 55 mmol/mol. As his TAG exceeded 4 mmol/L, David was advised to pay closer attention to his fat intake.

Additionally, he was encouraged to further increase his physical activity. Treatment with this medication combination continues to be ongoing for David, and regular monitoring and follow-up are being conducted.

Looking ahead: Identifying a treatment approach that can lead to relative values below 100% for both HbA_1c and body mass.

2.5 Case report Emma

Focus: A person with a long history of T2D with multiple pharmacologic approaches including DAPA, pioglitazone, saxagliptin, liraglutide, exenatide QW, SEMA IDegLira, MET, and insulin delivery through an insulin pump and its effect on body mass and HbA_1c.

History: Emma, born in 1958, was diagnosed with type 2 diabetes (T2D) in 2000 and has been on insulin therapy since 2005. In 2011, she was referred to our care due to her inability to adequately compensate for her diabetes.

Emma presented with multiple comorbidities, including obesity, hyperlipoproteinemia, retinopathy, and a history of postsurgical complications following ovarian cyst removal. At the time of referral, her HbA_1c was around 88 mmol/mol and prandial glycemia fluctuated between 10 and 15 mmol/L. The complexity of this case, notably attributed to the diverse pharmacological interventions, is depicted and emphasized with accompanied visual representations in Figures 14–16.

Figure 14.

Absolute values of Emma’s HbA_1c, BM, INS/d since her registration in our center until the year 2013. The purple line special study demarcates its duration period.

Figure 15.

Absolute values of HbA_1c, BM, INS/d in years 2014–2017.

Figure 16.

Absolute values of HbA_1c, BM, INS/d in years 2017–2023.

Not long after enrolling at our diabetes center, Emma became a participant in a specialized study [14]. During this study, the Paradigm Veo insulin pump was introduced, initially reducing her insulin dosage to 37 IU. Despite the reduction in insulin dosage, her HbA_1c improved, and she continued using the insulin pump even after the study concluded. Eventually, her insulin dosage increased to 68 IU (and remained this high until February 2016). On January 21, 2013, she was prescribed liraglutide 0.6 mg, and after 3 months, the dosage was escalated to 1.2 mg. Unfortunately, due to gastrointestinal issues, liraglutide was discontinued from her treatment plan on November 18, 2013. During this period, there were also adjustments to MET doses, since after an increase to a maximum dose of 3000 mg, Emma did not feel well. Figure 17 shows an overview of relative values since admission.

Figure 17.

Overview of Ema’s relative values from 2011 until 2023.

There is an overview of Ema’s medication in Table 2.

Medication	From	Up to
Metformin	Beginning	Present
Aspart insulin pump	04.11.2011	13.12.2017
Liraglutide	21.01.2013	18.11.2013
Dapagliflozin	12.09.2014	15.12.2014
Saxagliptine	15.12.2014	16.03.2015
Exenatide QX	16.03.2015	14.12.2015
Pioglitazone	14.12.2015	15.02.2016
Dapagliflozin	15.02.2016	27.04.2016
Exenatide QX	27.04.2016	27.03.2017
Pioglitazone	27.03.2017	Present
FIASP for insulin pump	13.12.2017	27.02.2018
IDegLira	27.02.2018	05.12.2022
Dapagliflozin	30.09.2019	Present
Semaglutide 1 mg	05.12.2022	Present
Insulin degludec	27.02.2023	Present

Table 2.

Overview of Emma’s medication.

Emma’s persistent struggle with exceedingly high HbA_1c levels, surpassing 100 mmol/mol, prompted the addition of DAPA to her treatment regimen on September 12, 2014. Nevertheless, owing to discomfort and gynecological inflammations, DAPA was discontinued on December 15, 2014, and saxagliptin was introduced as an alternative. With her HbA_1c level escalating to 112 mmol/mol, saxagliptin was subsequently halted and replaced with exenatide QW (EX QW). For her next visit on December 14, 2012, Emma’s body mass increased to 111 kg, despite a decline in her HbA_1c levels. As her treatment journey unfolded, exenatide QW was eventually phased out, and pioglitazone was prescribed. Over the following year, a therapeutic sequence involving DAPA, exenatide, and pioglitazone was established. Presently, Emma remains on pioglitazone as part of her ongoing treatment regimen.

On December 13, 2017, the insulin aspart was changed to the faster-acting insulin aspart within the insulin pump. Despite this adjustment, HbA_1c levels persisted in their ascent, peaking at 104 mmol/mol. In response, following a deliberation with Emma, the decision was made to discontinue CSII on February 27, 2018. As a substitution, IDegLira was introduced (initially at 40 units). The titration of IDegLira to 50 units, in conjunction with a combination of DAPA, MET, and pioglitazone, yielded a remarkable improvement, driving HbA_1c levels to 41 mmol/mol. This success led to the gradual reduction of IDegLira dosages—first to 38 units, then to 36 units. This adjustment in insulin degludec dosage influenced liraglutide levels as well, contributing to a rise in appetite, HbA_1c, and body mass. In light of these developments, a novel treatment approach was devised, involving the cessation of IDegLira and the initiation of SEMA on December 5, 2022. Despite the holiday season, this shift resulted in a reduction in body mass from 99 kg to 92 kg. Unfortunately, there was an increase in HbA_1c to 84 mmol/mol. This rise serves as a clear indication that Emma’s optimal glycemic control necessitates exogenous insulin supplementation, leading to the prescription of insulin degludec [16].

Looking ahead: Determining the lowest effective dosage of insulin to achieve optimal HbA_1c control, all the while carefully managing body mass.

2.6 Case report Fatima

Focus: Impact of oral SEMA on INS/d, BM, HbA_1c, and lifestyle modifications in a lady with T2D treated by means of CSII and DAPA.

History: Fatima, a 73-year-old woman, visited our diabetes center in 2011 for therapy adjustment and a transition to an insulin pump [14]. Prior to that, she had been treated with 68 IU of insulin aspart and 32 IU of insulin detemir, along with 1000 mg of metformin twice a day, for 3 years. Fatima was provided with the Paradigm 754 Veo pump equipped with insulin aspart in our clinic. Through gradual use of the pump, her average daily insulin dose stabilized at around 60 IU. She quickly adapted to using the pump and handled it very well.

After nearly 3 years of treatment with the pump and metformin (3x1000 mg/day), Fatima started experiencing higher PG during the day. She also developed moderate diabetic retinopathy. As a result, she was prescribed saxagliptin 5 mg once daily. During a follow-up after 4 months, her HbA_1c decreased from 64 mmol/mol to 57 mmol/mol.

After 10 months, her HbA_1c increased to 61 mmol/mol without any increase in body mass. Consequently, saxagliptin 5 mg was replaced with dapagliflozin 10 mg/day. As the desired effect was still not achieved, dapagliflozin treatment was supplemented with metformin in a fixed combination of dapagliflozin 5 mg and metformin 1000 mg (DAPA/MET), with a dosage of twice daily.

In 2017, the insulin aspart, that Fatima was taking, was switched to the same type but with a faster onset of action. Her daily insulin usage remained unchanged. Despite repeated education, dietary adjustments, and efforts to increase physical activity, her diabetes compensation was not satisfactory. In January 2018, she received a recommendation for comprehensive balneotherapy in Luhačovice spa.

Fatima continued taking her diabetes medication without changes for almost three more years. During this period, she was monitored for hypertension in our internal clinic. Fatima repeatedly reported frequent dizziness, nausea, and occasional unexplained falls. Consequently, she underwent several examinations by relevant physicians, but the findings were repeatedly negative. In August 2020, Fatima was scheduled for a planned hospitalization to address these problems. During her stay, attention was also focused on improving her diabetes compensation.

Due to the outbreak of the COVID-19 pandemic, Fatima did not return for further check-ups and blood tests until a year after her hospitalization. During this period, her HbA_1c increased by 8 mmol/mol, while her body mass remained unchanged. As part of her current treatment, she was prescribed oral SEMA at a starting dose of 3 mg daily, gradually increasing to 7 mg and eventually 14 mg, with increments every month.

The first follow-up after 3 months of using oral SEMA, DAPA/MET, and the insulin pump showed a decrease in HbA_1c from 60 mmol/mol to 43 mmol/mol with minimal body mass change. Fatima felt well and experienced no adverse effects from SEMA. Hypoglycemia did not occur. Her daily insulin dose gradually decreased to 55 IU and then to 36 IU per day. After a year of treatment combination consisting of oral SEMA, the insulin pump, and DAPA/MET, she lost 5 kg and her HbA_1c decreased by 23 mmol/mol (Figures 18 and 19).

Figure 18.

Absolute values of parameters from 2012 showing relatively constant body mass that slightly decreased after oral SEMA (SEMA p.o.) was added to the treatment plan, and insulin dosage was lowered to nearly half – from 60 IU to 36 IU. After adding dapagliflozin/metformin (DAPA/MET) in combination with SEMA p.o., the HbA_1c level lowered from 60 mmol/mol to 37 mmol/mol. A recent check-up in March 2023 showed an increase in HbA_1c.

Figure 19.

Relative values of HbA_1c, BMI, INS/d over time showing the values of given parameters being written in red, above URL. In 2022, her HbA1c improved and got under 100%, showing sufficient glycemic control. This led to an insulin dosage decrease, 90% of the upper reference limit (36 IU). This resulted in an HbA_1c increase.

Fatima continues with her established treatment, although her most recent check-up in March 2023 showed an increase in HbA_1c. Fatima was once again educated about the importance of adhering to proper lifestyle principles.

Looking ahead: Continue to adjust Fatima’s medication regimen based on her response to treatment and her glycemic control. Consider alternating or combining different classes of antidiabetic medication to achieve HbA_1c lower than 42 mmol/mol and body mass reduction (BMI under 28).

2.7 Case report Gerry

Focus: Effect of INS, IDegLira, and consequent complementation with DAPA/MET on BM, HbA_1c, cardiovascular complications, and lifestyle modifications.

History: Gerry, a 71-year-old man, arrives at our diabetes center due to the recommendation of his cardiologist. He is currently being monitored for heart failure with a left ventricular ejection fraction of 45% and falls under NYHA class I-II. Gerry has been managing diabetes since 2007 and has been receiving treatment with insulin detemir (18 IU) and gliclazide (a sulfonylurea derivative) at a dosage of 60 mg once a day. Under this treatment regimen, his HbA_1c level was recorded at 82 mmol/mol, and his body mass stood at 106 kg. It became evident that a change in medication was necessary.

As part of the revised treatment plan, insulin detemir was substituted with 16 IU of insulin degludec in a fixed combination with liraglutide, and gliclazide was discontinued. Unfortunately, Gerry faced challenges in the initial 2 months of this new treatment regimen. He struggled with proper insulin administration, often missing several daily doses. To address this issue, Gerry received repeated guidance on sticking to a dietary regimen and was motivated to avoid consuming foods high in fat content.

After 4 months of gradual titration, he successfully reached a stable daily insulin dose of 30 IU. Furthermore, after 3 months of treatment, there was a notable decrease in his HbA_1c level by 19 mmol/mol, accompanied by a body mass increase of 2 kg. Encouraged by these positive results, Gerry remained committed to the gradual titration of his medication and continued to make adjustments to his lifestyle. One of his dietary habits involved a high intake of carbohydrates, such as white bread, potatoes, and sweetened beverages. Over time, he made efforts to modify the composition of his diet, incorporating more vegetables. Gerry diligently adhered to this treatment regimen for nearly a year.

Given the development of ischemic heart disease and the ongoing insufficient control of his diabetes, a fixed combination of dapagliflozin and metformin (DAPA/MET) was added to his medication (as depicted in Figures 20 and 21).

Figure 20.

The absolute values of HbA_1c, BM, INS/d over 5 years period. Values of HbA_1c recorded a decrease from 82 to 63 mmol/mol during the first 3 months of using IDegLira. Through gradual titration, Gerry’s dose was stabilized at 50 units of IDegLira. When using this dose, HbA_1c values decreased to 47 mmol/mol. Body mass gradually increased from the beginning of IDegLira treatment, leading to the addition of a combination of DAPA/MET 5/1000 mg to the dose of 50 units IDegLira. This change resulted in a body mass decrease from 112 kg to 106 kg, which has been maintained.

Figure 21.

Relative values of HbA_1c, BMI, INS/d over time. Values over the upper reference limit (URL) are depicted in red. There is an apparent decreasing trend in the HbA_1c level, which started almost at 200% and got nearly to 100% of the reference range, signing a sufficient glycemic control.

Over the course of 4 years, during which Gerry has been taking DAPA/MET (5/1000 mg) alongside 50 IU of insulin degludec, his blood pressure readings at our clinic have predominantly demonstrated normal values. Additionally, his HbA_1c level has decreased from 60 mmol/mol to 45 mmol/mol. His body mass has remained relatively stable, consistently above 100 kg.

Despite Gerry’s consistent efforts and adherence to dietary modifications, he has faced challenges in achieving body mass below 100 kg and maintaining HbA_1c within the physiological range. Over a period of 7 years under our monitoring, Gerry’s left ventricular ejection fraction (LVEF) has declined to 30%. The inclusion of SEMA in his medication regimen is being contemplated due to its potential cardioprotective effects [17].

Gerry continues to prioritize the improvement of his dietary choices and lifestyle habits with ongoing support from his healthcare team.

Looking ahead: A potential switch from IDegLira to SEMA is being considered in the future.

2.8 Case report Henry

Focus: Impact of SEMA p.o. on BM and HbA_1c in a man treated with metformin and DAPA without insulin.

History: Henry came to the clinic on the recommendation of his general practitioner due to the detection of hyperglycemia of 10.8 mmol/L and 13.1 mmol/L in June 2018. The general practitioner prescribed MET, which Henry tolerates well without any gastrointestinal issues. In addition to type 2 diabetes mellitus, Henry has also been diagnosed with hypertension and dyslipidemia. He was advised to quit smoking, and the dose of MET was increased to 1500 mg per day. Due to elevated TAG reaching 5.9 mmol/L, fenofibrate 200 mg once daily was also prescribed (Table 3). Henry received counseling and was recommended to reduce caloric intake and achieve a reduction of body mass of at least 5 kg.

Medication	From	Up to	Dosage
metformin 1000 mg	June 2018	21.09.2018	1/2-1/2-1/2
metformin 1000 mg	10.12.2018	present	0-1-0
oral SEMA 3-7-14 mg	13.12.2021	present	1-0-0
dapagliflozin/metformin 5/1000 mg	21.09.2018	present	1-0-1
fenofibrate 200 mg	June 2018	present	1-0-0
atorvastatin 20 mg		present	0-0-1

Table 3.

Overview of Henry’s medication.

After 3 months of this treatment regimen, Henry returned for a follow-up visit. However, the HbA_1c remained at 65 mmol/mol (Figures 22 and 23). Considering the risk of his wife’s suicide and the potential misuse of insulin, a combination of DAPA/MET 5/1000 mg twice daily was initiated. He tolerates this medication well but has noticed increased urination.

Figure 22.

Absolute values showing the progression of parameters over 5 years. His treatment initially involved metformin (MET) with a dosage of 500 mg three times a day. Subsequently, dapagliflozin/metformin (DAPA/MET) was introduced, resulting in a decrease in HbA_1c. Further improvement in HbA_1c was observed upon adding oral SEMA (SEMA p.o.), demonstrating its effectiveness in reducing HbA_1c (yellow box).

Figure 23.

Over the course of 5 years, Henry’s HbA_1c and BMI values were consistently elevated, surpassing the highest reference values, as indicated by the red color.

After 3 months, HbA_1c decreased from 65 mmol/mol to 56 mmol/mol, and metformin 1000 mg was added, resulting in a total daily MET dose of 3000 mg.

Since starting the combination of DAPA/MET 5/1000 mg twice daily with metformin 1000 mg, Henry’s body mass has remained nearly the same, but there has been a gradual increase in HbA_1c. Therefore, oral SEMA is added. In the first month, Henry is instructed to take 3 mg of SEMA daily. In the second month, the dose is increased to 7 mg, and in the third month, it is further increased to 14 mg.

After 3 months of treatment with oral SEMA, no adverse effects have been reported, and Henry experienced a decrease in appetite. His body mass decreased from 100 kg to 94 kg, and his HbA_1c dropped from 58 mmol/mol to 48 mmol/mol.

During the subsequent 6-month follow-up, it was noted that Henry had gained 7 kg, with HbA_1c remaining the same. Henry was once again advised to increase physical activity and limit caloric intake. He is aware that his physical activity level is minimal and his dietary habits are not optimal.

Looking ahead: Both body mass and HbA_1c reductions are required by increasing his physical activity and improving his diet.

2.9 Case report Irene

Focus: Influence of the INS replacement with SEMA s.c., DAPA, and MET on BM, HbA_1c in a lady with recent T2D and heart failure.

History: Irene, a 65-year-old woman, was diagnosed with type 2 diabetes (T2D) in 2015 and initiated oral antidiabetic medication. Insulin was added to her treatment regimen in 2018.

In 2021, Irene experienced cardiopulmonary failure, leading to hospitalization in the intensive care unit of a local hospital. She was prescribed 46 IU of insulin (insulin aspart 36 IU and insulin glargine 10 IU) per day during her hospital stay. Following her discharge, Irene was referred to a diabetologist for ongoing management.

During her initial assessment at our diabetes center, Irene’s HbA_1c was measured at 110 mmol/mol, and her body mass was recorded as 112 kg. Based on these results, insulin therapy was temporarily discontinued, and Irene was prescribed a subcutaneous dose of 0.25 mg of SEMA. Irene’s medication is summed up in Table 4.

Medication	From	Up to	Dosage
Insulin aspart	Diagnosis of T2D	30.08.2021	14-14-8
Insulin glargin	Diagnosis of T2D	30.08.2021	0-0-0-10
Semaglutide	30.08.2021	Present	Once a week
DAPA/MET	07.02.2022	Present	1-0-1

Table 4.

Overview of Irene’s medication.

After 1 month of treatment, the dosage was increased to 0.5 mg. Over the course of 3 months, Irene experienced a 4 kg body mass loss, accompanied by a 32 mmol/mol reduction in HbA_1c. Consequently, the SEMA dosage was further increased to 1 mg (as depicted in Figures 24 and 25).

Figure 24.

The HbA_1c values of Irene, recorded since her registration at our diabetes center, demonstrate a notable reduction from 110 mmol/mol to 78 mmol/mol over a 3-month period after discontinuation of insulin therapy and initiation of semaglutide (SEMA) treatment following standard titration starting at a dose of 0.25 mg and gradually increasing to 1 mg subcutaneously once a week. Additionally, there is a clear and consistent downward trend observed in body mass and HbA_1c throughout the course of treatment.

Figure 25.

Despite the decreasing trend in HbA_1c levels and BMI following the discontinuation of insulin and implementation of a new treatment plan, it is important to note that the relative values still exceed the upper limit of the physiological range (depicted as red).

During the subsequent 3-month follow-up, no significant improvement was observed with SEMA treatment. Considering Irene’s cardiovascular comorbidities, a combination medication containing dapagliflozin 5 mg and metformin 1000 mg (DAPA/MET) was introduced. This combination therapy resulted in continued improvements in HbA_1c and body mass reduction. Irene occasionally experienced diarrhea after consuming fatty meals.

During a subsequent check-up, Irene reported frequent morning nausea and feelings of weakness, which subsided after breakfast.

Consequently, Irene’s treatment was adjusted to semaglutide and a fixed combination of dapagliflozin and metformin (DAPA/MET), with insulin being discontinued. This modification led to a decrease in HbA_1c from 110 mmol/mol to 57 mmol/mol, as well as a reduction in body mass from 117 kg to 104 kg. Irene continued with this combination therapy.

Given the gradual deterioration of Irene’s vision over the past year, an ophthalmic examination was indicated. The examination ruled out diabetic retinopathy and confirmed a diagnosis of senile cataract (cataracta senilis).

Due to the unavailability of the subcutaneous form of SEMA, Irene’s medication was switched to the tablet form in May 2023.

Looking ahead: The tolerance and the effect of oral SEMA will be observed, and further medication adjustments will be made if needed. Body mass reduction is needed.

2.10 Case report Jacob

Focus: Impact of slow insulin replacement with SEMA and MET on BM and HbA_1c in a man with recent T2D diagnosis.

History: Jacob, a 52-year-old man, presented to his general practitioner with a hyperglycemia reading of 24.1 mmol/L during a routine check-up. Further laboratory tests, including measurements of C-peptide and autoantibodies, confirmed the diagnosis of type 2 diabetes mellitus. Jacob’s medical history revealed that his father and cousin also have type 2 diabetes.

Upon diagnosis, Jacob’s treatment plan was initiated by his general practitioner, who prescribed the following medication: Insulin aspart at a dosage of 40 IU per day and insulin detemir at a dosage of 30 IU per day.

Upon referral to our diabetes center, Jacob’s treatment plan was reevaluated and modified. The new treatment regimen comprised several medications. Insulin degludec was prescribed at a dosage of 20 IU per day to address his glycemic control. SEMA was initiated at a starting dosage of 0.25 mg in the first month, which was subsequently increased to 0.5 mg from the second month onwards to further enhance glucose management. MET was prescribed at a dosage of 850 mg twice daily, providing additional support in glycemic control. In addition to these diabetes-specific medications (Table 5), Jacob continued his treatment with atorvastatin for cholesterol management and perindopril/amlodipine for hypertension management.

Medication	From	Up to	Dosage
Semaglutide 1 mg s.c.	21.06.2021	Present	Once weekly
Metformin 850 mg	21.06.2021	Present	1-0-1
Atorvastatin 20 mg		Present	0-0-1/2
Indacaterol/glycopyrronium 85/43 MCG		Present	1-0-0
Insulin degludec	22.06.2021	22.07.2022	20-0-0 IU

Table 5.

Overview of all Jacob’s medication.

Over a span of 6 months, Jacob showed a notable improvement in his condition. His body mass decreased from an initial 130 kg to 112 kg, demonstrating successful body mass management. Moreover, his HbA_1c decreased from 130 to 37 mmol/mol, indicating effective blood glucose control and an improved metabolic state. (Depicted in Figures 26 and 27).

Figure 26.

The absolute values of HbA_1c demonstrate a consistent downward trend despite the gradual reduction and eventual discontinuation of insulin degludec usage. Jacob’s body mass initially decreased and remained relatively stable, with a slight increase observed in June 2022. Following the adjustment of semaglutide (SEMA) to 1 mg and the discontinuation of insulin, his body mass started decreasing again. These findings suggest that the combination of medication adjustments, including increased SEMA dosage and insulin discontinuation, contributed to improved glycemic control and body mass management.

Figure 27.

The relative HbA_1c values demonstrate a noteworthy improvement in Jacob’s response to treatment, decreasing from an initial value of 307–110% in relationship with the reference value. This indicates an effective treatment combination. Over 6 months, HbA_1c levels continued to decrease and remained below the highest reference value, shown in black. Insulin usage gradually declined and was discontinued in July 2022. Jacob’s body mass initially decreased and remained relatively stable thereafter.

In June 2022, a modification to Jacob’s treatment regimen was necessary due to a noticeable increase in body mass. He had gained 7 kg in the previous 6 months, necessitating adjustments to his medication. The dose of insulin degludec was reduced, while the dose of SEMA was increased to 1 mg. This treatment adjustment resulted in further improvement in Jacob’s condition.

By the end of July 2022, insulin degludec was completely discontinued, and Jacob continued his treatment with SEMA and MET alone. Despite the discontinuation of insulin, Jacob’s HbA_1c remained stable at 39 mmol/mol, indicating sustained blood glucose control. Additionally, there was a slight decrease in body mass by 3 kg, demonstrating the ongoing success of the treatment approach in managing Jacob’s body mass.

Looking ahead: To continue Jacob’s treatment regimen to keep HbA_1c and INS/d under 100% of relative values. Reduction of his body mass is needed.

3. Discussion

Amy’s case report highlights the important role of healthcare providers and families in managing the challenges imposed by both poorly regulated diabetes and advancing cognitive impairment.

Bejamin’s case underscores the potential benefits of GLP-1 agonists in managing complex metabolic conditions. It provides valuable insights into developing personalized and effective treatment plans for individuals diagnosed with DM2 and Metabolic Syndrome, emphasizing the importance of body mass management in their overall health improvement.

Connor’s case report highlights the significance of a comprehensive and tailored approach to managing T2D. Ongoing monitoring, frequent communication, and the timely implementation of interventions contributed to his improved glycemic control and overall well-being. This case underscores the importance of patient engagement and individualized care in optimizing the management of chronic conditions. The question is whether a person with T2D should have lower levels of HbA_1c at the expense of having a higher body mass or vice versa.

David’s case report illuminates a pathophysiological approach to type 2 diabetes management, emphasizing the intricate interplay between external insulin utilization, glycemic control, and body mass modulation.

Managing diabetes in polymorbid patients like Emma requires a tailored and evolving treatment approach. Her successful glycemic optimization with the GLP-1 agonist and insulin therapy highlights the importance of exploring novel therapeutic options to address changing patient needs. Continuous monitoring and adjustments in treatment remain crucial to achieving and sustaining optimal glycemic control and mitigating the impact of comorbidities.

Fatima’s case report underscores the intricate management approach in diabetes, emphasizing the synergistic use of insulin pump therapy, medication adjustments, and lifestyle modifications. Despite challenges, her glycemic control notably improved with a combination of oral SEMA, DAPA/MET, and the insulin pump, leading to a notable body mass decrease and reduced HbA_1c levels.

Henry’s case report exemplifies the effectiveness of a comprehensive therapeutic approach utilizing a combination of MET, DAPA, and oral SEMA in HbA_1c and appetite control. Despite initial challenges in glycemic control, the incorporation of this medication resulted in improvements. The introduction of oral SEMA led to notable appetite reduction, body mass reduction, and decreased HbA_1c levels. This case emphasizes the potential of tailored multi-drug interventions in addressing complex metabolic conditions and underscores the importance of addressing lifestyle factors alongside pharmaceutical interventions for long-term success.

Gerry’s case report highlights the intricate management of T2D and heart failure, emphasizing the significance of tailored medication adjustments and lifestyle modifications. The individualized approach employed to address Gerry’s comorbid conditions led to improvements in glycemic control and cardiovascular health. Despite challenges in achieving optimal body mass and HbA_1c levels, his case underscores the complexity of managing multiple conditions and the need for adaptable treatment strategies.

Irene’s case report complex medical history and combination therapy facilitated improvements in glycemic control and body mass reduction. The cautious adjustment of medication in response to her evolving needs, along with considerations for her cardiovascular health, played a pivotal role in achieving positive outcomes. Irene’s case underscores the importance of tailoring treatment plans to address individual patient characteristics and comorbidities, with ongoing adjustments guided by both therapeutic efficacy and potential side effects.

Jacob’s case exemplifies the potential benefits of a pathophysiology-oriented approach to treating type 2 diabetes mellitus. By combining SEMA and MET, Jacob achieved not only considerable body mass loss but also remarkable improvements in glycemic control. The tailored treatment regimen not only led to reduced reliance on external insulin but also demonstrated the dynamic relationship between body mass, glycemic control, and medication management.

4. Conclusion

Pathophysiology-oriented approach to treating type 2 diabetes, with early utilization of medication such as metformin and incretin-based therapies, offers a promising outcome of improvement of well-being. By targeting the underlying mechanisms driving insulin resistance and glucose dysregulation, this approach holds the potential to improve glycemic control and mitigate associated risks. Pairing pharmaceutical interventions with lifestyle modifications and education amplifies the efficiency of this strategy. As treatment plans continue to evolve, tailoring treatments to individual pathophysiological profiles could further refine type 2 diabetes management, leading to a more personalized and effective era of care.

Acknowledgments

Our deepest thanks go to the Department of Internal Medicine II – Gastroenterology and Geriatrics, University Hospital Olomouc, along with the Department of Physiology, Faculty of Medicine and Dentistry, Palacký University Olomouc, Czech Republic.

Abbreviations

ADA	American Diabetes Association
BM	Body mass
BMI	Body mass index
CGM	Continuous glucose monitoring
CSII	Continuous subcutaneous insulin infusion
INS/d	Insulin used per day
DAPA	Dapagliflozin
EASD	European Association for the Study of Diabetes
eGFR	Estimated glomerular filtration rate
Fiasp	Faster insulin aspart
GIP	Glucoso-dependent insulinotropic peptide
GLP-1 RA	Glucagon-like peptide receptor agonist
HbA1c	Hemoglobin A1c, glycated hemoglobin
HDL	High-density lipoprotein
IDegLira	Insulin degludec and liraglutide *fixed combination
INS/d	Insulin/day
LDL	Low-density lipoprotein
MDI	Multiple daily insulin
MET	Metformin
PG	Plasma glucose
SEMA	Semaglutide
SGLT2	Sodium-glucose cotransporter 2
SMPG	Self-monitoring of plasma glucose
T2D	Type 2 diabetes
TAG	Triacylglycerols
URL	Upper reference limit
IU	International unit of insulin