Intensification of the treatment of type 2 diabetes mellitus

In a 63-year-old patient, although glucose metabolic control is quite good, there is still potential for optimizing diabetes management. Thus, with a change in therapy, his pre-existing cardiovascular conditions can be better addressed and his cardio-renal risk reduced.

Background

A 63-year-old patient presented to the Metabolic Center with a request to adjust his diabetes treatment. The ex-smoker had already suffered from type 2 diabetes mellitus for 16 years and now wanted a change in therapy. The patient had already received a triple coronary artery bypass for coronary artery disease and a left ileofemoral bypass for peripheral arterial disease. Ejection fraction was currently good and there was no known heart failure.

Anamnesis and diagnostics

The physical examination revealed a weight of 78 kg with a height of 172 cm, which corresponds to a BMI of 26.4 kg/m² and thus to overweight. Systolic and diastolic blood pressure were elevated with values of 145/93 mmHg. The heart rate was 73/min.

With regard to diabetes, no symptoms were currently present. Retinopathy was not known and signs of diabetic foot syndrome could not be detected either. Vibration sensation in the metatarsophalangeal joints of the big toes was 4/8 bilaterally. The HbA1c value was 7.2% and the LDL-C value 1.6 mmol/L according to laboratory tests.

Creatinine was 147 µmol/L and estimated glomerular filtration rate (eGFR by CKD-EPI) was 43.1 mL/min, already indicating moderate renal function impairment. In addition, there was moderately increased albuminuria with an albumin-to-creatinine ratio of 27 mg/mmol. According to the KDIGO classification, this results in renal insufficiency G3b, A2.

Therapy

The patient had been receiving metformin (1000 mg, 1-0-1), the DPP-4 inhibitor linagliptin (Trajenta®, 5mg, 1-0-0), and insulin glargine (Toujeo®, 46 units/day) for several years to treat his type 2 diabetes mellitus. In addition, his hypertension was treated with candesartan/hydrochlorothiazide (32 mg/25 mg, 1-0-0) and amlodipine (10 mg, 1-0-0) and bisoprolol (5 mg, 1-0-0). For his hypercholesterolemia, he received ezetimibe/rosuvastatin (10 mg/20 mg, 1-0-0). Furthermore, acetylsalicylic acid (100mg, 1-0-0) was also dispensed.

For better control of type 2 diabetes mellitus, the patient also received treatment with the SGLT-2 inhibitor canagliflozin (Invokana®, 100mg, 1-0-0). The metformin dose was halved (500 mg, 1-0-1) and the insulin glargine dose was also reduced (38 units/day). Linagliptin, on the other hand, was passed on unchanged. Other medication for hypertension and hypercholesterolemia was primarily not changed to avoid too many adjustments at once.

Present situation

After three months, the patient had lost 2 kg of weight (currently 76 kg) and his blood pressure was slightly reduced at 139/92 mmHg. The HbA1c value was relatively constant at 7.1%. Creatinine was 158 µmol/L and estimated glomerular filtration rate (eGFR by CKD-EPI) was 39.5 mL/min. In contrast, microalbuminuria was no longer present.

Comment by Prof. Dr. med. Bernd Schultes

There are a number of points to learn from these case studies, although the patient’s overall situation can be considered stable and fairly well controlled even before the change in therapy. However, there were still some points to optimize:

Metformin should be given at an eGFR of < 45 mL/min only at a dose of 2 x 500 mg, otherwise the risk of lactic acidosis increases. It should be noted, however, that the scientific basis for this generally applicable recommendation is rather small.
The SGLT-2 inhibitor canagliflozin was additionally introduced to take advantage of the nephroprotective as well as the cardioprotective effects of the compound. The aim was not so much to achieve an improvement in glucose metabolic control, since this was already sufficient against the background of the cardiovascular pre-existing conditions and the existing insulin therapy. Studies have very clearly shown that SGLT-2 inhibitors improve renal and cardiovascular endpoints, independent of glucose metabolic improvement and even in patients already on insulin therapy.
With relatively good glucose metabolism control under insulin therapy, the insulin dose can and should be reduced when an SGLT-2 inhibitor is introduced, since the substance class reduces blood glucose independently of insulin and an insulin dose that is accordingly too high can provoke hypoglycemia. The at best minimal improvement of the HbA1c value after the therapy change is therefore not surprising.
Based on the slight increase in creatinine, renal function appears to have worsened somewhat after initiation of canagliflozin therapy. However, the preceding microalbuminuria was no longer detectable thereafter. This is a very typical pattern after administration of an SGLT-2 inhibitor, similar to what we know from therapy with blockers of the renin-angiotensin-aldosterone system (RAAS), such as ACE inhibitors or angiotensin receptor antagonists. The background of this typical change is the reduction of glomerular filtration pressure by the corresponding substances, which has a long-term preservative effect on renal function.
SGLT-2 inhibitors lead to a moderate reduction in blood pressure, which was desirable in the patient presented. However, the reduction in blood pressure achieved by the change in therapy is not yet sufficient, so that an escalation of antihypertensive therapy should be considered in the further course.

Author: Prof. Dr. med. Bernd Schultes with editorial support from Dr. rer. nat. Christin Döring, IACULIS GmbH

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